Crystalline and salt forms of organic compounds and pharmaceutical compositions thereof

Abstract

The present invention provides various salts of compounds represented by the following structural formula, including tris(hydroxymethyl)aminomethane salt and sodium salt, and various crystalline forms: #imgabs0# Also provided are pharmaceutical compositions containing these salts and crystalline forms, methods for preparing the same, and uses thereof for treating conditions, including but not limited to conditions that would benefit from the inhibition of dihydroorotate dehydrogenase (DHODH).

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 784,083, filed on December 21, 2018; U.S. Provisional Application No. 62 / 791,571, filed on January 11, 2019; and U.S. Provisional Application No. 62 / 882,712, filed on August 5, 2019, the disclosures of each of which are incorporated by reference in their entirety. Background Art

[0003] Dihydroorotate dehydrogenase (DHODH) is an enzyme that catalyzes a step in the de novo pyrimidine nucleotide biosynthesis pathway. It catalyzes the only oxidation / reduction reaction in the pathway, which is the step that converts DHO (dihydroorotate) to orotate with the help of a flavin cofactor and an electron acceptor. Inhibitors of dihydroorotate dehydrogenase have been found to have wider application as chemotherapeutic agents.

[0004] 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 identified as an inhibitor of DHODH. See, for example, International Patent Application Publication No. WO 2014 / 128669 and U.S. Patent No. 9,630,932, the contents of which are incorporated herein by reference.

[0005]

[0006] Compound 1 is being developed for the treatment of diseases and disorders that would benefit from DHODH inhibition, such as, but not limited to, solid cancers, hematological cancers, virally mediated diseases, transplant rejection, rheumatoid arthritis, psoriasis, autoimmune diseases, and inflammatory disorders. Given the therapeutic benefits of Compound 1, and its great promise for treating a wide variety of 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 to improve storage stability. Summary of the invention

[0007] As described in more detail in the following paragraphs, it has now been discovered 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 other Tris salt forms.

[0008] In the salt screening study described herein, more than 50 different salt hits of Compound 1 were evaluated, including 10 counterions, and 5 different solvents were evaluated. 12 different crystalline forms were identified (see Table 8). Among these crystalline salt forms, the Tris salt form was found to be superior. Specifically, Tris salt form A and Tris salt form C of Compound 1 are the leading crystalline salt forms with sharp XRPD peaks (see Example 3, Table 8 and Figure 6 ). Good crystallinity of a drug substance generally translates into better physical and chemical stability, and is therefore an ideal property of an active pharmaceutical ingredient (API). In addition, thermogravimetric analysis (TGA) data reflects negligible weight loss of Tris salt form A and Tris salt form C of compound 1 (see Table 9), thus indicating minimal residual solvent and anhydrous polymorphs, which are generally preferred over solvated / hydrated forms in oral solid dosage form development. Differential scanning calorimetry (DSC) data of Tris salt form A and Tris salt form C of compound 1 (see Table 9) further indicate an endothermic process of rapid melting before decomposition, indicating a low probability of polymorphic change and a low probability of phase transition that is generally undesirable from the perspective of API physical stability.

[0009] Comparing the 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 was thermodynamically more stable (see Example 5). In addition, it was also found that the Tris salt form C of compound 1 has lower hygroscopicity than its Tris salt form A counterpart, making it easier to disintegrate in the solvent during formulation development.

[0010] Comparing the pharmacokinetic properties of the free acid and Tris salt of Compound 1, the Tris salt form showed a shorter duration (i.e., lower T max ) to a higher maximum concentration (i.e., a higher C max ) is significantly superior (see Example 8 and Table 13). Although the initial form of the free acid with low crystallinity and purity showed comparable exposure to the Tris salt, as shown by the AUC values ​​(see Tables 13 and Fig. 10A ), but this high AUC value could not be reproduced with the near-final form of the free acid with improved crystallinity and purity, even when the particle size was reduced (see Tables 13 and Fig. 10B ).

[0011] The PK data showed that the Tris salt of Compound 1 exhibited superior exposure and faster and higher absorption compared to the free acid form. The relatively clear DSC curve with a sharp melting endotherm of the Tris salt Form C of Compound 1, combined with excellent thermodynamic properties and low hygroscopicity, indicates reliable solid-state properties for this particular salt form from the perspective of physical stability and suitability for oral solid dosage form development.

[0012] Provided herein are the tris(hydroxymethyl)aminomethane salt, the sodium salt, and crystalline forms of a compound referred to herein as Compound 1.

[0013] Also provided herein are pharmaceutical compositions comprising tris(hydroxymethyl)aminomethane (Tris) salt, sodium salt and other pharmaceutically acceptable salts and crystalline forms of Compound 1, methods for preparing the same and uses thereof for treating diseases, including but not limited to diseases that benefit from inhibition of dihydroorotate dehydrogenase (DHODH).

[0014] 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 preparing the same, and uses thereof for treating diseases, including but not limited to diseases that benefit from DHODH inhibition. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The XRPD of Forms A, B, C and D of Compound 1 are depicted.

[0016] Figure 2A The XRPD pattern of Form A of Compound 1 is described.

[0017] Figure 2B This is the XRPD peak list of Form A of Compound 1.

[0018] Figure 2C A combined DSC thermogram and TGA thermogram of Form A of Compound 1 is depicted.

[0019] Figure 3A The XRPD pattern of Form B of Compound 1 is described.

[0020] Figure 3B This is the XRPD peak list of Form B of Compound 1.

[0021] Figure 3C Depicted is a combined DSC thermogram and TGA thermogram of Form B of Compound 1.

[0022] Figure 4A The XRPD pattern of Form C of Compound 1 is described.

[0023] Figure 4B This is the XRPD peak list of Form C of Compound 1.

[0024] Figure 4C Depicted is a combined DSC thermogram and TGA thermogram of Form C of Compound 1.

[0025] Figure 5AThe XRPD pattern of Form D of Compound 1 is described.

[0026] Figure 5B This is the XRPD peak list of Form D of Compound 1.

[0027] Figure 5C A combined DSC thermogram and TGA thermogram of Form D of Compound 1 is depicted.

[0028] Figure 6 Depicted is an overlay of X-ray powder diffraction (XRPD) patterns of three crystalline forms of the tris(hydroxymethyl)aminomethane (Tris) salt of Compound 1.

[0029] Fig. 7A The XRPD pattern of Form A of the Tris salt of Compound 1 is described.

[0030] Figure 7B This is a list of XRPD peaks for Form A of the Tris salt of Compound 1.

[0031] Figure 7C Depicted is a combined differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) thermogram of Form A of the Tris salt of Compound 1.

[0032] Fig.7D The crystalline form A of the Tris salt of compound 1 is described 1 H NMR spectrum.

[0033] Fig. 8A The XRPD pattern of Form B of the Tris salt of Compound 1 is described.

[0034] Figure 8B This is a list of XRPD peaks for Form B of the Tris salt of Compound 1.

[0035] Figure 8C Depicted is a combined DSC thermogram and TGA thermogram of Form B of the Tris salt of Compound 1.

[0036] Fig.8D The crystalline form B of the Tris salt of compound 1 is described 1 H NMR spectrum.

[0037] Fig. 9A The XRPD pattern of Form C of the Tris salt of Compound 1 is described.

[0038] Fig. 9B This is a list of XRPD peaks for Form C of the Tris salt of Compound 1.

[0039] Fig. 9CDepicted is a combined DSC thermogram and TGA thermogram of Form C of the Tris salt of Compound 1.

[0040] Fig. 10A Pharmacokinetic (PK) profiles of free acid samples of Compound 1 (Batch A and Batch B) and Tris salt sample of Compound 1 (Batch F) are depicted.

[0041] Fig. 10B The pharmacokinetic (PK) profiles of free acid samples of Compound 1 (Batch C, Batch D, Batch E) and Tris salt sample of Compound 1 (Batch F) are described. DETAILED DESCRIPTION

[0042] definition

[0043] When used alone, when describing Compound 1, the terms "Form A", "Form B", "Form C", and "Form D" refer to Forms A, B, C, and D of Compound 1, respectively. In addition, when describing the tris (hydroxymethyl) aminomethane (tris) salt of Compound 1, the terms "Form A", "Form B", and "Form C" refer to Forms A, B, and C of the tris (hydroxymethyl) aminomethane salt of Compound 1, respectively. The terms "Form A", "Form A", referring to Form A of Compound 1 or the Tris salt of Compound 1, are used interchangeably. Similarly, "Form B" and "Form B", and "Form C" and "Form C", referring to Form B or Form C of Compound 1 or the Tris salt of Compound 1, respectively, and "Form D" and "Form D", referring to Form D of Compound 1, are used interchangeably.

[0044] The term "amorphous" refers to a solid that exists in a non-crystalline state or form. An amorphous solid is a disordered arrangement of molecules and therefore has no distinguishable lattice or unit cell, and therefore no definable long-range order. The solid state ordering of a solid can be determined by standard techniques known in the art, such as by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC). Amorphous solids can also be distinguished from crystalline solids, for example by birefringence using a polarizing microscope.

[0045] In general, compound 1 may contain any amount of one or more impurities. In some embodiments, the term "impurity" refers to chemical impurities, such as reaction byproducts. In the present application, this may also be referred to as chemical purity. In other embodiments, the term "impurity" refers to other solid forms of compound 1 or its salt. In these embodiments, other solid forms of compound 1 or its salt may include amorphous or other crystalline forms. As used herein, the term "substantially amorphous" refers to the form and composition of amorphous compound 1, which does not contain impurities and / or does not contain a specific weight percentage of the crystalline form of compound 1 (including crystalline salts of compound 1). The specific weight percentage is 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% is free of impurities and / or crystalline forms of Compound 1. In some embodiments, substantially amorphous refers to a free form or salt form of Compound 1 that is at least 90% pure. In other embodiments, the term substantially amorphous refers to a free form or salt form of Compound 1 that is at least 80% pure. In other embodiments, the term substantially amorphous refers to a free form or salt form that is at least 70% pure. 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.

[0046] As used herein, "crystal" refers to a solid form of Compound 1 or a Tris salt of Compound 1, in which there is a long-range atomic order of atomic positions. The crystalline nature of the solid can be confirmed by, for example, examining an X-ray powder diffraction pattern. If the XRPD shows a sharp intensity peak in the XRPD, the compound is a crystal. The solid form of Compound 1 or the Tris salt of Compound 1 as "crystalline" is a completely crystalline or partially crystalline solid, and contains at least 80% crystalline, 85% crystalline, 90% crystalline, 95% crystalline and 99% crystalline solids by weight. In contrast to the amorphous solid defined above, a crystalline solid is an orderly arrangement of molecules with a distinguishable lattice or unit cell, and therefore has a definable long-range order. In some embodiments, substantially crystalline refers to a solid form of Compound 1 or a Tris salt of Compound 1 that is at least 80% crystalline. In other embodiments, substantially crystalline refers to a solid form that is at least 90% crystalline.

[0047] As used herein, chemical purity refers to the extent to which the disclosed form does not contain materials with different chemical structures. The chemical purity of a compound in a disclosed crystalline form refers to the weight of the compound divided by the sum of the weight of the compound plus materials / impurities with different chemical structures multiplied by 100%, i.e., the weight percentage. In one embodiment, the compound in a disclosed crystalline form 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.

[0048] The term "solvate" refers to crystalline Compound 1 or 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.

[0049] The term "hydrate" refers to crystalline Compound 1 or a crystalline Tris salt of Compound 1, wherein 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 with respect to a compound refers to substantially no solvent incorporated into the crystal structure, e.g., less than 0.1% by weight as determined by Karl Fischer analysis. Anhydrous compounds are referred to herein as "anhydrates."

[0050] As used herein, the term "main peak" refers to the three most intense peaks in an XRPD data pattern, or to a peak having at least 50% of the 100% relative intensity of the most intense peak.

[0051] The single crystal form of Compound 1 or the Tris salt of Compound 1 refers to 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-carboxylic acid Tris salt in the form of a single crystal or multiple crystals, wherein each crystal has the same crystal form (i.e., Form A, B, C of the free acid or Form A, B, C of the Tris salt). When a crystal form is defined as a specific percentage of a specific single crystal form of the compound, the remainder is composed of an amorphous form and / or a crystal form other than the one or more specific forms. In one embodiment, the crystalline form is at least 60% single crystalline form, at least 70% single crystalline form, at least 80% single crystalline form, at least 90% single crystalline form, at least 95% single crystalline form, or at least 99% single crystalline form by weight. The weight percentage of a particular crystalline form is determined by dividing the weight of the particular crystalline form by the total weight of the particular crystalline form plus the weight of other crystalline forms present plus the weight of the amorphous form present times 100%.

[0052] The 2-θ values ​​of the X-ray powder diffraction patterns of the crystalline forms described herein may vary slightly from instrument to instrument, and also depend on differences in sample preparation and differences between batches. Therefore, unless otherwise defined, the XRPD patterns and / or 2-θ peaks described herein should not be interpreted as absolute and may vary by ±0.2 degrees. The 2-θ values ​​provided herein were obtained using Cu Kα1 radiation.

[0053] Temperature values ​​(e.g., DSC peak temperature and DSC onset temperature herein) may vary slightly from instrument to instrument and also depend on variations in sample preparation, the rate of temperature rise during the experiment, batch-to-batch variations in materials, and other environmental factors. Therefore, unless otherwise defined, the temperature values ​​stated herein should not be interpreted as absolute and may vary by ±5°.

[0054] By "substantially the same XRPD pattern" or "substantially similar X-ray powder diffraction pattern" as the defined figure is meant that, for comparison purposes, at least 90% of the displayed peaks are present. It should be further understood that, for comparison purposes, a certain variation in the 2-theta peak positions from the positions shown is allowed, for example, ±0.2 degrees. It should be understood that when the expression "X-ray powder diffraction peaks characterized by 2-theta angles (±0.2°)" is followed by a listing of 2-theta peak positions within ±0.2°, this applies to each peak position listed.

[0055] As described herein, 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., a non-crystalline or amorphous or partially crystalline Tris salt or Na salt of Compound 1) is an amount sufficient to provide a therapeutic benefit in the treatment of a disease or to delay or minimize one or more symptoms associated with the disease. 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 therapeutic agent or active agent, alone or in combination with other treatments, that provides a therapeutic benefit in the treatment of a disease. The terms "therapeutic agent" and "active agent" are used interchangeably. The term "therapeutically effective amount" may include an amount that improves overall treatment, reduces or avoids symptoms, signs or causes of a disease, and / or increases the therapeutic effect of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient to induce a therapeutic effect in the treatment of cancer (including solid tumors and hematological cancers, as further described herein), virally mediated diseases, transplant rejection, rheumatoid arthritis, psoriasis, autoimmune diseases, or inflammatory diseases. In certain embodiments, a therapeutically effective amount is an amount sufficient to induce a therapeutic effect in the treatment of cancer (including solid tumors and hematological cancers, as further described herein), virally mediated diseases, transplant rejection, rheumatoid arthritis, psoriasis, autoimmune diseases, or inflammatory diseases, wherein the disease is responsive to inhibition of dihydroorotate dehydrogenase (DHODH). In certain embodiments, a therapeutically effective amount is an amount sufficient to regulate DHODH levels, thereby improving overall treatment, reducing or avoiding symptoms, signs, or causes of the disease, and / or increasing the therapeutic effect of another therapeutic agent. The therapeutically effective amount of the compound is typically 0.1-100 mg / kg of body weight of the recipient (mammal) per day, in particular, typically 1-10 mg / kg of body weight per day. Therefore, the actual amount per day for an adult mammal weighing 70 kg is typically between 70-700 mg, wherein the amount can be administered as a single dose per day or typically in a series of partial doses per day (e.g., two, three, four, five, or six), so that the total daily dose is the same.

[0056] The terms "treatment method", "treatment" and "treatment" refer to reversing, alleviating, reducing the likelihood of developing or inhibiting the development of a disease or disorder or one or more symptoms thereof, as described herein. In some embodiments, treatment may be performed after the onset of one or more symptoms, i.e., therapeutic treatment. In other embodiments, treatment may be performed in the absence of symptoms. For example, susceptible individuals may be treated before symptoms develop (e.g., based on a history of symptoms and / or genetic or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms disappear, e.g., to reduce the likelihood of recurrence or delay recurrence.

[0057] As used herein, the terms "subject" and "patient" are used interchangeably and refer to mammals in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, 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 by inhibiting 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 human child no older than 18 years of age in need of treatment for a disease.

[0058] 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 formulated therewith and is safe for human use.

[0059] The term "pharmaceutically acceptable excipient" refers to one or more substances that facilitate administration of an active agent to a subject by, for example, altering the stability of the active drug or altering absorption by the subject after administration. Pharmaceutically acceptable excipients generally have no significant adverse toxicological effects on patients.

[0060] In this specification, "pharmaceutically acceptable salts" are pharmaceutically acceptable, organic or inorganic acid or base salts of the compounds described herein. Representative pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth metal 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, propionate lauryl sulfate, ethanesulfonate, fiunarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphate, iodide, isothiosulfate Pharmaceutically acceptable salts include, but are not limited to, succinate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine salt, 3-hydroxy-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methylene-di-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, toluenesulfonate, triethyl iodide (triethiodide) and valerate. Pharmaceutically acceptable salts may have more than one charged atom in their structure. In this case, pharmaceutically acceptable salts may have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0061] As used herein, the terms "about" and "approximately" when used in conjunction with a numerical value or numerical range used to characterize a specific crystalline form, amorphous form, or mixture thereof of a compound, mean that the numerical value or numerical range may deviate to a range that is reasonable to one of ordinary skill in the art when describing the specific crystalline form, amorphous form, or mixture thereof.

[0062] As used herein, "% w / w" refers to the percentage of the total weight used as the basis for calculating the weight percentage of a single component. For example, for a bulk composition, the % w / w of a single component can be calculated as a percentage of the total weight of all components of the bulk composition. As another example, for a single oral dosage form, the % w / w of a single component can be calculated as a percentage of the total weight of all components of the single oral dosage form. For example, when the single oral dosage form is a capsule, the total weight can be the total weight of all components of the capsule.

[0063] The term "intragranular excipients" refers to ingredients that are added to the formulation before granulation, ie, ingredients that are located inside the granular structure.

[0064] The term "extragranular excipients" refers to ingredients that are added after granulation, ie, outside the granule structure.

[0065] As used herein, the singular forms "a", "an" and "the" include the plural forms unless the context clearly dictates otherwise. For example, the term "an intragranular excipient" includes one or more intragranular excipients.

[0066] Compound

[0067] Tris(hydroxymethyl)aminomethane salt of compound 1

[0068] In a first embodiment, the present invention is directed to the tris(hydroxymethyl)aminomethane (tris) salt of a compound represented by the formula:

[0069]

[0070] 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.

[0071] In a third embodiment, the Tris salt according to the second embodiment is at least 60% single crystalline, at least 70% single crystalline, at least 80% single crystalline, at least 90% single crystalline, at least 95% single crystalline, or at least 99% single crystalline.

[0072] 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.

[0073] In a fifth embodiment, the Tris salt according to any one of the first, second, third and fourth embodiments is an anhydrate.

[0074] In a sixth embodiment, the Tris salt according to any one of the first, second, third, fourth and fifth embodiments is in Form A characterized by X-ray powder diffraction peaks at 2θ angles (±0.2°) of 4.4, 15.6 and 18.9.

[0075] In a seventh embodiment, the Tris salt according to any one of the first, second, third, fourth and fifth embodiments is in Form A, characterized by major X-ray powder diffraction peaks at 2θ angles (±0.2°) of 4.4°, 15.6° and 18.9°.

[0076] In an eighth embodiment, Form A according to any one of the sixth and seventh embodiments is further characterized by X-ray powder diffraction peaks at 2θ angles (±0.2°) of 11.5°, 16.4°, 19.6°, and 25.5°.

[0077] In a ninth embodiment, Form A according to any one of the sixth, seventh and eighth embodiments is further characterized by at least one X-ray powder diffraction peak at a 2θ angle (±0.2°) selected from 8.7°, 15.2°, 18.6°, 21.4° and 25.1°.

[0078] In a tenth embodiment, the crystalline form A according to any one of the sixth, seventh, eighth and ninth embodiments is characterized by Fig. 7A Basically similar X-ray powder diffraction patterns and Figure 7B XRPD peaks listed in .

[0079] In an eleventh embodiment, 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 of about 202.0°C ± 2°C (see Figure 7C ).

[0080] In a twelfth embodiment, Form A according to any one of the sixth, seventh, eighth, and ninth embodiments features a thermogravimetric analysis (TGA) thermogram comprising a weight loss of about 2.8% at up to about 150°C (see Figure 7C )

[0081] In a thirteenth embodiment, the Tris salt according to any one of the first, second, third, fourth and fifth embodiments is in Form B, characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 6.0°, 7.0° and 7.2°. In one embodiment, the X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 6.0°, 7.0° and 7.2° are major peaks.

[0082] In a fourteenth embodiment, Form B according to the thirteenth embodiment is further characterized by at least one X-ray powder diffraction peak at a 2θ angle (±0.2°) selected from 9.3° and 12.5°.

[0083] In a fifteenth embodiment, Form B according to any one of the thirteenth and fourteenth embodiments is further characterized by at least one X-ray powder diffraction peak at a 2θ angle (±0.2°) selected from 15.6° and 19.0°.

[0084] In a sixteenth embodiment, Form B according to any one of the thirteenth, fourteenth and fifteenth embodiments is characterized by being substantially similar to Fig. 8A The X-ray powder diffraction pattern of Figure 8B XRPD peaks listed in .

[0085] In a seventeenth embodiment, 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 of about 129.9°C ± 0.2° and an endothermic peak temperature of about 205.8°C ± 0.2° (see Figure 8C ).

[0086] In an eighteenth embodiment, 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 Figure 8C ).

[0087] In a nineteenth embodiment, the Tris salt according to any one of the first, second, third, fourth and fifth embodiments is in Form C, characterized by X-ray powder diffraction peaks at 2θ angles (±0.2°) of 4.5°, 13.5° and 18.0°.

[0088] In a twentieth embodiment, the Tris salt according to any one of the first, second, third, fourth and fifth embodiments is in Form C, characterized by major X-ray powder diffraction peaks at 2θ angles (±0.2°) of 4.5°, 13.5° and 18.0°.

[0089] In a twenty-first embodiment, Form C according to any one of the nineteenth and twentieth embodiments is further characterized by at least one X-ray powder diffraction peak at a 2θ angle (±0.2°) selected from 14.3°, 18.3°, and 23.5°.

[0090] In a twenty-second embodiment, Form C according to any one of the nineteenth, twentieth, and twenty-first 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°.

[0091] In a twenty-third embodiment, Form C according to any one of the nineteenth, twentieth, twenty-first and twenty-second embodiments is characterized by being substantially similar to Fig. 9A The X-ray powder diffraction pattern of Fig. 9B XRPD peaks listed in .

[0092] In a twenty-fourth embodiment, 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 of about 196.9°C ± 2°C (see Fig. 9C ).

[0093] In a twenty-fifth embodiment, 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 Fig. 9C ).

[0094] In a twenty-sixth embodiment, the invention relates to the sodium salt of the compound represented by the following formula:

[0095]

[0096] The sodium salt of Compound 1 is preferably a solid or a solid crystalline form.

[0097] In a twenty-seventh embodiment, the present invention relates to a crystalline form of a compound represented by the following formula:

[0098]

[0099] In a twenty-eighth embodiment, the crystalline form according to the twenty-seventh embodiment is an anhydrate.

[0100] In a twenty-ninth embodiment, the crystalline form according to the twenty-seventh embodiment is a solvate.

[0101] In the thirtieth embodiment, the crystalline form according to any one of the twenty-seventh and twenty-eighth embodiments is Form A characterized by X-ray powder diffraction peaks at 2θ angles (±0.2°) of 5.8°, 11.6°, and 12.8°.

[0102] In a thirty-first embodiment, the crystalline form according to any one of the twenty-seventh and twenty-eighth embodiments is Form A, characterized by major X-ray powder diffraction peaks at 2θ angles (±0.2°) of 5.8°, 11.6° and 12.8°.

[0103] In a thirty-second embodiment, Form A according to any one of the thirtieth and thirty-first embodiments is further characterized by X-ray powder diffraction peaks at 2θ angles (±0.2°) of 8.1° and 16.9°.

[0104] In a thirty-third embodiment, Form A according to any one of the thirtieth, thirty-first and thirty-second embodiments is further characterized by at least one X-ray powder diffraction peak at a 2θ angle (±0.2°) selected from 11.4°, 18.4°, 21.9°, 24.6°, 24.9° and 25.1°.

[0105] In a thirty-fourth embodiment, Form A according to any one of the thirtieth, thirty-first, thirty-second and thirty-third embodiments is characterized by being substantially similar to Figure 2A The X-ray powder diffraction pattern of Figure 2B XRPD peaks listed in .

[0106] In a thirty-fifth embodiment, Form A according to any one of the thirtieth, thirty-first, thirty-second, thirty-third, and thirty-fourth embodiments is characterized by a differential scanning calorimetry (DSC) thermogram comprising peak temperatures of about 212.1°C ± 2°C (exothermic) and 328.9°C ± 2°C (endothermic) (see Figure 2C ).

[0107] In a thirty-sixth embodiment, Form A according to any one of the thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, and thirty-fifth embodiments is characterized by a differential scanning calorimetry (DSC) thermogram comprising a weight loss of about 1.0% up to about 200 °C (see Figure 2C ).

[0108] In the thirty-seventh embodiment, the crystalline form according to any one of the twenty-seventh and twenty-eighth embodiments is Form B characterized by X-ray powder diffraction peaks at 2θ angles (±0.2°) of 6.5°, 12.9°, and 25.1°.

[0109] In a thirty-eighth embodiment, the crystalline form according to any one of the twenty-seventh and twenty-eighth embodiments is Form B, characterized by major X-ray powder diffraction peaks at 2θ angles (±0.2°) of 6.5°, 12.9°, and 25.1°.

[0110] In a thirty-ninth embodiment, Form B according to any one of the thirty-seventh and thirty-eighth embodiments is further characterized by X-ray powder diffraction peaks at 2θ angles (±0.2°) of 13.1° and 15.7°.

[0111] In the 40th embodiment, Form B according to any one of the 37th, 38th and 39th embodiments is further characterized by at least one X-ray powder 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°.

[0112] In the forty-first embodiment, Form B according to any one of the thirty-seventh, thirty-eighth, thirty-ninth and fortieth embodiments is characterized by being substantially similar to Figure 3A The X-ray powder diffraction pattern of Figure 3B XRPD peaks listed in .

[0113] In the forty-second embodiment, Form B according to any one of the thirty-seventh, thirty-eighth, thirty-ninth, fortieth and forty-first embodiments is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak temperature of about 325.6°C ± 2°C (see Figure 3C ).

[0114] In the forty-third embodiment, Form B according to any one of the thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first and forty-second embodiments is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of about 2.9% up to about 200 ° C (see Figure 3C ).

[0115] In the forty-fourth embodiment, the crystalline form according to any one of the twenty-seventh and twenty-eighth embodiments is Form C, characterized by X-ray powder diffraction peaks at 2θ angles (±0.2°) of 5.7°, 11.4°, and 25.0°.

[0116] In the forty-fifth embodiment, the crystalline form according to any one of the twenty-seventh, twenty-eighth and twenty-ninth embodiments is Form C, characterized by major X-ray powder diffraction peaks at 2θ angles (±0.2°) of 5.7°, 11.4° and 25.0°.

[0117] In the forty-sixth embodiment, Form C according to any one of the forty-fourth and forty-fifth embodiments is further characterized by X-ray powder diffraction peaks at 2θ angles (±0.2°) of 3.2°, 17.4°, and 18.4°.

[0118] In the forty-seventh embodiment, Form C according to any one of the forty-fourth, forty-fifth and forty-sixth embodiments is further characterized by at least one X-ray powder diffraction peak at a 2θ angle (±0.2°) selected from 12.8°, 16.2°, 19.0°, 27.5° and 31.7°.

[0119] In the forty-eighth embodiment, Form C according to any one of the forty-fourth, forty-fifth, forty-sixth and forty-seventh embodiments is characterized by being substantially similar to Figure 4A The X-ray powder diffraction pattern of Figure 4B XRPD peaks listed in .

[0120] In the forty-ninth embodiment, Form C according to any one of the forty-fourth, forty-fifth, forty-sixth, forty-seventh and forty-eighth embodiments is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak temperature of about 326.1°C ± 2°C (see Figure 4C ).

[0121] In a fiftieth embodiment, Form C according to any one of the forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty-eighth and forty-ninth embodiments is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of about 3.6% up to about 200 °C (see Figure 4C ).

[0122] In a fifty-first embodiment, the crystalline form according to any one of the twenty-seventh and twenty-eighth embodiments is Form D, characterized by X-ray powder diffraction peaks at 2θ angles (±0.2°) of 5.9°, 11.9°, and 17.1°.

[0123] In the fifty-second embodiment, the crystalline form according to any one of the twenty-seventh, twenty-eighth and twenty-ninth embodiments is Form D, characterized by major X-ray powder diffraction peaks at 2θ angles (±0.2°) of 5.9°, 11.9° and 17.1°.

[0124] In the fifty-third embodiment, Form D according to any one of the fifty-first and fifty-second embodiments is further characterized by X-ray powder diffraction peaks at 2θ angles (±0.2°) of 11.2° and 23.3°.

[0125] In the fifty-fourth embodiment, Form D according to any one of the fifty-first, fifty-second, and fifty-third embodiments is further characterized by at least one X-ray powder 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°.

[0126] In a fifty-fifth embodiment, Form D according to any one of the fifty-first, fifty-second, fifty-third and fifty-fourth embodiments is characterized by being substantially similar to Figure 5A X-ray powder diffraction patterns and Figure 5B XRPD peaks listed in .

[0127] In the fifty-sixth embodiment, Form D according to any one of the fifty-first, fifty-second, fifty-third, fifty-fourth and fifty-fifth embodiments is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak temperature of about 329.4°C ± 2°C (see Figure 5C ).

[0128] In a fifty-seventh embodiment, Form D according to any one of the fifty-first, fifty-second, fifty-third, fifty-fourth, fifty-fifth, and fifty-sixth 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 ).

[0129] In a fifty-eighth embodiment, the crystalline form according to any one of embodiments twenty-seven to fifty-seven is at least 60% single crystalline, at least 70% single crystalline, at least 80% single crystalline, at least 90% single crystalline, at least 95% single crystalline, or at least 99% single crystalline (by weight).

[0130] In a fifty-ninth embodiment, the crystalline form according to any one of embodiments twenty-seven to fifty-eight 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.

[0131] Another embodiment of the present invention is Compound 1 or a Tris salt of Compound 1 in amorphous form.

[0132] Composition and administration

[0133] The present invention provides a pharmaceutical composition comprising: i) a Tris salt of Compound 1, such as an amorphous form of a Tris salt or one of the disclosed crystalline forms; or ii) one of the disclosed crystalline forms of Compound 1; or iii) an amorphous form of Compound 1; or iv) a 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: i) a Tris salt of Compound 1, such as an amorphous form of a Tris salt or one of the disclosed crystalline forms; or ii) one of the disclosed crystalline forms of Compound 1; or iii) an amorphous form of Compound 1; or iv) a sodium salt of Compound 1; or v) a pharmaceutically acceptable salt of Compound 1 as an active agent; and one or more intragranular excipients. Also provided are pharmaceutical compositions comprising: i) a Tris salt of Compound 1, such as an amorphous form of a Tris salt or one of the disclosed crystalline forms; or ii) one of the disclosed crystalline forms of Compound 1; or iii) an amorphous form of Compound 1; or iv) a sodium salt of Compound 1; or v) a pharmaceutically acceptable salt of Compound 1 as an active agent, and one or more intragranular excipients and one or more extragranular excipients. Also provided are compositions comprising: i) a Tris salt of Compound 1, such as an amorphous form of a Tris salt or one of the disclosed crystalline forms; or ii) one of the disclosed crystalline forms of Compound 1; or iii) an amorphous form of Compound 1; 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 other embodiments, such compositions comprise a partially crystalline solid dispersion. In other embodiments, such compositions comprise a substantially crystalline solid dispersion. Also provided are pharmaceutical compositions comprising: i) a Tris salt of Compound 1, such as an amorphous form of a Tris salt or one of the disclosed crystalline forms; or ii) one of the disclosed crystalline forms of Compound 1; or iii) an amorphous form of Compound 1; or iv) a sodium salt of Compound 1 or v) a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers as part of a solid dispersion. Suitable pharmaceutical compositions are described in U.S. Pat. Nos. 9,360,932 et seq.

[0134] The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, transmucosally or in ophthalmic preparations. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In one aspect, the pharmaceutical compositions provided by the invention are administered orally in an orally acceptable dosage form, including but not limited to capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.

[0135] The amount of the crystalline or amorphous form provided that can be combined with a carrier material to produce a single dosage form of the composition will vary according to the subject to be treated and the specific mode of administration. For example, the specific dose and treatment regimen for any particular subject will depend on a variety of factors, including age, weight, general health, sex, diet, administration time, excretion rate, drug combination, judgment of the treating physician, and the severity of the specific disease being treated. The amount of the crystalline form provided in the composition also depends on the specific form in the composition (e.g., Form A, B, C, D of the crystalline form of Compound 1 or Form A, B, C of the crystalline form of the Tris salt of Compound 1). In one aspect, the composition provided can be formulated into a dose equivalent of about 0.001 to about 100 mg / kg body weight / day of Compound 1.

[0136] 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 a composition, Compound 1 may be provided as, for example: i) one of the disclosed crystalline forms of Compound 1; or ii) an amorphous form of Compound 1, or iii) a mixture thereof. In other embodiments of such a composition, Compound 1 may be provided as a Tris salt of Compound 1, for example: i) an amorphous form; or a disclosed crystalline form of a Tris salt, or iii) a mixture thereof. In other embodiments of such a pharmaceutical composition, Compound 1 may be provided in a non-salt form, a Tris salt form, or a mixture thereof. In one aspect, the pharmaceutical composition is in the form of a capsule. In another aspect, the pharmaceutical composition is in the form of a tablet.

[0137] In certain embodiments, the pharmaceutical composition is a capsule composition comprising a crystalline form of Compound 1 as an active agent and one or more intragranular excipients. In one embodiment, the capsule composition comprises Form A of Compound 1 as an active agent and one or more intragranular excipients. In one embodiment, the capsule composition comprises Form B of Compound 1 as an active agent and one or more intragranular excipients. In one embodiment, the capsule composition comprises Form C of Compound 1 as an active agent and one or more intragranular excipients. In one embodiment, the capsule composition comprises Form D of Compound 1 as an active agent and one or more intragranular excipients.

[0138] In certain embodiments, the pharmaceutical composition is a capsule composition comprising a crystalline form of Compound 1 as an 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 an 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 an 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 an 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 an active agent, one or more intragranular excipients, and one or more extragranular excipients.

[0139] 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. In one embodiment, the active agent used in the capsule composition is one of the disclosed crystalline forms of the Tris salt of Compound 1. In one embodiment, the capsule composition comprises Tris salt Form A as an active agent and one or more intragranular excipients. In one embodiment, the capsule composition comprises Tris salt Form B as an active agent and one or more intragranular excipients. In one embodiment, the capsule composition comprises Tris salt Form C as an active agent and one or more intragranular excipients.

[0140] In certain embodiments, the pharmaceutical composition is a capsule composition comprising a Tris salt of Compound 1 as an 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 one of the disclosed crystalline forms of the Tris salt of Compound 1. In one embodiment, the capsule composition comprises Tris salt Form A as an active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the capsule composition comprises Tris salt Form B as an active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the capsule composition comprises Tris salt Form C as an active agent, one or more intragranular excipients, and one or more extragranular excipients.

[0141] In certain embodiments, the pharmaceutical composition is a capsule composition comprising a sodium salt of Compound 1 as an active agent and one or more intragranular excipients. In certain embodiments, the pharmaceutical composition is a capsule composition comprising a sodium salt of Compound 1 as an active agent, one or more intragranular excipients, and one or more extragranular excipients.

[0142] In certain embodiments, the pharmaceutical composition is a tablet composition comprising a crystalline form of Compound 1 as an active agent and one or more intragranular excipients. In one embodiment, the tablet composition comprises Form A of Compound 1 as an active agent and one or more intragranular excipients. In one embodiment, the tablet composition comprises Form B of Compound 1 as an active agent and one or more intragranular excipients. In one embodiment, the tablet composition comprises Form C of Compound 1 as an active agent and one or more intragranular excipients. In one embodiment, the tablet composition comprises Form D of Compound 1 as an active agent and one or more intragranular excipients.

[0143] In certain embodiments, the pharmaceutical composition is a tablet composition comprising a crystalline form of Compound 1 as an 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 an 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 an 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 an 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 an active agent, one or more intragranular excipients, and one or more extragranular excipients.

[0144] In certain embodiments, the pharmaceutical composition is a tablet composition comprising a Tris salt of Compound 1 as an active agent and one or more intragranular excipients. In one embodiment, the active agent used in the tablet composition is one of the disclosed crystalline forms of the Tris salt of Compound 1. In one embodiment, the tablet composition comprises Tris salt Form A as an active agent and one or more intragranular excipients. In one embodiment, the tablet composition comprises Tris salt Form B as an active agent and one or more intragranular excipients. In one embodiment, the tablet composition comprises Tris salt Form C as an active agent and one or more intragranular excipients.

[0145] In certain embodiments, the pharmaceutical composition is a tablet composition comprising a Tris salt of Compound 1 as an 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 one of the disclosed crystalline forms of the Tris salt of Compound 1. In one embodiment, the tablet composition comprises Tris salt Form A as an active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the tablet composition comprises Tris salt Form B as an active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the tablet composition comprises Tris salt Form C as an active agent, one or more intragranular excipients, and one or more extragranular excipients.

[0146] In certain embodiments, the pharmaceutical composition is a tablet composition comprising a sodium salt of Compound 1 as an active agent, and one or more intragranular excipients. In certain embodiments, the pharmaceutical composition is a tablet composition comprising a sodium salt of Compound 1 as an active agent, one or more intragranular excipients, and one or more extragranular excipients.

[0147] In certain embodiments, the pharmaceutical compositions provided herein contain Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 10 wt % to about 90 wt % (e.g., about 20% w / w to about 80% w / w; about 30% w / w to about 70% w / w; about 40% w / w to about 60% w / w; or about 10% to 20% w / w), based on the total weight of the pharmaceutical composition.

[0148] In certain embodiments, the pharmaceutical compositions provided herein comprise about 15% to about 65% by weight based on the total weight of the pharmaceutical composition; about 45% to about 65% by weight; or about 15% to about 17% by weight of Compound 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, based on the total weight of the pharmaceutical composition, the pharmaceutical compositions provided herein comprise about 16%, about 45%, about 54% or about 60% by weight of Compound 1 or a Tris salt of Compound 1. In certain embodiments, based on the total weight of the pharmaceutical composition, the pharmaceutical compositions provided herein comprise 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 of Compound 1 or a Tris salt of Compound 1. In certain embodiments, the Tris salt of Compound 1 is Tris Salt Form C.

[0149] In certain embodiments, the pharmaceutical compositions provided herein may include one or more intragranular excipients and one or more extragranular excipients. In certain embodiments, intragranular excipients include diluents, disintegrants, binders, surfactants, glidants and lubricants. In certain embodiments, intragranular excipients include diluents, disintegrants, binders, surfactants and lubricants. In certain embodiments, intragranular excipients include diluents, disintegrants, binders, glidants and lubricants. In certain embodiments, intragranular excipients include diluents, disintegrants, binders and lubricants. In certain embodiments, intragranular excipients include diluents, disintegrants, binders and lubricants. In certain embodiments, intragranular excipients include diluents, disintegrants and lubricants. In certain embodiments, extragranular excipients include glidants and lubricants. In certain embodiments, extragranular excipients include glidants. In certain embodiments, extragranular excipients include lubricants. In certain embodiments, extragranular excipients are not used. In other embodiments, intragranular or extragranular excipients are not used.

[0150] 1. Intragranular excipients

[0151] In one embodiment, the pharmaceutical compositions provided herein comprise one or more intragranular excipients selected from the group consisting of diluents, disintegrants, binders, surfactants, glidants, and lubricants.

[0152] Diluent is an excipient used for pharmaceutical preparations in various amounts, which helps to increase weight, and helps fluidity, solubility, content uniformity, encapsulation, compressibility, reduce viscosity and impart stability. It should be understood that unless clearly stated to the contrary, the terms diluent, filler or extender used herein can be 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, icing 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 partially pregelatinized starch.

[0153] In certain embodiments, the pharmaceutical composition comprises a diluent (or one or more diluents) in an amount of about 5 to about 80 weight % based on the total weight of the pharmaceutical composition (e.g., about 10% w / w to about 75% w / w; about 15% w / w to about 70% w / w; about 25% w / w to about 65% w / w; about 30% w / w to about 60% w / w; about 35% w / w to about 55% w / w; about 40% w / w to about 50% w / w). In certain embodiments, the pharmaceutical composition comprises a diluent (or one or more diluents) in an amount of about 5% to about 15%; about 5% to about 45%; about 25% to about 45%; 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%, about 6%, about 8%, about 9%, about 10%, about 11%, 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% based on the total weight of the pharmaceutical composition.

[0154] 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, for example, about 5% to about 15%, about 20% to about 40%, 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 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 based on the total weight of the pharmaceutical composition.

[0155] 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, for example, about 5% to about 15%, about 20% to about 40%, or about 20% to about 80% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises mannitol 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 based on the total weight of the pharmaceutical composition.

[0156] In certain embodiments, the pharmaceutical composition comprises starch in an amount of about 5 wt % to about 80 wt % based on the total weight of the pharmaceutical composition, e.g., about 5 wt % to about 15 wt %, about 20 wt % to about 40 wt %, or about 20 wt % to about 80 wt % 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 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 based on the total weight of the pharmaceutical composition.

[0157] In certain embodiments, the pharmaceutical composition comprises partially pregelatinized starch in an amount of about 5 wt % to about 80 wt % based on the total weight of the pharmaceutical composition, e.g., about 5 wt % to about 15 wt %, about 20 wt % to about 40 wt % or about 20 wt % to about 80 wt % based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises 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%, 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 based on the total weight of the pharmaceutical composition.

[0158] Disintegrants are excipients for improving the disintegration of pharmaceutical preparations, more specifically, they are excipients added to disintegrate capsules or tablets by absorbing body fluids, swelling and thereby promoting the release of active ingredients after administration. 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 the desired range. In certain embodiments, the amount of disintegrant in the capsule or tablet is about 10% by weight or less of the total weight of the capsule or tablet.

[0159] Exemplary disintegrants include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked polyvinyl pyrrolidone (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methyl cellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof. In one embodiment, the disintegrant includes cross-linked polyvinyl pyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, and mixtures thereof. In one embodiment, the disintegrant is cross-linked polyvinyl pyrrolidone. In one embodiment, the disintegrant is sodium starch glycolate. In one embodiment, the disintegrant is cross-linked sodium carboxymethyl cellulose.

[0160] In certain embodiments, the amount of disintegrant in the pharmaceutical composition is about 0.5% to about 8%, for example, about 0.5% to about 5% or about 2% to about 5% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the amount of disintegrant in the pharmaceutical composition is about 2% to about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the amount of disintegrant in the pharmaceutical composition is about 3% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the amount of disintegrant in the pharmaceutical composition is about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the amount of disintegrant in the pharmaceutical composition is about 5% by weight, based on the total weight of the pharmaceutical composition.

[0161] In certain embodiments, the pharmaceutical composition comprises about 0.5% to about 8% by weight of cross-linked polyvinylpyrrolidone, e.g., 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 about 2% to about 4% by weight of cross-linked polyvinylpyrrolidone, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 3% by weight of cross-linked polyvinylpyrrolidone, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 4% by weight of cross-linked polyvinylpyrrolidone, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 5% by weight of cross-linked polyvinylpyrrolidone, based on the total weight of the pharmaceutical composition.

[0162] In certain embodiments, the pharmaceutical composition comprises from about 0.5% to about 8% by weight of sodium starch glycolate, e.g., from about 0.5% to about 5% by weight or from about 2% to about 5% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises from about 2% to about 4% by weight of sodium starch glycolate, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 3% by weight of sodium starch glycolate, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 4% by weight of sodium starch glycolate, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 5% by weight of sodium starch glycolate, based on the total weight of the pharmaceutical composition.

[0163] In certain embodiments, the pharmaceutical composition comprises about 0.5% to about 8% by weight of cross-linked sodium carboxymethylcellulose, e.g., 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 about 2% to about 4% by weight of cross-linked sodium carboxymethylcellulose, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 3% by weight of cross-linked sodium carboxymethylcellulose, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 4% by weight of cross-linked sodium carboxymethylcellulose, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 5% by weight of cross-linked sodium carboxymethylcellulose, based on the total weight of the pharmaceutical composition.

[0164] Binders are classified as excipients that impart the cohesiveness required for the manufacturability of solid oral dosage forms. The amount of binder in a tablet or capsule provided herein varies based on, for example, the type of binder (properties such as molecular weight, solubility, and viscosity), the type and amount of other excipients, the type and amount of the complex, and its dosage form and formulation (granulation method and tableting method).

[0165] Exemplary binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose 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 hydroxypropyl methylcellulose, povidone, methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone / vinyl acetate (PVPVA), hydroxypropyl methylcellulose acetate succinate (HPMCAS) and mixtures thereof. In one embodiment, the binder includes hydroxypropyl methylcellulose. 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 polyvinyl pyrrolidone / vinyl acetate (PVPVA). In one embodiment, the binder includes hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0166] In certain embodiments, based on the gross weight of the pharmaceutical composition, the pharmaceutical composition comprises an adhesive of an amount of about 0.5 % by weight to about 10 % by weight. In certain embodiments, based on the gross weight of the pharmaceutical composition, the pharmaceutical composition comprises an adhesive of an amount of about 0.5 % by weight to about 5 % by weight, about 2 % by weight to about 8 % by weight, or about 2 % by weight to about 5 % by weight. In certain embodiments, based on the gross weight of the pharmaceutical composition, the pharmaceutical composition comprises an adhesive of 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.

[0167] In certain embodiments, based on the total weight of the pharmaceutical composition, the pharmaceutical composition comprises about 0.5% by weight to about 10% by weight of hypromellose. In certain embodiments, based on the total weight of the pharmaceutical composition, the pharmaceutical composition comprises about 0.5% by weight to about 5% by weight, about 2% by weight to about 8% by weight, or about 2% by weight to about 5% by weight of hypromellose. In certain embodiments, based on the total weight of the pharmaceutical composition, the pharmaceutical composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% by weight of hypromellose.

[0168] In certain embodiments, based on the gross weight of the pharmaceutical composition, the pharmaceutical composition comprises the povidone of about 0.5 wt % to about 10 wt %. In certain embodiments, based on the gross weight of the pharmaceutical composition, the pharmaceutical composition comprises the povidone of about 0.5 wt % to about 5 wt %, about 2 wt % to about 8 wt % or about 2 wt % to about 5 wt %. In certain embodiments, based on the gross weight of the pharmaceutical composition, the pharmaceutical composition comprises the povidone of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% weight.

[0169] In certain embodiments, based on the gross weight of the pharmaceutical composition, the pharmaceutical composition comprises about 0.5% by weight to about 10% by weight of methylcellulose. In certain embodiments, based on the gross weight of the pharmaceutical composition, the pharmaceutical composition comprises about 0.5% by weight to about 5% by weight, about 2% by weight to about 8% by weight, or about 2% by weight to about 5% by weight of methylcellulose. In certain embodiments, based on the gross weight of the pharmaceutical composition, the pharmaceutical composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% by weight of methylcellulose.

[0170] In certain embodiments, based on the gross weight of the pharmaceutical composition, the pharmaceutical composition comprises about 0.5% by weight to about 10% by weight of hydroxypropyl cellulose. In certain embodiments, based on the gross weight of the pharmaceutical composition, the pharmaceutical composition comprises about 0.5% by weight to about 5% by weight, about 2% by weight to about 8% by weight, or about 2% by weight to about 5% by weight of hydroxypropyl cellulose. In certain embodiments, based on the gross weight of the pharmaceutical composition, the pharmaceutical composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% by weight of hydroxypropyl cellulose.

[0171] In certain embodiments, the pharmaceutical composition comprises polyvinyl pyrrolidone / vinyl acetate (PVPVA) in an amount of about 0.5% by weight to about 10% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises PVPVA in an amount of about 0.5% by weight to about 5% by weight, about 2% by weight to about 8% by weight, or about 2% by weight to about 5% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises PVPVA 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.

[0172] In certain embodiments, based on the total weight of the pharmaceutical composition, the pharmaceutical composition comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS) in an amount of about 0.5% by weight to about 10% by weight. In certain embodiments, based on the total weight of the pharmaceutical composition, the pharmaceutical composition comprises HPMCAS in an amount of about 0.5% by weight to about 5% by weight, about 2% by weight to about 8% by weight, or about 2% by weight to about 5% by weight. In certain embodiments, based on the total weight of the pharmaceutical composition, 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.

[0173] In some embodiments, the pharmaceutical composition further comprises a glidant, which is an excipient used in solid oral dosage forms to improve the flowability of the powder. 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.

[0174] 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 the 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 the 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.

[0175] In certain embodiments, the pharmaceutical composition comprises colloidal silicon dioxide in an amount of about 0.1% to about 2% by weight, about 0.1% to about 1%, 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 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.

[0176] In certain embodiments, the pharmaceutical composition comprises starch 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 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.

[0177] In certain embodiments, the pharmaceutical composition comprises 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 of talc based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises talc in an amount of about 0.5%, about 0.75%, about 1%, or about 1.5% by weight in the intragranular excipient based on the total weight of the pharmaceutical composition.

[0178] In some embodiments, the pharmaceutical composition also includes a lubricant, which is an excipient that reduces intergranular friction and adhesion / adhesion to tablet punches and molds. Exemplary lubricants include magnesium stearate (vegetable grade), calcium stearate, zinc stearate, sucrose stearate, stearic acid, silicon dioxide, talcum, maltose (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, magnesium lauryl sulfate and mixtures thereof. In certain embodiments, lubricants are sodium stearyl fumarate, magnesium stearate, talcum, silicon dioxide, stearic acid and glyceryl behenate. In one embodiment, lubricant is sodium stearyl fumarate. In one embodiment, lubricant is magnesium stearate. In one embodiment, lubricant is talcum. In one embodiment, lubricant is silicon dioxide. In one embodiment, lubricant is stearic acid. In one embodiment, the lubricant is glyceryl behenate.

[0179] 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 the 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 the 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.

[0180] In certain embodiments, the pharmaceutical composition comprises sodium stearyl fumarate in an amount of about 0.25% to about 3% based on the total weight of the pharmaceutical composition; about 0.5% to about 2%; or about 0.75% to about 1.5% by weight. 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.

[0181] In certain embodiments, the pharmaceutical composition comprises magnesium stearate in an amount of about 0.25% to about 3% by weight; 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 pharmaceutical composition comprises about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75% or about 2% by weight of magnesium stearate, based on the total weight of the pharmaceutical composition.

[0182] In certain embodiments, the pharmaceutical composition comprises talc in an amount of about 0.25% to about 3% by weight, 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 pharmaceutical composition comprises talc 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.

[0183] In certain embodiments, the pharmaceutical composition comprises silicon dioxide in an amount of about 0.25% to about 3% by weight, 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 pharmaceutical composition comprises silicon dioxide 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.

[0184] In certain embodiments, the pharmaceutical composition comprises stearic acid in an amount of about 0.25% to about 3% by weight, 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 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.

[0185] In certain embodiments, the pharmaceutical composition comprises glyceryl behenate in an amount of about 0.25% to about 3% by weight; 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 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.

[0186] Surfactant or wetting agent is to improve the excipient of wetting property and contribute to active agent solubilization.Exemplary surfactant and wetting agent include sodium lauryl sulfate (SLS), vitamin E or its derivatives (such as vitamin E TPGS), docusate sodium, sodium lauryl sulfate, polysorbate (such as Tween 20 and Tween 80), poloxamer (such as poloxamer 335 and poloxamer 407), glyceryl monooleate, Span 65, Span 25, Capryol90, Pluronic copolymer (such as Pluronic F108, Pluronic P-123) and mixture thereof.In some embodiments, surfactant is sodium lauryl sulfate, poloxamer, Pluronic copolymer and polysorbate.In one embodiment, surfactant is sodium lauryl sulfate.In one embodiment, surfactant is poloxamer.In one embodiment, surfactant is Pluronic copolymer.In one embodiment, surfactant is polysorbate.

[0187] In certain embodiments, the surfactant is present in an amount of about 0.1% by weight to about 3% by weight based on the total weight of the pharmaceutical composition. In one embodiment, the amount of the surfactant is about 0.5% by weight to about 1.5% by weight or about 1% by weight 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.

[0188] In certain embodiments, the pharmaceutical composition comprises sodium lauryl sulfate in an amount of about 0.1 wt % to about 3 wt %, 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 wt % to about 1.5 wt % or about 1 wt % to about 2 wt %, 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 wt %, about 1 wt %, about 1.5 wt %, or about 2 wt %, based on the total weight of the pharmaceutical composition.

[0189] In certain embodiments, the pharmaceutical composition comprises from about 0.1% to about 3% by weight of the poloxamer, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises from about 0.5% to about 1.5% by weight or from about 1% to about 2% by weight of the poloxamer, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises from about 0.5%, about 1%, about 1.5%, or about 2% by weight of the poloxamer, based on the total weight of the pharmaceutical composition.

[0190] In certain embodiments, the pharmaceutical composition comprises a Pluronic copolymer in an amount of about 0.1 wt % to about 3 wt %, based on the gross weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises a Pluronic copolymer in an amount of about 0.5 wt % to about 1.5 wt % or about 1 wt % to about 2 wt %, based on the gross weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a Pluronic copolymer in an amount of about 0.5 wt %, about 1 wt %, about 1.5 wt %, or about 2 wt %, based on the gross weight of the pharmaceutical composition.

[0191] In certain embodiments, the pharmaceutical composition comprises polysorbate in an amount of about 0.1 wt % to about 3 wt % based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises polysorbate in an amount of about 0.5 wt % to about 1.5 wt % or about 1 wt % to about 2 wt % based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises polysorbate in an amount of about 0.5 wt %, about 1 wt %, about 1.5 wt % or about 2 wt % based on the total weight of the pharmaceutical composition.

[0192] The pharmaceutical compositions provided herein may also contain one or more additional pharmaceutically acceptable intragranular excipients in addition to the above excipients. Examples of these additional excipients include, but are not limited to, solubility enhancers, stabilizers, pH adjusters, coating agents and pigments.

[0193] In certain embodiments, the pharmaceutical compositions provided herein are in the form of tablets, and may include a coating agent, such as polyvinyl alcohol.

[0194] In certain embodiments, the pharmaceutical compositions provided herein are in tablet form and may contain a pigment, such as titanium dioxide.

[0195] 2. Extragranular excipients

[0196] In certain embodiments, the pharmaceutical compositions provided herein comprise one or more extragranular excipients selected from glidants and lubricants.

[0197] 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.

[0198] 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 the glidant in the extragranular excipient is 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 amount of the 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.

[0199] In certain embodiments, the pharmaceutical composition comprises colloidal silicon dioxide 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 the extragranular excipient. In one embodiment, the pharmaceutical composition comprises colloidal silicon dioxide in an amount of about 0.5%, about 0.75%, or about 1% by weight based on the total weight of the pharmaceutical composition in the extragranular excipient.

[0200] In certain embodiments, the pharmaceutical composition comprises starch 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 the extragranular excipient. In one embodiment, the pharmaceutical composition comprises starch in an amount of about 0.5%, about 0.75%, or about 1% by weight based on the total weight of the pharmaceutical composition in the extragranular excipient.

[0201] In certain embodiments, the pharmaceutical composition comprises talc 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 the extragranular excipient. In one embodiment, the pharmaceutical composition comprises talc in an amount of about 0.5%, about 0.75%, or about 1% by weight based on the total weight of the pharmaceutical composition in the extragranular excipient.

[0202] In certain embodiments, the lubricant used in the extragranular excipient is sodium stearyl fumarate, magnesium stearate, talc, silicon dioxide, 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 silicon dioxide. In one embodiment, the lubricant is stearic acid. In one embodiment, the lubricant is glyceryl behenate.

[0203] In certain embodiments, the lubricant is present in the extragranular excipient in an amount of about 0.25 wt % to about 1.5 wt % based on the total weight of the pharmaceutical composition. In 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 wt % based on the total weight of the pharmaceutical composition.

[0204] In certain embodiments, the pharmaceutical composition comprises sodium stearyl fumarate in an amount of about 0.25 wt % to about 1.5 wt % in the extragranular excipients, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises sodium stearyl fumarate in an intragranular excipient at about 0.5 wt %, about 0.75 wt %, about 1 wt %, about 1.25 wt % or about 1.5 wt % based on the total weight of the pharmaceutical composition.

[0205] In certain embodiments, the pharmaceutical composition comprises magnesium stearate in an amount of about 0.25% by weight to about 1.5% by weight in the extragranular excipients, 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 in the extragranular excipients, based on the total weight of the pharmaceutical composition.

[0206] In certain embodiments, the pharmaceutical composition comprises talc in an amount of about 0.25% to about 1.5% by weight in the extragranular excipients, 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 1.25%, about 1.5%, about 1.75% or about 2% by weight in the extragranular excipients, based on the total weight of the pharmaceutical composition.

[0207] In certain embodiments, the pharmaceutical composition comprises silicon dioxide in an amount of about 0.25% by weight to about 1.5% by weight in the extragranular excipients, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises silicon dioxide 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 in the extragranular excipients, based on the total weight of the pharmaceutical composition.

[0208] In certain embodiments, the pharmaceutical composition comprises stearic acid in an amount of about 0.25% by weight to about 1.5% by weight in the extragranular excipients, 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 in the extragranular excipients, based on the total weight of the pharmaceutical composition.

[0209] In certain embodiments, the pharmaceutical composition comprises glyceryl behenate in an amount of about 0.25 wt % to about 1.5 wt % in the extragranular excipients, based on the total weight of the pharmaceutical composition. In 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 in the extragranular excipients, based on the total weight of the pharmaceutical composition.

[0210] The pharmaceutical compositions provided herein may contain various extragranular excipients in addition to the above excipients, which are pharmaceutically acceptable and used as excipients. Examples of other excipients include, but are not limited to, diluents, disintegrants, colorants, coating agents, and flavoring agents.

[0211] 3. Pharmaceutical Composition

[0212] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof comprises about 10% w / w to about 20% w / w of the pharmaceutical composition, the diluent comprises about 76.5% w / w to about 83% w / w of the pharmaceutical composition, the disintegrant comprises about 3% w / w to about 5% w / w of the pharmaceutical composition, and the lubricant comprises about 0.5% w / w to 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.

[0213] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof comprises about 48% w / w to about 60% w / w of the pharmaceutical composition, the diluent comprises about 37.5% w / w to about 44% w / w of the pharmaceutical composition, the disintegrant comprises about 2% w / w to about 6% w / w of the pharmaceutical composition, and the lubricant comprises about 0.5% w / w to 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.

[0214] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof comprises about 36% w / w to about 54% w / w of the pharmaceutical composition, the diluent comprises about 40.5% w / w to about 45% w / w of the pharmaceutical composition, the disintegrant comprises about 2% w / w to about 4% w / w of the pharmaceutical composition, the binder comprises about 2% w / w to about 8% w / w of the pharmaceutical composition, the surfactant comprises about 0.5% w / w to about 3% w / w of the pharmaceutical composition, the glidant comprises about 0.5% w / w to about 2.0% w / w of the pharmaceutical composition, and the lubricant comprises about 0.5% w / w to about 2.0% w / w of the pharmaceutical composition, thereby totaling 100% by weight of the composition. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a Tris salt.

[0215] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof comprises about 42% w / w to about 63% w / w of the pharmaceutical composition, the diluent comprises about 32.5% w / w to about 38% w / w of the pharmaceutical composition, the disintegrant comprises about 2% w / w to about 4% w / w of the pharmaceutical composition, the binder comprises about 2% w / w to about 8% w / w of the pharmaceutical composition, the surfactant comprises about 0% w / w to about 2% w / w of the pharmaceutical composition, the glidant comprises about 0% w / w to about 3% w / w of the pharmaceutical composition, and the lubricant comprises about 0.5% w / w to about 3.0% w / w of the pharmaceutical composition, thereby totaling 100% by weight of the composition. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a Tris salt.

[0216] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof comprises about 47% w / w to about 70% w / w of the pharmaceutical composition, the diluent comprises about 26.5% w / w to about 32% w / w of the pharmaceutical composition, the disintegrant comprises about 2% w / w to about 4% w / w of the pharmaceutical composition, the binder comprises about 1% w / w to about 9% w / w of the pharmaceutical composition, the surfactant comprises about 0% w / w to about 2% w / w of the pharmaceutical composition, the glidant comprises about 0% w / w to about 3% w / w of the pharmaceutical composition, and the lubricant comprises about 0.5% w / w to about 3.0% w / w of the pharmaceutical composition, thereby totaling 100% by weight of the composition. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a Tris salt.

[0217] 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 an additional amount of a glidant and a lubricant.

[0218] In some embodiments, the intragranular part 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 part of the pharmaceutical composition of the present application comprises an additional amount of a lubricant.

[0219] 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, the pharmaceutical composition does not have an extragranular portion.

[0220] In some embodiments, the intragranular portion of the pharmaceutical composition of the present application comprises: Compound 1 or a Tris salt of Compound 1 in an amount of about 37% w / w to about 50% w / w of the pharmaceutical composition, a diluent (or one or more diluents) of about 41% w / w to about 45% w / w of the pharmaceutical composition, a disintegrant of about 2% w / w to about 4% w / w of the pharmaceutical composition, a binder of about 2% w / w to about 8% w / w of the pharmaceutical composition, a surfactant of about 0.5% w / w to about 3% w / w of the pharmaceutical composition, a glidant of about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition, and a lubricant of about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition.

[0221] In some embodiments, the intragranular portion of the pharmaceutical composition comprises: about 42% w / w to about 63% w / w of Compound 1 or a Tris salt of Compound 1 of the pharmaceutical composition, about 32% w / w to about 38% w / w of a diluent (or one or more diluents) of the pharmaceutical composition, about 2% w / w to about 4% w / w of a disintegrant of the pharmaceutical composition, about 2% w / w to about 8% w / w of a binder of the pharmaceutical composition, about 0% w / w to about 2% w / w of a surfactant of the pharmaceutical composition, about 0% w / w to about 1.5% w / w of a glidant of the pharmaceutical composition, and about 0.5% w / w to about 1.5% w / w of a lubricant of the pharmaceutical composition.

[0222] In some embodiments, the intragranular portion of the pharmaceutical composition comprises: about 51% w / w to about 68% w / w of Compound 1 or a Tris salt of Compound 1 of the pharmaceutical composition, about 26% w / w to about 32% w / w of a diluent (or one or more diluents) of the pharmaceutical composition, about 2% w / w to about 4% w / w of a disintegrant of the pharmaceutical composition, about 1% w / w to about 9% w / w of a binder of the pharmaceutical composition, about 0% w / w to about 2% w / w of a surfactant of the pharmaceutical composition, about 0% w / w to about 1.5% w / w of a glidant of the pharmaceutical composition, and about 0.5% w / w to about 2.0% w / w of a lubricant of the pharmaceutical composition.

[0223] In some embodiments, the extragranular portion of the pharmaceutical composition comprises: an additional amount of a glidant in an amount of about 0.5% w / w to about 1% w / w of the pharmaceutical composition, and an additional amount of a lubricant in an amount of about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition. In some embodiments, the extragranular portion of the pharmaceutical composition comprises an additional amount of a lubricant in an amount of about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition.

[0224] 4. Solid dispersion

[0225] Pharmaceutical compositions comprising solid dispersions of therapeutically active compounds in a matrix can provide improved chemical and physical properties and can be prepared by forming a homogeneous solution or melt of the therapeutically active compound and the matrix material and then solidifying the mixture by cooling or removing the solvent. Such solid dispersions of therapeutically active compounds generally exhibit enhanced bioavailability when administered orally relative to oral compositions comprising the undispersed compound.

[0226] As used herein, the term "dispersion" refers to a dispersed system in which one substance (the dispersed phase) is distributed as discrete units throughout a second substance (the continuous phase or medium). Typically, the dispersed phase can be a solid, liquid, or gas. In the case of a solid dispersion, both the dispersed phase and the continuous phase are solid.

[0227] As used herein, the term "amorphous solid dispersion" generally refers to a solid dispersion of two or more components, typically a therapeutically active compound and a polymer (or multiple polymers), but may include other components, such as surfactants or other pharmaceutical excipients, wherein the therapeutically active compound is in an amorphous phase. In some embodiments, the amorphous solid dispersion includes a polymer (and optional surfactant) constituting the dispersed phase, and the therapeutically active compound constitutes a continuous phase. In some embodiments, the amorphous solid dispersion includes a polymer (and optional surfactant) constituting the continuous phase, and the therapeutically active compound constitutes a dispersed phase. In some embodiments, the therapeutically active compound is substantially amorphous. In other embodiments, the therapeutically active compound is substantially crystalline.

[0228] In some embodiments, the solid dispersion comprises 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 one or more polymers. In some embodiments, the solid dispersion comprises compound 1, or a pharmaceutically acceptable salt of compound 1, or 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, or a pharmaceutically acceptable salt of compound 1, or 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, or a pharmaceutically acceptable salt of compound 1, or a Tris salt of compound 1, or a sodium salt of compound 1, a polymer and a surfactant. In certain embodiments, 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.

[0229] In some embodiments, 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 cellulose-based polymer, such as HPMC, HPMCAS, HPC and ethyl cellulose. In other embodiments, the polymer is HPMCAS.

[0230] In some embodiments, the polymer is present in the solid dispersion in an amount of about 10% w / w to 90% w / w (e.g., about 20% w / w to about 80% w / w; about 30% w / w to about 70% w / w; about 40% w / w to about 60% w / w; or between about 15% w / w to about 35% w / w). In some embodiments, the polymer (or one or more polymers) is present in the solid dispersion in an amount of about 10% w / w to about 80% w / w, such as 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, such as about 46% w / w, about 47% w / w, about 48% w / w, about 49%, 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.

[0231] In some embodiments, Compound 1, a pharmaceutically acceptable salt of Compound 1, 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 90% w / w (e.g., about 20% w / w to about 80% w / w; about 30% w / w to about 70% w / w; about 40% w / w to about 60% w / w; or between about 15% w / w to about 35% w / w). In some embodiments, Compound 1, a pharmaceutically acceptable salt of Compound 1, 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, a pharmaceutically acceptable salt of Compound 1, 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.

[0232] In some embodiments, the solid dispersion further comprises a surfactant. In some embodiments, the surfactant is selected from sodium lauryl sulfate (SLS), vitamin E or a derivative thereof (e.g., vitamin E TPGS), sodium docusate, sodium lauryl sulfate, polysorbate (e.g., Tween 20 and Tween 80), poloxamer (e.g., poloxamer 335 and poloxamer 407), glyceryl monooleate, Span 65, Span 25, Capryol 90, Pluronic copolymer (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).

[0233] In some embodiments, the surfactant is present in the solid dispersion in an amount of about 0.1% w / w to about 10% w / w, such as 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.

[0234] In some embodiments, the solid dispersion comprises 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 mainly 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 about 3:1 to about 1:3, or about 2:1 to about 1:2, or about 1.5:1 to 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.

[0235] In another aspect, the present disclosure relates to a method for preparing a solid dispersion 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.

[0236] In some embodiments, the method comprises spray drying a mixture comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a Tris salt of Compound 1, or a sodium salt of Compound 1, a polymer, and a suitable solvent or solvent mixture.

[0237] In some embodiments, the solvent is a volatile solvent (eg, dichloromethane, acetone, methanol, ethanol, chloroform, tetrahydrofuran (THF), or a mixture thereof). In some embodiments, the solvent is acetone.

[0238] 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 can be used as a starting material in a spray drying process to prepare a solid dispersion. In some embodiments, a crystalline form described herein can be used as a starting material in a spray drying process.

[0239] Spray drying includes atomizing a liquid solution comprising, for example, a solid and a solvent or a solvent mixture, and removing the solvent or solvent mixture. Atomization can be performed by, for example, a two-fluid or pressure or electrosonic nozzle or on a rotating disk. Removing the solvent or solvent mixture may require a subsequent drying step, such as tray drying, fluidized bed drying (e.g., from about room temperature to about 100 ° C), vacuum drying, microwave drying, drum drying, or double cone vacuum drying (e.g., from about room temperature to about 200 ° C). The techniques and methods of spray drying can be found in Perry's Chemical Engineering Handbook, 6th Ed., RH Perry, DW Green & J.O. Maloney, eds., McGraw-Hill Book Co. (1984); and Marshall "Atomization and Spray-Drying" 50, Chem. Eng. Prog. Monogr. Series 2 (1954).

[0240] 5. Exemplary Capsule Formulations

[0241] Formulations for oral use can also be prepared as hard gelatin or hydroxypropylmethylcellulose (HPMC) capsules, in which the active ingredient is mixed with an inert solid diluent (e.g. calcium carbonate, calcium phosphate or clay and mixtures thereof), or as soft gelatin capsules, in which the active ingredient is mixed with water or an oil medium (e.g. peanut oil, liquid paraffin or olive oil).

[0242] In some embodiments, the capsule compositions provided herein comprise about 10% w / w to about 20% w / w of the Tris salt of Compound 1 based on the total weight of the capsule and an excipient comprising about 76.5% w / w to about 83% w / w of a diluent (or one or more diluents) of the capsule, about 3% w / w to about 5% w / w of a disintegrant of the capsule, and about 0.5% w / w to about 2.0% of a lubricant of the capsule, all based on the total weight of the capsule. In one embodiment, the Tris salt comprises Tris salt Form C.

[0243] In some embodiments, the capsule compositions provided herein comprise about 48% w / w to about 60% w / w of the Tris salt of Compound 1 based on the total weight of the capsule, and excipients comprising about 37.5% w / w to about 44% w / w of a diluent (or one or more diluents) of the capsule, about 2% w / w to about 6% w / w of a disintegrant of the capsule, and about 0.5% w / w to about 2.0% w / w of a lubricant of the capsule. In one embodiment, the Tris salt comprises Tris salt Form C.

[0244] In some embodiments, based on the total weight of the capsule, the capsule composition provided herein comprises about 37% w / w to about 50% w / w of the Tris salt of Compound 1; an intragranular excipient comprising about 41% w / w to about 45% w / w of a diluent, about 2% w / w to about 4% w / w of a disintegrant, about 2% w / w to about 8% w / w of a binder, about 0.5% w / w to about 3% w / w of a surfactant, about 0.5% w / w to about 2.0% w / w of a glidant, and about 0.5% w / w to about 2.0% w / w of a lubricant; and an extragranular excipient comprising about 0.5% w / w to about 2.0% w / w of a glidant and about 0.5% w / w to about 2.0% w / w of a lubricant, all based on the total weight of the capsule. In one embodiment, the Tris salt comprises Tris salt Form C.

[0245] In some embodiments, the capsule compositions provided herein comprise about 42% w / w to about 63% w / w of the Tris salt of Compound 1 based on the total weight of the capsule; intragranular excipients comprising about 32% w / w to about 38% w / w of a diluent, about 2% w / w to about 4% w / w of a disintegrant, about 2% w / w to about 8% w / w of a binder, about 0% w / w to about 2% w / w of a surfactant, about 0% w / w to about 3.0% w / w of a glidant, and about 0.5% w / w to about 3.0% w / w of a lubricant; and extragranular excipients comprising about 0% w / w to about 2.0% w / w of a glidant and about 0.5% w / w to about 2.0% w / w of a lubricant, all based on the total weight of the capsule. In one embodiment, the Tris salt comprises Tris salt Form C.

[0246] In some embodiments, the capsule compositions provided herein comprise about 51% w / w to about 68% w / w of the Tris salt of Compound 1 based on the total weight of the capsule; intragranular excipients comprising about 26% w / w to about 32% w / w of a diluent, about 2% w / w to about 4% w / w of a disintegrant, about 1% w / w to about 9% w / w of a binder, about 0% w / w to about 2% w / w of a surfactant, about 0% w / w to about 3.0% w / w of a glidant, about 0.5% w / w to about 3.0% w / w of a lubricant; and extragranular excipients comprising about 0% w / w to about 2.0% w / w of a glidant and about 0.5% w / w to about 2.0% w / w of a lubricant, all based on the total weight of the capsule. In one embodiment, the Tris salt comprises Tris salt Form C.

[0247] 6. Exemplary Tablet Formulations

[0248] For tablet compositions, a mixture of Compound 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients for tablet production can be used. Examples of these excipients include, but are not limited to, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known coating techniques to delay decomposition and absorption in the gastrointestinal tract, thereby providing a sustained therapeutic effect over a desired period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used.

[0249] In certain embodiments, the tablet is a coated tablet. In certain embodiments, the coating is a film coating. In certain embodiments, the coating agent is Opadry II. In certain embodiments, the coating agent comprises polyvinyl alcohol.

[0250] Any conventional method for obtaining tablets may be used, for example, methods described in pharmacopoeias such as the United States Pharmacopoeia and the European Pharmacopoeia may be used.

[0251] In some embodiments, the tablet compositions provided herein comprise about 10% w / w to about 20% w / w of the Tris salt of Compound 1 based on the total weight of the tablet and an excipient comprising about 76.5% w / w to about 83% w / w of a diluent (or one or more diluents) of the tablet, about 3% w / w to about 5% w / w of a disintegrant of the tablet, and about 0.5% w / w to about 2.0% of a lubricant of the tablet, all based on the total weight of the tablet. In one embodiment, the Tris salt comprises Tris salt Form C.

[0252] In some embodiments, the tablet compositions provided herein comprise about 48% w / w to about 60% w / w of the Tris salt of Compound 1 based on the total weight of the tablet, and an excipient comprising about 37.5% w / w to about 44% w / w of a diluent (or one or more diluents) of the tablet, about 2% w / w to about 6% w / w of a disintegrant of the tablet, and about 0.5% w / w to about 2.0% w / w of a lubricant of the tablet. In one embodiment, the Tris salt comprises Tris salt Form C.

[0253] In some embodiments, the tablet compositions provided herein comprise about 37% w / w to about 50% w / w of the Tris salt of Compound 1 based on the total weight of the tablet; intragranular excipients comprising about 41% w / w to about 45% w / w of a diluent, about 2% w / w to about 4% w / w of a disintegrant, about 2% w / w to about 8% w / w of a binder, about 0.5% w / w to about 3% w / w of a surfactant, about 0.5% w / w to about 2.0% w / w of a glidant, and about 0.5% w / w to about 2.0% w / w of a lubricant; and extragranular excipients comprising about 0.5% w / w to about 2.0% w / w of a glidant and about 0.5% w / w to about 2.0% w / w of a lubricant, all based on the total weight of the tablet. In one embodiment, the Tris salt comprises Tris salt Form C.

[0254] In some embodiments, the tablet compositions provided herein comprise about 42% w / w to about 63% w / w of the Tris salt of Compound 1 based on the total weight of the tablet; intragranular excipients comprising about 32% w / w to about 38% w / w of a diluent, about 2% w / w to about 4% w / w of a disintegrant, about 2% w / w to about 8% w / w of a binder, about 0% w / w to about 2% w / w of a surfactant, about 0% w / w to about 3.0% w / w of a glidant, and about 0.5% w / w to about 3.0% w / w of a lubricant; and extragranular excipients comprising about 0% w / w to about 2.0% w / w of a glidant and about 0.5% w / w to about 2.0% w / w of a lubricant, all based on the total weight of the tablet. In one embodiment, the Tris salt comprises Tris salt Form C.

[0255] In some embodiments, the tablet compositions provided herein comprise about 51% w / w to about 68% w / w of the Tris salt of Compound 1 based on the total weight of the tablet; intragranular excipients comprising about 26% w / w to about 32% w / w of a diluent, about 2% w / w to about 4% w / w of a disintegrant, about 1% w / w to about 9% w / w of a binder, about 0% w / w to about 2% w / w of a surfactant, about 0% w / w to about 3.0% w / w of a glidant, about 0.5% w / w to about 3.0% w / w of a lubricant; and extragranular excipients comprising about 0% w / w to about 2.0% w / w of a glidant and about 0.5% w / w to about 2.0% w / w of a lubricant, all based on the total weight of the tablet. In one embodiment, the Tris salt comprises Tris salt Form C.

[0256] 7. Other preparations

[0257] For aqueous suspensions, the compounds of the present disclosure are mixed with excipients 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 arabic.

[0258] Oral suspensions may also include dispersants or wetting agents, such as naturally occurring phosphatides (e.g., lecithin), or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxides with long-chain aliphatic alcohols (e.g., heptadecenyloxycetyl alcohol), or condensation products of ethylene oxides with partial esters derived from fatty acids and hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxides with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions may also include one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0259] Oily suspensions can be formulated by suspending the compound of the invention in a vegetable oil (eg, peanut oil, olive oil, sesame oil or coconut oil) or a mineral oil (eg, liquid paraffin). Oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol.

[0260] Sweetening agents (such as those set forth above) and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0261] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water can be formulated by providing a mixture of the disclosed compound with a dispersant or wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersants or wetting agents and suspending agents are described above. Additional excipients such as sweeteners, flavoring agents and coloring agents may also be present.

[0262] The pharmaceutical composition of the present disclosure can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin and a mixture thereof. Suitable emulsifiers can be naturally occurring gums, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, such as sorbitan monooleate; and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweeteners and flavorings.

[0263] Syrups and elixirs can be formulated with sweeteners (e.g., glycerol, propylene glycol, sorbitol, or sucrose). These preparations may also contain demulcents, preservatives, flavoring agents, and coloring agents. Pharmaceutical compositions may be in the form of sterile injections, aqueous suspensions, or oily suspensions. Such suspensions may be formulated using one or more of the above-mentioned suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are traditionally used as solvents or suspension media. For this purpose, any mild non-volatile oil may be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid may be used to prepare injections.

[0264] Compound 1 or its pharmaceutically acceptable salt can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. These materials are cocoa butter, beeswax and polyethylene glycol.

[0265] Compositions for parenteral administration are administered in a sterile medium. Depending on the medium used and the concentration of the drug in the preparation, the parenteral preparation can be a suspension or a solution containing a dissolved drug. Excipients such as local anesthetics, preservatives and buffers can also be added to the parenteral composition.

[0266] Another embodiment of the present invention is a liquid formulation comprising the sodium salt of Compound 1, which is suitable for oral or parenteral administration. Typically, the liquid formulation is aqueous. For oral administration, certain sweeteners and / or flavoring agents and / or coloring agents may be added.

[0267] The amount of active ingredient that can be combined with one or more pharmaceutical excipients to produce a single dosage form will vary depending on the patient being treated and the specific mode of administration. In certain embodiments, the pharmaceutical composition comprises about 10 mg to 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 conformational isomers, salt-forming agents, hydrated water, solvated solvents, etc.). In some embodiments, the pharmaceutical composition comprises about 90 mg to about 240 mg; about 100 mg to about 240 mg; about 10 mg to about 500 mg; or about 10 mg to 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 an orally acceptable dosage form, such as a capsule, and comprises 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 the Tris salt of Compound 1.

[0268] Method of treatment, use of a drug, salt or crystal form for the manufacture of a drug for the treatment of a disease

[0269] In one aspect, the crystalline and amorphous forms and pharmaceutical compositions thereof described herein are inhibitors of DHODH (but not limited thereto) and are generally useful for treating diseases underlying DHODH. The tris (hydroxymethyl) aminomethane salt of compound 1 described in the following paragraphs includes any Tris salt according to the first to twenty-fifth embodiments described above. The crystalline form of compound 1 described in the following paragraphs includes any crystalline form according to any one of the twenty-seventh to fifty-ninth embodiments described above.

[0270] In one aspect, the present disclosure relates to a method for treating cancer in a subject, comprising administering to the subject an effective amount of a tris(hydroxymethyl)aminomethane salt of Compound 1, a 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 a tris(hydroxymethyl)aminomethane salt of Compound 1, a sodium salt of Compound 1, a crystalline form of Compound 1, or a pharmaceutical composition thereof in the preparation of a medicament for treating cancer. In yet another aspect, the present disclosure relates to a tris(hydroxymethyl)aminomethane salt of Compound 1, a sodium salt of Compound 1, a crystalline form of Compound 1, or a pharmaceutical composition thereof for use in treating cancer.

[0271] In some embodiments, cancer includes solid tumors. In some embodiments, the cancer is selected from lung cancer, breast cancer, triple-negative breast cancer, melanoma, glioblastoma, prostate cancer, colon cancer, pancreatic cancer, bone cancer, head and neck cancer, skin cancer, skin or intraocular malignant endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, solid tumors in children, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) tumors, tumor angiogenesis, spinal cord tumors (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 cancer or ampulla of Vater cancer, non-small cell lung cancer, bronchoalveolar carcinoma, liver cancer, ovarian cancer and upper aerodigestive tract cancer. In another embodiment, cancer is a blood cancer. In one embodiment, the blood cancer is selected from the group consisting of myeloma, lymphoma, and leukemia. In one embodiment, the blood cancer is selected from the group consisting of acute myeloid leukemia, multiple myeloma, B-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, bladder lymphocytic lymphoma, primary CNS lymphoma, and T-cell lymphoma; in one embodiment, the blood cancer is selected from the group consisting of chemotherapeutic group therapy-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 neoplasms, 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 blood cancer is selected from angioimmunoblastic lymphoma, Burkitt's lymphoma, Burkitt-like lymphoma, blastic NK-cell lymphoma, cutaneous T-cell lymphoma, lymphoblastic lymphoma, MALT lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma, small lymphocytic lymphoma, thyroid lymphoma, follicular lymphoma, Waldenstrom's macroglobulinemia, essential thrombocythaemia, chronic idiopathic myelofibrosis, and polycythemia vera.

[0272] On the other hand, the present disclosure relates to a method for treating cancer in a subject, wherein the cancer responds to inhibition of dihydroorotate dehydrogenase, the method comprising administering to the subject an effective amount of a tris(hydroxymethyl)aminomethane salt of compound 1 (or one of the disclosed crystalline forms thereof), a sodium salt of compound 1, a crystalline form of compound 1, or a pharmaceutical composition thereof. On the other hand, the present invention relates to the use of a tris(hydroxymethyl)aminomethane salt of compound 1, a sodium salt of compound 1, a crystalline form of compound 1, or a pharmaceutical composition thereof in the preparation of a medicament for treating cancer, wherein the cancer responds to inhibition of dihydroorotate dehydrogenase. On yet another aspect, the present disclosure relates to a tris(hydroxymethyl)aminomethane salt of compound 1, a sodium salt of compound 1, a crystalline form of compound 1, or a pharmaceutical composition thereof for use in treating cancer, wherein the cancer responds to inhibition of dihydroorotate dehydrogenase. In one embodiment, the cancer may be selected from the above-mentioned cancer list.

[0273] On the other hand, the present disclosure relates to a method for treating a condition or disease in a subject, wherein the condition or disease is selected from a viral-mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, an autoimmune disease, or an inflammatory disease, the method comprising administering to the subject an effective amount of a tris(hydroxymethyl)aminomethane salt of compound 1 (or one of its disclosed crystalline forms), a sodium salt of compound 1, a crystalline form of compound 1, or a pharmaceutical composition thereof. On the other hand, the present invention relates to the use of a tris(hydroxymethyl)aminomethane salt of compound 1, a sodium salt of compound 1, a crystalline form of compound 1, or a pharmaceutical composition thereof in the preparation of a medicament for treating a condition or disease, wherein the condition or disease is selected from a viral-mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, an autoimmune disease, or an inflammatory disease. On yet another aspect, the present disclosure relates to a tris(hydroxymethyl)aminomethane salt of compound 1, a sodium salt of compound 1, a crystalline form of compound 1, or a pharmaceutical composition thereof, for treating a condition or disease selected from a viral-mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, an autoimmune disease, or an inflammatory disease.

[0274] In another aspect, the present disclosure relates to a method for inhibiting tumor cell growth and / or metastasis in a subject, wherein the tumor cells are responsive to inhibition of dihydroorotate dehydrogenase, the method comprising administering to the subject an effective amount of a tris(hydroxymethyl)aminomethane salt of Compound 1 (or one of the disclosed crystalline forms thereof), a sodium salt of Compound 1, a crystalline form of Compound 1, or a pharmaceutical composition thereof.

[0275] In another aspect, the present disclosure relates to a method of inhibiting dihydroorotate dehydrogenase in a subject, wherein tumor cells are responsive to inhibition of dihydroorotate dehydrogenase, the method comprising administering to the subject an effective amount of a tris(hydroxymethyl)aminomethane salt of Compound 1 (or one of its disclosed crystalline forms), a sodium salt of Compound 1, a crystalline form of Compound 1, or a pharmaceutical composition thereof.

[0276] Another embodiment of the present invention is a method of treating a subject with cancer with Compound 1 or a pharmaceutically acceptable salt thereof. Compound 1 or a pharmaceutically acceptable salt thereof is preferably provided as i) a Tris salt (e.g., in an 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 to be treated is a blood cancer selected from myeloma, lymphoma, leukemia, such as acute myeloid leukemia (AML), chronic myeloproliferative disease, monoclonal gammopathy of unknown significance, myelodysplastic syndrome, amyloidosis, and myelodysplastic / myeloproliferative neoplasms; the myeloma to be treated is selected from multiple myeloma, amyloidosis, plasmacytoma, monoclonal gammopathy of unknown significance, asymptomatic myeloma, symptomatic myeloma, and Kahler's disease; the lymphoma to be treated is selected from anaplastic large cell lymphoma, Burkitt's 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 macroglobulinemia; the chronic myeloproliferative disease to be treated is selected from essential thrombocythaemia, chronic idiopathic myelofibrosis and 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.

[0277] In yet another aspect, the present disclosure relates to a method for treating cancer in a subject, comprising administering to the 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 a tris (hydroxymethyl) aminomethane (Tris) salt of Compound 1 as described herein (including all partially crystalline or crystalline Tris salt forms of Compound 1 as described herein), a sodium salt of Compound 1 as described herein, or a free acid Compound 1 (including all partially crystalline or crystalline forms of free acid Compound 1 as described herein), wherein one of the dosing regimens described in the following paragraphs is implemented. In one embodiment, the subject is treated by administering to the subject an effective amount of a crystalline Tris salt of Compound 1. In a specific embodiment, the crystalline Tris salt is a crystalline Tris salt Form C as 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.

[0278] In one embodiment, the dosing regimen for the cancer treatment methods described in the preceding paragraphs 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 described herein, or a sodium salt of Compound 1) once a week in one or more 28-day or 4-week cycles.

[0279] 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 described herein, or a sodium salt of Compound 1) 2-5 days per week, and one treatment cycle is defined as 4 consecutive weeks of treatment.

[0280] 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 described herein, or a sodium salt of Compound 1) for 2-4 consecutive days per week, followed by a 3-5 day break, for one or more cycles of 28 days or 4 weeks.

[0281] 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 described herein, or a sodium salt of Compound 1) for 2 consecutive days per week in one or more 28-day or 4-week cycles, followed by a 5-day break.

[0282] 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 described herein, or a sodium salt of Compound 1) for 3 consecutive days per week in one or more 28-day or 4-week cycles, followed by a 4-day break.

[0283] 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 described herein, or a sodium salt of Compound 1) for 4 consecutive days per week in one or more 28-day or 4-week cycles, followed by a 3-day break.

[0284] 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 described herein, or a sodium salt of Compound 1) for 2-4 consecutive days per week in one or more 28-day or 4-week cycles, followed by a 3-5 day break, wherein the number of consecutive treatment days is increased in at least one week 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 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., Tris salt of Compound 1, including amorphous forms and all partially crystalline or crystalline Tris salt forms of Compound 1 described herein, or sodium salt of Compound 1) for 2-4 consecutive days per week in one or more 28-day or 4-week cycles, followed by a 3-5 day break, wherein the number of consecutive treatment days is reduced in at least one week of the 28-day or 4-week cycle.

[0285] In another embodiment, 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) is administered to a subject for 2 consecutive days in the first week of a 28-day or 4-week cycle, followed by a 5-day break, wherein the number of consecutive treatment days is increased in at least one week of the 28-day or 4-week cycle. In another embodiment, 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) is administered to a subject for 2 consecutive days in the first week of a 28-day or 4-week cycle, followed by a 5-day break, wherein the number of consecutive treatment days is reduced in at least one week of the 28-day or 4-week cycle.

[0286] In another embodiment, 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) is administered to a subject for 3 consecutive days in the first week of a 28-day or 4-week cycle, followed by a 4-day break, wherein the number of consecutive treatment days increases in at least one week of the 28-day or 4-week cycle. In another embodiment, 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) is administered to a subject for 3 consecutive days in the first week of a 28-day or 4-week cycle, followed by a 4-day break, wherein the number of consecutive treatment days decreases in at least one week of the 28-day or 4-week cycle.

[0287] In another embodiment, 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) is administered to a subject for 4 consecutive days in the first week of a 28-day or 4-week cycle, followed by a 3-day break, wherein the number of consecutive treatment days increases in at least one week of the 28-day or 4-week cycle. In another embodiment, 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) is administered to a subject for 4 consecutive days in the first week of a 28-day or 4-week cycle, followed by a 3-day break, wherein the number of consecutive treatment days decreases in at least one week of the 28-day or 4-week cycle.

[0288] In one embodiment, the dosing regimen of the cancer treatment method described in the preceding paragraph comprises orally 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 described herein, including amorphous forms and all partially crystalline or crystalline Tris salt forms of Compound 1, or a sodium salt of Compound 1). In one embodiment, 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 described herein, or a sodium salt of Compound 1) is administered as an oral capsule. In another embodiment, 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 described herein, or a sodium salt of Compound 1) is administered as an oral tablet.

[0289] In one embodiment, the dosing regimen of 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 described herein, or a sodium salt of Compound 1) once daily (QD). In another embodiment, the dosing regimen of 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 described herein, or a sodium salt of Compound 1) twice daily (BID).

[0290] In one embodiment, the cancer treated by the methods described in the foregoing two paragraphs is selected from the list of solid tumors and hematological cancers provided herein. In one embodiment, cancer is non-Hodgkin's lymphoma or Hodgkin's lymphoma. In a specific embodiment, the treated subject belongs to a subgroup of patients with non-Hodgkin's lymphoma or Hodgkin's lymphoma, wherein the non-Hodgkin's lymphoma or Hodgkin's lymphoma has progressed despite previous treatment, and no other effective (curative or life-extending) standard treatment is available. In other words, the treated subject belongs to a subgroup of drug-resistant or refractory non-Hodgkin's lymphoma or Hodgkin's lymphoma. In one embodiment, standard curative therapy is high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT). In one embodiment, the non-Hodgkin's lymphoma or Hodgkin's lymphoma of the subject relapses after HD-ASCT. In other words, the treated subject belongs to a subgroup of relapsed non-Hodgkin's lymphoma or Hodgkin's lymphoma (e.g., HD-ASCT relapsed). In another embodiment, the subject is not suitable for HD-ASCT. In another embodiment, the subject refuses HD-ASCT.

[0291] In one embodiment, the lymphoma according to the present disclosure is:

[0292] a) Mature B cell tumors

[0293] b) Mature T-cell and NK-cell tumors

[0294] c) Hodgkin's lymphoma

[0295] d) Immunodeficiency-associated lymphoproliferative disease

[0296] The present invention is illustrated by the following examples, which are not intended to limit the invention. DETAILED DESCRIPTION

[0298] The crystalline and amorphous forms were prepared according to the following general procedures as described in the examples below.

[0299] Example 1 - Abbreviations, solutions, instruments, synthesis of compound 1

[0300] Typical abbreviations used are outlined below.

[0301] Table 1. Abbreviations

[0302]

[0303]

[0304] unit

[0305]

[0306]

[0307] Solution

[0308] FaSSGF / SGF (fasting state simulated gastric fluid)

[0309] Weigh 100 mg of sodium chloride into a 50 mL volumetric flask. Add an appropriate volume of pure water and sonicate until all solids are completely dissolved. Add enough pure water to bring it close to the target volume and adjust to pH 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 pure water and mix thoroughly.

[0310] FaSSIF (Fasting State Simulated Intestinal Fluid)

[0311] Weigh 0.170 g of sodium dihydrogen phosphate, 0.021 g of sodium hydroxide, and 0.31 g of sodium chloride into a 50 ml volumetric flask. Add an appropriate volume of purified water and sonicate until all solids are completely dissolved. Add enough purified water to approach the target volume and adjust to pH 6.5. Weigh 110 mg of FaSSIF / FeSSIF / FaSSGF powder in a volumetric flask and sonicate until the powder is completely dissolved. Dilute to target volume with purified water and mix thoroughly.

[0312] FeSSIF (Feed State Simulated Intestinal Fluid)

[0313] Weigh 0.41 ml of glacial acetic acid, 0.202 g of sodium hydroxide, and 0.594 g of sodium chloride into a 50 ml volumetric flask. Add an appropriate volume of purified water and sonicate until all solids are completely dissolved. Add enough purified water to approach the target volume and adjust to pH 5.0. Weigh 560 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.

[0314] XRPD

[0315] Using PANalytical X'Pert 3 XRPD data were collected by X-ray powder diffractometer. The sample was dispersed in the middle of a zero-background silicon support. Table 2 lists the XRPD parameters.

[0316] Table 2. XRPD parameters

[0317]

[0318] TGA and DSC

[0319] Thermogravimetric analysis data were collected using a TA Q500 / Q5000 TGA from TA Instruments, and DSC was performed using a TA Q200 / Q2000 DSC from TA Instruments. Detailed parameters are shown in Table 3.

[0320] Table 3. Parameters of TGA and DSC

[0321] parameter TGA DSC method tilt tilt Sample tray Aluminum, open Aluminum, curled temperature Room temperature - desired temperature 25℃-Required temperature Heating rate 10℃ / min 10℃ / min Purge gas <![CDATA[N2]]> <![CDATA[N2]]>

[0322] DVS

[0323] DVS was measured by SMS (Surface Measurement Systems) DVS Intrinsic. The relative humidity at 25°C was calibrated according to the deliquescent points of LiCl, Mg(NO3)2 and KCl. Table 4 lists the parameters of the DVS test.

[0324] Table 4. DVS parameters

[0325]

[0326] HPLC

[0327] An Agilent 1260 HPLC with a DAD detector was used, and the detailed chromatographic conditions for the solubility analysis are listed in Table 5.

[0328] Table 5. Chromatographic conditions for solubility analysis

[0329]

[0330]

[0331] Solution 1 H NMR

[0332] The solution was collected using DMSO-d6 on a Bruker 400MNMR spectrometer 1 H NMR.

[0333] Synthesis of compound 1

[0334] The synthesis of non-crystalline Compound 1 (i.e., non-crystalline free acid) was previously described in International Patent Application Publication No. WO2014 / 128669 and U.S. Patent No. 9,630,932.

[0335] Other methods for synthesizing amorphous Compound 1 are described in Schemes 1 and 2.

[0336] Solution 1

[0337]

[0338] Solution 2

[0339]

[0340] Tetrasubstituted aromatic compound S3 is synthesized from S1 according to an earlier precedent. See International Patent Application Publication No. WO2012 / 142513 and Chi-Linh et al., J.Agricultural&Food Chem.2016, 64(18)3533, supplementary info, S7 page. In the presence of an aqueous substrate and ethyl acetate, S3 is subjected to an amination reaction by replacing the chloro group with a nucleophilic aromatic methylamine to provide S4. The nitro functional group of S4 is reduced using iron in the presence of an acid (e.g., acetic acid), platinum carbon (containing or not containing vanadium), or palladium carbon. In some cases, palladium carbon is used to cause debromination. The intermediate diamine (S5) can be used directly in the next step, as shown in Scheme 1, or separated as a salt (hydrochloric acid or sulfuric acid), as shown in Scheme 2. S5 in free alkali or salt form is converted to bromotriazole S6 by reaction with sodium nitrite in aqueous hydrogen chloride solution.

[0341] In parallel, 2-methylboronic acid (S7) was coupled with 4-iodobromobenzene (S8) under Suzuki coupling conditions to give biphenyl S9. The bromine in S9 was replaced by a boronic acid functional group (S10) by low-temperature lithium-halogen exchange and reaction with triisopropylboronic acid.

[0342] A solution of bromotriazole (S6) and boronic acid (S10) in toluene was coupled (Suzuki coupling) in the presence of aqueous potassium carbonate under Pd catalysis to afford S11. The methyl ester in S11 was hydrolyzed to the carboxylic acid using aqueous sodium hydroxide in methanol to generate compound 1 as the free acid.

[0343] Example 2 - Amorphous Solid Dispersion of Compound 1

[0344] Compound 1 and hydroxypropyl methylcellulose acetate succinate-MG (hydroxypropyl methylcellulose acetate succinate, MG grade, Shin-Etsu Chemical Co.) (HPMCAS) (50% / 50%, w / w) were weighed, dissolved in methanol, and spray dried on a Büchi B-290 to produce an amorphous compound 1 and hydroxypropyl methylcellulose acetate succinate (HPMCAS) solid dispersion. The spray drying process parameters include nitrogen as a drying gas, an inlet temperature of about 80°C to 95°C, an outlet temperature of about 37°C to 45°C, and a spray solution concentration of about 15% w / w / . The amorphous solid dispersion is further dried in a vacuum oven at 40°C for 12-18 hours and then sieved. The amorphous solid dispersion can be packaged in double polyethylene bags, tied with twisted nylon bands, and placed in a high-density polyethylene (HDPE) container containing a desiccant and stored at 2-8°C until the next processing step.

[0345] Example 3 - Screening of polymorphs and salt forms of compound 1

[0346] Polymorph screening

[0347] A total of 74 polymorph screening experiments were performed using different solution crystallization and solid phase transformation methods, as shown in Table 6. The isolated solids were characterized using XRPD, thermogravimetric analysis, and DSC (see Table 7). Figure 1 The comparison results of the spectra in show that four different crystal forms were obtained.

[0348] Table 6. Summary of polymorph screening experiments for free acid compound 1

[0349] method Experimental volume Identification of solid forms Antisolvent addition 10 Free acid form C Slow evaporation 3 Free acid form C Slow cooling 5 Free acid form C Beating at room temperature 20 Free acid form A / B / C / D Beating at 50℃ 10 Free acid form B / C / D Solid Vapor Diffusion 10 Free acid form A / C Liquid vapor diffusion 7 Free acid form A / C Polymer-induced crystallization 6 Free acid form C Manual grinding 3 Free acid form A total 74 Free acid form A / B / C / D

[0350] Table 7. Summary of solid state characterization of free acids A / B / C / D

[0351]

[0352] *: Free form Type C was heat treated to 150°C with a weight loss of 2.3% and no change in solid form was observed. **: Exothermic peak, peak temperature.

[0353] Characterization of the identified free acid compound 1 crystalline form

[0354] Representative samples of each identified form (Form A / B / C / D) were characterized using TGA and DSC. Heating experiments were also performed to investigate the relationship between the different forms.

[0355] Free acid form A

[0356] The XRPD pattern of free acid form A is shown in Figure 2A , peak list see Figure 2B . Figure 3C The TGA / DSC curve in Figure 2 shows a weight loss of 1.0% at a maximum of 200°C, with a weak exotherm at 212.1°C (peak temperature) before a sharp endotherm at 326.8°C (onset temperature). Heat treatment of the free acid Form A showed no form change 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 heating experiment results, the free Form A was presumed to be an anhydrous form.

[0357] Free acid form B

[0358] Free acid Form B can be obtained by heating experiments and slurrying at room temperature / 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 at Figure 3A In the , the peak list is shown in Figure 3B ,and Figure 3C The TGA / DSC curve of Form B shows a weight loss of 2.9% up to 200° C. and a single sharp endotherm at 321.9° C. (onset temperature). Combining the preparation method (conversion from anhydrous free acid Form A) and the neat TGA / DSC curve, free acid Form B is presumed to be a hygroscopic anhydrous form.

[0359] Free acid form C

[0360] The free acid form C can be obtained by anti-solvent addition, evaporation, slow cooling and slurrying, etc. The free acid form C was obtained by slurrying the starting material compound 1 in 1,4-dioxane for ~2 days at room temperature, and the XRPD pattern is shown in Figure 4A The corresponding peaks are shown in Figure 4B . Figure 4C The TGA / DSC curve in shows that the weight loss is 3.6% at a maximum of 200°C, and a single sharp endotherm occurs at 322.5°C (onset temperature). After heating to 150°C, the heat treatment does not show a change in form for the free acid form C, and it is converted to form B after heating to 300°C. Further TGA characterization of the heated free acid form C was performed, and a decrease in TGA weight loss (from 3.6% to 2.3% at a maximum of 200°C) was observed. Based on the TGA / DSC and heating experiment results, the free acid form C is presumed to be a hygroscopic anhydrous form.

[0361] Free acid form D

[0362] The free acid form D can be obtained by slurrying in a variety of solvent systems. The free acid form D was obtained by slurrying the starting material compound 1 in ethyl acetate for ~7 days at room temperature, and the XRPD pattern is shown in Figure 5A The corresponding peaks are shown in Figure 5B . Figure 5C The TGA / DSC curve in Figure 4 shows a maximum weight loss of 1.0% at 200°C, a weak endotherm at 286.7°C (onset temperature), followed by a sharp endotherm at 327.4°C (onset temperature). The heating treatment shows that the free acid form D is converted to form B after heating to 305°C. Based on the low TGA weight loss and heating experiment results, the free acid form D is presumed to be an anhydrous form.

[0363] Thermodynamic stability studies

[0364] In order to study and compare the thermodynamic stability among the four crystalline forms of compound 1 identified (free acid forms A / B / C / D), a two-stage slurry competition experiment was performed, in which the first stage studied the anhydrous solvent system and the second stage studied the crystalline forms with different water activities (a w ) solvent system.

[0365] In the first stage, first physically mix each solid form (free acid form A / B / C / D) ~ 2mg, then add 0.5mL solvent to form a suspension. Under various beating conditions, a small amount of solid is separated for XRPD test after about 7 days. Characterized by XRPD, after beating at room temperature, 50°C and 70°C, free acid form A / B / C is converted into form D, indicating that between room temperature and 70°C, form D is thermodynamically more stable than form A / B / C.

[0366] To further explore the effect of water content on the conversion relationship, six conditions with different water activities and temperatures were used. About 2 mg of each solid form (free acid form A / B / C / D) was mixed and suspended in 1.0 ml of the corresponding solvent system. After slurrying for about 1 month, the solid was separated for XRPD testing. By XRPD characterization, free acid form A / B / C was converted to form D after slurrying at room temperature, 50°C and 70°C, indicating that form D was converted to form D at different water activities (a w : 0~1) is more stable than form A / B / C.

[0367] Salt screening

[0368] Solvent-mediated reactive crystallization was used for salt screening. A total of 55 salt screening experiments were conducted, including 10 counterions and 5 different solvents, as well as 5 blank experiments.

[0369] The specific experimental process is as follows:

[0370] 1. Weigh approximately 15 mg of free form A and a molar equivalent of the counterion into each HPLC vial;

[0371] 2. Add 0.5-1.0 mL of the corresponding solvent to form a suspension or solution;

[0372] 3. The mixture was magnetically stirred (~1000 rpm) at room temperature (25±3°C) for ~2 days;

[0373] 4. Separate the remaining solids by centrifugation (10,000 rpm, 2 minutes);

[0374] 5. After drying at 50°C for ~2 hours, the solid was characterized by XRPD.

[0375] As summarized in Table 8, a total of 12 potential salt hits were identified, including five Na salt hits (A-E types), three Ca salt hits (A-C types), one Mg salt hit (A type), two Tris salt hits (A and B types) and one betaine salt hit (A type) (highlighted in bold in Table 8). Table 9 describes the solid-state characteristics of the identified salt hits.

[0376] Table 8. Summary of the salt screening results of compound 1

[0377]

[0378]

[0379] *: A clear solution was obtained after slurrying at room temperature or 5°C and then transferred to room temperature for evaporation to separate any solids.

[0380] Table 9. Summary of characterization of different potential salt hits

[0381]

[0382] 1 This Tris salt Form A was prepared in -15 mg batches during salt screening using the procedure described above. 2 This Tris salt Form A was re-prepared in -200.7 mg batches.

[0383] *: Onset temperature. **: Na salt type A was obtained by humidity-induced conversion for amorphous Na salt. N / A: Due to the weak crystallinity observed for the isolated solid, no further characterization was performed.

[0384] Example 4 - Polymorph Screening and Analysis of Tris Salt Form A, Tris Salt Form B and Tris Salt Form C of Compound 1 Characterization

[0385] Polymorph screening

[0386] A total of 107 polymorph screening experiments were performed using the Tris salt form of Compound 1 and the free acid form of Compound 1 and using 11 solvent crystallization methods or solid transition methods, as shown in Table 10. A total of 105 experiments isolated solids for XRPD characterization. In addition to the crystalline free acid forms A / B / C / D identified in Example 3, 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). Figure 6 The comparison of the spectra in the results showed that three different crystal forms were obtained.

[0387] Table 10. Summary of polymorph screening experiments for free acid compound 1 and Tris salt of compound 1

[0388]

[0389]

[0390] Characterization of the crystalline form of the identified Tris salt compound 1

[0391] Representative samples of each identified form (Form A / B / C) were characterized using XRPD, TGA and DSC. Heating experiments were also performed to investigate the relationship between the different forms.

[0392] Tris Salt Form A

[0393] Tris salt Form A was obtained by slurrying the free acid Form A with Tris in acetone at room temperature for ~2 days. Fig. 7A The corresponding peak list is shown in Figure 7B shown. Figure 7C The TGA / DSC curve in shows that the weight loss is 2.8% at a maximum of 150°C and a sharp endotherm occurs at 198.6°C (onset temperature). Fig.7D In 1 The stoichiometry of the Tris salt Form A was determined to be 1.0:1.1 (free acid / Tris) by H NMR.

[0394] Tris Salt Form B

[0395] Tris salt Form B was obtained by slurrying the free acid Form A with Tris in EtOH at room temperature for ~2 days. Fig. 8A The corresponding peak list is shown in Figure 8B shown. Figure 8CThe TGA / DSC curve in shows a two-step weight loss of 10.8% at a maximum of 190°C, with an overlapping endotherm / exotherm at 125.3°C (onset temperature) before a sharp endotherm at 201.4°C (onset temperature). After heating to 150°C and subsequent cooling to ambient conditions, Tris salt Form B is converted to Tris salt Form A. Based on Fig.8D In 1 By H NMR results, the stoichiometry of Tris salt Form B was determined to be 1.0:1.0 (free acid / Tris).

[0396] Tris Salt Form C

[0397] Tris salt form C was obtained by slurrying the free acid form of compound 1 with Tris in DMSO at room temperature for about 2 days. 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 room temperature, and no solid was formed at room temperature. 320 mL of EtOH was then slowly added to the reaction solution, which was then stirred at room temperature for 30 minutes. This step was repeated. After the second addition of EtOH and stirring, a solid was formed. The reaction mixture containing the formed solid was stirred overnight at 20-25 ° C and then filtered. The filter cake was washed with 2×320 mL of EtOH and vacuum dried 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 cooled to room temperature for about 1 hour, stirred at room temperature for 3 hours, and then filtered. The filter cake was washed with 2×32 mL of EtOH and vacuum dried at 50 ° C for 20 hours to obtain 29.8 g of 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 hours. As a further and final purification step, the off-white / white powder obtained was redissolved in DMSO (45 mL) at 100 ° C for more than 15 minutes. The solution was then cooled to 45 ° C, and EtOH (500 mL) was then added dropwise. After the addition of 150 mL of EtOH, the reaction mixture began to become turbid. The resulting slurry was stirred at 25-30 ° C for 20 hours and then filtered. The filter cake was washed with 2×100 mL of EtOH. The resulting Tris salt was ground in 20 volumes of EtOH at 70 ° C for 5 hours, then cooled to 25-30 ° C for more than 2 hours and stirred at the same temperature for 3 hours. This process was repeated three times before 28 g of Tris salt was obtained in the form of an off-white solid. The XRPD spectrum of Tris salt form C is shown in Fig. 9A , the corresponding peak list is shown in Fig. 9B . Fig. 9CThe TGA / DSC curve in shows that the weight loss is 1.2% at a maximum of 150°C, with a sharp endotherm at 193.1°C (onset temperature) and a peak at 196.9°C. 1 H NMR (data not shown) confirmed the stoichiometry to be 1.00:1.02 (free acid / Tris).

[0398] Other procedures that can be used to obtain Tris salt form C are described below. 4 g of compound 1 in free acid form was slurried with 1.5 grams of Tris in 10 ml of dimethyl sulfoxide at room temperature. The reaction solution was cooled to about 30 ° C and 20 ml of EtOH was added. 10 mg of Tris salt form A was added and stirred for 5 minutes to form a turbid solution. The mixture was stirred for 2 hours and diluted with 60 mL of EtOH to form a slurry. The slurry was stirred at 28-32 ° C overnight. The solid was collected by filtration, washed with 2×20 mL of EtOH and dried to obtain Tris salt form C as an off-white solid.

[0399] The free acid form of compound 1 and 1.05 equivalents of Tris are mixed with 2.5 volumes of DMSO in a flask. The mixture is heated to ~100 ° C and stirred for 0.5-1 hour to form a clear solution. The solution is cooled to 60-70 ° C and slowly diluted with an additional volume of EtOH (which can be in the range of 5-15 volumes). The seeds of Tris salt form C are added, and then an additional volume of EtOH (which can be in the range of 5-15 volumes) is slowly added within 2 hours. The mixture is stirred at 60-70 ° C for 16-24 hours and cooled to 20-30 ° C. The mixture is stirred at 20-30 ° C for 2-4 hours. The solid is collected by filtration, washed with EtOH, and vacuum dried at 40-50 ° C for 8-12 hours to obtain Tris salt form C as an off-white solid.

[0400] Example 5 - Comparative Thermodynamic Stability Study of Tris Salt Form A and Tris Salt Form C

[0401] The thermodynamic stability relationship between Tris salt Form A and Form C was investigated by slurry competition experiments in two process-relevant solvent systems, DMSO / EtOH (1:8, v / v) and EtOH, at four temperature conditions (5°C / room temperature / 50°C / 75°C). Two stages of slurry competition experiments were performed, with the first stage using temperature as the variable and the second stage using freshly opened reagents to minimize the effect of absorbed water. The typical experimental procedure is described below.

[0402] First, about 5-10 mg of crystalline Tris salt form C was dissolved in 1.0 mL of the corresponding solvent to form a solution close to saturation at the corresponding temperature (equilibrium method: magnetic stirring, 1000 rpm, 2 hours). Then, 15 mg of each form (crystalline Tris salt form A and C) was physically mixed, and then a close to saturated solution was added to form a suspension. The suspension was then stirred (1000 rpm) for 7 days at the corresponding temperature (a small amount of solid was sampled at the 2-day point of the second phase experiment). The solid obtained was separated by centrifugation (10000 rpm, 2 minutes) and tested by XRPD to confirm the form.

[0403] The conversion of Tris salt Form A to Tris salt Form C is shown, indicating that Tris salt Form C is thermodynamically more stable between 5°C and 50°C.

[0404] Example 6 - Comparative Dynamic Solubility Study of Free Acid Form D, Tris Salt Form A and Tris Salt Form C

[0405] The dynamic solubility of Tris salt form A and free acid form D at 37°C in three biologically relevant media (SGF, FaSSIF and FeSSIF) was measured. Specifically, approximately 30 mg of solid was initially suspended in 4.0 mL of each medium and balanced by shaking (500 rpm) at 37°C. Approximately 0.8 mL of suspension was extracted at each time point of 15 / 30 / 60 / 120 minutes and 24 hours. Supernatant and precipitate were separated by centrifugation (10000 rpm, ~3 minutes), and the supernatant was then concentrated (HPLC) and pH measured, and the corresponding solid form was characterized by XRPD.

[0406] As shown in the data summarized in Table 11, the solubility of the free acid form D was measured to be 3-8 μg / mL in FaSSIF and FeSSIF and <1 μg / mL in SGF. Compared with the free acid form D, an increase in the solubility of the Tris salt form A in all SGF / FaSSIF / FeSSIF media was observed during the equilibrium process (>100 μg / mL at 24 hours). At the same time, a change in pH was observed in the three media, especially to 7.4 (24 hours) in SGF (pH: 1.8), which may have led to the increase in solubility because this free form exhibits acidity in the aqueous phase.

[0407] Table 11. Summary of kinetic solubility data for free acid form D and Tris salt form A in SGF / FaSSIF / FeSSIF

[0408]

[0409] Due to the thermodynamic stability of Tris salt Form C, further evaluations were performed, including dynamic solubility in three biorelevant media (FaSSGF / FaSSIF / FeSSIF) and H2O 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 fasted and fed conditions (FaSSIF and FeSSIF), with progressively decreasing API concentration values ​​detected in FaSSIF / FeSSIF / H2O (FaSSIF: from 0.39 mg / mL to 0.17 mg / mL; FeSSIF: from 0.33 mg / mL to 0.04 mg / mL; H2O: from 0.81 mg / mL to 0.40 mg / mL).

[0410] Table 12. Summary of kinetic solubility data of Tris salt form C in SGF / FaSSIF / FeSSIF

[0411]

[0412] *: Precipitation occurred during HPLC / pH testing (samples for HPLC testing were diluted until clear).

[0413] Example 7 - Comparative Hygroscopicity Study of Free Acid Form D, Tris Salt Form A and Tris Salt Form C

[0414] In order to evaluate the hygroscopicity of free acid form D, Tris salt form A and Tris salt form C of compound 1, dynamic vapor sorption (DVS) data of each sample was collected at 25°C. When the humidity was changed from 0% relative humidity to 80% relative humidity at 25°C, ~5% weight water absorption was observed for both free form type D and Tris salt form A. The hygroscopicity of Tris salt form C was lower, where only about 0.04% weight water absorption was observed in the same humidity range. It was confirmed by XRPD that the solid form remained as Tris salt form C after the DVS test (data not shown).

[0415] Example 8 - Pharmacokinetic study comparing free acid and Tris salt

[0416] 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, multiple batches of Compound 1 free acid and Tris salt of Compound 1 (not tested for crystallinity) from different production batches and with different particle size distributions were formulated at a concentration of 100 mg / mL with 0.5% (w / v) methylcellulose and 0.2% (v / v) Tween 80 in water. All animals had free access to food and water, and Compound 1 or Tris salt Form C of the compound was orally administered at 100 mg / kg (100 mg / kg). About 110 μL of whole blood was collected by tail vein bleeding into tubes containing the anticoagulant K2EDTA before and 0.083, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours after dosing, processed to obtain plasma, and stored at about -70°C until analysis. The concentration of active pharmaceutical ingredient in plasma samples was quantified using an unvalidated liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. (Version 6.4; Pharsight Corporation, Mountain View, CA, USA) Pharmacokinetic analysis was performed on individual plasma concentration data. Pharmacokinetic parameters were estimated using a non-ventricular extravascular model approach. The area under the concentration-time curve (AUC) was calculated using the linear trapezoidal rule. For the calculation of PK parameters, AG-636 concentrations below the limit of quantification (BLQ) at the end of the phase were excluded. Concentrations below 80% of the LLOQ were designated as BLQ.

[0417] The results of the PK experiment using SD male rats are summarized in Table 13 below. The PK curves of the Tris salt and free base of Compound 1 are shown in Table 13. Figures 10A-10B Among the free acid forms evaluated, batches A and B achieved some of the highest exposure increases, such as Fig. 10A However, batch A and batch B are early batches of the free acid of compound 1, which are only partially crystalline and characterized by the presence of a large amount of residual organic solvents and are therefore not suitable for formulation development. In addition, batch A and batch B are produced by a process that is considered unsuitable for large-scale synthesis.

[0418] Therefore, in order to identify a final form with similar exposure to Batch A and Batch B, a new free form of Compound 1 with better crystallinity and acceptable residual solvent levels was synthesized using an improved process. This new free form of Compound 1 was also synthesized in different particle size distributions (i.e., Batch C, Batch D, and Batch E), as summarized in Table 13, to evaluate the effect of particle size reduction on the exposure of the free form in PK studies. Unfortunately, despite the improved crystallinity and purity, Batch C, Batch D, and Batch E did not show equivalent exposure to that previously observed (see Fig. 10B ).

[0419] In summary, referring to Table 13, the T of the Tris salt of compound 1 max and C max (representing the time when the maximum API concentration occurs and the maximum API concentration itself, respectively) are significantly better than the corresponding parameters observed for the free acid. Specifically, the Tris salt allows for faster absorption of higher maximum API concentrations, as evidenced by lower T and T values, compared to the free acid for all batches. max Value and higher C max It is noteworthy that even when comparing the Tris salt to the best free acid batch B, T max It is also about 2 times lower, C max Based on the in vivo PK data, it is expected that the in vitro solubility and / or dissolution rate of the Tris salt will be significantly higher.

[0420] Table 13. PK parameters of free acid and Tris salt of compound 1

[0421]

[0422]

[0423] Example 9 - Capsule composition

[0424] A 10 mg strength capsule (free form equivalent) can be prepared as described in Table A using a dry granulation process and a direct encapsulation process.

[0425] Table A: Batch formulation composition

[0426]

[0427] Hard capsules (free form equivalent) of 50, 100 and 125 mg doses can be prepared as described in Table B using dry granulation process and direct encapsulation process.

[0428] Table B: Batch formulation composition

[0429]

[0430] Hard capsules (free form equivalent) of 100 and 125 mg doses can be prepared as described in Tables C and D using the following dry granulation process and direct encapsulation process.

[0431] Table C: Batch formulation composition

[0432]

[0433] Table D: Batch formulation composition

[0434]

[0435] The Tris salt of Compound 1 and the excipients listed in Table C and Table D were weighed and sieved for mixing. The Tris salt of Compound 1 and the intragranular ingredients (diluent, disintegrant, binder, surfactant, glidant and lubricant) were mixed in a suitable blender. The intragranular mixture was rolled (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 mixture was granulated and the granulated mixture was sized.

[0436] The extragranular ingredients (glidants and lubricants) are weighed and sieved for mixing. The extragranular ingredients and the milled granules are sieved and then added to a suitable blender for mixing.

[0437] The mixed material was then encapsulated into size 1 capsules by hand filling capsules. The capsules were stored at ambient conditions (15-25°C).

[0438] Although multiple embodiments have been described, the scope of the present disclosure will be limited by the appended claims rather than by the specific embodiments that have been represented by way of example. The contents of all references (including literature references, published patents, published patent applications, and co-pending patent applications) cited in this application in full are hereby fully and explicitly incorporated into this application by reference. Unless otherwise defined, all scientific and technological terms used in this application have meanings well known to those of ordinary skill in the art.

Claims

1. A tris(hydroxymethyl)aminomethane salt of a compound, wherein the compound is represented by the following formula:

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

3. The tris(hydroxymethyl)aminomethane salt according to claim 1, wherein the salt is at least 60% by mass in a single crystalline form.

4. The tris(hydroxymethyl)aminomethane salt of claim 1, wherein the salt is at least 70% by mass in a single crystalline form.

5. The tris(hydroxymethyl)aminomethane salt of claim 1, wherein the salt is at least 80% by mass in a single crystalline form.

6. The tris(hydroxymethyl)aminomethane salt of claim 1, wherein the salt is at least 90% by mass in a single crystalline form.

7. The tris(hydroxymethyl)aminomethane salt of claim 1, wherein the salt is at least 95% by mass in a single crystalline form.

8. The tris(hydroxymethyl)aminomethane salt of claim 1, wherein the salt is at least 99% by mass in a single crystalline form.

9. The tris(hydroxymethyl)aminomethane salt according to claim 1, wherein the salt has a chemical purity of at least 60% by mass.

10. The tris(hydroxymethyl)aminomethane salt according to claim 1, wherein the salt has a chemical purity of at least 70% by mass.

11. The tris(hydroxymethyl)aminomethane salt according to claim 1, wherein the salt has a chemical purity of at least 80% by mass.

12. The tris(hydroxymethyl)aminomethane salt according to claim 1, wherein the salt has a chemical purity of at least 90% by mass.

13. The tris(hydroxymethyl)aminomethane salt according to claim 1, wherein the salt has a chemical purity of at least 95% by mass.

14. The tris(hydroxymethyl)aminomethane salt according to claim 1, wherein the salt has a chemical purity of at least 99% by mass.

15. The tris(hydroxymethyl)aminomethane salt according to claim 1, wherein the salt is an anhydrate.

16. The tris(hydroxymethyl)aminomethane salt of claim 15, wherein the salt is Form A characterized by X-ray powder diffraction peaks at 2θ of 4.4°, 11.5°, 15.6°, 16.4°, 18.9°, 19.6°, and 25.5°±0.2°.

17. The tris(hydroxymethyl)aminomethane salt of claim 16, wherein the crystalline form A is further characterized by at least one X-ray powder diffraction peak at 2θ selected from 8.7°, 15.2°, 18.6°, 21.4°, and 25.1°±0.2°.

18. The tris(hydroxymethyl)aminomethane salt of claim 17, wherein the crystalline Form A is characterized by an X-ray powder diffraction pattern substantially the same as that of FIG. 7A.

19. The tris(hydroxymethyl)aminomethane salt of claim 15, wherein the salt is Form B characterized by X-ray powder diffraction peaks at 2θ of 6.0°, 7.0°, 7.2°, 9.3°, 12.5°, 15.6°, and 19.0°±0.2°.

20. The tris(hydroxymethyl)aminomethane salt of claim 19, wherein the crystalline Form B is characterized by an X-ray powder diffraction pattern substantially the same as that of FIG. 8A.

21. The tris(hydroxymethyl)aminomethane salt of claim 15, wherein the salt is Form C characterized by X-ray powder diffraction peaks at 2θ of 4.5°, 13.5°, 14.3°, 18.0°, 18.3°, and 23.5°±0.2°.

22. The tris(hydroxymethyl)aminomethane salt of claim 21, wherein the crystalline Form C is further characterized by at least one X-ray powder diffraction peak at 2θ selected from 16.3°, 19.0°, 21.2°, 22.5°, and 22.8°±0.2°.

23. The tris(hydroxymethyl)aminomethane salt of claim 22, wherein the Form C is characterized by an X-ray powder diffraction pattern substantially the same as that of Figure 9A.

24. A pharmaceutical composition comprising the tris(hydroxymethyl)aminomethane salt of any one of claims 1 to 23 and one or more pharmaceutically acceptable excipients.

25. A pharmaceutical composition comprising the tris(hydroxymethyl)aminomethane salt of any one of claims 16 to 18 and one or more pharmaceutically acceptable excipients.

26. A pharmaceutical composition comprising the tris(hydroxymethyl)aminomethane salt of claim 19 or 20 and one or more pharmaceutically acceptable excipients.

27. A pharmaceutical composition comprising the tris(hydroxymethyl)aminomethane salt of any one of claims 21-23 and one or more pharmaceutically acceptable excipients.

28. A pharmaceutical composition comprising the tris(hydroxymethyl)aminomethane salt of any one of claims 1-23 and one or more intragranular excipients.

29. A pharmaceutical composition comprising the tris(hydroxymethyl)aminomethane salt of any one of claims 16-18 and one or more intragranular excipients.

30. A pharmaceutical composition comprising the tris(hydroxymethyl)aminomethane salt of claim 19 or 20 and one or more intragranular excipients.

31. A pharmaceutical composition comprising the tris(hydroxymethyl)aminomethane salt of any one of claims 21-23 and one or more intragranular excipients.

32. The pharmaceutical composition of claim 31 , further comprising one or more extragranular excipients.

33. A pharmaceutical composition comprising the tris(hydroxymethyl)aminomethane salt of any one of claims 1 to 23 and a pharmaceutically acceptable carrier as a solid dispersion.

34. Use of a tris(hydroxymethyl)aminomethane salt according to any one of claims 1 to 23 in the preparation of a medicament for treating cancer, wherein the tris(hydroxymethyl)aminomethane salt or the pharmaceutical composition according to any one of claims 24 to 33 is optionally combined with an additional therapeutic agent.

35. The use according to claim 34, wherein the cancer is a solid tumor.

36. The use according to claim 35, wherein the cancer is selected from Lung cancer, breast cancer, melanoma, glioblastoma, prostate cancer, colon cancer, pancreatic cancer, bone cancer, head and neck cancer, skin cancer, skin or intraocular malignancy of the endometrium, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethra cancer, penile cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system tumors, tumor angiogenesis, spinal cord tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancers, and PTEN mutant cancers; and Biliary tract cancer or ampulla of Vater cancer, liver cancer, ovarian cancer, and upper aerodigestive tract cancer.

37. The use according to claim 36, wherein the breast cancer is triple-negative breast cancer.

38. The use according to claim 36, wherein the lung cancer is non-small cell lung cancer.

39. The use according to claim 38, wherein the non-small cell lung cancer is bronchoalveolar carcinoma.

40. The use according to claim 34, wherein the cancer is a blood cancer.

41. The use according to claim 40, wherein the blood cancer is selected from myeloma, lymphoma and leukemia.

42. The use according to claim 41, wherein the blood cancer is selected from Acute myeloid leukemia, multiple myeloma, B-prolymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, follicular lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, bladder lymphocytic lymphoma, primary CNS lymphoma, and T-cell lymphoma; Chemotherapy-resistant acute myeloid leukemia, cytarabine-resistant acute myeloid leukemia, acute monocytic leukemia, B-cell lymphoma, diffuse mixed cell lymphoma, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, primary effusion lymphoma, erythroleukemia, chronic myeloid leukemia, and chronic monocytic leukemia; Angioimmunoblastic lymphoma, Burkitt's lymphoma, Burkitt-like lymphoma, blastic NK-cell lymphoma, cutaneous T-cell lymphoma, lymphoblastic lymphoma, MALT lymphoma, small lymphocytic lymphoma, thyroid lymphoma, Waldenstrom's macroglobulinemia, essential thrombocythaemia, chronic idiopathic myelofibrosis, and polycythemia vera.

43. The use according to claim 42, wherein the B cell lymphoma is selected from diffuse large B cell lymphoma, mediastinal large B cell lymphoma and nodal marginal zone B cell lymphoma.

44. The use according to claim 43, wherein the diffuse large B-cell lymphoma is selected from double-hit diffuse large B-cell lymphoma and triple-hit diffuse large B-cell lymphoma.

45. The use according to claim 35, wherein the cancer is selected from pediatric solid tumors.

46. ​​Use of a tris(hydroxymethyl)aminomethane salt according to any one of claims 1 to 23 in the preparation of a medicament for treating cancer, wherein the cancer is responsive to inhibition of dihydroorotate dehydrogenase.

47. Use of a tris(hydroxymethyl)aminomethane salt according to any one of claims 1 to 23 in the preparation of a medicament for treating a condition or disease selected from a virally mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, an autoimmune disease or an inflammatory disease.

48. Use of a tris(hydroxymethyl)aminomethane salt as claimed in any one of claims 1 to 23 in the preparation of a medicament for inhibiting the growth and / or metastasis of tumor cells in a subject, wherein the tumor cells are responsive to inhibition of dihydroorotate dehydrogenase.

49. Use of the tris(hydroxymethyl)aminomethane salt of any one of claims 1-23 in the preparation of a medicament for inhibiting dihydroorotate dehydrogenase in a subject.

Images