Crystalline and salt forms of organic compounds and pharmaceutical compositions thereof

Abstract

To provide alternative forms of compounds developed for treating conditions and diseases in which inhibition of dihydroorotate dehydrogenase (DHODH) would be beneficial.SOLUTION: Provided are various salts, including tris (hydroxymethyl) aminomethane salts and sodium salts, of a compound of the following formula, as well as various crystalline forms of a compound of the following formula, and pharmaceutical compositions comprising these salts and crystalline forms, methods of making the same.SELECTED DRAWING: None

Description

[Technical Field]

[0001]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 784,083, filed December 21, 2018, U.S. Provisional Patent Application No. 62 / 791,571, filed January 11, 2019, and U.S. Provisional Patent Application No. 62 / 882,712, filed August 5, 2019, the disclosures of each of which are incorporated by reference in their entirety. [Background technology]

[0002] Dihydroorotate dehydrogenase (DHODH) is an enzyme that catalyzes one of the steps in the de novo pyrimidine nucleotide biosynthetic pathway. It catalyzes the only oxidation / reduction reaction in this pathway, which is the step that converts DHO (dihydroorthoic acid) to orotic acid with the help of a flavin cofactor and an electron acceptor. Inhibitors of dihydroorotate dehydrogenase have found wide utility as chemotherapeutic agents.

[0003] 1-Methyl-5-(2'-methyl-[1,1'-biphenyl]-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid, hereinafter also referred to as "Compound 1" (structural formula shown below), has been characterized as an inhibitor of DHODH. See, e.g., International Patent Application Publication No. 2014 / 128669 and U.S. Patent No. 9,630,932, the contents of which are incorporated herein by reference. [ka]

[0004] Compound 1 was developed to treat conditions and diseases in which inhibition of DHODH would be beneficial, including, but not limited to, solid cancers, hematological cancers, viral-mediated diseases, transplant rejection, rheumatoid arthritis, psoriasis, autoimmune diseases, and inflammatory disorders. Given this therapeutic benefit and the considerable promise it holds for treating numerous different diseases, there is a need to develop alternative forms of Compound 1 in an effort to facilitate isolation, manufacture, and formulation development for various routes of administration, as well as enhance storage stability. Summary of the Invention

[0005] As described in more detail in the following paragraphs, it has now been found that the Tris salt of Compound 1 has superior properties relative to the free acid and other salt forms of the compound. Tris salt Form C has also been found to be superior to the other Tris salt forms.

[0006] During the salt screening studies described herein, over 50 different salt hits of Compound 1, including 10 counterions, and 5 different solvents were evaluated. Twelve different crystalline forms were identified (see Table 8). Of these crystalline salt forms, the Tris salt form was found to be superior. Specifically, the Tris salt form of Compound 1 Salt Form A and Tris Salt Form C stood out as the major crystalline salt forms with sharp XRPD peaks (see Example 3, Table 8, and Figure 6). Good crystallinity of a drug substance typically translates to better physical and chemical stability, and is therefore a desirable characteristic of an active pharmaceutical ingredient (API). Furthermore, thermogravimetric analysis (TGA) data reflected negligible weight loss in Tris Salt Form A and Tris Salt Form C of Compound 1 (see Table 9), thus indicating minimal residual solvent and anhydrate polymorph. , which is often preferred over solvated / hydrated forms for the development of oral solid dosage forms. Differential scanning calorimetry (DSC) data for Tris Salt Form A and Tris Salt Form C of Compound 1 (see Table 9) further show one sharp melting endotherm before decomposition, indicating a low likelihood of polymorphic change and a low likelihood of phase transitions, which are often undesirable from the perspective of physical stability of the API.

[0007]

[0007] Comparing tris salt form A and tris salt form C of Compound 1, thermodynamic stability studies using slurry competition experiments showed that tris salt form C is thermodynamically more stable (see Example 5). Furthermore, tris salt form C of Compound 1 has also been found to be less hygroscopic than the corresponding tris salt form A, making it more susceptible to degradation in solvents during formulation development.

[0008]

[0008] Comparing the pharmacokinetic properties of the free acid and the tris salt of Compound 1, the tris salt form exhibits a shorter time (i.e., a lower T max ) within the range of a higher maximum concentration (i.e., a higher C max ), is clearly superior (see Example 8 and Table 13). While the initial form of the free acid with low crystallinity and purity exhibits comparable exposure to the Tris salt as shown by the AUC values ​​(see Table 13 and Figure 10A), such high AUC values ​​are not observed for the near-final form of the free acid, despite the improved crystallinity and purity and reduced particle size. This could not be reproduced (see Table 13 and Figure 10B).

[0009] PK data indicate that the tris salt of Compound 1 exhibits superior exposure as well as rapid, high absorption compared to the free acid form. The relatively well-defined DSC profile with a sharp melting endotherm of tris salt Form C of Compound 1, combined with excellent thermodynamic properties and low hygroscopicity, indicates reliable solid-state properties of this particular salt form in terms of physical stability and suitability for the development of oral solid dosage forms.

[0010]

[0010] Provided herein are the tris(hydroxymethyl)aminomethane salt, sodium salt and crystalline forms of the compound designated herein as Compound 1.

[0011]

[0011] Also provided herein are pharmaceutical compositions comprising the tris(hydroxymethyl)aminomethane (tris) salt, sodium salt and other pharmaceutically acceptable salts, and crystalline forms of Compound 1, methods for their preparation, and uses for the treatment of conditions, including, but not limited to, conditions in which inhibition of dihydroorotate dehydrogenase (DHODH) would be beneficial.

[0012] Also provided herein are solid dispersions comprising Compound 1 or a pharmaceutically acceptable salt thereof, a Tris salt of Compound 1, or a sodium salt of Compound 1, and one or more polymers. Also provided herein are pharmaceutical compositions comprising these solid dispersions, methods for their preparation, and uses for the treatment of conditions, including, but not limited to, conditions in which inhibition of DHODH would be beneficial. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 shows XRPD for Forms A, B, C, and D of Compound 1. [Figure 2A]

[0014] FIG. 1 shows the XRPD pattern for crystalline form A of Compound 1. [Figure 2B]

[0015] FIG. 1 shows the XRPD peak list for crystalline form A of Compound 1. [Figure 2C]

[0016] FIG. 1 shows the combined DSC and TGA thermograms for crystalline Form A of Compound 1. [Figure 3A]

[0017] FIG. 1 shows the XRPD pattern for crystalline form B of Compound 1. [Figure 3B]

[0018] FIG. 1 shows the XRPD peak list for crystalline form B of Compound 1. [Figure 3C]

[0019] FIG. 1 shows the combined DSC and TGA thermograms for crystalline Form B of Compound 1. [Figure 4A]

[0020] FIG. 1 shows the XRPD pattern for crystalline form C of Compound 1. [Figure 4B]

[0021] FIG. 1 shows the XRPD peak list for crystalline form C of Compound 1. [Figure 4C]

[0022] FIG. 1 shows the combined DSC and TGA thermograms for crystalline Form C of Compound 1. [Figure 5A]

[0023] FIG. 1 shows the XRPD pattern for crystalline form D of Compound 1. [Figure 5B]

[0024] FIG. 1 shows the XRPD peak list for crystalline form D of Compound 1. [Figure 5C]

[0025] FIG. 1 shows the combined DSC and TGA thermograms for crystalline form D of Compound 1. [Figure 6]

[0026] FIG. 1 shows an overlay of powder X-ray diffraction (XRPD) patterns for three crystalline forms of the tris(hydroxymethyl)aminomethane (tris) salt of Compound 1. [Figure 7A]

[0027] FIG. 1 shows the XRPD pattern for crystalline Form A of the tris salt of Compound 1. [Figure 7B]

[0028] FIG. 1 shows the XRPD peak list for crystalline Form A of the tris salt of Compound 1. [Figure 7C]

[0029] FIG. 1 shows a combined differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermogram for crystalline Form A of the tris salt of Compound 1. [Figure 7D]

[0030] FIG. 1 shows the 1H NMR pattern for crystalline form A of the tris salt of Compound 1. [Figure 8A]

[0031] FIG. 1 shows the XRPD pattern for crystalline Form B of the tris salt of Compound 1. [Figure 8B]

[0032] FIG. 1 shows the XRPD peak list for crystalline Form B of the tris salt of Compound 1. [Figure 8C]

[0033] FIG. 1 shows a combined DSC and TGA thermogram for crystalline Form B of the tris salt of Compound 1. [Figure 8D]

[0034] FIG. 1 shows the 1H NMR pattern for crystalline form B of the tris salt of Compound 1. [Figure 9A]

[0035] FIG. 1 shows the XRPD pattern for crystalline Form C of the tris salt of Compound 1. [Figure 9B]

[0036] FIG. 1 shows the XRPD peak list for crystalline Form C of the tris salt of Compound 1. [Figure 9C]

[0037] FIG. 1 shows a combined DSC and TGA thermogram for crystalline Form C of the tris salt of Compound 1. [Figure 10A]

[0038] FIG. 1 shows the pharmacokinetic (PK) profiles of free acid samples Compound 1 (Lot A and Lot B) and a Tris salt sample of Compound 1 (Lot F). [Figure 10B]

[0039] FIG. 1 shows the pharmacokinetic (PK) profiles of free acid samples Compound 1 (Lot C, Lot D, Lot E) and a Tris salt sample of Compound 1 (Lot F). DETAILED DESCRIPTION OF THE INVENTION

[0014] definition

[0040] When used alone, the terms "Form A," "Form B," "Form C," and "Form D," when describing Compound 1, refer to crystalline Forms A, B, C, and D of Compound 1, respectively. Moreover, the terms "Form A," "Form B," and "Form C," when describing the tris(hydroxymethyl)aminomethane (tris) salt of Compound 1, refer to crystalline Forms A, B, and C of the tris(hydroxymethyl)aminomethane salt of Compound 1, respectively. The terms "Form A" and "crystalline Form A" are used interchangeably to refer to either crystalline Form A of Compound 1 or the tris salt of Compound 1. Similarly, "Form B" and "crystalline Form B," and "Form C" and "crystalline Form C," refer to either crystalline Form B or Form C of Compound 1 or the tris salt of Compound 1, respectively, and "Form D" and "crystalline Form D" refer to crystalline Form D of Compound 1, interchangeably.

[0015]

[0041] The term "amorphous" refers to a solid that exists in a non-crystalline state or form. Amorphous solids have disordered molecular arrangements and therefore do not have a distinguishable crystal lattice or unit cell, and consequently, no definable long-range ordering. The solid-state ordering of a solid can be determined by standard techniques known to those skilled in the art, such as powder X-ray diffraction (XRPD) or differential scanning calorimetry (DSC). Amorphous solids can also be distinguished from crystalline solids by birefringence, for example, using polarized light microscopy.

[0016]

[0042] In general, Compound 1 may contain any amount of one or more impurities. In some embodiments, the term "impurities" refers to chemical impurities, such as reaction by-products. In the present application, this may also be referred to as chemical purity. In other embodiments, the term "impurities" refers to other solid-state forms of Compound 1 or its salts. In such embodiments, other solid-state forms of Compound 1 or its salts may include amorphous or other crystalline forms. As used herein, the term "substantially amorphous" refers to forms and compositions of amorphous Compound 1 that are free of impurities and / or free of crystalline forms of Compound 1 (including crystalline salts of Compound 1) in a specified weight percentage. The specified weight percentages are 60%, 65%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 60% and 100% free of impurities and / or crystalline forms of Compound 1. In some embodiments, substantially amorphous refers to at least 90% pure free or salt form of Compound 1. In other embodiments, substantially amorphous refers to at least 80% pure free or salt form of Compound 1. In other embodiments, substantially amorphous refers to at least 70% pure free or salt form of Compound 1. In other embodiments, substantially amorphous refers to a composition comprising Compound 1 having less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 1% crystalline Compound 1.

[0017]

[0043] As used herein, "crystalline" refers to a solid form of Compound 1 or a tris salt of Compound 1 in which there is long-range atomic order in the positions of the atoms. The crystallinity of a solid can be confirmed, for example, by examining a powder X-ray diffraction pattern. A compound is crystalline if the XRPD shows sharp intensity peaks in the XRPD. A solid form of Compound 1 or a tris salt of Compound 1 that is "crystalline" can be a solid that is fully crystalline or partially crystalline. The term "substantially crystalline" encompasses solids that are at least 80% crystalline, 85% crystalline, 90% crystalline, and 99% crystalline by weight. In contrast to amorphous solids as defined above, crystalline solids have an ordered arrangement of molecules and possess a distinct crystal lattice or unit cell, resulting in definable long-range ordering. In some embodiments, substantially crystalline refers to a solid form of Compound 1 that is at least 80% pure or a tris salt of Compound 1. In other embodiments, substantially crystalline refers to a solid form of Compound 1 that is at least 90% pure.

[0018]

[0044] As used herein, chemical purity refers to the degree to which the disclosed form does not contain substances with different chemical structures. The chemical purity of the disclosed crystalline form of a compound is calculated by dividing the weight of the compound by the sum of the weights of the compound and substances / impurities with different chemical structures, multiplied by 100%, i.e., weight percent. In one embodiment, the disclosed crystalline form of a compound has a chemical purity of at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight.

[0019]

[0045] The term "solvate" refers to crystalline Compound 1 or a crystalline tris salt of Compound 1, wherein a stoichiometric or non-stoichiometric amount of a solvent or solvent mixture is incorporated into the crystal structure.

[0020]

[0046] The term "hydrate" refers to crystalline Compound 1 or a crystalline tris salt of Compound 1, in which a stoichiometric or non-stoichiometric amount of water is incorporated into the crystal structure. A hydrate is a solvate in which the solvent incorporated into the crystal structure is water. The term "anhydrous," when used in reference to a compound, means that the solvent is substantially not incorporated into the crystal structure, e.g., less than 0.1% by weight as determined by Karl Fischer analysis. A compound that is anhydrous is referred to herein as an "anhydrous."

[0021]

[0047] As used herein, the term "major peak" refers to the three most intense peaks in an XRPD data pattern, or a peak having at least 50% of the 100% relative intensity of the most intense peak.

[0022]

[0048] A single crystalline form of Compound 1 or a tris salt of Compound 1 means that 1-methyl-5-(2'-methyl-[1,1'-biphenyl]-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid or 1-methyl-5-(2'-methyl-[1,1'-biphenyl]-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylate tris salt exists as a single crystal or multiple crystals, each of which has the same crystalline form (i.e., Form A, B, C, or D of the free acid, or Form A, B, or C of the tris salt). When a crystalline form is defined as a specific percentage of one specific single crystalline form of the compound, the remainder is made up of amorphous form and / or crystalline forms other than the specific form(s) identified. In one embodiment, the crystalline form is at least 60% by weight single crystalline form, at least 70% by weight single crystalline form, at least 80% by weight single crystalline form, at least 90% by weight single crystalline form, at least 95% by weight single crystalline form, or at least 99% by weight single crystalline form. The weight percent of a particular crystalline form is determined by dividing the weight of the particular crystalline form by the sum of the weight of the particular crystal, the weight of any other crystalline forms present, and the weight of any amorphous form present, and multiplying by 100%.

[0023]

[0049] The 2-theta values ​​of the powder X-ray diffraction patterns of the crystalline forms described herein may vary slightly from instrument to instrument, and also depending on sample preparation and batch-to-batch variations. Therefore, unless otherwise defined, the 2-theta peak values ​​listed in the XRPD patterns and / or herein should not be interpreted as absolute values ​​and may vary by ±0.2 degrees. The 2-theta values ​​provided herein were obtained using Cu Kα1 radiation.

[0024]

[0050] Temperature values, such as the DSC peak temperature and DSC onset temperature herein, may vary slightly from instrument to instrument, and also depending on sample preparation, temperature ramp rate during the course of an experiment, batch-to-batch variations in materials, and other environmental factors. Therefore, unless otherwise defined, the temperature values ​​listed herein should not be interpreted as absolute values ​​and may vary by ±5 degrees.

[0025]

[0051] "Substantially the same XRPD pattern" or "powder X-ray diffraction pattern substantially similar" to a determination diagram means that, for purposes of comparison, at least 90% of the peaks shown are present. It should further be understood that, for purposes of comparison, some variation in 2-theta peak positions in those shown, e.g., ±0.2 degrees, is acceptable. When the phrase "characterized by powder X-ray diffraction peaks at 2-theta angles (±0.2°)" is followed by a list of 2-theta peak positions, it should be understood that ±0.2 degrees applies to each and every one of the listed peak positions.

[0026]

[0052] A "therapeutically effective amount" of a crystalline form of Compound 1, or a crystalline Tris salt form of Compound 1, or a salt of Compound 1 (e.g., an amorphous, amorphous, or partially crystalline Tris salt or Na salt of Compound 1) described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with a condition. The terms "therapeutically effective amount" and "effective amount" are used interchangeably. In one aspect, a therapeutically effective amount of a compound refers to an amount of a therapy or active agent, alone or in combination with other therapeutic agents, that provides a therapeutic benefit in the treatment of a condition. The terms "therapeutic agent" and "active agent" are used interchangeably. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids symptoms, signs, or causes of a condition, and / or enhances the therapeutic effectiveness of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient to elicit a therapeutic effect in the treatment of cancer (including solid tumors and hematological cancers described further herein), viral-mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, autoimmune disease, or inflammatory disorder. In certain embodiments, a therapeutically effective amount is an amount sufficient to elicit a therapeutic effect in the treatment of cancer (including solid tumors and hematological cancers described further herein), viral-mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, autoimmune disease, or inflammatory disorder, where the condition is responsive to inhibition of dihydroorotate dehydrogenase (DHODH). In certain embodiments, a therapeutically effective amount is an amount sufficient to modulate DHODH levels so as to improve overall treatment, reduce or avoid symptoms, signs, or causes of a condition, and / or enhance the therapeutic effectiveness of another therapeutic agent. A therapeutically effective amount of a compound generally ranges from 0.1 to 100 mg / kg of recipient (mammal) body weight per day, typically from 1 to 10 mg / kg of body weight per day. Thus, the actual amount per day for an adult mammal weighing 70 kg will usually be between 70 and 700 mg, which may be administered as an individual dose per day or as a series of partial doses (e.g., 2, 3, 4, 5 or 6 times per day) which usually add up to the same total daily dose.

[0027]

[0053] The terms "treatment," "treat," and "treating" refer to reversing the likelihood of onset, alleviating, reducing, or inhibiting progression of a disease or disorder described herein, or one or more symptoms thereof. 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 before symptoms begin (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, e.g., to reduce the likelihood of or delay recurrence.

[0028]

[0054] As used herein, the terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as a companion animal (e.g., dog, cat, etc.), livestock (e.g., cow, pig, horse, sheep, goat, etc.), and laboratory animal (e.g., rat, mouse, guinea pig, etc.). 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 for a disease. In certain embodiments, the term "subject" refers to a human subject in need of treatment with inhibition of DHODH. In certain embodiments, the term "subject" refers to an adult over 18 years of age in need of treatment for a disease. In certain embodiments, the term "subject" refers to a minor under 18 years of age in need of treatment for a disease.

[0029]

[0055] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not adversely affect the pharmacological activity of the compound with which it is formulated and that is safe for human use.

[0030]

[0056] The term "pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject, for example, by modifying the stability of the active agent or by modifying its absorption by the subject upon administration. Pharmaceutically acceptable excipients typically do not have significant adverse toxicological effects on patients.

[0031]

[0057] In this description, a "pharmaceutically acceptable salt" is a pharmaceutically acceptable organic or inorganic salt or base of a compound described herein. Representative pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth salts, ammonium salts, water soluble and water insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate. , hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate ), iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methionine bromide Nitrate, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate Acid salt, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate Salts / diphosphates, picrates, polygalacturonates, propionates, p-toluenesulfonates, salicylates, stearates, diacetates, succinates, sulfates, sulfosaliclates, suramates, tannates, tartrates Pharmaceutically acceptable salts include tetrahydrofuran, ...

[0032]

[0058] As used herein, the terms "about" and "approximately," when used in conjunction with a numerical value or range of values ​​used to characterize a particular crystalline form, amorphous form, or mixture thereof of a compound, mean that the value or range of values ​​is reasonable to one of ordinary skill in the art and may deviate to an extent that would be recognized as describing the particular crystalline form, amorphous form, or mixture thereof.

[0033]

[0059] As used herein, "% w / w" is used to mean weight as a percentage of the total weight used as the basis for calculating the weight percentage of an individual component. As an example, in a bulk composition, the % w / w of an individual component can be calculated as a percentage of the total weight of all components of the bulk composition. As another example, in a single oral dosage form, the % w / w of an individual component can be calculated as a percentage of the total weight of all components of the single oral dosage form. For example, if the single oral dosage form is a capsule, the total weight can be the total weight of all components of the capsule.

[0034]

[0060] The term "intragranular excipient" refers to an ingredient that is incorporated into a formulation prior to granulation. That is, it refers to the components that are located inside the granular structure.

[0035]

[0061] The term "extragranular excipient" refers to an ingredient that is incorporated into a formulation after granulation; That is, it refers to components that are located outside the granular structure.

[0036]

[0062] As used herein, the singular forms "a," "an," and "one" are used interchangeably. and "the" include plural references unless the context clearly indicates otherwise. The term "intragranular excipient" includes one or more intragranular excipients.

[0037] compound Tris(hydroxymethyl)aminomethane salt of compound 1

[0063] In a first embodiment, the present disclosure is directed to a tris(hydroxymethyl)aminomethane (tris) salt of a compound represented by the formula: [ka]

[0038]

[0064] In a second embodiment, at least 80% by weight of the Tris salt according to the first embodiment is crystalline. In other embodiments, at least 85%, at least 90%, at least 95%, or at least 99% by weight of the Tris salt according to the first embodiment is crystalline.

[0039]

[0065] In a third embodiment, the tris salt according to the second embodiment is at least 60% by weight in single crystalline form, at least 70% by weight in single crystalline form, at least 80% by weight in single crystalline form, at least 90% by weight in single crystalline form, at least 95% by weight in single crystalline form, or at least 99% by weight in single crystalline form.

[0040]

[0066] In a fourth embodiment, the Tris salt according to any one of the first, second and third embodiments has a chemical purity of at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight.

[0041]

[0067] In a fifth embodiment, the tris salt according to any one of the first, second, third and fourth embodiments is anhydrous.

[0042]

[0068] In a sixth embodiment, the tris salt according to any one of the first, second, third, fourth and fifth embodiments is crystalline form A, characterized by powder X-ray diffraction peaks at 2θ angles of 4.4°, 15.6° and 18.9° (±0.2°).

[0043]

[0069] In a seventh embodiment, the tris salt according to any one of the first, second, third, fourth and fifth embodiments is crystalline form A, characterized by principal powder X-ray diffraction peaks at 2θ angles of 4.4°, 15.6° and 18.9° (±0.2°).

[0044]

[0070] In an eighth embodiment, crystalline form A according to any one of the sixth and seventh embodiments is further characterized by powder X-ray diffraction peaks at 2θ angles of 11.5°, 16.4°, 19.6° and 25.5° (±0.2°).

[0045]

[0071] In a ninth embodiment, crystalline form A according to any one of the sixth, seventh and eighth embodiments is further characterized by at least one powder X-ray diffraction peak at a 2θ angle (±0.2°) selected from 8.7°, 15.2°, 18.6°, 21.4° and 25.1°.

[0046]

[0072] In a tenth embodiment, crystalline form A according to any one of the sixth, seventh, eighth and ninth embodiments is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 7A and the XRPD peaks listed in FIG. 7B.

[0047]

[0073] In an eleventh embodiment, crystalline form A according to any one of the sixth, seventh, eighth and ninth embodiments is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak temperature at about 202.0°C ± 2°C (see Figure 7C).

[0048]

[0074] In a twelfth embodiment, crystalline form A according to any one of the sixth, seventh, eighth and ninth embodiments is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of about 2.8% up to about 150° C. (see FIG. 7C).

[0049]

[0075] In a thirteenth embodiment, the Tris salt according to any one of the first, second, third, fourth and fifth embodiments is crystalline form B, characterized by powder X-ray diffraction peaks at 2θ angles of 6.0°, 7.0° and 7.2° (±0.2°). The powder X-ray diffraction peaks at 2θ angles of 6.0°, 7.0° and 7.2° (±0.2°) are, in one embodiment, major peaks.

[0050]

[0076] In a fourteenth embodiment, crystalline form B according to the thirteenth embodiment is further characterized by at least one powder X-ray diffraction peak at a 2θ angle selected from 9.3° and 12.5° (±0.2°).

[0051]

[0077] In a fifteenth embodiment, crystalline form B according to any one of the thirteenth and fourteenth embodiments is further characterized by at least one powder X-ray diffraction peak at a 2θ angle selected from 15.6° and 19.0° (±0.2°).

[0052]

[0078] In a sixteenth embodiment, crystalline form B according to any one of the thirteenth, fourteenth and fifteenth embodiments is characterized by a powder X-ray diffraction pattern substantially similar to FIG. 8A and the XRPD peaks listed in FIG. 8B.

[0053]

[0079] In a seventeenth embodiment, crystalline form B according to any one of the thirteenth, fourteenth, fifteenth and sixteenth embodiments is characterized by a differential scanning calorimetry (DSC) thermogram comprising an overlapping endothermic / exothermic peak temperature at about 129.9°C ± 2°C and an endothermic peak temperature at about 205.8°C ± 2°C (see Figure 8C).

[0054]

[0080] In an eighteenth embodiment, crystalline form B according to any one of the thirteenth, fourteenth, fifteenth, sixteenth and seventeenth embodiments is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of about 10.8% up to about 190° C. (see FIG. 8C).

[0055]

[0081] In a nineteenth embodiment, the tris salt according to any one of the first, second, third, fourth and fifth embodiments is crystalline form C, characterized by powder X-ray diffraction peaks at 2θ angles of 4.5°, 13.5° and 18.0° (±0.2°).

[0056]

[0082] In a twentieth embodiment, the tris salt according to any one of the first, second, third, fourth and fifth embodiments is crystalline form C, characterized by principal powder X-ray diffraction peaks at 2θ angles of 4.5°, 13.5° and 18.0° (±0.2°).

[0057]

[0083] In a 21st embodiment, crystalline form C according to any one of the 19th and 20th embodiments is further characterized by at least one powder X-ray diffraction peak at a 2θ angle (±0.2°) selected from 14.3°, 18.3°, and 23.5°.

[0058]

[0084] In a 22nd embodiment, crystalline form C according to any one of the 19th, 20th and 21st embodiments is further characterized by at least one X-ray powder diffraction peak at a 2θ angle (±0.2°) selected from 16.3°, 19.0°, 21.2°, 21.4°, 22.5° and 22.8°.

[0059]

[0085] In a twenty-third embodiment, crystalline form C according to any one of the nineteenth, twentieth, twenty-first and twenty-second embodiments is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 9A and the XRPD peaks listed in FIG. 9B.

[0060]

[0086] In a twenty-fourth embodiment, crystalline form C according to any one of the nineteenth, twentieth, twenty-first, twenty-second and twenty-third embodiments is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak temperature at about 196.2°C ± 2°C (see Figure 9C).

[0061]

[0087] In a twenty-fifth embodiment, crystalline form C according to any one of the nineteenth, twentieth, twenty-first, twenty-second, twenty-third and twenty-fourth embodiments is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of about 1.2% up to about 150°C (see Figure 9C).

[0062]

[0088] In a twenty-sixth embodiment, the present disclosure is directed to a sodium salt of a compound represented by the formula: [ka] The sodium salt of Compound 1 is preferably in solid or solid crystalline form.

[0063]

[0089] In a twenty-seventh embodiment, the present disclosure is directed to a crystalline form of a compound represented by the formula: [ka]

[0064]

[0090] In a 28th embodiment, the crystalline form according to the 27th embodiment is anhydrous.

[0065]

[0091] In a 29th embodiment, the crystalline form according to the 27th embodiment is a solvate.

[0066]

[0092] In a 30th embodiment, the crystalline form according to any one of the 27th and 28th embodiments is crystalline form A, characterized by powder X-ray diffraction peaks at 2θ angles of 5.8°, 11.6°, and 12.8° (±0.2°).

[0067]

[0093] In a thirty-first embodiment, the crystalline form according to any one of the twenty-seventh and twenty-eighth embodiments is crystalline form A, characterized by principal powder X-ray diffraction peaks at 2θ angles of 5.8°, 11.6°, and 12.8° (±0.2°).

[0068]

[0094] In a thirty-second embodiment, crystalline form A according to any one of the thirty- and thirty-first embodiments is further characterized by powder X-ray diffraction peaks at 2θ angles of 8.1° and 16.9° (±0.2°).

[0069]

[0095] In a thirty-third embodiment, crystalline form A according to any one of the thirty-first, thirty-first and thirty-second embodiments is further characterized by at least one powder X-ray diffraction peak at a 2θ angle (±0.2°) selected from 11.4°, 18.4°, 21.9°, 24.6°, 24.9° and 25.1°.

[0070]

[0096] In a thirty-fourth embodiment, crystalline form A according to any one of the thirty-first, thirty-second and thirty-third embodiments has an X-ray powder diffraction pattern substantially similar to that of FIG. 2A and and characterized by the XRPD peaks listed in Figure 2B.

[0071]

[0097] In a thirty-fifth embodiment, crystalline form A according to any one of the thirty-first, thirty-first, thirty-second, thirty-third and thirty-fourth embodiments is characterized by a differential scanning calorimetry (DSC) thermogram comprising peak temperatures at about 212.1°C ± 2°C (exotherm) and 328.9°C ± 2°C (endotherm) (see Figure 2C).

[0072]

[0098] In a thirty-sixth embodiment, crystalline form A according to any one of the thirty-first, thirty-second, thirty-third, thirty-fourth and thirty-fifth embodiments is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of about 1.0% up to about 200° C. (see FIG. 2C).

[0073]

[0099] In a 37th embodiment, the crystalline form according to any one of the 27th and 28th embodiments is crystalline form B, characterized by powder X-ray diffraction peaks at 2θ angles of 6.5°, 12.9°, and 25.1° (±0.2°).

[0074]

[0100] In a thirty-eighth embodiment, the crystalline form according to any one of the twenty-seventh and twenty-eighth embodiments is crystalline form B, characterized by principal powder X-ray diffraction peaks at 2θ angles of 6.5°, 12.9°, and 25.1° (±0.2°).

[0075]

[0101] In a thirty-ninth embodiment, crystalline form B according to any one of the thirty-seventh and thirty-eighth embodiments is further characterized by powder X-ray diffraction peaks at 2θ angles of 13.1° and 15.7° (±0.2°).

[0076]

[0102] In a fortieth embodiment, crystalline form B according to any one of the thirty-seventh, thirty-eighth and thirty-ninth embodiments is further characterized by at least one powder X-ray diffraction peak at a 2θ angle (±0.2°) selected from 8.5°, 11.1°, 11.4°, 17.3°, 20.5°, 21.9° and 25.9°.

[0077]

[0103] In a forty-first embodiment, crystalline form B according to any one of the thirty-seventh, thirty-eighth, thirty-ninth and fortieth embodiments is characterized by a powder X-ray diffraction pattern substantially similar to FIG. 3A and the XRPD peaks listed in FIG. 3B.

[0078]

[0104] In a 42nd embodiment, crystalline form B according to any one of the 37th, 38th, 39th, 40th and 41st embodiments is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak temperature at about 325.6°C ± 2°C (see Figure 3C).

[0079]

[0105] In a 43rd embodiment, crystalline form B according to any one of the 37th, 38th, 39th, 40th, 41st and 42nd embodiments is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of about 2.9% up to about 200° C. (see FIG. 3C).

[0080]

[0106] In a 44th embodiment, the crystalline form according to any one of the 27th and 28th embodiments is crystalline form C, characterized by powder X-ray diffraction peaks at 2θ angles of 5.7°, 11.4°, and 25.0° (±0.2°).

[0081]

[0107] In a 45th embodiment, the crystalline form according to any one of the 27th, 28th and 29th embodiments is crystalline form C, characterized by principal powder X-ray diffraction peaks at 2θ angles of 5.7°, 11.4° and 25.0° (±0.2°).

[0082]

[0108] In a 46th embodiment, crystalline form C according to any one of the 44th and 45th embodiments is further characterized by powder X-ray diffraction peaks at 2θ angles of 3.2°, 17.4°, and 18.4° (±0.2°).

[0083]

[0109] In a 47th embodiment, crystalline form C according to any one of the 44th, 45th, and 46th embodiments is further characterized by at least one powder X-ray diffraction peak at a 2θ angle (±0.2°) selected from 12.8°, 16.2°, 19.0°, 27.5°, and 31.7°.

[0084]

[0110] In a 48th embodiment, crystalline form C according to any one of the 44th, 45th, 46th and 47th embodiments is characterized by a powder X-ray diffraction pattern substantially similar to FIG. 4A and the XRPD peaks listed in FIG. 4B.

[0085]

[0111] In a 49th embodiment, crystalline form C according to any one of the 44th, 45th, 46th, 47th and 48th embodiments is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak temperature at about 326.1°C ± 2°C (see Figure 4C).

[0086]

[0112] In a 50th embodiment, crystalline form C according to any one of the 44th, 45th, 46th, 47th, 48th and 49th embodiments is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of about 3.6% up to about 200° C. (see FIG. 4C ).

[0087]

[0113] In a 51st embodiment, the crystalline form according to any one of the 27th and 28th embodiments is crystalline form D characterized by powder X-ray diffraction peaks at 2θ angles of 5.9°, 11.9° and 17.1° (±0.2°).

[0088]

[0114] In a 52nd embodiment, the crystalline form according to any one of the 27th, 28th and 29th embodiments is crystalline form D, characterized by principal powder X-ray diffraction peaks at 2θ angles of 5.9°, 11.9° and 17.1° (±0.2°).

[0089]

[0115] In a 53rd embodiment, crystalline form D according to any one of the 51st and 52nd embodiments is further characterized by powder X-ray diffraction peaks at 2θ angles of 11.2° and 23.3° (±0.2°).

[0090]

[0116] In a 54th embodiment, crystalline form D according to any one of the 51st, 52nd and 53rd embodiments is further characterized by at least one powder X-ray diffraction peak at a 2θ angle (±0.2°) selected from 12.7°, 13.4°, 18.8°, 19.7°, 20.8°, 22.0°, 22.5°, 22.7° and 24.6°.

[0091]

[0117] In a 55th embodiment, crystalline form D according to any one of the 51st, 52nd, 53rd and 54th embodiments is characterized by a powder X-ray diffraction pattern substantially similar to FIG. 5A and the XRPD peaks listed in FIG. 5B.

[0092]

[0118] In a 56th embodiment, crystalline form D according to any one of the 51st, 52nd, 53rd, 54th and 55th embodiments is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak temperature at about 329.4°C ± 2°C (see Figure 5C).

[0093]

[0119] In a 57th embodiment, crystalline form D according to any one of the 51st, 52nd, 53rd, 54th, 55th and 56th embodiments is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of about 1.0% up to about 200°C (see Figure 5C).

[0094]

[0120] In a 58th embodiment, the crystalline form according to any one of the 27th to 57th embodiments is at least 60% by weight single crystalline form, at least 70% by weight single crystalline form, at least 80% by weight single crystalline form, at least 90% by weight single crystalline form, at least 95% by weight single crystalline form, or at least 99% by weight single crystalline form.

[0095]

[0121] In a 59th embodiment, the crystalline form according to any one of the 27th to 58th embodiments has a chemical purity of at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight.

[0096]

[0122] Another embodiment of the present invention is an amorphous form of Compound 1 or a tris salt of Compound 1.

[0097] Composition and Administration

[0123] Provided herein is a pharmaceutical composition comprising i) a Tris salt of Compound 1, e.g., the Tris salt in amorphous form or one of the disclosed crystalline forms, or ii) Compound 1 in one of the disclosed crystalline forms, or iii) Compound 1 in amorphous form, or iv) the sodium salt of Compound 1, or v) a pharmaceutically acceptable salt of Compound 1, and a pharmaceutically acceptable carrier. Also provided is a pharmaceutical composition comprising as an active agent i) a Tris salt of Compound 1, e.g., the Tris salt in amorphous form or one of the disclosed crystalline forms, or ii) Compound 1 in one of the disclosed crystalline forms, or iii) Compound 1 in amorphous form, or iv) the sodium salt of Compound 1, or v) a pharmaceutically acceptable salt of Compound 1, and one or more intragranular excipients. Also provided are pharmaceutical compositions comprising as an active agent: i) a Tris salt of Compound 1, e.g., a Tris salt in amorphous form or one of the disclosed crystalline forms; or ii) Compound 1 in one of the disclosed crystalline forms; or iii) Compound 1 in amorphous form; or iv) a sodium salt of Compound 1; or v) a pharmaceutically acceptable salt of Compound 1; and one or more intragranular excipients and one or more extragranular excipients. Also provided are pharmaceutical compositions comprising: i) a Tris salt of Compound 1, e.g., a Tris salt in amorphous form or one of the disclosed crystalline forms; or ii) Compound 1 in one of the disclosed crystalline forms; or iii) Compound 1 in amorphous form; or iv) a sodium salt of Compound 1; or v) a pharmaceutically acceptable salt of Compound 1, as part of a solid dispersion. In some embodiments, such compositions comprise an amorphous solid dispersion. In other embodiments, such compositions comprise a substantially amorphous solid dispersion. In yet other embodiments, such compositions comprise a partially crystalline solid dispersion. In still other embodiments, such compositions comprise a substantially crystalline solid dispersion.Also provided is a pharmaceutical composition comprising, as part of a solid dispersion, i) a Tris salt of Compound 1, e.g., the Tris salt in amorphous form or one of the disclosed crystalline forms, or ii) Compound 1 in one of the disclosed crystalline forms, or iii) Compound 1 in amorphous form, or iv) the sodium salt of Compound 1, or v) a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers. Suitable pharmaceutical compositions are described in U.S. Pat. No. 9,360,932 and below.

[0098]

[0124] The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, transmucosally, or in ophthalmic formulations. As used herein, includes subcutaneous, intravenous, intramuscular, intraarterial, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In one aspect, the pharmaceutical compositions provided herein may be orally administered in orally acceptable dosage forms, including, but not limited to, capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions.

[0099]

[0125] The amount of the provided crystalline or amorphous form that can be combined with the carrier material to produce a single-dosage composition will vary depending on the subject being treated and the particular mode of administration. For example, the specific dosage and treatment regimen for a particular subject will depend on various factors, including age, body weight, general health, sex, diet, time of administration, excretion rate, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of the crystalline form provided in the composition will depend on the particular form of the composition (e.g., Forms A, B, C, and D of the crystalline form of Compound 1, or Forms A, B, and C of the crystalline form of the tris salt of Compound 1). In one embodiment, the provided composition contains a dosage equivalent of about 0.001 to about 100 mg / kg body weight of Compound 1. It can be formulated to be administered daily.

[0100]

[0126] In one embodiment, the pharmaceutical composition comprises i) Compound 1 or a pharmaceutically acceptable salt thereof, ii) a diluent, iii) a disintegrant, and iv) a lubricant. In another embodiment, the pharmaceutical composition comprises i) Compound 1 or a pharmaceutically acceptable salt thereof, ii) a diluent, iii) a disintegrant, iv) a binder, v) a surfactant, vi) a glidant, and vii) a lubricant. In another embodiment, the pharmaceutical composition comprises i) Compound 1 or a pharmaceutically acceptable salt thereof, ii) a diluent, iii) a disintegrant, iv) a binder, and v) a lubricant. In such compositions, Compound 1 can be provided, for example, as i) one of the disclosed crystalline forms of Compound 1, or an amorphous form of Compound 1, or a mixture thereof. In other embodiments of such compositions, Compound 1 can be provided as a Tris salt of Compound 1, for example, as i) an amorphous form, or ii) one of the disclosed crystalline forms of the Tris salt, or iii) a mixture thereof. In yet other embodiments of such pharmaceutical compositions, Compound 1 may be provided in a non-salt form, a tris salt form, or a mixture thereof. In one embodiment, the pharmaceutical composition is in the form of a capsule. In another embodiment, the pharmaceutical composition is in the form of a tablet.

[0101]

[0127] In certain embodiments, the pharmaceutical composition is a capsule composition comprising a crystalline form of Compound 1 as the active agent and one or more intragranular excipients. In one embodiment, the capsule composition comprises Form A of Compound 1 as the active agent and one or more intragranular excipients. In one embodiment, the capsule composition comprises Form B of Compound 1 as the active agent and one or more intragranular excipients. In one embodiment, the capsule composition comprises Form C of Compound 1 as the active agent and one or more intragranular excipients. In one embodiment, the capsule composition comprises Form D of Compound 1 as the active agent and one or more intragranular excipients.

[0102]

[0128] In certain embodiments, the pharmaceutical composition is a capsule composition comprising a crystalline form of Compound 1 as the active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the capsule composition comprises Form A of Compound 1 as the active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the capsule composition comprises Form B of Compound 1 as the active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the capsule composition comprises Form C of Compound 1 as the active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the capsule composition comprises Form D of Compound 1 as the active agent, one or more intragranular excipients, and one or more extragranular excipients.

[0103]

[0129] In certain embodiments, the pharmaceutical composition is a capsule composition comprising a Tris salt of Compound 1 as an active agent and one or more intragranular excipients. The active agent used in the composition is a Tris salt of Compound 1 in one of the disclosed crystalline forms. In one embodiment, the capsule composition comprises Form A of the Tris salt as the active agent and one or more intragranular excipients. In one embodiment, the capsule composition comprises Form B of the Tris salt as the active agent and one or more intragranular excipients. In one embodiment, the capsule composition comprises Form C of the Tris salt as the active agent and one or more intragranular excipients.

[0104]

[0130] In certain embodiments, the pharmaceutical composition is a capsule composition comprising a Tris salt of Compound 1 as the active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the active agent used in the capsule composition is a Tris salt of Compound 1 in one of the disclosed crystalline forms. In one embodiment, the capsule composition comprises a Tris salt of Form A as the active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the capsule composition comprises a Tris salt of Form B as the active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the capsule composition comprises a Tris salt of Form C as the active agent, one or more intragranular excipients, and one or more extragranular excipients.

[0105]

[0131] In certain embodiments, the pharmaceutical composition is a capsule composition comprising the sodium salt of Compound 1 as the active agent and one or more intragranular excipients. In certain embodiments, the pharmaceutical composition is a capsule composition comprising the sodium salt of Compound 1 as the active agent and one or more intragranular excipients and one or more extragranular excipients.

[0106]

[0132] In certain embodiments, the pharmaceutical composition is a tablet composition comprising a crystalline form of Compound 1 as the active agent and one or more intragranular excipients. In one embodiment, the tablet composition comprises Form A of Compound 1 as the active agent and one or more intragranular excipients. In one embodiment, the tablet composition comprises Form B of Compound 1 as the active agent and one or more intragranular excipients. In one embodiment, the tablet composition comprises Form C of Compound 1 as the active agent and one or more intragranular excipients. In one embodiment, the tablet composition comprises Form D of Compound 1 as the active agent and one or more intragranular excipients.

[0107]

[0133] In certain embodiments, the pharmaceutical composition is a tablet composition comprising a crystalline form of Compound 1 as the active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the tablet composition comprises Form A of Compound 1 as the active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the tablet composition comprises Form B of Compound 1 as the active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the tablet composition comprises Form C of Compound 1 as the active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the tablet composition comprises Form D of Compound 1 as the active agent, one or more intragranular excipients, and one or more extragranular excipients.

[0108]

[0134] In certain embodiments, the pharmaceutical composition is a tablet composition comprising a Tris salt of Compound 1 as the active agent and one or more intragranular excipients. In one embodiment, the active agent used in the tablet composition is a Tris salt of Compound 1 in one of the disclosed crystalline forms. In one embodiment, the tablet composition comprises a Tris salt of Form A as the active agent and one or more intragranular excipients. In one embodiment, the tablet composition comprises a Tris salt of Form B as the active agent and one or more intragranular excipients. In one embodiment, the tablet composition comprises a Tris salt of Form C as the active agent and one or more intragranular excipients.

[0109]

[0135] In certain embodiments, the pharmaceutical composition is a tablet composition comprising a Tris salt of Compound 1 as the active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the active agent used in the tablet composition is a Tris salt of Compound 1 as disclosed herein. The Tris salt is one of the crystalline forms of the Tris salt. In one embodiment, a tablet composition comprises a Tris salt of Form A as the active agent, one or more intragranular excipients and one or more extragranular excipients. In one embodiment, a tablet composition comprises a Tris salt of Form B as the active agent, one or more intragranular excipients and one or more extragranular excipients. In one embodiment, a tablet composition comprises a Tris salt of Form C as the active agent, one or more intragranular excipients and one or more extragranular excipients.

[0110]

[0136] In certain embodiments, the pharmaceutical composition is a tablet composition comprising the sodium salt of Compound 1 as the active agent and one or more intragranular excipients. In certain embodiments, the pharmaceutical composition is a tablet composition comprising the sodium salt of Compound 1 as the active agent and one or more intragranular excipients and one or more extragranular excipients.

[0111]

[0137] In certain embodiments, the pharmaceutical compositions provided herein comprise Compound 1 or a pharmaceutically acceptable salt thereof in an amount of about 10% to about 90% by weight (e.g., between about 20% w / w and about 80% w / w, between about 30% w / w and about 70% w / w, between about 40% w / w and about 60% w / w, or between about 10% w / w and about 20% w / w) based on the total weight of the pharmaceutical composition.

[0112]

[0138] In certain embodiments, the pharmaceutical compositions provided herein comprise Compound 1 or a pharmaceutically acceptable salt thereof in an amount of about 15% to about 65%, about 45% to about 65%, or about 15% to about 17% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical compositions provided herein comprise Compound 1 or a Tris salt of Compound 1 in an amount of about 16%, about 45%, about 54%, or about 60% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical compositions provided herein comprise Compound 1 or a Tris salt of Compound 1 in an amount of about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, or about 65% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the Tris salt of Compound 1 is Form C of the Tris salt.

[0113]

[0139] In certain embodiments, the pharmaceutical compositions provided herein can comprise one or more intragranular excipients and one or more extragranular excipients. In certain embodiments, the intragranular excipients comprise a diluent, disintegrant, binder, surfactant, glidant, and lubricant. In certain embodiments, the intragranular excipients comprise a diluent, disintegrant, binder, surfactant, and lubricant. In certain embodiments, the intragranular excipients comprise a diluent, disintegrant, binder, glidant, and lubricant. In certain embodiments, the intragranular excipients comprise a diluent, disintegrant, binder, and lubricant. In certain embodiments, the intragranular excipients comprise a diluent, disintegrant, binder, and lubricant. In certain embodiments, the intragranular excipients comprise a diluent, disintegrant, and lubricant. In certain embodiments, the extragranular excipients comprise a glidant and a lubricant. In certain embodiments, the extragranular excipients comprise a glidant. In certain embodiments, the extragranular excipients comprise a lubricant. In certain embodiments, no extragranular excipients are used. In other embodiments, no intragranular or extragranular excipients are used.

[0114] 1. Intragranular excipients

[0140] In one embodiment, the pharmaceutical compositions provided herein comprise one or more intragranular excipients selected from diluents, disintegrants, binders, surfactants, glidants, and lubricants.

[0115]

[0141] Diluents are used in varying amounts to aid in weight gain and to aid in flowability, solubility, content uniformity, encapsulation, compressibility, reduced stickiness, and stability of pharmaceutical products. It is an excipient used in formulations. As used herein, unless otherwise clearly stated, it should be understood that the terms diluent, filler, and bulking agent are used interchangeably. Exemplary diluents 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, starch, pregelatinized starch, corn starch, partially pregelatinized starch, powdered sugar, ethyl cellulose, isomalt, and mixtures thereof. In some embodiments, the diluent is starch, partially pregelatinized starch, microcrystalline cellulose, and mannitol, and mixtures thereof. In some embodiments, the diluent is dicalcium phosphate, starch, lactose, isomalt, and mixtures thereof. In some embodiments, the diluent is microcrystalline cellulose and mannitol, and mixtures thereof. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is mannitol. In some embodiments, the diluent is starch. In some embodiments, the diluent is a partially pregelatinized starch.

[0116]

[0142] In certain embodiments, the pharmaceutical composition comprises a diluent (or one or more diluents) in an amount of about 5 to about 80% by weight (e.g., between about 10% w / w and about 75% w / w, between about 15% w / w and about 70% w / w, between about 25% w / w and about 65% w / w, between about 30% w / w and about 60% w / w, between about 35% w / w and about 55% w / w, or between about 40% w / w and about 50% w / w) based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises a diluent (or one or more diluents) in an amount of 5% to about 15% by weight, about 5% to about 45% by weight, about 25% to about 45% by weight, or about 25% to about 80% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises a diluent (or one or more diluents) in an amount of about 5% by weight, about 6% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 15% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 27% by weight, about 28% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 37% by weight, about 40% by weight, about 41% by weight, about 42% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, about 65% by weight, about 70% by weight, about 75% by weight, about 78% by weight, about 79% by weight, or about 80% by weight, based on the total weight of the pharmaceutical composition.

[0117]

[0143] In certain embodiments, the pharmaceutical composition comprises microcrystalline cellulose in an amount of about 5% to about 80% by weight based on the total weight of the pharmaceutical composition, such as about 5% to about 15% by weight, about 20% to about 40% by weight, or about 20% to about 80% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises microcrystalline cellulose in an amount of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 7% by weight, about 28% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 37% by weight, about 40% by weight, about 41% by weight, about 42% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, about 65% by weight, about 70% by weight, about 75% by weight, about 78% by weight, about 79% by weight, or about 80% by weight.

[0118]

[0144] In certain embodiments, the pharmaceutical composition comprises mannitol in an amount of about 5% to 80% by weight based on the total weight of the pharmaceutical composition, such as about 5% to about 15% by weight, about 20% to about 40% by weight, or about 20% to about 80% by weight based on the total weight of the pharmaceutical composition. Based on the total weight, the composition may be present in an amount of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 27%, about 28%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 37%, about 40%, about 41%, about 42%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 78%, about 79%, or about 80% by weight.

[0119]

[0145] In certain embodiments, the pharmaceutical composition comprises starch in an amount of about 5% to about 80% by weight based on the total weight of the pharmaceutical composition, such as about 5% to about 15% by weight, about 20% to about 40% by weight, or about 20% to about 80% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises starch in an amount of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 7% by weight, about 28% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 37% by weight, about 40% by weight, about 41% by weight, about 42% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, about 65% by weight, about 70% by weight, about 75% by weight, about 78% by weight, about 79% by weight, or about 80% by weight.

[0120]

[0146] In certain embodiments, the pharmaceutical composition comprises the partially pregelatinized starch in an amount of about 5% to about 80% by weight based on the total weight of the pharmaceutical composition, such as about 5% to about 15% by weight, about 20% to about 40% by weight, or about 20% to about 80% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises the partially pregelatinized starch in an amount of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% by weight based on the total weight of the pharmaceutical composition. , about 27%, about 28%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 37%, about 40%, about 41%, about 42%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 78%, about 79%, or about 80% by weight.

[0121]

[0147] Disintegrants are excipients used to improve the disintegration of pharmaceutical preparations. More specifically, they are excipients added to absorb body fluids after administration, expand, and disintegrate the capsule or tablet, thereby promoting the release of the active ingredient. In certain embodiments, the amount of disintegrant in the capsules and tablets provided herein is selected so that the disintegration rate and / or dissolution rate of the capsule or tablet falls within a desired range. In certain embodiments, the amount of disintegrant in the capsules and tablets is about 10% by weight or less, based on the total weight of the capsule or tablet.

[0122]

[0148] Illustrative examples of disintegrants include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, Alginic acid, guar gum, citrus pulp, agar, bentonite, cell Rosin and wood products, natural sponges, cation exchange trees Fat, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked carboxymethyl Sodium croscarmellose, methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-soluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (magnesium aluminum silicate) (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof. In one embodiment, the disintegrant includes crospovidone, sodium starch glycolate, croscarmellose sodium, and mixtures thereof. In one embodiment, the disintegrant is crospovidone. In one embodiment, the disintegrant is sodium starch glycolate. In one embodiment, the disintegrant is croscarmellose sodium.

[0123]

[0149] In certain embodiments, the amount of disintegrant in the pharmaceutical composition is about 0.5% by weight to about 8% by weight, such as about 0.5% by weight to about 5% by weight or about 2% by weight to about 5% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the amount of disintegrant is about 2% by weight to about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the disintegrant is present in the pharmaceutical composition in an amount of about 3% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the disintegrant is present in the pharmaceutical composition in an amount of about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the disintegrant is present in the pharmaceutical composition in an amount of about 5% by weight, based on the total weight of the pharmaceutical composition.

[0124]

[0150] In certain embodiments, the pharmaceutical composition comprises crospovidone in an amount of about 0.5% to about 8% by weight, such as about 0.5% to about 5% by weight or about 2% to about 5% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises crospovidone in an amount of about 2% to about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises crospovidone in an amount of about 3% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises crospovidone in an amount of about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises crospovidone in an amount of about 5% by weight, based on the total weight of the pharmaceutical composition.

[0125]

[0151] In certain embodiments, the pharmaceutical composition comprises sodium starch glycolate in an amount of about 0.5% to about 8% by weight, such as about 0.5% to about 5% by weight or about 2% to about 5% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises sodium starch glycolate in an amount of about 2% to about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises sodium starch glycolate in an amount of about 3% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises sodium starch glycolate in an amount of about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises sodium starch glycolate in an amount of about 5% by weight, based on the total weight of the pharmaceutical composition.

[0126]

[0152] In certain embodiments, the pharmaceutical composition contains croscarmellose sodium in an amount of about 0.5% to about 8% by weight, such as about 0.5% to about 5% by weight or about 2% to about 5% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition contains croscarmellose sodium in an amount of about 2% to about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition contains croscarmellose sodium in an amount of about 3% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition contains croscarmellose sodium in an amount of about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition contains croscarmellose sodium in an amount of about 5% by weight, based on the total weight of the pharmaceutical composition.

[0127]

[0153] Binders are classified as excipients that impart cohesiveness necessary for the manufacturability of solid oral dosage forms. The amount of binder in the tablets or capsules provided herein depends, for example, on the type of binder (properties such as molecular weight, solubility, and viscosity), the type and amount of other excipients, the type and amount of complexes, and The dosage and amount will vary based on the dosage form and formulation (granulation and tableting methods).

[0128]

[0154] Exemplary binders include hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate, methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl starch, povidone, corn starch, potato starch, rice starch, and gelatin, and mixtures thereof. In one embodiment, the binder includes hypromellose, povidone, methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone / vinyl acetate (PVPVA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and mixtures thereof. In one embodiment, the binder includes hypromellose. In one embodiment, the binder includes povidone (PVPK-30). In one embodiment, the binder includes methylcellulose. In one embodiment, the binder includes hydroxypropyl cellulose. In one embodiment, the binder includes polyvinylpyrrolidone / vinyl acetate (PVPVA). In one embodiment, the binder comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0129]

[0155] In certain embodiments, the pharmaceutical composition comprises the binder in an amount of about 0.5% to about 10% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises the binder in an amount of about 0.5% to about 5%, about 2% to about 8%, or about 2% to about 5% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises the binder in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight, based on the total weight of the pharmaceutical composition.

[0130]

[0156] In certain embodiments, the pharmaceutical composition comprises hypromellose in an amount of about 0.5% to about 10% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises hypromellose in an amount of about 0.5% to about 5% by weight, about 2% to about 8% by weight, or about 2% to about 5% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises hypromellose in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight, based on the total weight of the pharmaceutical composition.

[0131]

[0157] In certain embodiments, the pharmaceutical composition comprises povidone in an amount of about 0.5% to about 10% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises povidone in an amount of about 0.5% to about 5% by weight, about 2% to about 8% by weight, or about 2% to about 5% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises povidone in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight, based on the total weight of the pharmaceutical composition.

[0132]

[0158] In certain embodiments, the pharmaceutical composition comprises methylcellulose in an amount of about 0.5% to about 10% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises methylcellulose in an amount of about 0.5% to about 5%, about 2% to about 8%, or about 2% to about 5% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises methylcellulose in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight, based on the total weight of the pharmaceutical composition.

[0133]

[0159] In certain embodiments, the pharmaceutical composition comprises hydroxypropyl cellulose. The hydroxypropyl cellulose is contained in an amount of about 0.5% to about 10% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition contains hydroxypropyl cellulose in an amount of about 0.5% to about 5% by weight, about 2% to about 8% by weight, or about 2% to about 5% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition contains hydroxypropyl cellulose in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight based on the total weight of the pharmaceutical composition.

[0134]

[0160] In certain embodiments, the pharmaceutical composition comprises polyvinylpyrrolidone / vinyl acetate (PVPVA) in an amount of about 0.5% to about 10% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises PPVVA in an amount of about 0.5% to about 5%, about 2% to about 8%, or about 2% to about 5% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises PPVVA in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight, based on the total weight of the pharmaceutical composition.

[0135]

[0161] In certain embodiments, the pharmaceutical composition comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS) in an amount of about 0.5% to about 10% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises HPMCAS in an amount of about 0.5% to about 5%, about 2% to about 8%, or about 2% to about 5% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises HPMCAS in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight, based on the total weight of the pharmaceutical composition.

[0136]

[0162] In some embodiments, the pharmaceutical composition also comprises a glidant, which is an excipient used in solid oral dosage forms to increase powder flowability.Exemplary glidants include silicon dioxide, colloidal silicon dioxide, tricalcium phosphate, magnesium stearate, magnesium trisilicate, powdered cellulose, talc, starch, and mixtures thereof.In some embodiments, the glidant is colloidal silicon dioxide, starch, and talc.In one embodiment, the glidant is colloidal silicon dioxide.In one embodiment, the glidant is starch.In one embodiment, the glidant is talc.

[0137]

[0163] In certain embodiments, the glidant is present in an amount of about 0.1% to about 2% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the amount of glidant is about 0.1% to about 1%, about 0.25% to about 1.5%, or about 0.5% to about 1.0% by weight based on the total weight of the pharmaceutical composition. In one embodiment, the amount of glidant is about 0.5%, about 0.75%, about 1%, or about 1.5% by weight based on the total weight of the pharmaceutical composition.

[0138]

[0164] In certain embodiments, the pharmaceutical composition comprises colloidal silicon dioxide in an amount of about 0.1% to about 2%, about 0.1% to about 1%, about 0.25% to about 1.5%, or about 0.5% to about 1.0% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises colloidal silicon dioxide in an amount of about 0.5%, about 0.75%, about 1%, or about 1.5% by weight, based on the total weight of the pharmaceutical composition.

[0139]

[0165] In certain embodiments, the pharmaceutical composition comprises from about 0.1% to about 2% by weight, from about 0.1% to about 1% by weight, from about 0.25% to about 1% by weight, ... In one embodiment, the pharmaceutical composition comprises starch in an amount of about 0.5 wt%, about 0.75 wt%, about 1 wt%, or about 1.5 wt%, based on the total weight of the pharmaceutical composition.

[0140]

[0166] In certain embodiments, the pharmaceutical composition comprises talc in an amount of about 0.1% to about 2%, about 0.1% to about 1%, about 0.25% to about 1.5%, or about 0.5% to about 1.0% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises talc as an intragranular excipient in an amount of about 0.5%, about 0.75%, about 1%, or about 1.5% by weight, based on the total weight of the pharmaceutical composition.

[0141]

[0167] In some embodiments, the pharmaceutical composition also includes a lubricant, which is an excipient that reduces interparticle friction and sticking / adhesion to tablet punches and dies. Exemplary lubricants include magnesium stearate (vegetable grade), calcium stearate, zinc stearate, sucrose stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, sodium stearyl fumarate, polyvinyl alcohol, lauric acid ... In certain embodiments, the lubricant is sodium stearyl fumarate, magnesium stearate, talc, silica, stearic acid, and glyceryl behenate. In one embodiment, the lubricant is sodium stearyl fumarate. In one embodiment, the lubricant is magnesium stearate. In one embodiment, the lubricant is talc. In one embodiment, the lubricant is silica. In one embodiment, the lubricant is stearic acid. In one embodiment, the lubricant is glyceryl behenate.

[0142]

[0168] In certain embodiments, the lubricant is present in an amount of about 0.25% to about 3% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the amount of lubricant is about 0.5% to about 2% by weight or about 0.75% to about 1.5% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the amount of lubricant is about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, or about 2% by weight based on the total weight of the pharmaceutical composition.

[0143]

[0169] In certain embodiments, the pharmaceutical composition comprises sodium stearyl fumarate in an amount of about 0.25% to about 3%, about 0.5% to about 2%, or about 0.75% to about 1.5% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises sodium stearyl fumarate in an amount of about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, or about 2% by weight, based on the total weight of the pharmaceutical composition.

[0144]

[0170] In certain embodiments, the pharmaceutical composition comprises magnesium stearate in an amount of about 0.25% to about 3%, about 0.5% to about 2%, or about 0.75% to about 1.5% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises magnesium stearate in an amount of about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, or about 2% by weight, based on the total weight of the pharmaceutical composition.

[0145]

[0171] In certain embodiments, the pharmaceutical composition comprises talc in an amount of about 0.25% to about 3%, about 0.5% to about 2%, or about 0.75% to about 1.5% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises talc in an amount of about 0.5%, about 0.75%, about 1%, about 1.5%, based on the total weight of the pharmaceutical composition. 25%, about 1.5%, about 1.75%, or about 2% by weight.

[0146]

[0172] In certain embodiments, the pharmaceutical composition comprises silica in an amount of about 0.25% to about 3%, about 0.5% to about 2%, or about 0.75% to about 1.5% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises silica in an amount of about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, or about 2% by weight based on the total weight of the pharmaceutical composition.

[0147]

[0173] In certain embodiments, the pharmaceutical composition comprises stearic acid in an amount of about 0.25% to about 3%, about 0.5% to about 2%, or about 0.75% to about 1.5% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises stearic acid in an amount of about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, or about 2% by weight, based on the total weight of the pharmaceutical composition.

[0148]

[0174] In certain embodiments, the pharmaceutical composition comprises glyceryl behenate in an amount of about 0.25% to about 3%, about 0.5% to about 2%, or about 0.75% to about 1.5% by weight based on the total weight of the pharmaceutical composition, hi certain embodiments, the pharmaceutical composition comprises glyceryl behenate in an amount of about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, or about 2% by weight based on the total weight of the pharmaceutical composition.

[0149]

[0175] Surfactants or wetting agents are excipients that improve the wetting properties of active agents and aid in solubilization. Exemplary surfactants and wetting agents include sodium lauryl sulfate (SLS), vitamin E or its derivatives (e.g., vitamin E TPGS), docusate sodium, sodium dodecyl sulfate, polysorbates (e.g., Tween 20 and Tween 80), poloxamers (e.g., 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 sodium lauryl sulfate, poloxamers, Pluronic copolymers, and polysorbates. In one embodiment, the surfactant is sodium lauryl sulfate. In one embodiment, the surfactant is a poloxamer. In one embodiment, the surfactant is a Pluronic copolymer. In one embodiment, the surfactant is a polysorbate.

[0150]

[0176] In certain embodiments, the surfactant is present in an amount of about 0.1% to about 3% by weight based on the total weight of the pharmaceutical composition. In one embodiment, the amount of surfactant is about 0.5% to about 1.5% by weight, or about 1% to about 2% by weight based on the total weight of the pharmaceutical composition. In some embodiments, the surfactant is present in an amount of about 0.5%, about 1%, about 1.5%, or about 2% by weight based on the total weight of the pharmaceutical composition.

[0151]

[0177] In certain embodiments, the pharmaceutical composition comprises sodium lauryl sulfate in an amount of about 0.1% to about 3% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises sodium lauryl sulfate in an amount of about 0.5% to about 1.5% by weight, or about 1% to about 2% by weight, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises sodium lauryl sulfate in an amount of about 0.5%, about 1%, about 1.5%, or about 2% by weight, based on the total weight of the pharmaceutical composition.

[0152]

[0178] In certain embodiments, the pharmaceutical composition comprises a poloxamer in an amount of about 1000 ppm by weight of the total pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises the poloxamer in an amount of about 0.5% to about 1.5% by weight, or about 1% to about 2% by weight, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises the poloxamer in an amount of about 0.5%, about 1%, about 1.5%, or about 2% by weight, based on the total weight of the pharmaceutical composition.

[0153]

[0179] In certain embodiments, the pharmaceutical composition comprises the Pluronic copolymer in an amount of about 0.1% to about 3% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises the Pluronic copolymer in an amount of about 0.5% to about 1.5% by weight, or about 1% to about 2% by weight, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises the Pluronic copolymer in an amount of about 0.5%, about 1%, about 1.5%, or about 2% by weight, based on the total weight of the pharmaceutical composition.

[0154]

[0180] In certain embodiments, the pharmaceutical composition comprises polysorbate in an amount of about 0.1% to about 3% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises polysorbate in an amount of about 0.5% to about 1.5% by weight, or about 1% to about 2% by weight, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises polysorbate in an amount of about 0.5%, about 1%, about 1.5%, or about 2% by weight, based on the total weight of the pharmaceutical composition.

[0155]

[0181] The pharmaceutical compositions provided herein may also contain one or more additional pharmaceutically acceptable intragranular excipients in addition to the excipients described above. Examples of such additional excipients include, but are not limited to, solubility enhancers, stabilizers, pH adjusters, coating agents, and pigments.

[0156]

[0182] In certain embodiments, the pharmaceutical compositions provided herein are in the form of a tablet and can include a coating, such as, for example, polyvinyl alcohol.

[0157]

[0183] In certain embodiments, the pharmaceutical compositions provided herein are in the form of a tablet and can include a pigment, such as, for example, titanium dioxide.

[0158] 2. Extragranular excipients

[0184] In certain embodiments, the pharmaceutical compositions provided herein comprise one or more extragranular excipients selected from glidants and lubricants.

[0159]

[0185] In certain embodiments, the glidants used in the extragranular excipients are colloidal silicon dioxide, starch, and talc. In one embodiment, the glidant is colloidal silicon dioxide. In one embodiment, the glidant is starch. In one embodiment, the glidant is talc.

[0160]

[0186] In some embodiments, the glidant is present in the extragranular excipient in an amount of about 0.1% to about 2% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the amount of glidant in the extragranular excipient is about 0.1% to about 1%, about 0.25% to about 1.5%, or about 0.5% to about 1.0% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the amount of glidant in the extragranular excipient is about 0.5%, about 0.75%, or about 1% by weight, based on the total weight of the pharmaceutical composition.

[0161]

[0187] In certain embodiments, the pharmaceutical composition comprises colloidal silicon dioxide in an extragranular excipient in an amount of about 0.1% to about 2% by weight, about 0.1% to about 1% by weight, about 0.25% to about 1.5% by weight, or about 0.5% to about 1.0% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises colloidal silicon dioxide in an extragranular excipient in an amount of about 0.5 wt %, about 0.75 wt %, or about 1 wt %, based on the total weight of the pharmaceutical composition.

[0162]

[0188] In certain embodiments, the pharmaceutical composition comprises starch in the extragranular excipient in an amount of about 0.1% to about 2%, about 0.1% to about 1%, about 0.25% to about 1.5%, or about 0.5% to about 1.0% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises starch in the extragranular excipient in an amount of about 0.5%, about 0.75%, or about 1% by weight, based on the total weight of the pharmaceutical composition.

[0163]

[0189] In certain embodiments, the pharmaceutical composition comprises talc in the extragranular excipient in an amount of about 0.1% to about 2%, about 0.1% to about 1%, about 0.25% to about 1.5%, or about 0.5% to about 1.0% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises talc in the extragranular excipient in an amount of about 0.5%, about 0.75%, or about 1% by weight, based on the total weight of the pharmaceutical composition.

[0164]

[0190] In certain embodiments, the lubricant used in the extragranular excipient is sodium stearyl fumarate, magnesium stearate, talc, silica, stearic acid, and glyceryl behenate. In one embodiment, the lubricant is sodium stearyl fumarate. In one embodiment, the lubricant is magnesium stearate. In one embodiment, the lubricant is talc. In one embodiment, the lubricant is silica. In one embodiment, the lubricant is stearic acid. In one embodiment, the lubricant is glyceryl behenate.

[0165]

[0191] In certain embodiments, the lubricant is present in the extragranular excipient in an amount of about 0.25% to about 1.5% by weight based on the total weight of the pharmaceutical composition, hi certain embodiments, the amount of lubricant in the extragranular excipient is about 0.5%, about 0.75%, about 1%, about 1.25%, or about 1.5% by weight based on the total weight of the pharmaceutical composition.

[0166]

[0192] In certain embodiments, the pharmaceutical composition comprises sodium stearyl fumarate in an extragranular excipient in an amount of about 0.25% to about 1.5% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises sodium stearyl fumarate in an extragranular excipient in an amount of about 0.5%, about 0.75%, about 1%, about 1.25%, or about 1.5% by weight, based on the total weight of the pharmaceutical composition.

[0167]

[0193] In certain embodiments, the pharmaceutical composition comprises magnesium stearate in an extragranular excipient in an amount of about 0.25% to about 1.5% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises magnesium stearate in an extragranular excipient in an amount of about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, or about 2% by weight, based on the total weight of the pharmaceutical composition.

[0168]

[0194] In certain embodiments, the pharmaceutical composition comprises talc in the extragranular excipient in an amount of about 0.25% to about 1.5% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises talc in the extragranular excipient in an amount of about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, or about 2% by weight, based on the total weight of the pharmaceutical composition.

[0169]

[0195] In certain embodiments, the pharmaceutical composition comprises silica in the extragranular excipient in an amount of about 0.25% to about 1.5% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises silica in the extragranular excipient in an amount of about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1. 75% by weight, or about 2% by weight.

[0170]

[0196] In certain embodiments, the pharmaceutical composition comprises stearic acid in the extragranular excipient in an amount of about 0.25% to about 1.5% by weight, based on the total weight of the pharmaceutical composition, hi certain embodiments, the pharmaceutical composition comprises stearic acid in the extragranular excipient in an amount of about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, or about 2% by weight, based on the total weight of the pharmaceutical composition.

[0171]

[0197] In certain embodiments, the pharmaceutical composition comprises glyceryl behenate in an extragranular excipient in an amount of about 0.25% to about 1.5% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises glyceryl behenate in an extragranular excipient in an amount of about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, or about 2% by weight, based on the total weight of the pharmaceutical composition.

[0172]

[0198] The pharmaceutical compositions provided herein may contain various pharmaceutically acceptable excipients other than those described above, which are used as excipients. Examples of other excipients include, but are not limited to, diluents, disintegrants, colorants, coating agents, and flavoring agents.

[0173] 3. Pharmaceutical Compositions

[0199] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof comprises between about 10% w / w and about 20% w / w of the pharmaceutical composition, the diluent comprises between about 76.5% w / w and about 83% w / w of the pharmaceutical composition, the disintegrant comprises between about 3% w / w and about 5% w / w of the pharmaceutical composition, and the lubricant comprises between about 0.5% w / w and about 2.0% w / w of the pharmaceutical composition, totaling 100% by weight of the composition. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a Tris salt.

[0174]

[0200] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof comprises between about 48% w / w and about 60% w / w of the pharmaceutical composition, the diluent comprises between about 37.5% w / w and about 44% w / w of the pharmaceutical composition, the disintegrant comprises between about 2% w / w and about 6% w / w of the pharmaceutical composition, and the lubricant comprises between about 0.5% w / w and about 2.0% w / w of the pharmaceutical composition, totaling 100% by weight of the composition. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a Tris salt.

[0175]

[0201] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof comprises between about 36% w / w and about 54% w / w of the pharmaceutical composition, the diluent comprises between about 40.5% w / w and about 45% w / w of the pharmaceutical composition, the disintegrant comprises between about 2% w / w and about 4% w / w of the pharmaceutical composition, the binder comprises between about 2% w / w and about 8% w / w of the pharmaceutical composition, the surfactant comprises between about 0.5% w / w and about 3% w / w of the pharmaceutical composition, the glidant comprises between about 0.5% w / w and about 2.0% w / w of the pharmaceutical composition, and the lubricant comprises between about 0.5% w / w and about 2.0% w / w of the pharmaceutical composition, totaling 100% by weight of the composition. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a Tris salt.

[0176]

[0202] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof comprises between about 42% w / w and about 63% w / w of the pharmaceutical composition, the diluent comprises between about 32.5% w / w and about 38% w / w of the pharmaceutical composition, the disintegrant comprises between about 2% w / w and about 4% w / w of the pharmaceutical composition, the binder comprises between about 2% w / w and about 8% w / w of the pharmaceutical composition, the surfactant comprises between about 0% w / w and about 2% w / w of the pharmaceutical composition, the glidant comprises between about 0% w / w and about 3% w / w of the pharmaceutical composition, and the lubricant comprises between about 0.5% w / w and about 3.0% w / w of the pharmaceutical composition, totaling 100% by weight of the composition. In this embodiment, the pharmaceutically acceptable salt of Compound 1 is a Tris salt.

[0177]

[0203] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof comprises between about 47% w / w and about 70% w / w of the pharmaceutical composition, the diluent comprises between about 26.5% w / w and about 32% w / w of the pharmaceutical composition, the disintegrant comprises between about 2% w / w and about 4% w / w of the pharmaceutical composition, the binder comprises between about 1% w / w and about 9% w / w of the pharmaceutical composition, the surfactant comprises between about 0% w / w and about 2% w / w of the pharmaceutical composition, the glidant comprises between about 0% w / w and about 3% w / w of the pharmaceutical composition, and the lubricant comprises between about 0.5% w / w and about 3.0% w / w of the pharmaceutical composition, totaling 100% by weight of the composition. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a Tris salt.

[0178]

[0204] In certain embodiments, the pharmaceutical composition comprises an intragranular portion and an extragranular portion. In some embodiments, the intragranular portion of the pharmaceutical composition of the present application comprises Compound 1 or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, a binder, a surfactant, a glidant, and a lubricant. In some embodiments, the extragranular portion of the pharmaceutical composition of the present application comprises additional amounts of a glidant and a lubricant.

[0179]

[0205] In some embodiments, the intragranular portion of the pharmaceutical composition of the present application comprises Compound 1 or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the extragranular portion of the pharmaceutical composition of the present application comprises an additional amount of a lubricant.

[0180]

[0206] In some embodiments, the intragranular portion of the pharmaceutical composition of the present application comprises Compound 1 or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, and a lubricant. In some embodiments, there is no extragranular portion in the pharmaceutical composition.

[0181]

[0207] In some embodiments, the intragranular portion of the pharmaceutical composition of the present application comprises Compound 1 or a pharmaceutically acceptable salt thereof in an amount of about 37% w / w to about 50% w / w of the pharmaceutical composition, a diluent (or one or more diluents) in an amount of about 41% w / w to about 45% w / w of the pharmaceutical composition, a disintegrant in an amount of about 2% w / w to about 4% w / w of the pharmaceutical composition, a binder in an amount between about 2% w / w and about 8% w / w of the pharmaceutical composition, a surfactant in an amount between about 0.5% w / w and about 3% w / w of the pharmaceutical composition, a glidant in an amount between about 0.5% w / w and about 1.5% w / w of the pharmaceutical composition, and a lubricant in an amount between about 0.5% w / w and about 1.5% w / w of the pharmaceutical composition.

[0182]

[0208] In some embodiments, the intragranular portion of the pharmaceutical composition comprises Compound 1 or a Tris salt of Compound 1 in an amount between about 42% w / w and about 63% w / w of the pharmaceutical composition, a diluent (or one or more diluents) in an amount between about 32% w / w and about 38% w / w of the pharmaceutical composition, a disintegrant in an amount between about 2% w / w and about 4% w / w of the pharmaceutical composition, a binder in an amount between about 2% w / w and about 8% w / w of the pharmaceutical composition, a surfactant in an amount between about 0% w / w and about 2% w / w of the pharmaceutical composition, a glidant in an amount between about 0% w / w and about 1.5% w / w of the pharmaceutical composition, and a lubricant in an amount between about 0.5% w / w and about 1.5% w / w of the pharmaceutical composition.

[0183]

[0209] In some embodiments, the intragranular portion of the pharmaceutical composition comprises Compound 1 or a Tris salt of Compound 1 in an amount between about 51% w / w and about 68% w / w of the pharmaceutical composition, a diluent (or one or more diluents) in an amount between about 26% w / w and about 32% w / w of the pharmaceutical composition, a disintegrant in an amount between about 2% w / w and about 4% w / w of the pharmaceutical composition, a binder in an amount between about 1% w / w and about 9% w / w of the pharmaceutical composition, a surfactant in an amount between about 0% w / w and about 2% w / w of the pharmaceutical composition, a glidant in an amount between about 0% w / w and about 1.5% w / w of the pharmaceutical composition, and a lubricant in an amount between about 0.5% w / w and about 2.0% w / w of the pharmaceutical composition.

[0184]

[0210] In some embodiments, the extragranular portion of the pharmaceutical composition may contain an additional amount of glidant. In some embodiments, the extragranular portion of the pharmaceutical composition comprises an additional amount of lubricant in an amount of about 0.5% to about 1% w / w of the pharmaceutical composition, and an additional amount of lubricant in an amount of about 0.5% to about 1.5% w / w of the pharmaceutical composition.

[0185] 4.Solid dispersion

[0211] A pharmaceutical composition comprising a solid dispersion of a therapeutically active compound in a matrix, They can have improved chemical and physical properties and can be prepared by forming a homogeneous solution or melt of the therapeutically active compound and matrix material, followed by cooling to solidify the mixture or remove the solvent. Such solid dispersions of therapeutically active compounds often demonstrate enhanced bioavailability when administered orally, compared to oral compositions containing the undispersed compound.

[0186]

[0212] As used herein, the term "dispersion" refers to a dispersion in which a second substance (a continuous or A dispersion system refers to a system in which a substance (the dispersed phase) is distributed in discrete units throughout a liquid vehicle. Generally, the dispersed phase can be a solid, liquid, or gas. In the case of a solid dispersion, both the dispersed and continuous phases are solids.

[0187]

[0213] As used herein, the term "amorphous solid dispersion" generally refers to a dispersion of two or more By "solid dispersion" is meant a solid dispersion of the above components, typically a therapeutically effective compound and a polymer (or polymers), but may contain other components, such as surfactants or other pharmaceutical excipients, wherein the therapeutically effective compound is in the form of an amorphous phase. In some embodiments, the amorphous solid dispersion comprises a polymer (and optionally a surfactant) that constitutes the dispersed phase, and the therapeutically effective compound constitutes the continuous phase. In some embodiments, the amorphous solid dispersion comprises a polymer (and optionally a surfactant) that constitutes the continuous phase, and the therapeutically effective compound constitutes the dispersed phase. In some embodiments, the therapeutically effective compound is substantially amorphous. In other embodiments, the therapeutically effective compound is substantially crystalline.

[0188]

[0214] In some embodiments, the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises Compound 1, a pharmaceutically acceptable salt of Compound 1, a Tris salt of Compound 1, or a sodium salt of Compound 1, one or more polymers, and one or more surfactants. In some embodiments, the solid dispersion comprises Compound 1, a pharmaceutically acceptable salt of Compound 1, a Tris salt of Compound 1, or a sodium salt of Compound 1, one or more polymers, and one or more surfactants. In some embodiments, the solid dispersion comprises Compound 1, a pharmaceutically acceptable salt of Compound 1, a Tris salt of Compound 1, or a sodium salt of Compound 1, and a polymer. In some embodiments, the solid dispersion comprises Compound 1, a pharmaceutically acceptable salt of Compound 1, a Tris salt of Compound 1, or a sodium salt of Compound 1, a polymer, and a surfactant. In certain embodiments, the free form of Compound 1 is used in the solid dispersion. In other embodiments, a pharmaceutically acceptable salt of Compound 1 is used in the solid dispersion. In certain embodiments, the pharmaceutically acceptable salt of Compound 1 used in the solid dispersion is the Tris salt of Compound 1. In other embodiments, the pharmaceutically acceptable salt of Compound 1 used in the solid dispersion is the sodium salt of Compound 1.

[0189]

[0215] In some embodiments, the polymer is hydroxypropyl methylcellulose (H The polymer is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, and polyvinylpyrrolidone (PVP), and mixtures thereof. In some embodiments, the polymer is a cellulosic polymer, such as HPMC, HPMCAS, HPC, and ethyl cellulose. In other embodiments, the polymer is HPMCAS.

[0190]

[0216] In some embodiments, the polymer is between about 10% w / w and 90% w / w (e.g., For example, between about 20% w / w and about 80% w / w; between 30% w / w and about 70% w / w; between about 40% w / w and about 60% w / w; or between about 15% w / w and about 35% w / w. In some embodiments, the polymer (or one or more polymers) is present in the solid dispersion in an amount of between about 10% w / w and about 80% w / w, e.g., between about 30% w / w and about 75% w / w, or between about 40% w / w and about 65% w / w, or between about 45% w / w and about 55% w / w, e.g., 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. In some embodiments, the polymer (or one or more polymers) is present in the solid dispersion in an amount of about 48% w / w, about 48.5% w / w, about 49% w / w, about 49.5% w / w, about 50% w / w, about 50.5% w / w, about 51% w / w, about 51.5% w / w, about 52% w / w, or about 52.5% w / w.

[0191]

[0217] In some embodiments, Compound 1, or a pharmaceutically acceptable salt of Compound 1, or or the Tris salt of Compound 1, or the sodium salt of Compound 1, is present in the solid dispersion in an amount of about 10% w / w to 90% w / w (e.g., between about 20% w / w and about 80% w / w; between about 30% w / w and about 70% w / w; between about 40% w / w and about 60% w / w; or between about 15% w / w and about 35% w / w). In some embodiments, Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a Tris salt of Compound 1, or a sodium salt of Compound 1, is present in the solid dispersion in an amount of about 10% w / w to about 80% w / w, e.g., about 30% w / w to about 75% w / w, or about 40% w / w to about 65% w / w, or about 45% w / w to about 55% w / w, e.g., 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, about 54% w / w, or about 60% w / w. In some embodiments, Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a Tris salt of Compound 1, or a sodium salt of Compound 1, is present in the amorphous solid dispersion in an amount of about 48% w / w, about 48.5% w / w, about 49% w / w, about 49.5% w / w, about 50% w / w, about 50.5% w / w, about 51% w / w, about 51.5% w / w, about 52% w / w, or about 52.5% w / w.

[0192]

[0218] In some embodiments, the solid dispersion further comprises a surfactant. In embodiments, the surfactant is selected from sodium lauryl sulfate (SLS), vitamin E or a derivative thereof (e.g., vitamin E TPGS), sodium docusate, sodium dodecyl sulfate, polysorbates (e.g., Tween 20 and Tween 80), poloxamers (e.g., 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).

[0193]

[0219] In some embodiments, the surfactant may be present in an amount of from about 0.1% w / w to about 10% w / w, e.g. For example, the surfactant is present in the solid dispersion in an amount of about 0.5% w / w to about 2% w / w, or about 1% w / w to about 3% w / w, about 1% w / w to about 4% w / w, or 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.

[0194]

[0220] In some embodiments, the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the solid dispersion comprises Compound 1, a pharmaceutically acceptable salt of Compound 1, or a Tris salt of Compound 1, or a sodium salt of Compound 1, and HPMCAS. In some embodiments, the solid dispersion consists essentially of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a Tris salt of Compound 1, or a sodium salt of Compound 1, and HPMCAS. In some embodiments, the solid dispersion consists of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a Tris salt of Compound 1, or a sodium salt of Compound 1, and HPMCAS. In some embodiments, Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a Tris salt of Compound 1, or a sodium salt of Compound 1, and HPMCAS are present in a weight ratio of between about 3:1 and about 1:3, or between about 2:1 and about 1:2, or between about 1.5:1 and about 1:1.5. In some embodiments, Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a Tris salt of Compound 1, or a sodium salt of Compound 1, and HPMCAS are present in a weight ratio of about 1:1.

[0195]

[0221] In another aspect, the present disclosure provides Compound 1, or a pharmaceutically acceptable salt of Compound 1. or a method for preparing a solid dispersion of the tris salt of Compound 1, or the sodium salt of Compound 1.

[0196]

[0222] In some embodiments, the method comprises administering Compound 1, or a pharmaceutically acceptable salt thereof, to a patient receiving the compound. The method includes spray-drying a mixture comprising the salt, or the Tris salt of Compound 1, or the sodium salt of Compound 1, the polymer, and a suitable solvent or solvent mixture.

[0197]

[0223] In some embodiments, the solvent is a volatile solvent (e.g., methylene chloride, acetone). , methanol, ethanol, chloroform, tetrahydrofuran (THF), or mixtures thereof). In some embodiments, the solvent is acetone.

[0198]

[0224] In some embodiments, Compound 1, or a pharmaceutically acceptable salt of Compound 1, or or the Tris salt of Compound 1, or the sodium salt of Compound 1, can be used as a starting material in a spray-drying process to prepare a solid dispersion. In some embodiments, one of the crystalline forms described herein can be used as a starting material in a spray-drying process.

[0199]

[0225] Spray drying involves the drying of a liquid solution, e.g., containing a solid and a solvent or solvent mixture. and removal of the solvent or solvent mixture. Atomization can be carried out, for example, through a two-fluid or pressure or electrosonic nozzle or in a rotating disk. Removal of the solvent or solvent mixture may require a subsequent drying step, for example, tray drying, fluidized bed drying (e.g., from about room temperature to about 100°C), vacuum drying, microwave drying, rotary drum drying, or double-cone vacuum drying (e.g., from about room temperature to about 200°C). Techniques and methods for spray drying are described in Perry's Chemical Engineering Handbook, 6th Edition, edited by R.H.Perry, D.W.Green & J.O.Maloney, McGraw-Hill Book Co. (1984); and Marshall, "Atomization and Spray-Drying," Vol. 50, Chem. Eng. Prog. Monogr. Series 2 (1954).

[0200] 5. Exemplary Capsule Formulations

[0226] Formulations for oral use are made from hard gelatin or hydroxypropylmethylcellulose. It can also be presented as HPMC capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, and mixtures thereof, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0201]

[0227] In some embodiments, the capsule compositions provided herein comprise a total capsule volume of 1000 sachets. The Tris salt of Compound 1 comprises about 10% w / w to about 20% w / w by weight, the excipients comprise all of the total weight of the capsule, the diluent (or diluents) comprises about 76.5% w / w to about 83% w / w of the capsule, the disintegrant comprises about 3% w / w to about 5% w / w of the capsule, and the lubricant comprises about 0.5% w / w to about 2.0% w / w of the capsule. In one embodiment, the Tris salt comprises Tris Salt Form C.

[0202]

[0228] In some embodiments, the capsule compositions provided herein comprise a total capsule volume of 1000 sachets. The Tris salt of Compound 1 comprises about 48% w / w to about 60% w / w of the capsule by weight, and the excipients include a diluent (or one or more diluents) in an amount of about 37.5% w / w to about 44% w / w of the capsule, a disintegrant in an amount of about 2% w / w to about 6% w / w of the capsule, and a lubricant in an amount of about 0.5% w / w to about 2.0% w / w of the capsule. In one embodiment, the Tris salt comprises Tris Salt Form C.

[0203]

[0229] In some embodiments, the capsule compositions provided herein comprise a total capsule volume of 1000 sachets. By weight, the Tris salt of Compound 1 accounts for about 37% w / w to about 50% w / w; the intragranular excipients comprise about 41% w / w to about 45% w / w of diluent, about 2% w / w to about 4% w / w of disintegrant, about 2% w / w to about 8% w / w of binder, about 0.5% w / w to about 3% w / w of surfactant, about 0.5% w / w to about 2.0% w / w of glidant, and about 0.5% w / w to about 2.0% w / w of lubricant, all based on the total capsule weight; and the extragranular excipients comprise about 0.5% w / w to about 2.0% w / w of glidant and about 0.5% w / w to about 2.0% w / w of lubricant. In one embodiment, the Tris salt comprises Tris Salt Form C.

[0204]

[0230] In some embodiments, the capsule compositions provided herein comprise a total capsule volume of 1000 sachets. By weight, the Tris salt of Compound 1 accounts for about 42% w / w to about 63% w / w; the intragranular excipients comprise about 32% w / w to about 38% w / w of diluent, about 2% w / w to about 4% w / w of disintegrant, about 2% w / w to about 8% w / w of binder, about 0% w / w to about 2% w / w of surfactant, about 0% w / w to about 3.0% w / w of glidant, and about 0.5% w / w to about 3.0% w / w of lubricant, all based on the total capsule weight; and the extragranular excipients comprise about 0% w / w to about 2.0% w / w of glidant and about 0.5% w / w to about 2.0% w / w of lubricant. In one embodiment, the Tris salt comprises Tris Salt Form C.

[0205]

[0231] In some embodiments, the capsule compositions provided herein comprise a total capsule volume of 1000 sachets. By weight, the Tris salt of Compound 1 accounts for about 51% w / w to about 68% w / w; the intragranular excipients comprise about 26% w / w to about 32% w / w of diluent, about 2% w / w to about 4% w / w of disintegrant, about 1% w / w to about 9% w / w of binder, about 0% w / w to about 2% w / w of surfactant, about 0% w / w to about 3.0% w / w of glidant, and about 0.5% w / w to about 3.0% w / w of lubricant, all based on the total capsule weight; and the extragranular excipients comprise about 0% w / w to about 2.0% w / w of glidant and about 0.5% w / w to about 2.0% w / w of lubricant. In one embodiment, the Tris salt comprises Tris Salt Form C.

[0206] 6. Exemplary Tablet Formulations

[0232] In the case of tablet compositions, one or more pharmaceutical agents used to prepare the tablet Compound 1 or its pharmaceutically acceptable salts can be used in combination with a pharmaceutically acceptable excipient. Examples of such excipients include, but are not limited to, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate, etc.; granulating and disintegrating agents such as corn starch or alginic acid, etc.; binders such as starch, gelatin, or acacia, etc., and lubricants such as magnesium stearate, stearic acid, or talc. Tablets can also be uncoated. Alternatively, they can be coated by known coating techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained therapeutic action over a desired period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used.

[0207]

[0233] In certain embodiments, the tablet is a coated tablet. In certain embodiments, the coating is a film coating. In certain embodiments, the coating is Opadry II. In certain embodiments, the coating comprises polyvinyl alcohol.

[0208]

[0234] Any conventional method for obtaining tablets can be used, for example those described in Pharmacopoeias, e.g. For example, the methods described in the United States Pharmacopoeia and the European Pharmacopoeia may be used.

[0209]

[0235] In some embodiments, the tablet compositions provided herein comprise a tablet containing 0.1% to 0.1% of the total tablet weight. In one embodiment, the Tris salt of Compound 1 comprises about 10% w / w to about 20% w / w of the total tablet weight, the excipient comprises all of the tablet weight, the diluent (or one or more diluents) comprises about 76.5% w / w to about 83% w / w of the tablet weight, the disintegrant comprises about 3% w / w to about 5% w / w of the tablet weight, and the lubricant comprises about 0.5% w / w to about 2.0% w / w of the tablet weight.

[0210]

[0236] In some embodiments, the tablet compositions provided herein comprise a tablet containing 0.1% to 0.1% of the total tablet weight. In one embodiment, the Tris salt of Compound 1 comprises about 48% to about 60% w / w of the tablet, the excipients being the diluent (or diluents) in an amount of about 37.5% to about 44% w / w of the tablet, the disintegrant in an amount of about 2% to about 6% w / w of the tablet, and the lubricant in an amount of about 0.5% to about 2.0% w / w of the tablet. In one embodiment, the Tris salt comprises Tris Salt Form C.

[0211]

[0237] In some embodiments, the tablet compositions provided herein comprise a tablet containing 0.1% to 0.1% of the total tablet weight. and the Tris salt of Compound 1 accounts for about 37% w / w to about 50% w / w; the intragranular excipients are about 41% w / w to about 45% w / w of diluent, about 2% w / w to about 4% w / w of disintegrant, about 2% w / w to about 8% w / w of binder, about 0.5% w / w to about 3% w / w of surfactant, about 0.5% w / w to about 2.0% w / w of glidant, and about 0.5% w / w to about 2.0% w / w of lubricant, all based on the total tablet weight; and the extragranular excipients are about 0.5% w / w to about 2.0% w / w of glidant, and about 0.5% w / w to about 2.0% w / w of lubricant, all based on the total tablet weight. In one embodiment, the Tris salt comprises Tris Salt Form C.

[0212]

[0238] In some embodiments, the tablet compositions provided herein comprise a tablet containing 0.1% to 0.1% of the total tablet weight. and the Tris salt of Compound 1 accounts for about 42% w / w to about 63% w / w; the intragranular excipients are about 32% w / w to about 38% w / w of diluent, about 2% w / w to about 4% w / w of disintegrant, about 2% w / w to about 8% w / w of binder, about 0% w / w to about 2% w / w of surfactant, about 0% w / w to about 3.0% w / w of glidant, and about 0.5% w / w to about 3.0% w / w of lubricant, all based on the total tablet weight; and the extragranular excipients are about 0% w / w to about 2.0% w / w of glidant, and about 0.5% w / w to about 2.0% w / w of lubricant, all based on the total tablet weight. In one embodiment, the Tris salt comprises Tris Salt Form C.

[0213]

[0239] In some embodiments, the tablet compositions provided herein comprise a tablet containing 0.1% to 0.1% of the total tablet weight. and the tris salt of Compound 1 accounts for about 51% w / w to about 68% w / w; and the intragranular excipients are, based on the total tablet weight, about 26% w / w to about 32% w / w of diluent, about 2% w / w to about 4% w / w of disintegrant, about 1% w / w to about 9% w / w of binder, about 0% w / w to about 2% w / w of surfactant, about 0% w / w to about 3.0% w / w of glidant, and about 0% w / w to about 4.0% w / w of lubricant. the extragranular excipients comprise from about 0% w / w to about 2.0% w / w of a glidant and from about 0.5% w / w to about 2.0% w / w of a lubricant. In one embodiment, the Tris salt comprises Tris Salt Form C.

[0214] 7. Other Compounds

[0240] In the case of aqueous suspensions, the compounds of the present disclosure are suitable for maintaining a stable suspension. Examples of such excipients include, but are not limited to, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia.

[0215]

[0241] Oral suspensions may contain a dispersing or wetting agent, such as, for example, naturally occurring phospholipids, e.g. For example, they may contain lecithin, or condensates of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensates of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensates of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate, or condensates of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0216]

[0242] The compounds of the present disclosure may be added to vegetable oils such as peanut oil, olive oil, sesame oil, or Oily suspensions can be formulated by suspending the compounds in coconut oil or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol.

[0217]

[0243] Sweetening agents, such as those described above, and flavoring agents may be added to provide a palatable oral These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0218]

[0244] Dispersible powders and granules suitable for preparation of an aqueous suspension by adding water include: The compound of the present disclosure can be prepared by providing it as a mixture with a dispersing agent or wetting agent, a suspending agent and one or more preservatives.Suitable dispersing agents or wetting agents and suspending agents are exemplified by those mentioned above.Additional excipients, such as sweeteners, flavoring agents and coloring agents, can also be present.

[0219]

[0245] The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion. The emulsifier may be an oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, and mixtures thereof. Suitable emulsifiers may be naturally occurring gums, such as gum arabic or gum tragacanth, naturally occurring phospholipids, such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitols, anhydrides, such as sorbitan monoleate, and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monoleate. The emulsion may also contain sweeteners and flavoring agents.

[0220]

[0246] Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, or the like. The pharmaceutical composition may be formulated with ethylene glycol, sorbitol, or sucrose. Such formulations may also contain demulcents, preservatives, and flavoring and coloring agents. The pharmaceutical composition may be in the form of a sterile injectable solution, aqueous suspension, or oily suspension. The suspension may be formulated according to techniques known in the art using one or more suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution, and isotonic saline. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectable solutions.

[0221]

[0247] Compound 1 or a pharmaceutically acceptable salt thereof may also be formulated as a suppository for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0222]

[0248] Compositions for parenteral administration are administered in a sterile medium. Depending on the dosage and concentration of the drug in the formulation, parenteral formulations may be either a suspension or a solution containing dissolved drug. Adjuvants such as local anesthetics, preservatives and buffering agents can also be added to parenteral compositions.

[0223]

[0249] Another embodiment of the present invention is a naphthalene derivative of Compound 1 suitable for oral or parenteral administration. The liquid formulation is typically aqueous. For oral administration, certain sweeteners and / or flavoring agents and / or coloring agents may be added.

[0224]

[0250] Active ingredients that can be combined with one or more pharmaceutical excipients to form a single dosage form. The amount of active ingredient will vary depending on the patient being treated and the particular mode of administration. In certain embodiments, the pharmaceutical composition comprises between about 10 mg and about 1500 mg of Compound 1 or a pharmaceutically acceptable salt thereof (based on the weight of the free form of Compound 1, excluding the weight of any conformers, salt formers, water of hydration, solvents of solvation, etc.). In some embodiments, the pharmaceutical composition comprises between about 90 mg and about 240 mg; between about 100 mg and about 240 mg; between about 10 mg and about 500 mg; or between about 10 mg and about 1000 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 275 mg, about 280 mg, about 290 mg, or about 300 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, or about 1450 mg, or about 1500 mg. In certain embodiments, the pharmaceutical composition is in an orally acceptable dosage form, such as a capsule, and contains about 50 mg, about 75 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 1450 mg, or about 1500 mg of the Tris salt of Compound 1. Including 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 275 mg, about 280 mg, about 290 mg, or about 300 mg.

[0225] Methods of treatment, uses for the manufacture of medicaments, salts or crystalline forms for use in the treatment of diseases

[0251] In one aspect, the crystalline and amorphous forms described herein and their The pharmaceutical compositions of the present invention are, but are not limited to, inhibitors of DHODH and are generally useful for treating conditions underlying DHODH. Tris(hydroxymethyl)aminomethane salts of Compound 1 described in the following paragraph include any of the Tris salts according to embodiments 1-25 described above. Crystalline forms of Compound 1 described in the following paragraph include any of the crystalline forms according to any one of embodiments 27-59 described above.

[0226]

[0252] In one aspect, the present disclosure provides a method of treating cancer in a subject, comprising administering to the subject: In another aspect, the disclosure relates to the use of the tris(hydroxymethyl)aminomethane salt of Compound 1, the sodium salt of Compound 1, a crystalline form of Compound 1, or a pharmaceutical composition thereof for the manufacture of a medicament for treating cancer. In yet another aspect, the disclosure relates to the tris(hydroxymethyl)aminomethane salt of Compound 1, the sodium salt of Compound 1, a crystalline form of Compound 1, or a pharmaceutical composition thereof for the treatment of cancer.

[0227]

[0253] In some embodiments, the cancer comprises a solid tumor. , lung cancer, breast cancer, triple-negative breast cancer, melanoma, glioblastoma, prostate cancer, colon cancer, pancreatic cancer, bone cancer, head and neck cancer, skin cancer, cutaneous or intraocular malignant endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, childhood solid tumors, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancer, and PTEN mutant cancer. In some embodiments, the cancer is selected from biliary tract cancer or cancer of the ampulla of Vater, non-small cell lung cancer, bronchoalveolar carcinoma, liver cancer, ovarian cancer, and cancer of the upper aerodigestive tract. In another embodiment, the cancer is a hematological cancer. In one embodiment, the hematological cancer is selected from myeloma, lymphoma, and leukemia. In one embodiment, the hematological cancer is acute myeloid leukemia, multiple myeloma, B-cell prolymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, and lymphocytic lymphoma. In one embodiment, the hematological cancer is selected from chemotherapy-resistant acute myeloid leukemia, cytarabine-resistant acute myeloid leukemia, acute monocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, diffuse mixed cell lymphoma, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, primary effusion lymphoma, erythroleukemia, chronic myeloid leukemia, chronic monocytic leukemia, double hit diffuse large B cell lymphoma, and triple hit diffuse large B cell lymphoma. In one embodiment, the hematological cancer is selected from angioimmunoblastic lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, blastic NK-cell lymphoma. The present invention relates to a lymphoma or tumor that is selected from: cutaneous T-cell lymphoma, lymphoblastic lymphoma, MALT lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma, small lymphocytic lymphoma, thyroid lymphoma, follicular lymphoma, Waldenstrom's macroglobulinemia, essential thrombocythemia, chronic idiopathic myelofibrosis, and polycythemia rubra vera.

[0228]

[0254] In a further aspect, the present disclosure provides a method for treating dihydroorotate dehydrogenase in a subject. The present disclosure relates to a method for treating a cancer responsive to the inhibition of dihydroorotate dehydrogenase, comprising administering to a subject an effective amount of the tris(hydroxymethyl)aminomethane salt of Compound 1 (or one of the disclosed crystalline forms thereof), the sodium salt of Compound 1, a crystalline form of Compound 1, or a pharmaceutical composition thereof. In another aspect, the present disclosure relates to the use of the tris(hydroxymethyl)aminomethane salt of Compound 1, the sodium salt of Compound 1, a crystalline form of Compound 1, or a pharmaceutical composition thereof for the manufacture of a medicament for treating a cancer responsive to the inhibition of dihydroorotate dehydrogenase. In yet another aspect, the present disclosure relates to the tris(hydroxymethyl)aminomethane salt of Compound 1, the sodium salt of Compound 1, a crystalline form of Compound 1, or a pharmaceutical composition thereof for treating a cancer responsive to the inhibition of dihydroorotate dehydrogenase. In one embodiment, the cancer can be selected from the list of cancers described above.

[0229]

[0255] In a further aspect, the present disclosure provides a method for treating a virally mediated disease in a subject. The present disclosure relates to a method for treating a condition or disease selected from virally mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, an autoimmune disease, or an inflammatory disorder, comprising administering to a subject an effective amount of the tris(hydroxymethyl)aminomethane salt of Compound 1 (or one of the disclosed crystalline forms thereof), the sodium salt of Compound 1, a crystalline form of Compound 1, or a pharmaceutical composition thereof. In another aspect, the present disclosure relates to the use of the tris(hydroxymethyl)aminomethane salt of Compound 1, the sodium salt of Compound 1, a crystalline form of Compound 1, or a pharmaceutical composition thereof for the manufacture of a medicament for treating a condition or disease selected from virally mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, an autoimmune disease, or an inflammatory disorder. In yet another aspect, the present disclosure relates to the tris(hydroxymethyl)aminomethane salt of Compound 1, the sodium salt of Compound 1, a crystalline form of Compound 1, or a pharmaceutical composition thereof for treating a condition or disease selected from virally mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, an autoimmune disease, or an inflammatory disorder.

[0230]

[0256] In another aspect, the present disclosure provides a method for detecting dihydroorotate dehydrogenase in a subject. The present invention relates to a method of inhibiting the growth and / or metastasis of tumor cells responsive to such inhibition, comprising administering to a subject an effective amount of the tris(hydroxymethyl)aminomethane salt of Compound 1 (or one of the disclosed crystalline forms thereof), the sodium salt of Compound 1, a crystalline form of Compound 1, or a pharmaceutical composition thereof.

[0231]

[0257] In another aspect, the disclosure provides a method for detecting dihydroorotate dehydrogenase in a subject. The present invention relates to a method of inhibiting, wherein tumor cells are responsive to inhibition of dihydroorotate dehydrogenase, the method comprising administering to a subject an effective amount of the tris(hydroxymethyl)aminomethane salt of Compound 1 (or one of the disclosed crystalline forms thereof), the sodium salt of Compound 1, a crystalline form of Compound 1, or a pharmaceutical composition thereof.

[0232]

[0258] Another embodiment of the present invention is a method for treating a patient with Compound 1 or a pharmaceutically acceptable salt thereof, comprising: A method for treating a subject with cancer. Compound 1, or a pharmaceutically acceptable salt thereof, is preferably administered as: i) a tris salt (e.g., in amorphous form or one of the disclosed crystalline forms). ii) a sodium salt of Compound 1; iii) one of the disclosed crystalline forms of Compound 1; or iv) an amorphous form of Compound 1. The cancer being treated is a hematological cancer, the hematological cancer being selected from myeloma, lymphoma, leukemia, e.g., acute myeloid leukemia (AML), chronic myeloproliferative disease, monoclonal gammopathy of undetermined significance, myelodysplastic syndrome, amyloidosis, and myelodysplastic / myeloproliferative neoplasm; the myeloma being treated is multiple myeloma, amyloidosis, plasmacytoma, monoclonal gammopathy of undetermined significance, asymptomatic myeloma, symptomatic myeloma, and Kahler's disease. the lymphoma to be treated is selected from anaplastic large cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, diffuse large B-cell lymphoma, lymphoblastic lymphoma, MALT lymphoma, mantle cell lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma, small lymphocytic lymphoma, thyroid lymphoma, and Waldenstrom's macroglobulinemia; the chronic myeloproliferative disorder to be treated is selected from essential thrombocythemia, chronic idiopathic myelofibrosis, and primary polycythemia vera; and the leukemia to be treated is selected from acute myeloid leukemia (AML), hairy cell leukemia, acute lymphoblastic leukemia, and chronic lymphoblastic leukemia.

[0233]

[0259] In yet another aspect, the present disclosure provides a method of treating cancer in a subject, comprising: The present invention relates to a method comprising administering to a subject an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is the tris(hydroxymethyl)aminomethane (tris) salt of Compound 1 described herein (including all partially crystalline or crystalline tris salt forms of Compound 1 disclosed herein), the sodium salt of Compound 1 described herein, or the free acid Compound 1 (including all partially crystalline or crystalline forms of the free acid Compound 1 disclosed herein), and one of the dosing regimens described in the following paragraphs is administered. In one embodiment, the subject is treated by administering to the subject an effective amount of a crystalline tris salt of Compound 1. In one particular embodiment, the crystalline tris salt is crystalline tris salt Form C described herein. In another embodiment, the subject is treated by administering to the subject an effective amount of a crystalline form of the free acid Compound 1.

[0234]

[0260] In one embodiment, the dosing regimen for the cancer treatment method described in the preceding paragraph comprises administering an effective amount of Compound 1 (including amorphous forms and all partially crystalline or crystalline forms of the free acid Compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of Compound 1, including amorphous forms and all partially crystalline or crystalline Tris salt forms of Compound 1 disclosed herein, or a sodium salt of Compound 1) once weekly for one or more 28-day or 4-week cycles.

[0235]

[0261] In one embodiment, the dosing regimen for the cancer treatment method described in the preceding paragraph comprises administering an effective amount of Compound 1 (including the amorphous form and all partially crystalline or crystalline forms of the free acid Compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1, including the amorphous form and all partially crystalline or crystalline Tris salt forms of Compound 1 disclosed herein, or the sodium salt of Compound 1) for 2 to 5 days each week (one cycle of therapy is defined as 4 consecutive weeks of treatment).

[0236]

[0262] In one embodiment, the dosing regimen for the cancer treatment method described in the preceding paragraph is a compound of Compound 1 (including amorphous forms and all partially crystalline or crystalline forms of the free acid Compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., amorphous forms and all partially crystalline or crystalline forms of Compound 1 disclosed herein). or the sodium salt of Compound 1) for 2-4 consecutive days followed by a 3-5 day break each week in one or more 28-day or 4-week cycles.

[0237]

[0263] In one embodiment, the dosing regimen for the cancer treatment method described in the preceding paragraph comprises administering an effective amount of Compound 1 (including the amorphous form and all partially crystalline or crystalline forms of the free acid Compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1, including the amorphous form and all partially crystalline or crystalline Tris salt forms of Compound 1 disclosed herein, or the sodium salt of Compound 1) for two consecutive days followed by a five-day break each week in one or more 28-day or four-week cycles.

[0238]

[0264] In one embodiment, the dosing regimen for the cancer treatment method described in the preceding paragraph comprises administering an effective amount of Compound 1 (including the amorphous form and all partially crystalline or crystalline forms of the free acid Compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1, including the amorphous form and all partially crystalline or crystalline Tris salt forms of Compound 1 disclosed herein, or the sodium salt of Compound 1) for three consecutive days, followed by four days off each week, in one or more 28-day or four-week cycles.

[0239]

[0265] In one embodiment, the dosing regimen for the cancer treatment method described in the preceding paragraph comprises administering an effective amount of Compound 1 (including the amorphous form and all partially crystalline or crystalline forms of the free acid Compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1, including the amorphous form and all partially crystalline or crystalline Tris salt forms of Compound 1 disclosed herein, or the sodium salt of Compound 1) for four consecutive days, followed by a three-day break each week, in one or more 28-day or four-week cycles.

[0240]

[0266] In one embodiment, the dosing regimen for the cancer treatment method described in the preceding paragraph comprises administering an effective amount of Compound 1 (including the amorphous form and all partially crystalline or crystalline forms of the free acid Compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1, including the amorphous form and all partially crystalline or crystalline Tris salt forms of Compound 1 disclosed herein, or the sodium salt of Compound 1) for 2-4 consecutive days, followed by a 3-5 day break each week, in one or more 28-day or 4-week cycles, wherein the number of consecutive days of treatment is increased by at least 1 week during each of the several weeks of the 28-day or 4-week cycle. In another embodiment, the dosing regimen for the cancer treatment method described in the preceding paragraph comprises administering an effective amount of Compound 1 (including the amorphous form and all partially crystalline or crystalline forms of the free acid Compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1, including the amorphous form and all partially crystalline or crystalline Tris salt forms of Compound 1 disclosed herein, or the sodium salt of Compound 1) for 2-4 consecutive days, followed by 3-5 days of rest each week, in one or more 28-day or 4-week cycles, wherein the number of consecutive days of treatment is reduced by at least 1 week during each of the weeks of the 28-day or 4-week cycle.

[0241]

[0267] In another embodiment, the amorphous form of the free acid Compound 1 (as described herein) and An effective amount of Compound 1 or a pharmaceutically acceptable salt thereof (e.g., a tris salt of Compound 1, including amorphous forms and all partially crystalline or crystalline tris salt forms of Compound 1 disclosed herein, or a sodium salt of Compound 1) is administered for two consecutive days, followed by administration for the first of a 28-day or 4-week cycle. In another embodiment, an effective amount of Compound 1 (including the amorphous form and all partially crystalline or crystalline forms of the free acid Compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1, including the amorphous form and all partially crystalline or crystalline Tris salt forms of Compound 1 disclosed herein, or the sodium salt of Compound 1) is administered to a subject for two consecutive days, followed by a 5-day break during the first week of a 28-day or 4-week cycle, wherein the number of consecutive days of treatment is increased by at least one week during the first few weeks of the 28-day or 4-week cycle.

[0242]

[0268] In another embodiment, the amorphous form of the free acid Compound 1 (as described herein) and In another embodiment, an effective amount of Compound 1 (including the amorphous form of the free acid Compound 1 and all partially crystalline or crystalline forms disclosed herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1, including the amorphous form and all partially crystalline or crystalline Tris salt forms disclosed herein, or the sodium salt of Compound 1) is administered to a subject for three consecutive days, followed by a four-day break during the first week of a 28-day or four-week cycle, wherein the number of consecutive days of treatment is increased by at least one week during the weeks of the 28-day or four-week cycle. In another embodiment, an effective amount of Compound 1 (including the amorphous form of the free acid Compound 1 and all partially crystalline or crystalline Tris salt forms disclosed herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1, including the amorphous form and all partially crystalline or crystalline Tris salt forms of Compound 1 disclosed herein) is administered to a subject for three consecutive days, followed by a four-day break during the first week of a 28-day or four-week cycle, wherein the number of consecutive days of treatment is decreased by at least one week during the weeks of the 28-day or four-week cycle.

[0243]

[0269] In another embodiment, the amorphous form of the free acid Compound 1 (as described herein) and In another embodiment, an effective amount of Compound 1 (including the amorphous form of the free acid Compound 1 and all partially crystalline or crystalline forms disclosed herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1, including the amorphous form and all partially crystalline or crystalline Tris salt forms disclosed herein, or the sodium salt of Compound 1) is administered to a subject for four consecutive days, followed by a three-day break during the first week of a 28-day or four-week cycle, increasing the number of consecutive days of treatment by at least one week during the first few weeks of a 28-day or four-week cycle. In another embodiment, an effective amount of Compound 1 (including the amorphous form of the free acid Compound 1 and all partially crystalline or crystalline forms disclosed herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1, including the amorphous form and all partially crystalline or crystalline Tris salt forms of Compound 1, or the sodium salt of Compound 1) is administered to a subject for four consecutive days, followed by a three-day break during the first week of a 28-day or four-week cycle, increasing the number of consecutive days of treatment by at least one week during the first few weeks of a 28-day or four-week cycle.

[0244]

[0270] In one embodiment, the dosing regimen for the cancer treatment method described in the preceding paragraph comprises orally administering an effective amount of Compound 1 (including the amorphous form and all partially crystalline or crystalline forms of the free acid Compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1, including the amorphous form and all partially crystalline or crystalline Tris salt forms of Compound 1 disclosed herein, or the sodium salt of Compound 1). In one embodiment, an effective amount of Compound 1 (including the amorphous form and all partially crystalline or crystalline forms of the free acid Compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1, including the amorphous form and all partially crystalline or crystalline Tris salt forms of Compound 1 disclosed herein) is administered as an oral capsule. In another embodiment, an effective amount of Compound 1 (including the amorphous form and all partially crystalline or crystalline forms of the free acid Compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1, including the amorphous form and all partially crystalline or crystalline Tris salt forms of Compound 1 disclosed herein) is administered as an oral capsule. or a Tris salt of Compound 1, including the crystalline Tris salt form, or a sodium salt of Compound 1) is administered as an oral tablet.

[0245]

[0271] In one embodiment, the dosing regimen for the cancer treatment method described in the preceding paragraph comprises administering once daily (QD) an effective amount of Compound 1 (including the amorphous form and all partially crystalline or crystalline forms of the free acid Compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of Compound 1, including the amorphous form and all partially crystalline or crystalline Tris salt forms of Compound 1 disclosed herein, or a sodium salt of Compound 1). In another embodiment, the dosing regimen for the cancer treatment method described in the preceding paragraph comprises administering twice daily (BID) an effective amount of Compound 1 (including the amorphous form and all partially crystalline or crystalline forms of the free acid Compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of Compound 1, including the amorphous form and all partially crystalline or crystalline Tris salt forms of Compound 1 disclosed herein).

[0246]

[0272] In one embodiment, the cancer treated in the methods described in the preceding two paragraphs is selected from the list of solid tumors and hematological cancers provided herein. In one embodiment, the cancer is non-Hodgkin's lymphoma or Hodgkin's lymphoma. In a particular embodiment, the subject to be treated belongs to a subpopulation of non-Hodgkin's lymphoma or Hodgkin's lymphoma patients, where the non-Hodgkin's lymphoma or Hodgkin's lymphoma progresses despite prior treatment, and for such patients, no additional effective (curative or life-prolonging) standard therapy is available. In other words, the subject to be treated belongs to a subpopulation of resistant or refractory non-Hodgkin's lymphoma or Hodgkin's lymphoma. In one embodiment, the standard curative therapy is high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HD-ASCT). In one embodiment, the subject's non-Hodgkin's lymphoma or Hodgkin's lymphoma has relapsed after HD-ASCT. In other words, the subject to be treated belongs to a subpopulation of relapsed non-Hodgkin's lymphoma or Hodgkin's lymphoma (e.g., HD-ASCT-relapsed). In another embodiment, the subject is ineligible for HD-ASCT. In another embodiment, the subject has rejected HD-ASCT.

[0247]

[0273] In one embodiment, the lymphoma according to the present disclosure is a) Mature B cell neoplasm b) Mature T and NK cell neoplasms c) Hodgkin's lymphoma d) Immunodeficiency-associated lymphoproliferative disorder.

[0248]

[0274] The present invention is illustrated by the following examples, which are not intended to be limiting. . Example

[0275] As illustrated in the examples below, the crystalline and amorphous forms can be prepared by the following general procedure. It is prepared in the following order. Example 1 – Abbreviations, Solutions, Apparatus, and Synthesis of Compound 1

[0249]

[0276] Typical abbreviations used are outlined below. [Table 1]

[0250] solution FaSSGF / SGF (gastric juice stimulated by fasting state)

[0277] Weigh 100 mg of sodium chloride into a 50 mL volumetric flask. Add purified water and sonicate until all solids are completely dissolved. Add enough purified water to approach the target volume and adjust the pH to 1.6. Weigh 3 mg of FaSSIF / FeSSIF / FaSSGF powder into a volumetric flask and sonicate until the powder is completely dissolved. Dilute to target volume with purified water and mix thoroughly.

[0251] FaSSIF (Fasting-stimulated intestinal fluid)

[0278] In a 50 mL volumetric flask, add 0.170 g of sodium dihydrogen phosphate, 0.170 g of sodium hydroxide, Weigh out 0.021 g of sodium and 0.31 g of sodium chloride. Add the appropriate volume of purified water and sonicate until all solids are completely dissolved. Approaching the target volume, add enough purified water to adjust the pH to 6.5. Weigh 110 mg of FaSSIF / FeSSIF / FaSSGF powder into a volumetric flask and sonicate until the powder is completely dissolved. Dilute to the target volume with purified water and mix thoroughly.

[0252] FeSSIF (Fasting-stimulated intestinal fluid)

[0279] In a 50 mL volumetric flask, add 0.41 mL of glacial acetic acid and 0.202 g of sodium hydroxide. Weigh out 0.594 g of FaSSIF / FeSSIF / FaSSGF powder and 0.594 g of sodium chloride. Add the appropriate volume of purified water and sonicate until all solids are completely dissolved. Approach the target volume and add enough purified water to adjust the pH to 5.0. Weigh out 560 mg of FaSSIF / FeSSIF / FaSSGF powder into a volumetric flask and sonicate until the powder is completely dissolved. Dilute to the target volume with purified water and mix thoroughly.

[0253] XRPD

[0280] XRPD data were analyzed using PANalytical X'Pert 3 Powder X-ray diffractometer The XRPD parameters are shown in Table 2. [Table 2]

[0254] TGA and DSC

[0281] TGA data was measured using a TA Instruments TA Q500 / Q5 The data were collected using a 000 TGA and DSC was performed using a TA Instruments TA Q200 / Q2000 DSC, with detailed parameters shown in Table 3. [Table 3]

[0255] DVS

[0282] DVS is a Surface Measurement System (SMS). The relative humidity at 25°C was calibrated against the deliquescence points of LiCl, Mg(NO3)2, and KCl. The parameters for the DVS test are shown in Table 4. [Table 4]

[0256] HPLC

[0283] An Agilent 1260 HPLC with a DAD detector was used to measure the solubility Detailed chromatographic conditions for the analysis are given in Table 5. [Table 5]

[0257] solution 1 H NMR

[0284] solution 1 H NMR was measured using a Bruker 400M NMR spectrometer in DMSO-d6. The data were collected on a R spectrometer.

[0258] Synthesis of Compound 1

[0285] The synthesis of amorphous compound 1, i.e., the amorphous free acid, was previously reported in International Patent Application No. As discussed in publication WO2014 / 128669 and U.S. Patent No. 9,630,932.

[0259]

[0286] Additional methods for synthesizing amorphous Compound 1 are described in Schemes 1 and 2. do. [ka]

[0260]

[0287] The tetra-substituted aromatic compound S3 was synthesized following the previous example starting with S1. See International Patent Application Publication No. WO 2012 / 142513 and Chi-Linh et al., J. Agricultural & Food Chem. 2016, Vol. 64 (No. 18) 3533, Supplementary Information, p. S7. S3 was aminated by nucleophilic aromatic substitution of the chloride group with methylamine in the presence of aqueous base and ethyl acetate to produce S4. The nitro functionality in S4 is reduced with either iron in the presence of an acid (e.g., acetic acid) containing platinum on carbon (with or without vanadium) or palladium on carbon. In some cases, the use of palladium on carbon results in debromination. The intermediate diamine (S5) can be used directly in the next step, as shown in Scheme 1, or isolated as a salt (HCl or H2SO4), as shown in Scheme 2. S5, either as the free base or as a salt, is converted to the bromotriazole S6 by reaction with sodium nitrite in aqueous hydrogen chloride.

[0261]

[0288] In parallel, 2-methylboronic acid (S7) was converted to 4- Coupling to iodo-bromobenzene (S8) gave the biphenyl S9. The bromide in S9 was replaced with a boronic acid functionality by low-temperature lithium-halogen exchange and reaction with tri-isopropylborate (S10).

[0262]

[0289] A solution of bromotriazole (S6) and boronic acid (S10) in toluene was Coupling under Pd-catalyzed conditions in the presence of aqueous potassium carbonate (Suzuki coupling) produced S11. The methyl ester in S11 was hydrolyzed to the carboxylic acid with aqueous sodium hydroxide in methanol to produce the free acid form of compound 1.

[0263] Example 2 - Amorphous solid dispersion of Compound 1

[0290] Compound 1 and hypromellose acetate succinate-MG (hypromellose acetate succinate-MG) Mellose acetate succinate (MG grade, Shin-Etsu Chemical Co.) (HPMCAS) (50% / 50%, w / w) was weighed, dissolved in methanol, and spray-dried in a Buchi B-290 to produce an amorphous Compound 1 and hypromellose acetate succinate (HPMCAS) solid dispersion. Spray-drying processing parameters included nitrogen as the drying gas, an inlet temperature of approximately 80°C to 95°C, an outlet temperature of approximately 37°C to 45°C, and a spray solution concentration of approximately 15% w / w. The amorphous solid dispersion was further dried in a vacuum oven at 40°C for 12 to 18 hours and then screened. The amorphous solid dispersion was packaged in a double polyethylene bag with twisted nylon ties, placed in a high-density polyethylene (HDPE) container containing a desiccant, and stored at 2 to 8°C until the next step in processing.

[0264] Example 3 - Polymorph and Salt Screening of Compound 1 Polymorphism Screening

[0291] A total of 74 polymorph screening experiments were performed on the crystals of different solutions, as shown in Table 6. The isolated solids were characterized using XRPD, TGA, and DSC (see Table 7), and the pattern comparison results in Figure 2 indicate that four different crystalline forms were obtained. [Table 6] [Table 7]

[0265] Characterization of the identified crystalline forms of free acid Compound 1

[0292] Representative samples of each identified form (forms A / B / C / D) were analyzed by TGA and D The SC was used to characterize the morphology. Heating experiments were performed to test the relationship between the different morphologies.

[0266] Free acid form A

[0293] The XRPD pattern of the free acid form A is shown in Figure 2A, and the peak list is shown in Figure 2B. The TGA / DSC curve in Figure 3C shows a 1.0% weight loss up to 200°C and a weak exotherm at 212.1°C (peak temperature) before a sharp endotherm at 326.8°C (onset temperature). Heat treatment showed no change in form for free acid Form A after heating to 150°C and cooling to ambient conditions. Form A converted to Form B after heating to 220°C. Based on the low TGA weight loss and the results of the heating experiment, free acid Type A was assumed to be the anhydrous form.

[0267] Free acid form B

[0294] Form B of the free acid can be obtained by heating experiments and slurries at RT / 50°C. Free acid Form B was obtained by heating the free acid Form A starting material to 220°C and then cooling to ambient conditions, and the XRPD pattern is shown in Figure 3A, with the peak list shown in Figure 3B and the TGA / DSC curve in Figure 3C showing a 2.9% weight loss up to 200°C and a single sharp endotherm at 321.9°C (onset temperature). Combining the preparation method (transformation from anhydrous free acid Form A) and the neat TGA / DSC curve, free acid Form B was hypothesized to be a hygroscopic anhydrous form.

[0268] Free acid form C

[0295] The free acid form C can be prepared by addition of an anti-solvent, evaporation, slow cooling, and slurrying. Form C of the free acid was obtained by slurrying starting material Compound 1 in 1,4-dioxane at RT for approximately 2 days; the XRPD pattern is shown in Figure 4A, and the corresponding peak list is shown in Figure 4B. The TGA / DSC curve in Figure 4C showed a 3.6% weight loss up to 200 °C and a single sharp endotherm at 322.5 °C (onset temperature). Heat treatment showed no change in morphology for Form C of the free acid after heating to 150 °C, which converted to Form B after heating to 300 °C. TGA characterization was further performed on the heated Form C of the free acid, and a reduction in TGA weight loss (from 3.6% to 2.3% up to 200 °C) was observed. Based on the results of the TGA / DSC and heating experiments, Form C of the free acid was assumed to be a hygroscopic anhydrous form.

[0269] Free acid form D

[0296] The free acid form D can be obtained by slurry in a multiple solvent system. Acid Form D was obtained by slurrying starting material Compound 1 in EtOAc at RT for approximately 7 days; the XRPD pattern is shown in Figure 5A, and the corresponding peak list is shown in Figure 5B. The TGA / DSC curve in Figure 5C showed a 1.0% weight loss up to 200°C and a weak endotherm at 286.7°C (onset temperature) before a sharp endotherm at 327.4°C (onset temperature). Heat treatment showed that free acid Form D converted to Form B after heating to 305°C. Based on the low TGA weight loss and the results of the heating experiment, free acid Form D was assumed to be an anhydrous form.

[0270] Thermodynamic Stability Test

[0297] Among the four identified crystalline forms of Compound 1 (free acid forms A / B / C / D) To investigate and compare thermodynamic stability, two stages of slurry competition experiments were performed, the first of which was to test anhydrous solvent systems, and the second of which was to test systems with different water activities (a w ) was the solvent system.

[0271]

[0298] In the first step, approximately 2 ml of each solid form (free acid forms A / B / C / D) The samples were first physically mixed, and then 0.5 mL of solvent was added to form a suspension. At various slurry conditions, a small amount of solid was isolated after approximately 7 days for XRPD testing. XRPD characterization showed that Forms A / B / C of the free acid converted to Form D after slurrying at RT, 50°C, and 70°C, and that Form D was thermodynamically more stable than Forms A / B / C between RT and 70°C.

[0272]

[0299] To further explore any effect of water content on the conversion relevance, different water Six conditions with different water activities (a) and temperatures were applied. Approximately 2 mg of each solid form (free acid forms A / B / C / D) were mixed and suspended in 1.0 mL of the corresponding solvent system. After approximately one month of slurrying, the solids were isolated for XRPD testing. XRPD characterization revealed that free acid forms A / B / C were converted to form D after slurrying at RT, 50°C, and 70°C, and form D was converted to form D at different water activities (a) w It was shown to be more stable than Forms A / B / C in solvent mixtures with α- and β-blockers (α- and β-blockers: 0-1).

[0273] Salt screening

[0300] Solvent-mediated reactive crystallization was applied to salt screening. A total of 5 Five salt screening experiments were performed, including 10 counterions and 5 different solvents, as well as 5 blank experiments. A specific experimental procedure was described as follows: 1. Weigh approximately 15 mg of free form Type A and a molar equivalent of counterion into each HPLC vial; 2. Add 0.5-1.0 mL of the corresponding solvent to form a suspension or solution; 3. Stir the mixture magnetically (approximately 1000 rpm) at RT (25±3°C) for approximately 2 days; 4. Isolate the remaining solids by centrifugation (10,000 rpm, 2 minutes); 5. After drying at 50° C. for approximately 2 hours, characterize the solid by XRPD.

[0274]

[0301] As summarized in Table 8, 12 potential salt hits were identified, along with 5 Na salt hits. Three hits (Types A-E), three Ca salt hits (Types A-C), one Mg salt hit (Type A), two Tris salt hits (Forms A and B) and one betaine salt hit (Type A) (highlighted in bold in Table 8) were identified. Solid state characterization of the identified salt hits is listed in Table 9. [Table 8] [Table 9]

[0275] Example 4 - Polymorph Screening and Characterization of Tris Salt Form A, Tris Salt Form B, and Tris Salt Form C of Compound 1 Polymorphism Screening

[0302] A total of 107 polymorph screening experiments were performed using 11 solution crystallization or solid The experiments were performed using the transition method and using the tris salt form of Compound 1 and the free acid form of Compound 1 as shown in Table 10. A total of 105 experiments isolated solids for XRPD characterization. Forms A / B / C / D of the crystalline free acid identified in Example 3 In addition, no new forms were obtained for the free acid. In addition to the crystalline tris salt forms A / B identified in Example 3, a new crystalline form C was obtained for the tris salt. The isolated solids were characterized using XRPD, TGA, and DSC (see Table 9), and the pattern comparison results in Figure 6 indicate that three different crystalline forms were obtained. [Table 10]

[0276] Characterization of the identified crystalline forms of tris salt compound 1

[0303] Representative samples of each identified form (Forms A / B / C) were analyzed by XRPD, TGA, and Further heating experiments were carried out to test the relationship between the different morphologies.

[0277] Tris Salt Form A

[0304] Tris salt Form A was incubated at RT for approximately 2 days. Free acid Form A was incubated in Tris in acetone. The XRPD pattern is shown in Figure 7A, and the corresponding peak list is shown in Figure 7B. The TGA / DSC curve in Figure 7C showed a 2.8% weight loss up to 150°C and a sharp endotherm at 198.6°C (onset temperature). 1 Based on the 1 H NMR results, the stoichiometry of Tris salt Form A was determined to be 1.0:1.1 (free acid / Tris).

[0278] Tris salt form B

[0305] Slurrying the free acid Form A in Tris in EtOH at RT for approximately 2 days to give tris salt form B. The XRPD pattern is shown in Figure 8A, and the corresponding peak list is shown in Figure 8B. The TGA / DSC curve in Figure 8C showed a two-step weight loss of 10.8% to 190°C and an overlapping endotherm / exotherm at 125.3°C (onset temperature) before a sharp endotherm at 201.4°C (onset temperature). Tris salt form B was converted to tris salt form A after heating to 150°C and then cooling to ambient conditions. 1 Based on the 1 H NMR results, the stoichiometry of Tris salt Type B was determined to be 1.0:1.0 (free acid / Tris).

[0279] Tris salt form C

[0306] The free acid form of compound 1 was slurried with Tris in DMSO at RT for approximately 2 days. Tris salt Form C was obtained by cleavage. The resulting slurry was heated to 100°C and stirred for 30 minutes, after which the reaction became a clear solution. The reaction solution was then cooled to RT; no solids formed at RT. 320 mL of EtOH was then slowly added to the reaction solution, followed by stirring at RT for 30 minutes. This step was repeated. After a second EtOH addition and stirring, a solid formed. The reaction mixture containing the formed solid was stirred overnight at 20-25°C and then filtered. The filtrate cake was washed with 2 x 320 mL of EtOH and dried in vacuo at 50°C to obtain a white solid. Next, 150 mL of EtOH was added to the white solid, and the slurry was mechanically stirred at 65°C for 4 hours. The reaction solution was allowed to cool to RT for approximately 1 hour, stirred at RT for 3 hours, and then filtered. The filtrate cake was washed with 2 x 32 mL of EtOH and dried in vacuo at 50 °C for 20 h to yield 29.8 g of an off-white or white powder. Next, 150 mL of EtOH was added to the white solid, and the slurry was mechanically stirred at 65 °C for 4 h. As a further and final purification step, the resulting off-white / white powder was redissolved in DMSO (45 mL) at 100 °C for 15 min. The solution was then cooled to 45 °C, and EtOH (500 mL) was added dropwise. The reaction mixture became cloudy after the addition of 150 mL of EtOH. The resulting slurry was stirred at 25-30 °C for 20 h and then filtered. The filtrate cake was washed with 2 x 100 mL of EtOH. The resulting tris salt was triturated in 20 volumes of EtOH at 70°C for 5 hours, then cooled to 25-30°C over 2 hours and stirred at the same temperature for 3 hours. This procedure was repeated three times, after which 28 g of tris salt Form C was obtained as an off-white solid. The XRPD pattern of tris salt Form C is shown in Figure 9A, and the corresponding peak list is shown in Figure 9B. The TGA / DSC curve in Figure 9C showed a 1.2% weight loss up to 150°C and a sharp endotherm at 193.1°C (onset temperature) with a peak at 196.9°C. The stoichiometry was 1 1 H NMR (data not shown) confirmed a ratio of 1.00:1.02 (free acid / Tris).

[0280]

[0307] An additional procedure that can be used to obtain Tris Salt Form C is described below. Four grams of the free acid form of Compound 1 was slurried with 1.5 g of Tris in 10 mL of DMSO at RT. The reaction solution was cooled to approximately 30°C, and 20 mL of EtOH was added. 10 mg of Tris salt Form A was charged and stirred for 5 minutes to form a cloudy solution. The mixture was stirred for 2 hours and diluted with 60 mL of EtOH to form a slurry. The slurry was stirred overnight at 28-32°C. The solid was collected by filtration, washed with 2 x 20 mL of EtOH, and dried to yield Tris salt Form C as an off-white solid.

[0281]

[0308] The free acid form of Compound 1 and 1.05 eq. of Tris were added to a flask in DMSO. The mixture was mixed with 2.5 volumes of SO. The mixture was heated to approximately 100°C and stirred for 0.5-1 hr to form a clear solution. The solution was cooled to 60-70°C and slowly diluted with an additional volume of EtOH (which may range from 5-15 volumes). Seeds of Tris Salt Form C were added, followed by slowly charging an additional volume of EtOH (which may range from 5-15 volumes) over 2 hr. The mixture was stirred at 60-70°C for 16-24 hr and cooled to 20-30°C. The mixture was stirred at 20-30°C for 2-4 hr. The solid was collected by filtration, washed with EtOH, and dried under vacuum at 40-50°C for 8-12 hr to produce Tris Salt Form C as an off-white solid.

[0282] Example 5 - Thermodynamic Stability Study Comparing Tris Salt Form A and Tris Salt Form C

[0309] The thermodynamic stability relationship between tris salt forms A and C was investigated under four temperature conditions. Two processes involving the solvent systems DMSO / EtOH (1:8, v / v) and EtOH at (5°C / RT / 50°C / 75°C) were investigated by slurry competition experiments. Two stages of the slurry competition experiments were performed, the first of which included temperature as a variable, and the second of which used freshly opened reagents to minimize the effect of absorbed moisture. A typical experimental procedure is described below.

[0283]

[0310] Approximately 5-10 mg of crystalline tris salt Form C was first dissolved in approximately 1.0 mL of the corresponding solvent. The resulting solid was dissolved in 1 mL of crystalline tris salt Form A to form a nearly saturated solution at the corresponding temperature (equilibration method: magnetic stirring, approximately 1000 rpm, approximately 2 hrs). Approximately 15 mg of each form (crystalline tris salt Form A and C) was then physically mixed, and the nearly saturated solution was then added to form a suspension. The suspension was then stirred (approximately 1000 rpm) at the corresponding temperature for 7 days (a small amount of solid was sampled at 2 days in the second stage experiment). The resulting solid was isolated by centrifugation (10,000 rpm, 2 minutes) and tested by XRPD to confirm its form.

[0284]

[0311] Tris salt form A has been shown to convert to tris salt form C, and tris salt form C was shown to be thermodynamically more stable between 5°C and 50°C.

[0285] Example 6 - Kinetic solubility study comparing free acid form D, tris salt form A and tris salt form C

[0312] The kinetic solubility of Tris salt Form A and free acid Form D was determined at 37°C in three different solutions. Measurements were performed in biologically relevant media (SGF, FaSSIF, and FeSSIF). Specifically, approximately 30 mg of solid was initially suspended in 4.0 mL of each medium and equilibrated by shaking (500 rpm) at 37°C. Approximately 0.8 mL of the suspension was extracted at 15, 30, 60, 120 minutes, and 24 hours. The supernatant and precipitate were separated by centrifugation (10,000 rpm, approximately 3 minutes), then concentrated (HPLC). The pH of the supernatant was measured, and the corresponding solid form was characterized by XRPD.

[0286]

[0313] As shown by the data summarized in Table 11, the solubility of the free acid form D was 3-8 μg / mL in SSIF and FeSSIF, and <1 μg / mL in SGF The concentrations were measured to be 100 μg / mL. Compared to the free acid form D, enhanced solubility was observed for Tris salt form A in all SGF / FaSSIF / FeSSIF media at equilibrium (>100 μg / mL at 24 hours). Meanwhile, a change in pH was observed in the three media, especially in SGF (pH: 1.8), which changed to 7.4 (at 24 hours), which may cause enhanced solubility since the free form exhibited acidity in the aqueous phase. [Table 11]

[0287]

[0314] The thermodynamic stability of Tris salt form C prompted further evaluation of three biologically relevant Kinetic solubility studies were performed, including in culture media (FaSSGF / FaSSIF / FeSSIF) and HO at 37 °C. The solubility of Tris-salt Form C was also found to be significantly higher than that of the free acid form and comparable to that of Tris-salt Form A in simulated intestinal media reflecting both fasted and fed states (FaSSIF and FeSSIF), and a gradual decline in API concentration values ​​was detected in FaSSIF / FeSSIF / HO (FaSSIF: 0.39 mg / mL to 0.17 mg / mL; FeSSIF: 0.33 mg / mL to 0.04 mg / mL; HO: 0.81 mg / mL to 0.40 mg / mL). [Table 12]

[0288] Example 7 - Hygroscopicity study comparing free acid form D, tris salt form A and tris salt form C

[0315] To assess the hygroscopicity of the free acid form D, the tris salt forms A and D of compound 1 were Dynamic vapor sorption (DVS) data for each Tris Salt Form C sample was collected at 25°C. When varying from 0% to 80% RH at 25°C, approximately 5 wt% water uptake was observed for both free form Type D and Tris salt Form A. Tris salt Form C was less hygroscopic, with only approximately 0.04 wt% water uptake observed over the same humidity range. The solid form remained as Tris salt Form C after the DVS test, as confirmed by XRPD (data not shown).

[0289] Example 8 – Pharmacokinetic study comparing the free acid and Tris salt

[0316] The purpose of the pharmacokinetic (PK) study was to determine the pharmacokinetics of different forms of Compound 1 in intact Sprague-Dawley rats after oral (PO) administration. Briefly, several lots of Compound 1 free acid obtained from different manufacturing batches (crystallinity was not tested) and with different particle size distributions and the Tris salt of Compound 1 (crystallinity was not tested) were formulated at a concentration of 100 mg / mL in 0.5% (w / v) methylcellulose and 0.2% (v / v) Tween 80 in water. Food and water were available ad libitum to all animals, and Compound 1 or the Tris salt of Compound 1 was orally administered at 100 mg / kg (100 mL / kg). Approximately 110 μL of whole blood was collected into tubes containing the anticoagulant K2EDTA via tail vein bleeding predose and at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose, processed to obtain plasma, and stored at approximately -70°C until analysis. The concentrations of the active pharmaceutical ingredient in the plasma samples were quantified using an unvalidated liquid chromatography with tandem mass spectrometry (LC-MS / MS) method. Pharmacokinetic analysis of individual plasma concentration data was performed using WinNonlin® (Version 6.4; Pharsight Corporation, Mountain View, CA, USA). Pharmacokinetic parameters were estimated using a non-compartmental extravascular model method. The area under the concentration-time curve (AUC) was calculated using the linear trapezoidal rule. For PK parameter calculations, AG-636 concentrations that were below the limit of quantitation (BLQ) at the terminal phase were excluded. The concentration at which the LLOQ was <80% was designated as the BLQ.

[0290]

[0317] The results from the PK studies using male SD rats are summarized in Table 13 below. The PK profiles for both the Tris salt and free base of Compound 1 are shown in Figures 10A-10B. Among the free acid forms evaluated, Lot A and Lot B achieved some of the most elevated exposure, as can be seen in Figure 10A. However, Lot A and Lot B were early batches of the free acid of Compound 1 that were only partially crystalline and characterized by the presence of large amounts of residual organic solvent, and therefore were not suitable for use in formulation development. Furthermore, Lot A and Lot B were produced by methods not considered suitable for large-scale synthesis.

[0291]

[0318] Therefore, it was necessary to identify a final formulation that would have similar exposure to lots A and B. To achieve this, a new free form of Compound 1 with better crystallinity and acceptable levels of residual solvent was synthesized by an improved method. This new free form of Compound 1 was also synthesized with different particle size distributions than Lot C, Lot D, and Lot E, as summarized in Table 13, to evaluate the effectiveness of particle size reduction on the exposure of the free form in PK studies. Unfortunately, despite the enhanced crystallinity and purity (see Figure 10B), none of Lot C, Lot D, or Lot E exhibited the equivalent exposure previously observed.

[0292]

[0319] In summary and with reference to Table 13, the T of the Tris salt of Compound 1 max oh Call C max indicates the time at which the maximum API concentration occurs and the maximum API concentration itself, respectively, and are clearly superior to the corresponding parameters observed for the free acid. In particular, faster absorption of higher maximum API concentrations is associated with lower values ​​of T max and higher C max By As shown, a significant improvement can be observed for the Tris salt compared to all batches of free acid. Further comparison of the best free acid batch of Lot B with the Tris salt shows that T max is about twice as low as C maxis approximately 1.5-fold higher. Based on the in vivo PK data, the in vitro solubility and / or rate of dissolution of the Tris salt is expected to be significantly higher. [Table 13]

[0293] Example 9 – Capsule Composition

[0320] 10 mg dosage strength capsules (free form equivalent) are manufactured using dry granulation and direct granulation methods. The encapsulation method can be used to prepare the compounds as described in Table A. [Table 14]

[0294]

[0321] 50, 100, and 125 mg dosage strength capsules (free form equivalent) It can be prepared as described in Table B using dry granulation and direct encapsulation methods. [Table 15]

[0295]

[0322] 100 and 125 mg dosage strength capsules (free form equivalent) are listed below The compositions can be prepared as described in Tables C and D using dry granulation and direct encapsulation methods. [Table 16] [Table 17]

[0296]

[0323] To blend the Tris salt of Compound 1 and the excipients shown in Tables C and D, The tris salt of Compound 1 and the intragranular ingredients (excipients, disintegrants, binders, surfactants, glidants, and lubricants) were mixed in a suitable blender. The blend was roller compacted (Capsules E, F, H, I, J, M, and N) and the compacted material was sized to produce granules. For Capsules K and L, the intragranular blend was granulated and the granulated blend was sized.

[0297]

[0324] The extragranular ingredients (glidants and lubricants) are weighed and sieved for blending. The extragranular ingredients and milled granules were screened and then added to a suitable blender and blended.

[0298]

[0325] The blended material is then dispensed into size 1 capsules by hand filling the capsules. The capsules were stored at ambient conditions (15-25°C).

[0299]

[0326] Many embodiments have been described, and the scope of the present disclosure is defined by the appended claims. and not by any particular embodiment shown as an example. The contents of all references cited throughout this application (including literature references, issued patents, published patent applications, and co-pending patent applications) are expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein accord with the meaning commonly known to those of ordinary skill in the art.

Claims

1. The tris(hydroxymethyl)aminomethane salt of the compound represented by the formula Compound 1. 【Chemistry 1】

2. 2. The tris(hydroxymethyl)aminomethane salt of claim 1, which is at least 80% by weight crystalline.

3. 3. The tris(hydroxymethyl)aminomethane salt of claim 2, wherein the salt is at least 60% by weight in single crystalline form, at least 70% by weight in single crystalline form, at least 80% by weight in single crystalline form, at least 90% by weight in single crystalline form, at least 95% by weight in single crystalline form, or at least 99% by weight in single crystalline form.

4. 4. The tris(hydroxymethyl)aminomethane salt of claim 1, having a chemical purity of at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight.

5. 5. The tris(hydroxymethyl)aminomethane salt according to claim 1, which is a hydrate.

6. 6. The tris(hydroxymethyl)aminomethane salt according to any one of claims 1 to 5, which is crystalline form A characterized by powder X-ray diffraction peaks at 2θ angles of 4.4°, 15.6° and 18.9° (±0.2°).

7. 7. The tris(hydroxymethyl)aminomethane salt of claim 6, wherein the crystalline form A is further characterized by powder X-ray diffraction peaks at 2θ angles of 11.5°, 16.4°, 19.6°, and 25.5° (±0.2°).

8. 8. The tris(hydroxymethyl)aminomethane salt of claim 6 or 7, wherein the crystalline form A is further characterized by at least one powder X-ray diffraction peak at a 2θ angle (±0.2°) selected from 8.7°, 15.2°, 18.6°, 21.4°, and 25.1°.

9. 9. The tris(hydroxymethyl)aminomethane salt of any one of claims 6 to 8, wherein the crystalline form A is characterized by a powder X-ray diffraction pattern substantially similar to Figure 7A.

10. 6. The tris(hydroxymethyl)aminomethane salt according to any one of claims 1 to 5, wherein the crystalline form is crystalline form B characterized by powder X-ray diffraction peaks at 2θ angles of 6.0°, 7.0° and 7.2° (±0.2°).

11. 11. The tris(hydroxymethyl)aminomethane salt of claim 10, wherein the crystalline form B is further characterized by at least one powder X-ray diffraction peak at a 2θ angle (±0.2°) selected from 9.3° and 12.5°.

12. 12. The tris(hydroxymethyl)aminomethane salt of claim 10 or 11, wherein the crystalline form B is further characterized by at least one powder X-ray diffraction peak at a 2θ angle (±0.2°) selected from 15.6° and 19.0°.

13. 13. The tris(hydroxymethyl)aminomethane salt of any one of claims 10 to 12, wherein the crystalline form B is characterized by a powder X-ray diffraction pattern substantially similar to Figure 8A.

14. 6. The tris(hydroxymethyl)aminomethane salt of claim 1, wherein the crystalline form is crystalline form C characterized by powder X-ray diffraction peaks at 2θ angles of 4.5°, 13.5°, and 18.0° (±0.2°).

15. 15. The tris(hydroxymethyl)aminomethane salt of claim 14, wherein the crystalline form C is further characterized by at least one powder X-ray diffraction peak at a 2θ angle (±0.2°) selected from 14.3°, 18.3°, and 23.5°.

16. 15. The tris(hydroxymethyl)aminomethane salt of claim 13 or 14, wherein the crystalline form C is further characterized by at least one powder X-ray diffraction peak at a 2θ angle (±0.2°) selected from 16.3°, 19.0°, 21.2°, 22.5°, and 22.8°.

17. 17. The tris(hydroxymethyl)aminomethane salt of any one of claims 13 to 16, wherein the crystalline form C is characterized by a powder X-ray diffraction pattern substantially similar to Figure 9A.

18. The sodium salt of the compound represented by the formula Compound 1. 【Chemistry 2】

19. A crystalline form of a compound represented by the formula Compound 1. 【Transformation 3】

20. 20. The crystalline form of claim 19, wherein the compound is an anhydrate.

21. 21. The crystalline form of claim 19 or 20, which is crystalline form A characterized by powder X-ray diffraction peaks at 2θ angles of 5.8°, 11.6° and 12.8° (±0.2°).

22. 22. The crystalline form of claim 21, wherein the crystalline form A is further characterized by powder X-ray diffraction peaks at 2θ angles of 8.1° and 16.9° (±0.2°).

23. 23. The crystalline form of claim 21 or 22, wherein the crystalline form A is further characterized by at least one powder X-ray diffraction peak at a 2θ angle (±0.2°) selected from 11.4°, 24.6°, 24.9°, and 25.1°.

24. 24. The crystalline form of any one of claims 21 to 23, wherein said crystalline form A is characterized by a powder X-ray diffraction pattern substantially similar to Figure 2A.

25. 21. The crystalline form of claim 19 or 20, which is crystalline form B characterized by powder X-ray diffraction peaks at 2θ angles of 6.5°, 12.9° and 25.1° (±0.2°).

26. 26. The crystalline form of claim 25, wherein the crystalline form B is further characterized by at least one powder X-ray diffraction peak at a 2θ angle (±0.2°) selected from 13.1° and 15.7°.

27. 27. The crystalline form of claim 25 or 26, wherein the crystalline form B is further characterized by at least one powder X-ray diffraction peak at a 2θ angle (±0.2°) selected from 8.5°, 11.1°, 11.4°, 17.3°, 20.5°, 21.9°, and 25.9°.

28. 28. The crystalline form of any one of claims 25 to 27, wherein the crystalline form B is characterized by a powder X-ray diffraction pattern substantially similar to Figure 3A.

29. 21. The crystalline form of claim 19 or 20, which is crystalline form C characterized by powder X-ray diffraction peaks at 2θ angles of 5.7°, 11.4° and 25.0° (±0.2°).

30. 30. The crystalline form of claim 29, wherein the crystalline form C is further characterized by at least one powder X-ray diffraction peak at a 2θ angle (±0.2°) selected from 3.2°, 17.4°, and 18.4°.

31. The crystalline form C has the following structural variations: 12.8°, 16.2°, 19.0°, 27.5° and 31.7°.

31. The crystalline form of claim 29 or 30, further characterized by at least one powder X-ray diffraction peak at a 2θ angle selected from (±0.2°).

32. 32. The crystalline form of any one of claims 29 to 31, wherein the crystalline form C is characterized by a powder X-ray diffraction pattern substantially similar to Figure 4A.

33. 21. The crystalline form of claim 19 or 20, which is crystalline form D characterized by powder X-ray diffraction peaks at 2θ angles of 5.9°, 11.9° and 17.1° (±0.2°).

34. 34. The crystalline form of claim 33, wherein the crystalline form D is further characterized by powder X-ray diffraction peaks at 2θ angles of 11.2° and 23.3° (±0.2°).

35. 35. The crystalline form of claim 33 or 34, wherein the crystalline form D is further characterized by at least one powder X-ray diffraction peak at a 2θ angle (±0.2°) selected from 12.7°, 13.4°, 18.8°, 19.7°, 20.8°, 22.0°, 22.5°, 22.7°, and 24.6°.

36. 36. The crystalline form of any one of claims 33 to 35, wherein the crystalline form D is characterized by a powder X-ray diffraction pattern substantially similar to Figure 5A.

37. 37. The crystalline form of any one of claims 19 to 36, wherein the compound is at least 60% by weight in single crystalline form, at least 70% by weight in single crystalline form, at least 80% by weight in single crystalline form, at least 90% by weight in single crystalline form, at least 95% by weight in single crystalline form, or at least 99% by weight in single crystalline form.

38. 38. The crystalline form of any one of claims 19 to 37, wherein the compound has a chemical purity of at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight.

39. 39. A pharmaceutical composition comprising the tris(hydroxymethyl)aminomethane salt of any one of claims 1 to 17, the sodium salt of claim 18, or the crystalline form of any one of claims 19 to 38, and a pharmaceutically acceptable carrier.

40. 10. A pharmaceutical composition comprising crystalline form A of the tris(hydroxymethyl)aminomethane salt of any one of claims 6 to 9 and a pharmaceutically acceptable carrier.

41. 14. A pharmaceutical composition comprising crystalline form B of the tris(hydroxymethyl)aminomethane salt of any one of claims 10 to 13 and a pharmaceutically acceptable carrier.

42. 18. A pharmaceutical composition comprising crystalline form C of the tris(hydroxymethyl)aminomethane salt of any one of claims 14 to 17 and a pharmaceutically acceptable carrier.

43. 20. A pharmaceutical composition comprising the sodium salt of claim 18 and a pharmaceutically acceptable carrier.

44. 25. A pharmaceutical composition comprising crystalline form A of any one of claims 21 to 24 and a pharmaceutically acceptable carrier.

45. 29. A pharmaceutical composition comprising crystalline form B of any one of claims 25 to 28 and a pharmaceutically acceptable carrier.

46. 33. A pharmaceutical composition comprising crystalline form C of any one of claims 29 to 32 and a pharmaceutically acceptable carrier.

47. 37. A pharmaceutical composition comprising crystalline form D of any one of claims 33 to 36 and a pharmaceutically acceptable carrier.

48. 39. A pharmaceutical composition comprising the tris(hydroxymethyl)aminomethane salt of any one of claims 1 to 17, the sodium salt of claim 18, or the crystalline form of any one of claims 19 to 38, and one or more intragranular excipients.

49. 10. A pharmaceutical composition comprising crystalline form A of the tris(hydroxymethyl)aminomethane salt of any one of claims 6 to 9 and one or more intragranular excipients.

50. 14. A pharmaceutical composition comprising crystalline form B of the tris(hydroxymethyl)aminomethane salt of any one of claims 10 to 13 and one or more intragranular excipients.

51. 18. A pharmaceutical composition comprising crystalline form C of the tris(hydroxymethyl)aminomethane salt of any one of claims 14 to 17 and one or more intragranular excipients.

52. 20. A pharmaceutical composition comprising the sodium salt of claim 18 and one or more intragranular excipients.

53. 25. A pharmaceutical composition comprising crystalline form A of any one of claims 21 to 24 and one or more intragranular excipients.

54. 29. A pharmaceutical composition comprising crystalline form B of any one of claims 25 to 28 and one or more intragranular excipients.

55. 33. A pharmaceutical composition comprising crystalline form C of any one of claims 29 to 32 and one or more intragranular excipients.

56. 37. A pharmaceutical composition comprising crystalline form D of any one of claims 33 to 36 and one or more intragranular excipients.

57. 57. Any of claims 50 to 56, further comprising one or more extragranular excipients. The pharmaceutical composition according to any one of claims 1 to 4.

58. 39. A pharmaceutical composition comprising the tris(hydroxymethyl)aminomethane salt of any one of claims 1 to 17, the sodium salt of claim 18, or the crystalline form of any one of claims 19 to 38, and a pharmaceutically acceptable carrier as a solid dispersion.

59. Formula of Compound 1: 【Chemistry 4】 and a pharmaceutically acceptable carrier as a solid dispersion.

60. 60. A method of treating cancer in a subject, comprising administering to the subject an effective amount of a tris(hydroxymethyl)aminomethane salt of any one of claims 1 to 17, a sodium salt of claim 18, a crystalline form of any one of claims 19 to 38, or a pharmaceutical composition of any one of claims 39 to 59.

61. 61. The method of claim 60, wherein the cancer comprises a solid tumor.

62. The cancer is Lung cancer, breast cancer, triple-negative breast cancer, melanoma, glioblastoma, prostate cancer, colon cancer, pancreatic cancer, bone cancer, head and neck cancer, skin cancer, cutaneous or intraocular malignant endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, sarcoma of soft tissue, urethral cancer, penile cancer, solid tumors of childhood, kidney or or ureteral cancer, renal pelvic carcinoma, central nervous system (CNS) neoplasms, tumor angiogenesis, spinal axis tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma epithelial cancers, environmentally induced cancers, and PTEN mutant cancers, and Biliary tract cancer or cancer of the ampulla of Vater, non-small cell lung cancer, bronchoalveolar carcinoma, liver cancer, ovarian cancer, and cancer of the upper aerodigestive tract 62. The method of claim 60 or 61, wherein the

63. 61. The method of claim 60, wherein the cancer is a hematological cancer.

64. 64. The method of claim 63, wherein the hematological cancer is selected from myeloma, lymphoma, and leukemia.

65. The blood cancer is acute myeloid leukemia, multiple myeloma, B-cell prolymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, lymphocytic lymphoma, bladder cancer, primary CNS lymphoma, and T-cell lymphoma; chemotherapy-resistant acute myeloid leukemia, cytarabine-resistant acute myeloid leukemia, acute monocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, diffuse mixed cell lymphoma, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, primary effusion lymphoma, erythroleukemia, chronic myeloid leukemia, chronic monocytic leukemia, double hit diffuse large B-cell lymphoma, and triple hit diffuse large B-cell lymphoma; Angioimmunoblastic lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, blastic NK 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, follicular lymphoma, Waldenstrom's macroglobulinemia, essential thrombocythemia, chronic idiopathic myelofibrosis, and polycythemia rubra vera 65. The method of claim 63 or 64, wherein the

66. Use of a tris(hydroxymethyl)aminomethane salt according to any one of claims 1 to 17, a sodium salt according to claim 18, a crystalline form according to any one of claims 19 to 38, or a pharmaceutical composition according to any one of claims 39 to 59 for the manufacture of a medicament for treating cancer.

67. 67. The use of claim 66, wherein the cancer comprises a solid tumor.

68. The cancer is Lung cancer, breast cancer, triple-negative breast cancer, melanoma, glioblastoma, prostate cancer, colon cancer, pancreatic cancer, bone cancer, head and neck cancer, skin cancer, cutaneous or intraocular malignant endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, childhood solid tumors, kidney or ureter cancer, renal pelvis carcinoma, neoplasms of the central nervous system (CNS), tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancers, and PTEN-mutant cancers; Biliary tract cancer or cancer of the ampulla of Vater, non-small cell lung cancer, bronchoalveolar carcinoma, liver cancer, ovarian cancer, and cancer of the upper aerodigestive tract 68. The use according to claim 66 or 67, wherein the compound is selected from the group consisting of:

69. 67. The use of claim 66, wherein the cancer is a blood cancer.

70. 70. The use of claim 69, wherein the hematological cancer is selected from myeloma, lymphoma, and leukemia.

71. The blood cancer is acute myeloid leukemia, multiple myeloma, B-cell prolymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, lymphocytic lymphoma, bladder cancer, primary CNS lymphoma, and T-cell lymphoma; chemotherapy-resistant acute myeloid leukemia, cytarabine-resistant acute myeloid leukemia, acute monocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, diffuse mixed cell lymphoma, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, primary effusion lymphoma, erythroleukemia, chronic myeloid leukemia, chronic monocytic leukemia, double-hit diffuse large B-cell lymphoma, and triple-hit diffuse large B-cell lymphoma; Angioimmunoblastic lymphoma, Burkitt 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, follicular lymphoma, Waldenstrom's macroglobulinemia, essential thrombocythemia, chronic idiopathic myelofibrosis, and primary polycythemia vera 71. The use according to claim 69 or 70, wherein the

72. the tris(hydroxymethyl)aminomethane salt, the sodium salt, the crystalline form, or a tris(hydroxymethyl)aminomethane salt according to any one of claims 1 to 17, a sodium salt according to claim 18, a crystalline form according to any one of claims 19 to 38, or a pharmaceutical composition according to any one of claims 39 to 59 for treating cancer, wherein the pharmaceutical composition is optionally combined with an additional therapeutic agent.

73. 73. The tris(hydroxymethyl)aminomethane salt, sodium salt, crystalline form, or pharmaceutical composition of claim 72, wherein the cancer comprises a solid tumor.

74. The cancer is Lung cancer, breast cancer, triple-negative breast cancer, melanoma, glioblastoma, prostate cancer, colon cancer, pancreatic cancer, bone cancer, head and neck cancer, skin cancer, cutaneous or intraocular malignant endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, childhood solid tumors, kidney or ureter cancer, renal pelvis carcinoma, neoplasms of the central nervous system (CNS), tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancers, and PTEN-mutant cancers; Biliary tract cancer or cancer of the ampulla of Vater, non-small cell lung cancer, bronchoalveolar carcinoma, liver cancer, ovarian cancer, and cancer of the upper aerodigestive tract 74. The tris(hydroxymethyl)aminomethane salt, sodium salt, crystalline form, or pharmaceutical composition of claim 72 or 73, selected from:

75. 73. The tris(hydroxymethyl)aminomethane salt, sodium salt, crystalline form, or pharmaceutical composition of claim 72, wherein the cancer is a blood cancer.

76. 76. The tris(hydroxymethyl)aminomethane salt, sodium salt, crystalline form, or pharmaceutical composition of claim 72 or 75, wherein the hematological cancer is selected from myeloma, lymphoma, and leukemia.

77. The blood cancer is acute myeloid leukemia, multiple myeloma, B-cell prolymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, lymphocytic lymphoma, bladder cancer, primary CNS lymphoma, and T-cell lymphoma; chemotherapy-resistant acute myeloid leukemia, cytarabine-resistant acute myeloid leukemia, acute monocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, diffuse mixed cell lymphoma, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, primary effusion lymphoma, erythroleukemia, chronic myeloid leukemia, chronic monocytic leukemia, double-hit diffuse large B-cell lymphoma, and triple-hit diffuse large B-cell lymphoma; Angioimmunoblastic lymphoma, Burkitt 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, follicular lymphoma, Waldenstrom's macroglobulinemia, essential thrombocythemia, chronic idiopathic myelofibrosis, and primary polycythemia vera 77. The tris(hydroxymethyl)aminomethane salt, sodium salt, crystalline form, or pharmaceutical composition of any one of claims 72, 75, and 76, selected from:

78. 19. A method of treating cancer responsive to inhibition of dihydroorotate dehydrogenase in a subject, comprising administering to the subject a tris(hydroxymethyl)aminomethane salt of any one of claims 1 to 17, a sodium salt of claim 18, a crystalline form of any one of claims 19 to 38, or a pharmaceutical composition of any one of claims 39 to 59. administering an effective amount of the composition.

79. Use of a tris(hydroxymethyl)aminomethane salt according to any one of claims 1 to 17, a sodium salt according to claim 18, a crystalline form according to any one of claims 19 to 38, or a pharmaceutical composition according to any one of claims 39 to 59 for the manufacture of a medicament for treating cancer responsive to the inhibition of dihydroorotate dehydrogenase.

80. 60. A tris(hydroxymethyl)aminomethane salt according to any one of claims 1 to 17, a sodium salt according to claim 18, a crystalline form according to any one of claims 19 to 38, or a pharmaceutical composition according to any one of claims 39 to 59, for treating a cancer responsive to the inhibition of dihydroorotate dehydrogenase.

81. 60. A method of treating a condition or disease in a subject selected from a viral-mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, an autoimmune disease, or an inflammatory disorder, comprising administering to the subject an effective amount of a tris(hydroxymethyl)aminomethane salt of any one of claims 1 to 17, a sodium salt of claim 18, a crystalline form of any one of claims 19 to 38, or a pharmaceutical composition of any one of claims 39 to 59.

82. Use of a tris(hydroxymethyl)aminomethane salt according to any one of claims 1 to 17, a sodium salt according to claim 18, a crystalline form according to any one of claims 19 to 38, or a pharmaceutical composition according to any one of claims 39 to 59 for the manufacture of a medicament for treating a condition or disease selected from a viral-mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, an autoimmune disease, or an inflammatory disorder.

83. 60. A tris(hydroxymethyl)aminomethane salt according to any one of claims 1 to 17, a sodium salt according to claim 18, a crystalline form according to any one of claims 19 to 38, or a pharmaceutical composition according to any one of claims 39 to 59, for treating a condition or disease selected from a viral-mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, an autoimmune disease, or an inflammatory disorder.

84. 60. A method of inhibiting the growth and / or metastasis of tumor cells responsive to inhibition of dihydroorotate dehydrogenase in a subject, comprising administering to the subject an effective amount of a tris(hydroxymethyl)aminomethane salt of any one of claims 1 to 17, a sodium salt of claim 18, a crystalline form of any one of claims 19 to 38, or a pharmaceutical composition of any one of claims 39 to 59.

85. 60. A method of inhibiting dihydroorotate dehydrogenase in a subject, comprising administering to the subject an effective amount of a tris(hydroxymethyl)aminomethane salt of any one of claims 1-17, a sodium salt of claim 18, a crystalline form of any one of claims 19-38, or a pharmaceutical composition of any one of claims 39-59.

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