Pharmaceutical compositions

Abstract

Pharmaceutical compositions comprising an indazole FGFR inhibitor, as well as methods of using such pharmaceutical compositions in treating cancer and developmental disorders, are provided.

Description

PHARMACEUTICAL COMPOSITIONSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of United States Provisional Application No. 63 / 567,099, filed March 19, 2024, and United States Provisional Application No. 63 / 677,056, filed July 30, 2024. The entirety of each aforementioned application is incorporated by reference herein in its entirety.TECHNICAL FIELD

[0002] The disclosure pertains to pharmaceutical compositions containing an indazole FGFR inhibitor that is useful in treating cancer and developmental disorders, as well as methods of using such pharmaceutical compositions in treating cancer.BACKGROUND

[0003] Kinase inhibitors have been used to block the activity of kinases and thereby treat cancer (e.g., by inhibiting mitotic processes). These kinase inhibitors are often small molecules that target kinases to block the development, growth or spread of cancer.

[0004] Although various inhibitors of kinases are known, however, there remains a need for selective inhibitors to be used for the treatment of cancers, which offer one or more advantages over current compounds. Those advantages include: improved activity and / or efficacy; beneficial kinase selectivity profile according to the respective therapeutic need; improved side effect profile, such as fewer undesired side effects, lower intensity of side effects, or reduced (cyto)toxicity; improved targeting of mutant receptors in diseased cells; improved physicochemical properties, such as solubility / stability in water, body fluids, and / or pharmaceutical formulations; improved pharmacokinetic properties, allowing e.g. for dose reduction or an easier dosing scheme; easier drug substance manufacturing, e.g., by shorter synthetic routes or easier purification.

[0005] The compound of Formula (I), 5-[(lR)-l-(3,5-dichloro-4-pyridyl)ethoxy]-3- [6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-lH-indazole, and its preparation, are described in International Patent Application No. PCT / US2021 / 065679 (WO2022 / 147246), the entirety of which is incorporated by reference herein.

[0006] Pharmaceutically acceptable salts of Formula (I), including the besylate salt, as well as polymorphic forms of those salts, are described in International Patent Application No. PCT / US2023 / 069334 (W02024 / 006883), the entirety of which is incorporated by reference herein.

[0007] Therapeutic use of the compound of Formula (I) will depend in part on being able to achieve adequate bioavailability of the compound. The Developability Classification System (DCS) is an industry proven model designed to guide formulation. See Butler, J.M. and J.B. Dressman, The developability classification system: application of biopharmaceutics concepts to formulation development. J Pharm Sci, 2010. 99(12): p. 4940-54. This classification model is based upon the molecule’s dose / solubility ratio and the molecule’s permeability. DCS distinguishes poorly soluble molecules in three (3) scenarios: dissolution rate limited (DCS Ila), solubility limited (DCS lib), and solubility and permeability limited (DCS IV). Furthermore, a solubility-limited absorbable dose (SLAD), which informs the cutoff between DCS Ila and lib - may be calculated as shown in Equation 1.Equation 1: SLAD (mg)=500 x An x S where,S = API solubility in FaSSIF (or FeSSIF) expressed in mg / mL An = Absorption number which is equal to Peff ifPeff is >1 and equal to 1 if Peff is <1Peff = Predicted permeability in humans expressed in 10-4 cm / s

[0008] The DCS category and SLAD for Formula (I) were calculated in biorelevant media. A projected upper human dose of 50 mg was used for the calculation. Formula (I)should be considered a DCS IV (solubility and permeability limited absorption depending on dose with a SLAD of 30 mg in FeSSIF and 5 mg in FaSSIF).

[0009] Thus, there is a need for pharmaceutical compositions to enhance the bioavailability of the compound of Formula (I).SUMMARY

[0010] The disclosure provides pharmaceutical compositions for oral administration that provide adequate bioavailability of the compound of Formula (I) to facilitate its use in treating cancer.

[0011] The disclosure also provides methods of treating cancer in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising:(a) a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Fig. 1 shows an image of 20 mg Formula (I) besylate direct compression tablets showing “picking” defects (A0020640-01).

[0013] Fig. 2 shows the dissolution (RM 1953) of 20 mg Formula (I) besylate direct compression tablets, modified formulation with 1.0% magnesium stearate (A0020964-02).

[0014] Fig. 3 shows dissolution of 20 mg Formula (I) besylate direct compression tablets and 20 mg capsules (size 1, gelatin). Modified dissolution method Of 900 mL, apparatus II at 75 rpms with an infinity spin interval.

[0015] Fig. 4 shows a differential scanning calorimetry (DSC) profile of the Formula (I) besylate formulation blend containing 0.5% magnesium stearate.

[0016] Fig. 5 shows a DSC profile of the Formula (I) besylate tablet formulation with 0.5% magnesium stearate, prepared from a crushed tablet.

[0017] Fig. 6 shows a DSC profile of the Formula (I) besylate 10% drug load formulation blend (A0020940-02) with increased magnesium stearate to 1.0%.

[0018] Fig. 7 shows a DSC profile of the Formula (I) besylate 20 mg tablet formulation with an increased 1.0% magnesium stearate level (A0020940-02) prepared from a crushed tablet.

[0019] Fig. 8 shows dissolution of 20 mg Formula (I) Besylate 1% magnesium stearate (A002096-02) and 1% sodium stearyl fumarate (A0020964-03) tablets. Modified dissolution method Of 900 mL, apparatus II at 75 rpms with an infinity spin interval.

[0020] Fig. 9 shows dissolution of Formula (I) Besylate 20 mg formulations filled in capsules. A blend w / o lubricant or disintegrant (A0020964-04), blend w / 1.0% SSF lubricant but no disintegrant and Formula (I) Besylate drug substance in a capsule. A0020964-04 (N=3), A0020964-04A (N=6) and Formula (I) Besylate (N=3).

[0021] Fig. 10 shows dissolution of Formula (I) Besylate 20 mg tablets. Tablets from the A00200964-04A w / o disintegrant and A0020964-04B w / disintegrant are plotted.

[0022] Fig. 11 shows dissolution Testing of 10 and 30 mg Feasibility Batch Tablets.

[0023] Fig. 12 shows Formula (I) Besylate Tablet, 10 mg Dissolution Hardness Profile

[0024] Fig. 13 shows Formula (I) Besylate Tablet, 30 mg Dissolution Hardness Profile.

[0025] Fig. 14 shows Formula (I) Besylate Tablet, Final Coated Tablet vs. Capsule Dissolution.

[0026] Fig. 15 shows the effect of micronization on dissolution for DS lot 005NPM017.

[0027] Fig. 16 shows the kinetic solubility of micronized API.

[0028] Fig. 17 shows Formula (I) Lipid Prototype Set 3 Dissolution in FaSSGF Media.

[0029] Fig. 18 shows Formula (I) Lipid Prototype Set 3 Dissolution in FaSSIF Media.

[0030] Fig. 19 shows Formula (I) Lipid Prototype Set 5 Dissolution in FaSSIF Media

[0031] Fig. 20 shows Formula (I) Lipid Prototype Formulations (Set 5) 2 Step Dissolution

[0032] Fig. 21 shows Mean (± SD, n = 4) Plasma Concentration vs. Time Curves of Formula (I) after 2 mg / kg POA, 2 mg / kg POB, 2 mg / kg POC and 2 mg / kg POD and 2 mg / kg POE Administration to Male Beagle Dogs.

[0033] Fig. 22 shows Mean (± SD, n = 4) Plasma Concentration vs. Time Curves of Formula (I) after 2 mg / kg POA, 2 mg / kg POB, and 2 mg / kg POD Administration to Male Beagle DogsDETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0001] The disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. Certain features of the disclosed methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect. Alternatively, various features of the disclosed methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.

[0002] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0003] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and doesnot abrogate the biological activity and properties of the compound. In several embodiments, the salt is an acid addition salt of the compound.

[0004] In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (I) is the hydrochloride salt, besylate salt, maleate salt, tosylate salt, sulfate salt, 2-hydroxyethanesulfonate salt, ethanesulfonate (esylate) salt, mesylate salt, di-mesylate salt, A’-camsylate salt, 5-camsylate salt, or hydrobromide salt.

[0005] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. It is understood that, in any compound described herein having one or more chiral centers, all possible diastereomers are also envisioned. It is understood that, in any compound described herein all tautomers are envisioned. It is also understood that, in any compound described herein, all isotopes of the included atoms are envisioned. For example, any instance of hydrogen, may include hydrogen- 1 (protium), hydrogen-2 (deuterium), hydrogen-3 (tritium) or other isotopes; any instance of carbon may include carbon-12, carbon-13, carbon-14, or other isotopes; any instance of oxygen may include oxygen-16, oxygen-17, oxygen-18, or other isotopes; any instance of fluorine may include one or more of fluorine- 18, fluorine- 19, or other isotopes; any instance of sulfur may include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.

[0006] A “pharmaceutically acceptable excipient” refers to a substance that is nontoxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a compound of Formula (I) and that is compatible therewith.

[0007] As used herein, “subject,” “host,” “patient,” “participant,” and “individual” are used interchangeably and shall be given its ordinary meaning and shall also refer to an organism that has FGFR proteins. This includes mammals, e.g., a human, a non-humanprimate, ungulates, canines, felines, equines, mice, rats, and the like. The term “mammal” includes both human and non-human mammals.

[0008] The terms “treatment,” “treating,” “treat” and the like shall be given its ordinary meaning and shall also include herein to generally refer to obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and / or adverse effect attributable to the disease. “Treatment” as used herein shall be given its ordinary meaning and shall also cover any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, e.g., arresting its development; and / or (c) relieving the disease symptom, e.g., causing regression of the disease or symptom.

[0009] The term “administering,” when used in the context of administering a therapeutic agent to a patient, refers to introducing the therapeutic agent into the patient’s body. For example, therapeutic agents may be introduced into a patient’s body orally, nasally, subcutaneously, intravenously, intravesically, intramuscularly, transdermally, vaginally, rectally or in any combination thereof.

[0010] The terms “cancer,” “neoplasm,” and “tumor” are used interchangeably herein, shall be given its ordinary meaning and shall also refer to cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. In general, cells of interest for detection or treatment in the present application include precursors, precancerous e.g., benign), malignant, pre-metastatic, metastatic, and non-metastatic cells.

[0011] As used herein, “an activating FGFR3 gene alteration” refers to a mutation or rearrangement of the FGFR3 gene, relative to the wild-type FGFR3 gene, such that the FGFR3 gene having an activating FGFR3 gene alteration encodes an FGFR kinase that has greater FGFR3 kinase activity that the FGFR kinase that is encoded by the wild-type FGFR3 gene.

[0012] In some aspects, the disclosure provides pharmaceutical compositions for oral administration that provide adequate bioavailability of the compound of Formula (I) to facilitate its use in treating cancer.

[0013] In other aspects, the disclosure also provides methods of treating cancer in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition of the disclosure.

[0014] The disclosure provides pharmaceutical compositions that are capsules, tablets comprising micronized active ingredient, lipid based liquid formulations, and liquid aqueous solution formulations.CAPSULE FORMULATIONS

[0015] In some aspects, the disclosure is directed to capsules for oral administration.

[0016] In some embodiments, the capsules of the disclosure comprise a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent.

[0017] In some embodiments, the capsules of the disclosure comprise the compound of Formula (I) as the free base.

[0018] In other embodiments, the capsules of the disclosure comprise a pharmaceutically acceptable salt of the compound of Formula (I). In other embodiments, the capsules of the disclosure comprise a besylate salt of the compound of Formula (I). In yet other embodiments, the capsules of the disclosure comprise polymorphic Form I of the besylate salt of the compound of Formula (I). See W02024 / 006883 at

[0126] ,

[0821] -

[0823] (Form I of Compound 2).

[0019] In some aspects, the capsules of the disclosure comprise a pharmaceutically acceptable diluent, such as, for example, microcrystalline cellulose.

[0020] In some embodiments, the capsules of the disclosure comprise microcrystalline cellulose, sue as, for example, Avicel PH-102.

[0021] In some embodiments, the capsule is a gelatin capsule.

[0022] In some embodiments, the capsules of the disclosure comprise 5 mg - 30 mg (on a Formula (I) free base basis) of Formula (I), or a pharmaceutically acceptable salt thereof, such as, for example, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, or 30 mg.

[0023] In some embodiments, the capsules of the disclosure have the composition shown in the table below:a free base equivalent.TABLETS COMPRISING MICRONIZED API

[0024] In some aspects, the pharmaceutical compositions of the disclosure are tablets comprising of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0025] In some embodiments, the tablets of the disclosure comprise the compound of Formula (I) as a freebase.

[0026] In other embodiments, the tablets of the disclosure comprise the compound of Formula (I) as a pharmaceutically acceptable salt. In some embodiments, the tablets of the disclosure comprise the compound of Formula (I) as a besylate salt. In yet other embodiments, the tablets of the disclosure comprise polymorphic Form I of the besylate salt of the compound of Formula (I). See W02024 / 006883 at

[0126] ,

[0821] -

[0823] (Form I of Compound 2).

[0027] In some embodiments, the tablets comprise a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 5 mg - about 200 mg (on a Formula (I) basis) per tablet, such as, for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 mg per tablet.

[0028] In some embodiments, the tablets comprise a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 5 mg - about 40 mg (on a Formula (I) basis) per tablet, such as, for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg per tablet. In someembodiments, the tablets comprise a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg (on a Formula (I) basis) per tablet. In other embodiments, the tablets comprise a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 30 mg (on a Formula (I) basis) per tablet.

[0029] In some embodiments, the tablets comprise a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 7.5% - about 8.0% by weight (on a Formula (I) basis), such as about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, or about 8.0% by weight (on a Formula (I) basis). In some embodiments, the pharmaceutical tablets comprise a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 7.7% by weight (on a Formula (I) basis).

[0030] In other embodiments, the tablets comprise a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 4% - about 6% by weight (on a Formula (I) basis), such as about 4.0%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, or about 6.0% by weight (on a Formula (I) basis).

[0031] In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, that is used in the tablets is micronized. In some embodiments, the micronized compound of Formula (I), or pharmaceutically acceptable salt thereof, has a volume mean diameter of Xio<l pm; Xso<3 pm; and X90<10 pm.

[0032] In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, that is used in the tablets is micronized. In some embodiments, the micronized compound of Formula (I), or pharmaceutically acceptable salt thereof, has a volume mean diameter of Xio<l pm; Xso<3 pm; and X9o<5 pm.

[0033] . In some embodiments, the micronized compound of Formula (I), or pharmaceutically acceptable salt thereof, has a volume mean diameter of Xio<O.9 pm; Xso<1.8 pm; and X9o<4.3 pm.

[0034] In aspects, the tablets of the disclosure comprise a pharmaceutically acceptable excipient, such as, for example, a diluent / compression aid, a binder, a disintegrant a glidant, a lubricant, a surfactant, or a film coating, or a combination thereof.

[0035] In some embodiments, the tablets of the disclosure comprise a diluent / compression aid, such as, for example, lactose monohydrate, microcrystalline cellulose, mannitol, pregeletanized starch, or mixtures thereof.

[0036] In some embodiments, the tablets comprise a diluent / compression aid that is a mixture of lactose monohydrate and microcrystalline cellulose.

[0037] In some embodiments, the diluent / compression aid is present in the tablets of the disclosure in an amount of about 80% - about 90% by weight, such as about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or about 90% by weight. In some embodiments, the tablets comprise a about 87% by weight diluent / compression aid. In some embodiments, the tablets comprise a about 85.4% by weight diluent / compression aid.

[0038] In some embodiments, the tablets of the disclosure comprise a binder, such as, for example, hydroxypropyl methylcellulose or polyvinylpyrrolidone.

[0039] In some embodiments, the tablets of the disclosure comprise a disintegrant, such as, for example, croscarmellose sodium or crospovidone (i.e., cross-linked polyvinylpyrrolidone).

[0040] In some embodiments, the tablets of the disclosure comprise crospovidone disintegrant, such as, for example, VIVAPHARM® PVPP XL.

[0041] In other embodiments, the tablets of the disclosure comprise croscarmellose sodium as disintegrant.

[0042] In some embodiments, the tablets of the disclosure comprise 2% - 4% by weight (w / w) disintegrant, such as, for example, about 2%, about 2.5%, about 3%, about 3.5%, or about 4% by weight.

[0043] In some embodiments, the tablets of the disclosure comprise 1% - 2% by weight (w / w) disintegrant, such as, for example, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2.0% by weight.

[0044] In some embodiments, the tablets of the disclosure comprise 3% by weight (w / w) disintegrant. In some embodiments, the tablets of the disclosure comprise 3% by weight (w / w) crospovidone.

[0045] In other embodiments, the tablets of the disclosure comprise 1.8% (w / w) disintegrant. In some embodiments, the tablets of the disclosure comprise 1.8% (w / w) croscarmellose sodium.

[0046] In some embodiments, the tablets of the disclosure comprise a glidant, such as, for example, silicon dioxide. In some embodiments, the silicon dioxide is fumed silica. In some embodiments, the silicon dioxide is colloidal silicon dioxide.

[0047] In some embodiments, the glidant is present in the tablets of the disclosure in an amount of about 0.2% - about 0.7% by weight, such as about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, or about 0.7%, by weight. In some embodiments, the tablets comprise a about 0.5% by weight glidant.

[0048] In some embodiments, the tablet of the disclosure comprise 0.5% by weight fumed silica, such as, for example, CAB-O-SIL® M5P.

[0049] In other embodiments, the tablet of the disclosure comprise 0.45% by weight fumed silica, such as, for example, CAB-O-SIL® M5P.

[0050] In some embodiments, the tablets of the disclosure comprise a lubricant, such as, for example, magnesium stearate or sodium stearyl fumarate. In some embodiments, the lubricant is sodium stearyl fumarate.

[0051] In some embodiments, the lubricant is present in the tablets of the disclosure in an amount of about 1% - about 2% by weight, such as about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2%, about by weight. In some embodiments, the tablets comprise about 1.5% by weight lubricant. In some embodiments, the tablets comprise about 1.4% by weight lubricant.

[0052] In some embodiments, the tablets of the disclosure comprise a surfactant, such as, for example, sodium lauryl sulfate or Pluronic F68.

[0053] In some embodiments, the tablets of the disclosure have the compositions set forth in Example 8 below.

[0054] In some embodiments, the tablets of the disclosure have the compositions shown in the table below: Tablet - 10 mg and 30 mg Formulation Composition1Actual salt quantity determined using correction factor, CF = % Assay (Anhydrous and Solvent Free) / 100 x (100% - % Water - % Residual Solvent - % Impurities - % Counterion Content)

[0055] In some embodiments, the tablets of the disclosure further comprise a film coating, such as, for example, a hydroxypropyl methyl cellulose-based coating (e.g., Opadry) or a polyvinyl alcohol-based coating (e.g., Opadry II).

[0056] In some embodiments, the film coating has a composition as set forth in Example 8 below.

[0057] In some embodiments, the film coating adds between 2% - 4% by weight to the uncoated tablet, such as, for example, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, or about 4% by weight. As an example, an uncoated tablet that weighs 130 mg that is coated with a 5 mg film coating has had about 3.8% by weight added to the weight of the uncoated tablet.

[0058] In some embodiments, the film coating adds about 3.7% by weight to the weight of the uncoated tablet.

[0059] In some embodiments, the film coating comprises about 0.9% by weight of the coated tablet.

[0060] In some embodiments, the tablets comprise about 2% by weight of an antistatic agent, such as, for example, talc.

[0061] In other embodiments, the tablets of the disclosure have the compositions shown in the table below. In some embodiments, the tablets made using this formulation are mini-tabs.(1)58.179 mg / gram Formula (I) besylate salt is equivalent to 45.34 Formula (I) free base.

[0062] In some embodiments, the mini-tabs of the disclsoure have the compositions as set forth in Example 9 below.

[0063] In some embodiments, the minitabs are loaded into capsule to form sprinkle capsules. In some embodiments, the capsules contain 4 minitabs per capsule. In some embodiments, the capsules contain 20 minitabs per capsule. In some embodiments, the capsules contain 40 minitabs per capsule.

[0064] In some embodiments, the minitabs comprise a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 4% - about 6% by weight (on a Formula (I) basis), such as about 4.0%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, or about 6.0% by weight (on a Formula (I) basis). In some embodiments, the minitabs comprise a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 5% by weight (on a Formula (I) basis).

[0065] In some embodiments, the minitabs of the disclosure comprise a diluent / compression aid, such as, for example, lactose monohydrate, microcrystalline cellulose, mannitol, pregeletanized starch, or mixtures thereof.

[0066] In some embodiments, the minitabs comprise a diluent / compression aid that is a mixture of lactose monohydrate and microcrystalline cellulose. In some embodiments, the diluent / compression aid is present in the minitabs of the disclosure in an amount of about about 90% by weight.

[0067] In some embodiments, the minitabs of the disclosure comprise about 2% (w / w) disintegrant. In some embodiments, the tablets of the disclosure comprise 2% (w / w) croscarmellose sodium.

[0068] In some embodiments, a glidant is present in the mintabs of the disclosure in an amount of about 0.2% - about 0.7% by weight, such as about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, or about 0.7%, by weight. In some embodiments, the minitabs comprise about 0.5% by weight glidant. In some embodiments, the minitabs of the disclosure comprise 0.5% by weight colloidal silicon dioxide.

[0069] In some embodiments, the minitabs of the disclosure comprise a lubricant, such as, for example, magnesium stearate or sodium stearyl fumarate. In some embodiments, the lubricant is sodium stearyl fumarate.

[0070] In some embodiments, the lubricant is present in the minitabs of the disclosure in an amount of about 1% - about 2% by weight, such as about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2%, about by weight. In some embodiments, the mintabs comprise about 1.5% by weight lubricant. In some embodiments, the minitabs comprise about 1.5% by weight sodium stearyl fumarate.LIPID VEHICLE-BASED LIQUID COMPOSITIONS

[0071] In some aspects, the disclosure is directed to lipid vehicle-based liquid compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof; a lipid vehicle; an antioxidant; and a crystallization inhibitor.

[0072] In some embodiments, the lipid vehicle-based liquid compositions of the disclosure comprise the compound of Formula (I) as a freebase.

[0073] In other embodiments, the lipid vehicle-based liquid compositions of the disclosure comprise the compound of Formula (I) as a pharmaceutically acceptable salt. In some embodiments, the lipid vehicle-based liquid compositions of the disclosure comprise the compound of Formula (I) as a besylate salt. In yet other embodiments, the lipid vehiclebased liquid compositions of the disclosure comprise polymorphic Form I of the besylate salt of the compound of Formula (I). See W02024 / 006883 at

[0126] ,

[0821] -

[0823] (Form I of Compound 2).

[0074] In some aspects, the compositions comprise a lipid vehicle, such as, for example, mono- and diglycerides of medium chain fatty acids (e.g., Capric / Caprylic Glycerides), polyethylene glycol 660 12-hydroxy stearate, macrogol glycerol hydroxy stearate, lauroyl polyoxyl-32 glycerides, propylene glycol monocaprylate, Vitamin E TPGS, or mono-, di-, and triglycerides of linoleic and oleic acids, or mixtures thereof.

[0075] In some embodiments of the lipid vehicle-based liquid compositions, the lipid vehicle is mono- and diglycerides of medium chain fatty acids (e.g., Capric / Caprylic Glycerides). In some embodiments of the lipid vehicle-based liquid compositions, the lipid vehicle is Masester E8120.

[0076] In some embodiments of the lipid vehicle-based liquid compositions, the lipid vehicle is polyethylene glycol 660 12-hydroxy stearate. In some embodiments of the lipid vehicle-based liquid compositions, the lipid vehicle is Kolliphor HS15.

[0077] In some embodiments of the lipid vehicle-based liquid compositions, the lipid vehicle is macrogolglycerol hydroxy stearate. In some embodiments of the lipid vehiclebased liquid compositions, the lipid vehicle is Kolliphor RH40.

[0078] In some embodiments of the lipid vehicle-based liquid compositions, the lipid vehicle is lauroyl polyoxyl-32 glycerides. In some embodiments of the lipid vehiclebased liquid compositions, the lipid vehicle is Gelucire 44 / 14.

[0079] In some embodiments of the lipid vehicle-based liquid compositions, the lipid vehicle is propylene glycol monocaprylate. In some embodiments of the lipid vehiclebased liquid compositions, the lipid vehicle is Caproyl 90.

[0080] In some embodiments of the lipid vehicle-based liquid compositions, the lipid vehicle is Vitamin E TPGS.

[0081] In some embodiments of the lipid vehicle-based liquid compositions, the lipid vehicle is mono-, di-, and triglycerides of linoleic and oleic acids. In some embodiments of the lipid vehicle-based liquid compositions, the lipid vehicle is Maisine CC.

[0082] In some aspects, the lipid vehicle-based liquid compositions comprise an antioxidant, such as, for example, ascorbyl palmitate.

[0083] In some embodiments of the lipid vehicle-based liquid compositions of the disclosure, the antioxidant is ascorbyl palmitate.

[0084] In some aspects, the lipid vehicle-based liquid compositions comprise a crystallization inhibitor, such as, for example, polyvinylpyrollidone.

[0085] In some embodiments of the lipid vehicle-based liquid compositions of the disclosure, the crystallization inhibitor is polyvinylpyrollidone. In some embodiments, the polyvinylpyrollidone is Kollidon K30.

[0086] In some aspects, the lipid vehicle-based liquid compositions of the disclosure comprise about 1% to about 10% by weight of the compound of Formula (I), or pharmaceutically acceptable salt thereof (on a compound of Formula (I) basis), such as, for example, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%,3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5%, 5.1%,5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%,6.6%, 6.7%, 6.8%, 6.9%, 7%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8%,8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, or 10% by weight.

[0087] In some aspects, the lipid vehicle-based liquid compositions of the disclosure comprise about 1% to about 3% by weight of the compound of Formula (I), or pharmaceutically acceptable salt thereof (on a compound of Formula (I) basis), such as, for example, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3% by weight.

[0088] In some embodiments, the lipid vehicle-based liquid compositions of the disclosure comprise about 1% to about 2% by weight of the compound of Formula (I), or pharmaceutically acceptable salt thereof (on a compound of Formula (I) basis), such as, for example, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or 2%.

[0089] In some embodiments, the lipid vehicle-based liquid compositions of the disclosure is a liquid suspension.

[0090] In other embodiments, the lipid vehicle-based liquid compositions of the disclosure is a liquid solution.

[0091] In some embodiments, the lipid vehicle-based liquid compositions of the disclosure comprises one of:(a) Formula (I) free base (1.25% wt / wt), Masester E8120 (63.0% wt / wt), Kolliphor HS15 (18.75% wt / wt), Vitamin E TPGS (15.0% wt / wt), Ascorbyl Palmitate (1.0% wt / wt), and Kollidon K30 (1.0% wt / wt);(b) Formula (I) free base (1.25% wt / wt), Masester E8120 (54.0% wt / wt), Gelucire 44 / 14 (24.0% wt / wt), Capryol 90 (18.75% wt / wt), Ascorbyl Palmitate (1.0% wt / wt), and Kollidon K30 (1.0% wt / wt);(c) Formula (I) free base (1.0% wt / wt), Masester E8120 (54.0% wt / wt), and Kolliphor RH40 (20.0% wt / wt), Maisine CC (23.0% wt / wt), Ascorbyl Palmitate (1.0% wt / wt), Kollidon K30 (1.0% wt / wt); or(d) Formula (I) free base (2.0% wt / wt), Labrasol ALF (55.0% wt / wt), Kolliphor RH40 (26.0% wt / wt), Maisine CC (15.0% wt / wt), Ascorbyl Palmitate (1.0% wt / wt), and Kollidon K30 (1.0% wt / wt).

[0092] In some embodiments, the lipid vehicle-based liquid compositions of the disclosure comprises Formula (I) free base (1.25% wt / wt), Masester E8120 (63.0% wt / wt), Kolliphor HS15 (18.75% wt / wt), Vitamin E TPGS (15.0% wt / wt), Ascorbyl Palmitate (1.0% wt / wt), and Kollidon K30 (1.0% wt / wt).

[0093] In some embodiments, the lipid vehicle-based liquid compositions of the disclosure comprises Formula (I) free base (1.25% wt / wt), Masester E8120 (54.0% wt / wt), Gelucire 44 / 14 (24.0% wt / wt), Capryol 90 (18.75% wt / wt), Ascorbyl Palmitate (1.0% wt / wt), and Kollidon K30 (1.0% wt / wt).

[0094] In some embodiments, the lipid vehicle-based liquid compositions of the disclosure comprises Formula (I) free base (1.0% wt / wt), Masester E8120 (54.0% wt / wt), and Kolliphor RH40 (20.0% wt / wt), Maisine CC (23.0% wt / wt), Ascorbyl Palmitate (1.0% wt / wt), Kollidon K30 (1.0% wt / wt).

[0095] In some embodiments, the lipid vehicle-based liquid compositions of the disclosure comprises Formula (I) free base (2.0% wt / wt), Labrasol ALF (55.0% wt / wt), Kolliphor RH40 (26.0% wt / wt), Maisine CC (15.0% wt / wt), Ascorbyl Palmitate (1.0% wt / wt), and Kollidon K30 (1.0% wt / wt).

[0096] In some aspects, the lipid vehicle-based liquid compositions of the disclosure are such that the total impurities in the composition increases by less than 1% (HPLC area%) when the composition is stored at 40°C for two weeks.

[0097] In some aspects, the lipid vehicle-based liquid compositions of the disclosure are such that addition of the composition to fasted simulated intestinal fluid (FASSIF) in an amount of 12.5 mg of Formula (I) per 500 mL of media, results in 3- to 5- times moreFormula (I) dissolved in the FASSIF than results from adding micronized Formula (I) to FASSIF in an amount of 12.5 mg of Formula (I) per 500 mL of media.

[0098] In some embodiments, the lipid vehicle-based liquid compositions of the disclosure are such that addition of the composition to fasted simulated intestinal fluid (FASSIF) in an amount of 12.5 mg of Formula (I) per 500 mL of media, results in about 3- times more Formula (I) dissolved in the FASSIF than results from adding micronized Formula (I) to FASSIF in an amount of 12.5 mg of Formula (I) per 500 mL of media.

[0099] In some embodiments, the lipid vehicle-based liquid compositions of the disclosure are such that addition of the composition to fasted simulated intestinal fluid (FASSIF) in an amount of 12.5 mg of Formula (I) per 500 mL of media, results in about 3.5- times more Formula (I) dissolved in the FASSIF than results from adding micronized Formula (I) to FASSIF in an amount of 12.5 mg of Formula (I) per 500 mL of media.

[0100] In some embodiments, the lipid vehicle-based liquid compositions of the disclosure are such that addition of the composition to fasted simulated intestinal fluid (FASSIF) in an amount of 12.5 mg of Formula (I) per 500 mL of media, results in about 4- times more Formula (I) dissolved in the FASSIF than results from adding micronized Formula (I) to FASSIF in an amount of 12.5 mg of Formula (I) per 500 mL of media.

[0101] In some embodiments, the lipid vehicle-based liquid compositions of the disclosure are such that addition of the composition to fasted simulated intestinal fluid (FASSIF) in an amount of 12.5 mg of Formula (I) per 500 mL of media, results in about 4.5- times more Formula (I) dissolved in the FASSIF than results from adding micronized Formula (I) to FASSIF in an amount of 12.5 mg of Formula (I) per 500 mL of media.

[0102] In some embodiments, the lipid vehicle-based liquid compositions of the disclosure are such that addition of the composition to fasted simulated intestinal fluid (FASSIF) in an amount of 12.5 mg of Formula (I) per 500 mL of media, results in about 5- times more Formula (I) dissolved in the FASSIF than results from adding micronized Formula (I) to FASSIF in an amount of 12.5 mg of Formula (I) per 500 mL of media.SOLUTION FORMULATIONS

[0103] In some aspects, the pharmaceutical compositions of the disclosure are pharmaceutical solutions of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a diluent.

[0104] In some embodiments, the pharmaceutical solutions contain a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 1 mg / mL to 20 mg / mL, such as, for example, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, or about 20 mg / mL.

[0105] In other embodiments, the pharmaceutical solutions contain a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 1 mg / mL to 10 mg / mL, such as, for example, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, or about 10 mg / mL.

[0106] In some embodiments, the diluent comprises water.

[0107] In some embodiment, the pharmaceutical solutions comprise a solubilizer.

[0108] In some embodiments, the pharmaceutical solutions comprise 10%-40% by weight (w / w) of solubilizer, such as, for example, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40% by weight (w / w) of solubilizer.

[0109] In some embodiments, the solubilizer is a cyclodextrin, such as for example, a-cyclodextrin, P-cyclodextrin, y-cyclodextrin, carboxymethyl-p-cyclodextrin, carboxymethyl-ethyl-p-cycl odextrin , diethyl -p-cyclodextrin, dimethyl -p-cyclodextrin, glucosyl-p-cyclodextrin, hydroxybutenyl-p-cy cl odextrin, hydroxyethyl-p-cyclodextrin, hydroxypropyl-p-cycl odextrin, hydroxypropyl -y-cyclodextrin, maltosyl-P-cyclodextrin, methyl-P-cycl odextrin, random methyl-P-cyclodextrin, or sulfobutyl ether~P-cy cl odextrin. The structures of the aforementioned cyclodextrins are known to those of skill in the art, and can be found in, for example, Stella and He, Cyclodextrins, Toxicologic Pathology, 36:30-42, 2008.

[0110] In some embodiments, the pharmaceutical solutions comprise 10%-40% by weight (w / w) of a cyclodextrin, such as, for example, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40% by weight (w / w) of a cyclodextrin.

[0111] In some embodiments, the solubilizer is hydroxy propyl beta-cyclodextrin, such as for example, Kleptose HPB oral grade. In some embodiments, the pharmaceutical solutions comprise 10%-40% by weight (w / w) of solubilizer, such as, for example, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40% by weight (w / w) of solubilizer. In some embodiments, the pharmaceutical solutions comprise 10%-40% by weight (w / w) of hydroxy propyl beta-cyclodextrin.

[0112] In some embodiments, the solubilizer is sulfobutyl ether-p-cyclodextrin. In some embodiments, the pharmaceutical solutions comprise 10%-40% by weight (w / w) of sulfobutyl ether-p-cyclodextrin, such as, for example, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40% by weight (w / w) of sulfobutyl ether-P-cyclodextrin.

[0113] In some embodiments, the pharmaceutical solutions comprise a viscosity modifier, such as, for example, a pectin, agar, Alginates, acacia, tragacanth, Karaya gum, guar gum, starches, cellulose, locust bean, xanthan gum, dextran, gellan gum, pullulan, modified starches, cellulose ethers (methylcellulose, hydroxypropyl methyl cellulose, ethylcellulose, hydroxypropylcellulose and hydroxyethylcellulose), amidated pectin, propylene glycol alginate, gelatin, chitosan, caseinates, polyvinylpyrrolidone, copovidone, polyvinyl alcohol (PVA), clays such as bentonite, hectorite and magnesium aluminium silicate, Carbomers ( nonlinear polymers of polyacrylic acids, cross-linked with a polyalkenyl poly ether), polyols, sugars and oligosaccharides, sorbitol, maltitol, sucrose, fructose, dextrose, maltodextrin and polydextrose, polyethylene glycol and polyethylene oxide. Polyvinylpyrrolidone or hydroxypropyl methyl cellulose. In some embodiments, theviscosity modifier is polyvinylpyrrolidone, such as, for example, Povidone K30. In other embodiments, the viscosity modifier is hydroxypropyl methyl cellulose. In some embodiments, the pharmaceutical solutions comprise 1-5% by weight (w / w) of viscosity modifier, such as, for example, about 1%, about 2%, about 3%, about 4%, or about 5% by weight (w / w) of viscosity modifier.

[0114] In some embodiments, the pharmaceutical solutions comprise 3% by weight (w / w) of polyvinylpyrrolidone.

[0115] In some embodiments, the pharmaceutical solutions comprise 3% by weight (w / w) of hydroxypropyl methyl cellulose.

[0116] In some embodiments, the pharmaceutical solutions comprise a pH modifier, such as, for example, an acid, a base, or a buffering agent. In some embodiments, the pH modifier is an acid such as, for example, citric acid, lactic acid, acetic acid, ascorbic acid, benzoic acid, fumaric acid, malic acid, maleic acid, hydrochloric acid, phosphoric acid, sulfuric acid, and the like. In other embodiments, the pH modifier is a base such as, for example, sodium hydroxide, potassium hydroxide, and the like. In some embodiments, the pharmaceutical solutions comprise 0.1 - 5% by weight (w / w) of pH modifier, such as, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, or about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% by weight (w / w) of pH modifier.

[0117] In some embodiments, the pH modifier is citric acid, such as, for example, citric acid anhydrous. In some embodiments, the pharmaceutical solutions comprise 0.1 - 5% by weight (w / w) of , citric acid anhydrous, such as, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, or about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% by weight (w / w) of , citric acid anhydrous.

[0118] In some embodiments, the pharmaceutical solutions comprise 1% by weight (w / w) of citric acid anhydrous.

[0119] In some embodiments, the pharmaceutical solutions comprise a preservative. In some embodiments, the preservative is sodium benzoate, potassium sorbate, or a mixture of sodium benzoate and potassium sorbate in any proportion. In some embodiments, the pharmaceutical solutions comprise 0.1 - 0.5% by weight (w / w) ofpreservative, such as, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, or about 0.5% by weight (w / w) of the preservative.

[0120] In some embodiments, the pharmaceutical solutions comprise 0.1% by weight sodium benzoate and 0.1% by weight potassium sorbate.

[0121] In some embodiments, the pharmaceutical solutions comprise a sweetener. In some embodiments, the sweetener is sucralose. In some embodiments, the pharmaceutical solutions comprise 0.1 - 0.5% by weight (w / w) of sweetener, such as, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, or about 0.5% by weight (w / w) of the sweetener.

[0122] In some embodiments, the pharmaceutical solutions comprise 0.1% by weight (w / w) of sucralose.

[0123] In some embodiments, the pharmaceutical solutions of the disclosure have the composition shown in the following table:METHODS OF TREATING CANCER

[0124] In some aspects, the disclosure also provides methods of treating cancer in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition of the disclosure.

[0125] In some embodiments of the disclosed methods, the cancer has an activating FGFR3 gene alteration.

[0126] In some embodiments, the cancer is urothelial cancer, breast cancer, endometrial cancer, lung cancer, ovarian cancer, or bladder cancer.

[0127] In some embodiments, the cancer is urothelial cancer.

[0128] In other embodiments, the cancer is urothelial carcinoma.

[0129] In other me embodiments, the cancer is breast cancer.

[0130] In other embodiments, the cancer is endometrial cancer.

[0131] In other embodiments, the cancer is lung cancer.

[0132] In other embodiments, the cancer is ovarian cancer.

[0133] In other embodiments, the cancer is bladder cancer.

[0134] In some embodiments, the cancer is non-muscle invasive bladder cancer (NMIBC).

[0135] In other embodiments, the cancer is a locally advanced solid tumor.

[0136] In other embodiments, the cancer is a metastatic solid tumor.

[0137] In some aspects of the disclosed methods, the cancer has an activating FGFR3 gene alteration.

[0138] In some embodiments, the activating FGFR3 gene alteration is a mutation. As used in this context, the term “mutation” refers to a change in the FGFR3 gene that results in the encoded FGFR3 kinase having a different amino acid sequence that the wild-type FGFR3 kinase. Methods of identifying FGFR3 mutations are known in the art.

[0139] In some embodiments, the mutation is any one or more of the following:FGFR3 p.S84L;FGFR3 p.G380R;FGFR3 p.R621H;FGFR3 p.R248C;FGFR3 p.G380E;FGFR3 p.K650E;FGFR3 p.S249C;FGFR3 p.A391V;FGFR3 p.K650M;FGFR3 p.P250R;FGFR3 p.A391E;FGFR3 p.K650T;FGFR3 p.T264M;FGFR3 p.M528I;FGFR3 p.K650N;FGFR3 p.G370C;FGFR3 p.N540D;FGFR3 p.R669Q;FGFR3 p.S371C;FGFR3 p.N540S;FGFR3 p.G697C;FGFR3 p.Y373C; orFGFR3 p.N540K.

[0140] In other embodiments, the mutation is any one or more of the following:FGFR3 p.V553M;FGFR3 p.V555M; orFGFR3 p.V555L.

[0141] In other embodiments, the activating FGFR3 gene alteration is a fusion gene mutation. As used in this context, a “fusion” is a gene that results from the joining of two previously independent genes.

[0142] In some embodiments, the fusion is an FGFR3 rearrangement with an intact FGFR3 kinase domain and:Breakpoint in intron 17 or exon 18 of FGFR3 and a known partner gene (e g., TACC3, BAIAP2L1);Breakpoint in intron 17 or exon 18 of FGFR3 and an in-frame novel partner gene; orBreakpoint in intron 17 or exon 18 of FGFR3 and an intra-genic region or out-of-frame partner gene.

[0143] In some embodiments of the disclosed methods, the subject is administered a pharmaceutical composition of the disclosure in an amount and frequency such that the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is administered in an amount of 10 mg - 120 mg per day, such as, for example, one of 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day,80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, or 120 mg / day.

[0144] In other embodiments of the disclosed methods, the subject is administered a pharmaceutical composition of the disclosure in an amount and frequency such that the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is administered in an amount of 10 mg - 200 mg per day, such as, for example, one of 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, or 200 mg / day. When the compound of Formula (I) is administered as a pharmaceutically acceptable salt, the amount of the salt that is administered is based on the compound of Formula (I). That is, the amount of the salt that is administered is an amount that contains the specified amount of Formula (I) free base.

[0145] In some embodiments of the disclosed methods, the subject is administered a pharmaceutical composition of the disclosure in an amount and at a frequency such that the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is administered in an amount of 10 mg per day.

[0146] In some embodiments of the disclosed methods, the subject is administered a pharmaceutical composition of the disclosure in an amount and at a frequency such that the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is administered in an amount of 20 mg per day.

[0147] In some embodiments of the disclosed methods, the subject is administered a pharmaceutical composition of the disclosure in an amount and at a frequency such that the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is administered in an amount of 40 mg per day.

[0148] In some embodiments of the disclosed methods, the subject is administered a pharmaceutical composition of the disclosure in an amount and at a frequency such that the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is administered in an amount of 60 mg per day.

[0149] In some embodiments of the disclosed methods, the subject is administered a pharmaceutical composition of the disclosure in an amount and at a frequency such that the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is administered in an amount of 75 mg per day.

[0150] In some embodiments of the disclosed methods, the subject is administered a pharmaceutical composition of the disclosure in an amount and at a frequency such that the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is administered in an amount of 80 mg per day.

[0151] In some embodiments of the disclosed methods, the subject is administered a pharmaceutical composition of the disclosure in an amount and at a frequency such that the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is administered in an amount of 90 mg per day.

[0152] In some embodiments of the disclosed methods, the subject is administered a pharmaceutical composition of the disclosure in an amount and at a frequency such that the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is administered in an amount of 120 mg per day.

[0153] In some embodiments of the methods of the disclosure, the subject is administered a pharmaceutical composition of the disclosure in an amount and at a frequency such that the daily amount of the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is administered in a single dose.

[0154] In some embodiments of the methods of the disclosure, the subject is administered a pharmaceutical composition of the disclosure in an amount and at a frequency such that the daily amount of the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is given in a multiple doses, wherein each of the multiple doses contains a portion of the daily amount.

[0155] In some embodiments, the subject is administered a pharmaceutical composition of the disclosure in an amount and at a frequency such that the daily amount of the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is given in two doses, wherein each of the two doses contains a portion of the daily amount.

[0156] In some embodiments, the subject is administered a pharmaceutical composition of the disclosure in an amount and at a frequency such that the daily amount ofthe compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is given in two doses, wherein each of the two doses contains one half of the daily amount.

[0157] In some aspects of the disclosed methods, the subject is administered a pharmaceutical composition of the disclosure together with additional therapy.

[0158] In some embodiments, the additional therapy includes one or more of radiation therapy, chemotherapy, surgery (e.g., at least partial resection of the tumor).

[0159] In some embodiments, the additional therapy is chemotherapy, z.e., administering one or more additional therapeutic agents.

[0160] In some embodiments, the additional therapeutic agent is a checkpoint inhibitor.

[0161] In some embodiments, the checkpoint inhibitor is a PD-1 / PD-L1 inhibitor, such as, for example, one or more of pembrolizumab, nivolumab, avelumab, durvalumab, atezolizumab, cemiplimab, dostarlimab, JTX-4014, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012 (MGA012), AMP-224, or AMP-514 (MEDI0680).

[0162] In other embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor, such as, for example, one or more of ipilimumab, tremelimumab, or AGEN-1884.

[0163] In some embodiments, the additional therapeutic agent is an antibody-drug conjugate, such as, for example, enfortumab vendotin, sacituzumab govitecan, disitamab vedotin, or Vic-trastuzumab duocarmazine (SYD985).

[0164] In other embodiments, the additional therapeutic agent is cisplatin, carboplatin, gemcitabine, docetaxel, paclitaxel, vinflunine, methotrexate, vinblastine, mitomycin, valrubicin, or doxorubicin.

[0165] In some embodiments, the additional therapeutic agent is an MEK inhibitor, such as, for example, trametinib, cobimetinib, or binimetinib.

[0166] In some embodiments, the additional therapeutic agent is a PARP inhibitor, such as, for example, olaparib, veliparib, niraparib, rucaparib, or talazoparib.

[0167] In some embodiments, the additional therapeutic agent is an HER2 inhibitor, such as, for example, lapatinib, afatinib, AZD8931, AST-1306, AEE-788, canertinib (CI-1033), CP724, CP714, CUDC-101, TAK-285, AC-480 (BMS-599626), dacomitinib (PF299804 PF299) (Dacomitinib), or pelitinib (EKB-569).

[0168] In some embodiments, the additional therapeutic agent is an SHP2 inhibitor, such as, for example, TNO-155, or RMC-4630.

[0169] In some embodiments, the additional therapeutic agent is an antibody.

[0170] In some embodiments, the antibody is an HER2 antibody such as one or more of trastuzumab or pertuzumab.

[0171] In some embodiments, the antibody is a bispecific antibody such as one or more of MM- 111 or ertumaxomab.

[0172] In some embodiments, the additional therapy is a biologic immunotherapy such as, for example, intravesicle BCG (Bacillus Calmette-Guerin).

[0173] In embodiments of the disclosed methods in which the subject is administered a pharmaceutical composition of the disclosure together with additional therapy, the pharmaceutical composition of the disclosure is administered before, during, or after the administration or application of the additional therapy.

[0174] In some embodiments, the pharmaceutical composition of the disclosure is administered before administration or application of the additional therapy.

[0175] In some embodiments, the pharmaceutical composition of the disclosure is administered during administration or application of the additional therapy.

[0176] In some embodiments, the pharmaceutical composition of the disclosure is administered after administration or application of the additional therapy.

[0177] In some aspects of the methods of the disclosure, the cancer exhibits a complete response (CR) or a partial response (PR), as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria, to the administration of the pharmaceutical composition of the disclosure.

[0178] In some embodiments, the cancer exhibits a complete response (CR), as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria, to the administration of the pharmaceutical composition of the disclosure.

[0179] In other embodiments, the cancer exhibits a partial response (PR), as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria, to the administration of the pharmaceutical composition of the disclosure.METHODS OF TREATING DEVELOPMENTAL DISORDERS

[0180] In some aspects, the disclosure also provides methods of treating developmental disorders in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition of the disclosure.

[0181] In some embodiments, developmental disorders to be treated with pharmaceutical composition of the disclosure include Achondroplasia (Ach) and related chondrodysplasia syndromes, including Hypochondroplasia (Hch), Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (SADDAN), and Thanatophoric dysplasia (TD). ). Compounds of the disclosure may also be useful in Double dominant ACH. Compounds of the disclosure may also be useful in Craniosynostosis, e.g., Crouzon syndrome with acanthosis nigricans and Meunke syndrome. Compounds of the disclosure may also be useful in other genetic short stature conditions, e.g., Leri-Weill dyschondrosteosis, Turner syndrome, Osteogenesis imperfecta, Mucopolysaccaridoses IVA, Mucopolysaccaridoses VI, and Laron syndrome (growth hormone insensitivity). Compounds of the disclosure may also be useful in pediatric short stature conditions, e.g., Idiopathic short stature and Severe idiopathic short stature. Compounds of the disclosure may also be useful in Camptodactyly, Tall Stature, and Hearing Loss (CATSHL).

[0182] In some embodiments, the developmental disorder to be treated with pharmaceutical composition of the disclosure is Achondroplasia (Ach).

[0183] In some embodiments, the developmental disorder to be treated with pharmaceutical composition of the disclosure is Hypochondroplasia (Hch).

[0184] In some embodiments, the developmental disorder to be treated with pharmaceutical composition of the disclosure is Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (SADDAN).

[0185] In some embodiments, the developmental disorder to be treated with pharmaceutical composition of the disclosure is Thanatophoric dysplasia (TD).

[0186] In some embodiments, the developmental disorder to be treated with a pharmaceutical composition of the disclosure is Crouzon syndrome with acanthosis nigricans.

[0187] In some embodiments, the developmental disorder to be treated with a pharmaceutical composition of the disclosure is Meunke syndrome.

[0188] In some embodiments, the developmental disorder to be treated with a pharmaceutical composition of the disclosure is Leri-Weill dyschondrosteosis.

[0189] In some embodiments, the developmental disorder to be treated with a pharmaceutical composition of the disclosure is Turner syndrome.

[0190] In some embodiments, the developmental disorder to be treated with a pharmaceutical composition of the disclosure is Osteogenesis imperfecta.

[0191] In some embodiments, the developmental disorder to be treated with a pharmaceutical composition of the disclosure is Mucopolysaccaridoses IVA.

[0192] In some embodiments, the developmental disorder to be treated with a pharmaceutical composition of the disclosure is Mucopolysaccaridoses VI.

[0193] In some embodiments, the developmental disorder to be treated with a pharmaceutical composition of the disclosure is Laron syndrome.

[0194] In some embodiments, the developmental disorder to be treated with a pharmaceutical composition of the disclosure is Idiopathic short stature.

[0195] In some embodiments, the developmental disorder to be treated with a pharmaceutical composition of the disclosure is Severe idiopathic short stature.

[0196] In some embodiments, the developmental disorder to be treated with a pharmaceutical composition of the disclosure is Camptodactyly, Tall Stature, and Hearing Loss (CATSHL).EXAMPLES

[0197] The compound of Formula (I) besylate salt used in the Examples below is the polymorphic Form I, unless stated otherwise. See W02024 / 006883 at

[0126] ,

[0821] -

[0823] (Form I of Compound 2).Example 1 - Tablet Development

[0198] An excipient compatibility screen was conducted to support tablet development. This excipient compatibility study selected fifteen excipients across a variety of common tablet excipients including diluents, binders, disintegrants, glidants, lubricants, surfactants, and coating agents. Formula (I) besylate salt and excipient were blended at a 1 to 1 weight ratio. Each binary mixture was placed in a glass vial and blended to facilitate intimate contact.

[0199] The experimental conditions were as follows. Two sets of samples were prepared for both 40° C / 75% RH and 25° C / 60% RH storage conditions. All vials were sealed with a cap due to hydrolysis related instability discovered in the previous truncatedexcipient compatibility. The 40° C / 75% RH storage condition was the frontline storage condition and was tested at all three sampling intervals of 2, 4 and 8-weeks. The 25° C / 60% RH storage condition was reserve samples to be tested only if the frontline condition showed instability. Testing was conducted by UPLC using the method DUR-QCT-1751-TM.01. The method was modified to utilize a 2 pL injection volume.Table 1.1 Excipient Compatibility Samples - Binary Mixtures of Formula (I) besylate lot 006BJF062 with listed excipients

[0200] Generally, the screened excipients were stable under the 40° C / 75% RH sealed glass vial storage conditions. The area percent of Formula (I) besylate remained > 97% over the 8-week interval. Both Opadry I (HPMC based) and Opadry II (PVA based) did show degradation with Formula (I) area percent reaching 96.6% and 96.9%, respectively. Degradants were apparent at RRT values of 0.97 and 1.20 at the 8-week interval. At the 0.97 relative retention time the area percent was 0.88% and 0.56% for each coating. A small degradant was apparent RRT of 1.20 as well with area percents of 0.15% and 0.11%. This incompatibility should be monitored but this testing was conducted at a worst case 1 : 1 ratio while practical use levels would be much lower.

[0201] An initial direct compression formulation was prepared have the following composition:

[0202] A compression profile of this formulation showed that the formulation has more than sufficient compressibility with a linear trend through 6.9 kN of force and yielding a hardness value of 14.5 ± 0.5 kp (N = 6). However, a portion of compressed tablets showed picking. See Fig. 1.

[0203] To address the picking issue, a modified formulation (A0020964-02) in which the magnesium stearate lubricant level was increased to 1.0% was prepared:

[0204] Compression profiles for the 0.5% and 1.0% magnesium stearate (MgSt) formulations showed that both formulations have more than sufficient compressibility. The proposed 1.0% MgSt formulation has additional compressibility beyond 5.8 kN of force where tablet hardness averaged 13.8 ± 0.4 kp (N=6).

[0205] Approximately 100 tablets were compressed with the modified 1% lubricant formulation. These tablets were free from defects. The tooling used was 11 / 32 in round yielding tablets of 272.9 ± 6.2 mg. The tablet dimensions were 8.73 mm diameter and 4.83 ± 0.02 mm thickness (N=10). The aspect ratio (width / thickness) was 1.81.

[0206] Since these tablets were free of defects, a selection of tablets with hardness values approximately 6-7 kp were tested for friability, disintegration, and dissolution. The friability was conducted by USP testing (1216) and 15 tablets underwent 100 revolutions in a drop tester resulting a weight loss of 0.0090 g or 0.22% which is well below the 1% acceptable weight loss. Disintegration testing was conducted in deionized water at 37° C according to USP testing (701) with six tablets. The disintegration was very rapid all six tablets had undergone disintegration within 12 seconds.

[0207] Preliminary dissolution testing was conducted using UPLC. The method was developed to support the blended capsule drug product. Three tablets were tested in 500 mL of dissolution media (0.05% CTAB in 0.01 N HC1). A USP apparatus 1, baskets at 100 rpms, was utilized with 500 mL of dissolution in each vessel. The dissolution results are shown in Fig. 2.

[0208] The dissolution is initially rapid as expected for a quickly disintegrating tablet, however, the extent of release was only 79%. Various potential reasons for this limited release were investigated.

[0209] It was discovered that when the formulation blend containing 1% magnesium stearate was loaded into a gelatin capsule, the capsule gave a significantly higher extent of release versus the tableted blend. At 60 minutes the difference was 9.4% greater for capsules and after the infinite spin interval it was 10.1% greater. See Fig. 3.

[0210] The difference in extent of release between the tablet and the blend was investigated by DSC. One hypothesis is that the formulation and / or compression of the tablets may sponsor the formation of a salt or polymorph with reduced solubility. The recoveries in dissolution media show poorer recovery with higher levels of magnesium stearate, which suggests that contributing factors also may include tablet compression and / or salt exchange of besylate for a stearate.

[0211] DSC was used to investigate the drug substance within blends or tablets. The DSC of the Formula (I) besylate API shows several small endothermic transitions at onset temperatures of 26.2° C, 56.8° C and 68.3° C prior to the major melt at 189.7° C.Thermograms of the first direct compression formulation with 0.5% magnesium stearate is provided as the blend in Fig. 4 and as the tablet in Fig. 5. Briefly, onset temperatures of early endothermic transitions at 32.7° C, 75.0° C and 141.1° C can be assigned to tablet excipients. The endotherm at 183.8 - 185.6° C is likely primarily associated with melting of Formula (I) besylate. A melt transition at 165.8 - 166.2° C is not readily assigned to excipients or drug substance. This may be indicative of another drug substance form, whether a polymorph or salt.

[0212] The next set of thermograms are from the formulation with 1.0% magnesium stearate. As discussed previously, the increased magnesium stearate solved the picking problem that occurred with the initial direct compression tablet formulation containing only 0.5% magnesium stearate. Thermograms of the blend and tablet from the 1.0% magnesium stearate formulation are given in Figs. 6 and 7, respectively. The endotherm of interest at 166° C is nearly absent in the blend. In the tablet thermogram, however, a melt endotherm at 164.8° C is prevalent. Immediately after the melt endotherm at 165 - 166° C, a recrystallization exotherm occurs with a peak maxima of 177.4° C. This exothermic event occurs in both the 0.5% and 1.0% magnesium stearate formulations. An exotherm for Formula (I) besylate drug substance does not occur until after the melt onset at around 190° C and at a much higher temperature of 204° C. The formulations in this temperature region, have a series of melt endotherms without any evidence of recrystallization. All these thermal events occur prior to the decomposition temperature at 288° C.

[0213] A third tablet formulation utilizing sodium stearyl fumarate (SSF) was prepared to investigate the lubricant. This formulation is given in Table 1.2. The compression properties of the new formulation were similar to the previous 1.0% MgSt formulation.Table 1.2 20 mg Direct Compression Formulation (A0020964-03) with lubricant change from magnesium stearate to sodium stearyl fumarate

[0214] The dissolution of the 1.0% SSF tablets were evaluated with the 1.0% MgSt formulation in Fig. 8. The rate and extent of dissolution was faster for the SSF formulation. Specifically, the extent of dissolution was 90% at 60 minutes and 92% after the infinite spin. This was approximately 7% higher at each interval than the reference 1% magnesium stearate tablets. Additionally, when the new formulation blend was loaded into capsules, the capsules exhibited the same dissolution profile as the compressed tablets made from that blend.

[0215] The 1% SSF tablet formulation improves dissolution performance but does not achieve the target 95% release. Further investigation of excipients was conducted by preparing a formulation without lubricant or disintegrant. A 10% drug load formulation blend of Formula (I) was prepared without lubricant or disintegrant. The lubricant had accumulated some evidence that it maybe impacting the dissolution. A blend without lubricant could be evaluated in a capsule. The rapid tablet disintegration rate suggested this excipient maybe unnecessary. The initial blend A00200964-04 is given in Table 1.3. A portion of this blend then had sodium stearyl fumarate (SSF) lubricant added to form A0020964-04A provided in Table 1.4.Table 1.3 10% Drug Load Formulation Blend (A0020964-04) w / o lubricant or disintegrant.Table 1.4 10% Drug Load Formulation Blend (A0020964-04A) w / lubricant (SSF) but w / o disintegrant.

[0216] The two blends with and without lubricant were filled into size 1 gelatin capsules at a dose of 20 mg. As a comparator size 4 gelatin capsules were filled with neat Formula (I) besylate salt. Dissolution was conducted in 900 mL of 0.05% CTAB in 0.01 N HC1 dissolution media. Dissolution apparatus II was used at 75 rpm stirring with an additional 15 -minute sampling interval conducted as an infinite spin at 200 rpms, 75 -minute time point. The dissolution is provided in Fig. 9. Both blends showed similar dissolution profiles with or without lubricant. At the 60-minute interval drug release from the formulation w / o lubricant was 87% and w / lubricant was 89%. After the infinite spin interval (75i) the w / o lubricant release was 90% and w / lubricant was 91% which was low for capsule filled blends. Neat Formula (I) besylate provided poor dissolution performance likely due to slow wetting of the drug substance from the capsule.

[0217] The extent of release was below expectation for blend filled in a capsule versus the extent of release shown for previous formulations. Triplicate filled capsules at a dose of 20 mg prepared from the lubricant containing blend A0020964-04A were assayed. The results are given in Table 1.5.Table 1.5 Assay of 20 mg Formula (I) Besylate Dose Formulation Blend (A0020964- 04A) w / lubricant (SSF) filled into size 1 gelatin capsules (N=3)

[0218] It is suspected that the low assay results occur due to water uptake of the drug substance. The drug is known to be hygroscopic absorbing up to 4.6% water at 50% relative humidity. The loss of drying for this blend conducted at 105° C was 1.90%. Although the loss of drying was conducted on the formulation in which Formula (I) Besylate is only 10% weight fraction. Potentially water uptake is a contributor to the low assay results. Formulation preparation includes screening Formula (I) Besylate through a 30-mesh screen prior to weighing it into the formulation blend with the other prescreened excipients. This step may introduce moisture into the drug substance. A Karl Fisher water content of a 50 mg sample of Formula (I) Besylate, lot DAV1000371-07322-A, was measured along with the same drug substance screened through a 30-mesh screen. The certificate of analysis gives a water content of 0.3% while our analysis gives 0.7% water content for the standard, maintained in a sealed glass vial desiccated. The screened drug substance had a moisture content of 2.1%. The moisture content only compensates, however, for approximately one- third of the lower assay result.

[0219] Because dissolution performance appears to be independent of the presence of the selected lubricants, the blend was completed with the addition of crospovidone disintegrant. Only limited compression was conducted. The formulation with SSF lubricant but without disintegrant (A020964-04A) compressed with 3.3 kN of force yielded tablets of 6.9 kp hardness. The formulation with added disintegrant, 3.0% crospovidone, required 3.9 kN to yield tablets with a hardness of 8.2. These hardness values were considered acceptable for a 260 mg round tablet.Table 1.6 10% Drug Load Formulation Blend (A0020964-04B) including lubricant and disintegrant (3.0% crospovidone)Table 1.7 Disintegration of Formula (I) Besylate 20 mg tablets. Tablets from the A00200964-04A w / o disintegrant and A0020964-04B w / disintegrant are included.

[0220] Dissolution of three tablets from the A00200964-04A w / o disintegrant and A0020964-04B w / disintegrant was conducted. The dissolution profiles are given in Fig. 10. As can be observed these tablets with or without disintegrant have improved dissolution with final release of 94% for the tablet’s w / o disintegrant and 93% for the tablet’s w / disintegrant. The presence of disintegrant had no effect on release but the compression process may have improved extent of release.

[0221] Feasibility Batch

[0222] A feasibility batch was prepared with another lot of Formula (I) besylate. This drug substance was prepared and isolated initially as the free base and then converted to the besylate salt in subsequent processing step. The previous batches were converted directly into besylate salt form without isolation from the mother liquor.

[0223] The feasibility batch for the 10 and 30 mg doses was prepared from a common blend given in Table 1.8. A correction factor of 0.740 was used for Formula (I) besylate, lot 005NPM017. The feasibility was prepared to conform with the informal stability formulation.Table 1.8 Formula (I) Besylate Feasibility Blend Preparation

[0224] Tableting of the 10 mg dose is given in Table 1.9. The initial two runs were above target tablet weight, so the fill was adjusted down and only the runs 3-5 which achieved target weight are given. A hardness of 9.1 kp was selected as the target value (Run 5) final column. All additional testing was conducted with tablets prepared at these compression parameters.Table 1.9 10 mg Formula (I) Besylate Dose Tableting Properties

[0225] The 30 mg dose tableting properties is given in Table 1.10. A hardness of11.1 kp was selected as the target value (Run 4) last column. All additional testing was conducted with tablets prepared at these compression parameters.Table 1.10 30 mg Formula (I) Besylate Dose Tableting Properties

[0226] Both 10 mg and 30 mg dose Formula (I) tablets were tested for friability Table 1.11 and disintegration Table 1.12. The friability weight loss was 0.4% for both doses which is acceptable. The disintegration testing for both doses conducted in water at 37° C was fast at only 10 seconds. These values are considered acceptable and are consistent with the informal stability batch A002195.Table 1.11 Feasibility Batch Friability ResultsTable 1.12 30 mg Formula (I) Besylate Dose Tableting Properties

[0227] Dissolution testing of the feasibility tablets was conducted in 900 mL of dissolution media and apparatus II at 75 rpms, as modified for tablet dosage forms. The dissolution profiles are given in Fig. 11. They show a slower second phase of release and at 60 minutes the extent of release is only 75% for the 10 mg tablets and 79% for the 30 mg tablets. This was inconsistent with the dissolution results collected for the informal stability.Pilot Batch - Micronization

[0228] Feasibility batches prepared with drug substance lot 005NPM017 prior to the pilot batch resulted in poor dissolution. It was determined that the drug substance from lot 005NPM017 had a larger particle size distribution than the original drug substance used ininitial tablet development. Therefore, micronization was implemented as part of the drug substance manufacturing process to improve the dissolution profile.

[0229] Approximately 221 grams of drug substance lot 005NPM017 were screened through a 20-mesh sieve, then milled on a Sturtevant 4” Micronizer. The material was fed into the mill using a vibratory feeder at approximately 6 grams / minute. A feed air pressure of 60 psig and a grind air pressure of 40 psig were used. An overall yield of 192 g (-87%) was achieved. The particle size results for the un-micronized and micronized materials are provided in Table 1.13 below.Table 1.13. Formula (I) besylate Drug Substance Particle Size SummaryBlending

[0230] Half the required lactose was added to the bin and blended for 1 minute to coat the walls of the equipment with an inert material prior to addition of the drug substance. Then the Formula (I) besylate drug substance and remaining lactose were added to the bin and blended for 5 minutes at 15 RPM. The entire blend was discharged and screened through a 30-mesh sieve. Avicel® PH-102 MCC, crospovidone, and Cab-O-Sil were screened through a 30-mesh sieve. Half the screened blend was loaded back into the bin, with the screened MCC, crospovidone, and Cab-O-Sil sandwiched in the middle, and the other half of screened blend loaded on top. The bin was blended for 5 minutes at 15 RPM. The entire blend was discharged and screened through a 30-mesh sieve. The lubricant sodium stearyl fumarate was screened through a 30-mesh sieve with a portion of the blend. Half the screened blend was loaded back into the bin, with the lubricant sandwiched in the middle, and the other half of screened blend loaded on top. All materials were blended for an additional 5minutes at 15 rpm. The final blend was increased to 10 minutes for the subsequent pilot batch and for the proposed GMP process to improve lubrication of the blend.

[0231] A sample of the blend was evaluated for powder flow properties. The results are presented in Table 1.14 below. The compressibility index and Hausner ratio are indicative of a powder with borderline passable / poor flow properties. Though not ideal, compression was not adversely affected.Table 1.14. Formula (I) Besylate Tablet, Powder Flow Properties of Common BlendCompression

[0232] The blend was divided for each dosage prior to initiating compression. 450 grams of the common blend was allocated to manufacture the 10 mg tablets. The remainder of the blend, -1,350 g, was used to manufacture the 30 mg tablets.

[0233] Tablets were compressed across a range of forces on a Piccola rotary tablet press and evaluated for weight, hardness, thickness, friability, and disintegration. The averaged results are presented in Table 1.15 and Table 1.16.Table 1.15. Formula (I) besylate Tablet, 10 mg Tablet Hardness Profile1NT = Not Tested.Table 1.16. Formula (I) besylate Tablet, 30 mg Tablet Hardness Profile1NT = Not Tested.

[0234] Friability of core tablets is important to ensure that the tablets can withstand the attrition experienced during subsequent manufacturing steps. Traditionally, a friability result below 1.0% is considered acceptable for a film coating process. The results in Table 1.15 and Table 1.16 show an acceptable friability level is achieved across the entire proposed hardness range.

[0235] Low, target, and high hardness tablets for both were evaluated for dissolution using the conditions summarized in Table 1.17. The 10 mg tablets compressed at 14 kp were not evaluated for dissolution, since they were similar to the composite tablets prepared at a target of 13 kp for the pilot lot. The 30 mg tablets compressed at 12 kp were not evaluated for dissolution since the tablets disintegrated extremely fast.Table 1.17. Formula (I) besylate Tablet Dissolution Parameters

[0236] For the 10 mg tablet, the cores compressed at the low and target hardness (8 kp and 13 kp) have acceptable dissolution profiles. However, the tablets compressed at 18 kp demonstrate slower dissolution than the other tablets, with an average dissolution of 82% at 45 minutes. This does not meet the proposed finished product specification of Q = 80 at 45 minutes (85% release), reference A0023337. The results presented in Fig. 12 show the dissolution curve for each hardness. Based on dissolution data for the low and target hardness tablets and individual tablet hardness results, the proposed hardness target and range for the 10 mg tablet is 11 kp ± 4 kp.

[0237] For the 30 mg tablet, all cores compressed within the hardness range of 17 kp and 25 kp have acceptable dissolution profiles. All core tablets fall within the proposed finished product specification of Q = 80 at 45 minutes (85% release). The results presented in Fig. 13 show an acceptable rate of dissolution is achieved across the entire proposed hardness range. Based on these results the proposed hardness target and range for the for the 30 mg tablet is 20 kp ± 6 kp.

[0238] After tablets were generated at various hardnesses for dissolution evaluation, tablets were compressed at the target weight and hardness to generate material for stability. The compression parameters for the pilot batch were based on the formulation development compression results, the hardness profile study, and prior knowledge of similar products manufactured using the Piccola tablet press. At the start of compression, the weight and hardness were adjusted to their respective targets. Upon acceptable set-up, the compression process was started. See Table 1.18 for actual final compression parameters.Table 1.18. Formula (I) Besylate Tablet Compression ParametersCoating

[0239] The tablet cores were film-coated with an Opadry® II 85F 18422 WhitePVA-based coating system in a Vector perforated coating pan to achieve a uniform finalcoating. The film coating is not designed to offer any functional control on the dosage form in terms of release rate or stability. A coating level of 3.0% with respect to (w.r.t.) tablet core weight was selected and the solids concentration of the coating solution was set at 14.5% based on recommendations from the manufacturer and prior experience with similar nonfunctional coatings. For the second pilot, the coating level was increased to 3.7% w.r.t. the coated tablet weight to address slight color variation observed in the first pilot batch.

[0240] The equipment used was Vector HI-COATER® with a 16” Pan. Pan 1 was placebo only to confirm process parameters. For both Pans 2 and 3, there were not enough active tablets to meet the minimum required batch size for the 16” pan. Therefore, embossed placebo tablets were used to q.s. the batch up to 1.5 kg. The embossed tablets were removed from the batch at completion of the coating process.Table 1.19. Formula (I) Besylate Tablet, Coating Parameters13.0% (w.r.t. tablet core weight) was used for the pilot but increased to 3.7% (w.r.t. coated tablet weight) to address uneven color variation observed in Pan 2.

[0241] The process of separating active tablets from placebo tablets resulted in a slightly undercoated batch for Pan 2. The coating process was ended when a sample of 10 tablets met weight gain. However, when 100 tablets were weighed to confirm, weight gain was not quite met (2.8% instead of 3.0%). This resulted in slight color variation among the tablets. Therefore, the coat weight gain target was increased for the second pilot and GMP. Additionally, for GMP production, a whole milligram target weight (e.g., 5 mg) will be used for ease of operations.

[0242] After coating was completed, the tablets were evaluated for visual acceptability, and no erosion was observed.Evaluation of Final Composite Tablets

[0243] A composite sample of both dosage tablets was submitted to the lab for testing.Initial (T = 0) results for the non-GMP pilot batch are summarized in Table 1.20 and Table 1.21. The dissolution profile of the final coated tablet is presented in Figure 10.Table 1.20. Formula (I) Besylate Tablet, 10 mg Initial (T = 0) resultsTable 1.21. Formula (I) Besylate Tablet, 30 mg Initial (T = 0) results

[0244] The dissolution of the coated tablet compares well to the dissolution of the Formula (I) besylate capsule. The data for each pilot lot is presented in Fig. 14.

[0245] In the course of the tablet development, the effect of API micronization on tablet dissolution was investigated. The particle size distribution of lot 005NPM017 was generally larger than the previously used drug substance, which resulted in poor dissolution of the drug product (as demonstrated in A0022507-A). Therefore, particle size reduction (micronization) was implemented and tablets prepared to confirm the effect of micronization on drug product dissolution (A0022507-B). Particle size reduction successfully improved the dissolution, as can be seen in Fig. 15. Therefore, micronization was incorporated into the pilot batch (A0023274).

[0246] Formula (I) free base and Formula (I) besylate salt, were subjected to micronization using a Model 00 Jet-O-Mizer (2"). The micronization parameters are detailed in Table 1.22.Table 1.22 Micronization Parameters (Model 00 Jet-O-Mizer)

[0247] The particle sizes of micronized Formula (I) and unmicronized Formula (I) (for both, base and besylate salt) were analyzed using a Malvern Mastersizer 3000. The particle size distribution results are detailed in Table 1.23.Table 1.23, Particle Size Distribution for Formula (I) free base and Formula (I) Salt

[0248] Kinetic solubility studies on the micronized API were performed at 37 °C at a loading equivalent to 250pg / mL of Formula (I) per mL of bio-relevant media. As shown in Fig. 16, an increase in solubility was observed in all samples relative to the neat Formula (I). The highest sustained solubility was observed in the Micronized Salt API.

[0249] Minitabs of the disclosure containing 5.82% by weight Formula (I) besylate can be made by using standard weighing, screening, blending, compression, and coating techniques. In some embodiments, the batch is blended initially in a Gemco Double Cone Blender (0.5 cu. ft), screened and final blended in the Gemco Double Cone Blender (0.5 cu.ft). The final blend is compressed on a rotary tablet press into Mini-tablets and coated in Fluid bed coater. The coated mini-tablets are screened and blended with talc using Gemco double cone blender (0.5 cu. ft).Example 2 - Capsules

[0250] The drug substance, Formula (I) besylate salt lot 006BJF062, was evaluated for bulk and tapped density. The bulk density was 0.304 g / mL and the tapped density was 0.461 g / mL. The drug substance had poor flow properties, with a compressibility index is 34 with a Hausner ratio of 1.51. A (50:50) blend with drug substance and microcrystalline cellulose, Avicel 102, was developed to increase flow and utilize the Xcelodose to fill capsules. Specifically, size 4 gelatin capsules were filled as 5 and 10 mg doses. The dose was based on the free base form and the purity factor of drug substance lot 006BJF062 which is 0.7477. The fill weight of capsules was set at 10 mg for the 5 mg dose and 20 mg for the 10 mg dose. This drug product pilot batch, lot A0019265-01 5 mg dose and A0019265-02 10 mg dose was placed on stability.Table 2.1 Excipient Blend for Capsule Fill Formulationa free base equivalent

[0251] The drug in capsule formulation included the diluent, Avicel PH-102. An interim seven-day excipient compatibility study was conducted to support this formulation. Blends of Avicel PH102 and Formula (I) besylate were prepared in a glass vial for both the 40° C / 75% RH and 25° C / 60% RH storage conditions. Approximately 200 mg (potency corrected) of DS was placed in each vial with an appropriate amount of Avicel PHI 02 to make an approximate 400 mg fill. The stability study included HPLC assay only on days 0, 1, 3 and 7.

[0252] The 40° C / 75% RH sample was placed uncapped and exposed to the relative humidity. A significant increase in the RRT peak at 0.98 occurs over the 7-day interval, increasing to 0.45% of the total area.

[0253] The reserve 25° C / 60% RH was tightly sealed with a cap as this sample was a reserve sample showed no degradation at a RRT value of 0.98, suggesting that the stability is not related to Avicel PHI 02. This data set is inconclusive as to if temperature or the relative humidity, open or closed vial, is the contributing factor.

[0254] An expanded secondary excipient compatibility study was conducted to address the capsule formulation. The experiment was designed to determine if water or elevated temperature caused the degradation. Two of three samples were stored in closed vial configuration protecting the DS from water. The results indicate that only the open container configuration had a degradant peak at RRT of 0.97 which reached 0.40 area percent at the 7-day interval.Example 3 - Lipid Vehicle-Based Liquid CompositionsSolubility Screening of lot Formula (I) in Lipid Vehicles

[0255] Suspensions of Formula (I) free base were prepared in various lipid vehicles and allowed to mix in temperature-controlled vortex mixers. Sample mixing was performed at 25°C except for certain mixtures with semi-solid vehicles which were mixed at 35°C / 50°C.

[0256] Results of HPLC assays (Table 3.1) indicated that PEG400, Massester E8120, Gelucire 44 / 14, Kolliphor HS15, Kolliphor RH40, Capryol 90, Vit E TPGS and Tween 80 has reasonable solubility (>10mg / g).

[0257] The highest solubility in lipid excipient (Labrasol ALF) is at 41mg / g.

[0258] PXRD of residual solids from samples in Capryol 90, Masester E8120, Lauroglycol FCC, Oleic Acid, Miglyol 812N (MCT) and Olive Oil were consistent with the input API. All residual solids, from the other samples / vehicles, indicated a conversion from input material.Table 3.1 Summary of Solubility Screening of Formula (I) in Lipid VehiclesCompatibility Screening of Formula (I) in Lipid Vehicles

[0259] Ten excipients were selected to conduct the chemical compatibility study at 40 °C for 2 weeks. Formula (I) API (free base) was added to each excipient at 3mg / g to 10 mg / g target drug load and mixed well to solubilize. These compatibility samples were stored at 40°C in oven and assessed for degradation products. API oxidative degradation was expected with lipid excipients, therefore, BHT and a-Tocopherol, two different antioxidants with lipid excipients were evaluated for compatibility. Results for compatibility are presented in the Table 3.2. Massester E8120, Kolliphor HS15, Kolliphor RH40, Capryol 90, Vitamin E TPGS are compatible with Formula (I) API. Gellucire 44 / 14 and Maisine CC showed moderate degradation of Formula (I) API. Significant degradation was observed in Labrasol ALF, PEG400 and Tween 80.Table 3.2 Chemical Compatibility Screening of Formula (I) in Lipid Vehicles for T=2 week at 40°C

[0260] Based on the compatibility results - Masester E8120, Kolliphor HS15, Kolliphor RH40, Gelucire 44 / 14, Caproyl 90, Vitamin E TPGS and Mai sine CC were selected for formulation prototypes. Ascorbyl Palmitate was evaluated as antioxidant to prevent free glycerol degradation. One prototype with Labrasol ALF with Ascorbyl Palmitate was evaluated with the risk-based approach.

[0261] Based on the results from solubility and compatibility study, the following 4 prototypes were proposed to further evaluate and optimize for lipid based drug delivery platform.1) Formula (I) (1.5%): Masester E8120 (58.0%): Kolliphor HS15 (24.0%): Vitamin E TPGS (15.5%): Ascorbyl Palmitate (1.0%);2) Formula (I) (1.5%): Masester E8120 (50.0%): Gelucire 44 / 14 (27.0%): Capryol 90 (20.5%): Ascorbyl Palmitate (1.0%);3) Formula (I) (1.25%): Masester E8120 (50.0%): Kolliphor HS15 (20.0%): Maisine CC (27.75%): Ascorbyl Palmitate (1.0%); and4) Formula (I) (2.5%): Labrasol ALF (53.0%): Kolliphor RH40 (25.5%): Maisine CC (18.0%): Ascorbyl Palmitate (1.0%).

[0262] API was added to previously prepared placebo and homogenized to solubilize the Formula (I) API at 40°C to 45°C using a handheld homogenizer. After mixing for 2-3 hours, undissolved API was observed in each prototype. All prototypes were left in the oven at 40°C overnight and homogenized the next morning for additional 30-45 minutes. Clear solutions were not achieved after mixing and undissolved Formula (I) API particles were observed.

[0263] To solubilize the desired drug load in each of the above prototype, additional formulations (Set 2) were prepared with small change in the composition of each. Also order of addition was changed so that ascorbyl palmitate was added after the API was added and homogenized for 2-3 hours.

[0264] The Set 2 formulations are:1) Formula (I) (1.5%): Masester E8120 (64.0%): Kolliphor HS15 (18.5%): Vitamin E TPGS (15.0%): Ascorbyl Palmitate (1.0%);2) Formula (I) (1.5%): Masester E8120 (55.0%): Gelucire 44 / 14 (24.0%): Capryol 90 (18.5%): Ascorbyl Palmitate (1.0%);3) Formula (I) (1.25%): Masester E8120 (55.0%): Kolliphor HS15 (20.0%): Maisine CC (22.75%): Ascorbyl Palmitate (1.0%); and4) Formula (I) (2.5%): Labrasol ALF (56.0%): Kolliphor RH40 (25.5%): Maisine CC (15.0%): Ascorbyl Palmitate (1.0%).

[0265] Even with the change of formulation composition and order of addition, Formula (I) API solubilization was not achieved. Therefore, the drug load for each prototype was decreased to achieve complete solubilization of API and Kollidon K30 was included at 1% level in each formulation to prevent recrystallization of API from the formulation. Thus, new prototype formulations (Set 3) were prepared:1) Formula (I) (1.25%): Masester E8120 (63.0%): Kolliphor HS15 (18.75%): Vitamin E TPGS (15.0%): Ascorbyl Palmitate (1.0%): Kollidon K30 (1.0%)2) Formula (I) (1.25%): Masester E8120 (54.0%): Gelucire 44 / 14 (24.0%): Capryol90 (18.75%): Ascorbyl Palmitate (1.0%): Kollidon K30 (1.0%)3) Formula (I) (1.0%): Masester E8120 (54.0%): Kolliphor HS15 (20.0%): Maisine CC (23.0%): Ascorbyl Palmitate (1.0%): Kollidon K30 (1.0%)4) Formula (I) (2.0%): Labrasol ALF (55.0%): Kolliphor RH40 (26.0%): Maisine CC (15.0%): Ascorbyl Palmitate (1.0%): Kollidon K30 (1.0%)

[0266] In the Set 3 prototypes, placebo preparations without ascorbyl palmitate were prepared with all respective excipients. Ascorbyl palmitate and Formula (I) API were added in the respective placebo formulation for active formulation preparation and mixed using hand-held homogenizer to solubilize API and ascorbyl palmitate.

[0267] The Set 3 formulations were visually clear solutions at 40 °C. These formulations were evaluated using Pion Fiberoptic dissolution in Bio-Relevant Media along with API. Results for dissolution in biorelevant media are given in Fig. 17 and Fig. 18.

[0268] These Prototype formulations (Set 3) were also evaluated for Assay and degradation product by HPLC analysis. Results for Assay and degradation products are given in Table 3.3.Table 3.3 Lipid Prototype formulation (Set 3) HPLC Analysis Data

[0269] The impurities at RRT 0.94 and 1.13 are also present in the API, and therefore may be process-related impurities and not degradation products. The impurity at RRT 0.98 may be due to presence of free glycerol.

[0270] For all Set 3 prototype formulations, ascorbyl palmitate was added at the end after Formula (I) API was solubilized. Additional formulations (Set 4) were prepared to evaluate order of addition of ascorbyl palmitate prior to API.

[0271] Also, Set 3 Formulation 3 did not have good dispersion in bio-relevant media, therefore Kolliphor HS15 was replaced with Kolliphor RH40 for Set 4 / Set 5 prototypes preparation.

[0272] Prototype formulations preparation Set 4 and Set 5 were duplicate preparations of same composition. Set 5 was prepared after the assay value for Set 4 formulations was determined to be lower than target drug load. Formulation composition for each prototype (set 4 and Set 5) is given below.1) Formula (I) (1.25%): Masester E8120 (63.0%): Kolliphor HS15 (18.75%): Vitamin E TPGS (15.0%): Ascorbyl Palmitate (1.0%): Kollidon K30 (1.0%);2) Formula (I) (1.25%): Masester E8120 (54.0%): Gelucire 44 / 14 (24.0%): Capryol90 (18.75%): Ascorbyl Palmitate (1.0%): Kollidon K30 (1.0%);3) Formula (I) (1.0%): Masester E8120 (54.0%): Kolliphor RH40 (20.0%): Maisine CC (23.0%): Ascorbyl Palmitate (1.0%): Kollidon K30 (1.0%); and4) Formula (I) (2.0%): Labrasol ALF (55.0%): Kolliphor RH40 (26.0%): Maisine CC (15.0%): Ascorbyl Palmitate (1.0%): Kollidon K30 (1.0%)

[0273] Formulations prepared in Set 4 and Set 5 were evaluated with HPLC for Assay and degradation product. Results are presented below in Table 3.4.Table 3.4 Lipid Prototype Formulation (Set 4 and Set 5) HPLC Analysis Data

[0274] Formulation prototypes (Set 5) were evaluated using Pion Fiberoptic dissolution in Bio-Relevant Media along with API. Results for dissolution are provided in Fig. 19 and Fig. 20. As shown in those figures, each Set 5 formulation increases Formula (I) solubility in bio-relevant media by 3 to 5 times relative to the API.

[0275] The Set 5 formulations were further evaluated for stability at 40°C over 2- week time. Results for stability are given in Table 3.5. As shown in the table, each formulations showed increased in degradation product, specifically impurity at RRT 0.98.

[0276] Based on the dissolution in bio-relevant media and stability data for prototype formulations (Set 5), Formulation prototype 1, Prototype 3 and Prototype 4 were suggested for further evaluation for animal PK.Table 3.5 Formula (I) Lipid Formulation Prototypes (Set 5) T=2-week Stability at 40°CExample 5 - Pharmacokinetic Study #1

[0277] The objective of this study was to determine the plasma pharmacokinetic profiles of Formula (I) besylate in male Beagle dogs after oral administration.Study design

[0278] Total of four male Beagle dogs were dosed via a design as shown in Table 5.1. Formula (I) besylate was administered as PO doses (2 mg / kg for POA, 2 mg / kg for POB, 2 mg / kg for POC and 2 mg / kg for POD, 2 mg / kg for POE).Table 5.1: Dosing information* Five groups will share same four animals, after 7 day wash out, the animals of PO group will fasted overnight, then fed one hour before dosing.For capsule and tablets group, Oral with 20 mL water chaser (solid doses).Treatment Compositions:

[0279] Formula (I) Besylate Solution - Formula (I) (besylate salt) 0.4 mg / mL; Povidone K30 3.0%(w / w); Citric acid anhydrous 1.0%(w / w); Kleptose HPB oral grade (hydroxy propyl beta-cyclodextrin) 30%(w / w); Purified water q.s. to 100%.

[0280] Capsule - See Table 2.1 in Example 2.

[0281] Tablet - unmicronized drug - per tablet: 10 mg Formula (I) Besylate (on a free base basis); 58.7 mg NF Lactose Hydrate MOD;54.8 mg Avicel® PH-102 MCC; 3.9 mg VIVAPHARM® PVPP XL (Crospovidone); 0.65 mg CAB-O-SIL® M5P; 1.95 mg Sodium Stearyl Fumarate, NF.

[0282] Tablet - micronized drug - per tablet: 10 mg Formula (I) Besylate (on a free base basis) micronized; 58.7 mg NF Lactose Hydrate MOD;54.8 mg Avicel® PH-102 MCC; 3.9 mg VIVAPHARM® PVPP XL (Crospovidone); 0.65 mg CAB-O-SIL® M5P; 1.95 mg Sodium Stearyl Fumarate, NF.

[0283] Tablet - unmicronized drug - large particles - per tablet: 10 mg Formula (I) Besylate (on a free base basis); 58.7 mg NF Lactose Hydrate MOD;54.8 mg Avicel® PH- 102 MCC; 3.9 mg VIVAPHARM® PVPP XL (Crospovidone); 0.65 mg CAB-O-SIL® M5P; 1.95 mg Sodium Stearyl Fumarate, NF.Sample collection

[0284] For PO (2 mg / kg) administration, blood samples were collected from each animal at 0.00, 0.5, 1, 1.5, 2, 3, 4, 6, 9 and 24 hours post dose.

[0285] Blood samples (1.00 mL) were collected from each animal via peripheral veins. These blood samples were placed into tubes containing K2EDTA, and then centrifuged at 2000 g for 10 minutes at 4°C to produce plasma.

[0286] All samples were stored at -75±15 °C pending analysis.Preparation of standard solutions for LC-MS / MS analysis

[0287] Formula (I) Besylate was prepared in DMSO with vortex at 1 mg / mL as a standard stock solution.

[0288] Calibration standard working solutions were prepared at concentrations of 10, 20, 50, 100, 500, 1000, 5000, 10000 and 20000 ng / mL by serial dilution of the standard stock solution with 50% acetonitrile in water. Quality control working solutions at concentrations of 20, 50, 500, 8000 and 16000 ng / mL were prepared by serial dilution of the standard stock solution with 50% acetonitrile in water. These QC samples were prepared on the day of analysis in the same way as calibration standards.Sample treatment

[0289] 5 pL of each calibration standard working solution (10, 20, 50, 100, 500, 1000, 5000, 10000 and 20000 ng / mL) was added to 50 pL of blank Beagle dog plasma to achieve calibration standards of 1-2000 ng / mL (1, 2, 5, 10, 50, 100, 500, 1000 and 2000 ng / mL) in a total volume of 55 pL. Quality Control (QC) samples at 2 ng / mL (low-1), 5 ng / mL (low-2), 50 ng / mL (mid), 800 ng / mL (high-1) and 1600 ng / mL (high-2) in blankplasma were prepared independently from those used for the calibration curves. These QC samples were prepared on the day of analysis in the same way as calibration standards.

[0290] 55 pL of standards, 55 pL of QC samples or 55 pL of unknown samples (50 pL of plasma sample with 5 pL of 50% acetonitrile in water) were mixed with 200 pL of acetonitrile containing a deuterated (de) internal standard (IS; 50 ng / mL) to precipitate proteins. Then the samples were vortexed for 30 sec. After centrifugation at 4°C, 3900 rpm for 15 min, the supernatant was diluted at a ratio of 1 :2 with water (v / v: 1 / 2). 10 pL of diluted supernatant was injected into the LC-MS / MS system for quantitative analysis.LC-MS / MS conditions

[0291] The LC-MS / MS system consisted of Degasser DGU-20A5R, S, Liquid Chromatograph LC-30AD, Communications Bus Module CBM-20A, Auto Sampler SIL- 30AC, Rack changer II and an AB API 5500 LC / MS / MS instrument (Serial No. EX20351803).

[0292] Chromatographic separation was performed on a Waters Xselect HSS T3 2.5pm (50*2.1 mm) at room temperature. The mobile phase was composed of A: 5% acetonitrile (0.1% formic acid) in water; B: 95% acetonitrile (0.1% formic acid) in water. The flow rate was 0.6 mL / min. The injection volume was 10 pL.

[0293] Positive mode electrospray ionization (ESI) was performed on a Turbo V® ion source to obtain protonated ions of Formula (I) besylate and a deuterated (de) internal standard (IS). A multiple reaction monitoring (MRM) method was selected for quantitative analysis. The optimized transitions were 558.90 / 384.80 Da and 564.93 / 388.00 Da for Formula (I) besylate and IS, respectively. The instrument parameters were set as follows: ion spray voltage: 5500 V; curtain gas: 40 psi; nebulizer gas: 50 psi; turbo gas: 50 psi; collision gas: 10 psi; temperature: 450°C.Statistical analysis

[0294] Data acquisition was performed by Sciex Analyst 1.8.3 software (AB Sciex, Forster City, CA). All concentration data and pharmacokinetic parameters were reported with 3 significant figures, except ti / 2 and Tmax with one decimal point. BLOQ was set to zero in calculation. Data statistics were performed using Excel 2016 software.Pharmacokinetic sample analysis

[0295] The Formula (I) plasma concentration vs. time profiles are shown in Fig.21.Pharmacokinetic analysis

[0296] Formula (I) plasma concentrations for each animal following PO administration were used to calculate pharmacokinetic parameters by employing noncompartmental analysis (Phoenix TM WinNonlin® 8.3). The linear trapezoidal algorithm was used for AUC calculation. Plasma pharmacokinetic parameters are shown in Table 5.3- 5.7. In summary, Formula (I) maximum concentration (Cmax) of 649 ng / mL was observed at 3.25 hours following the 2 mg / kg POA dose for which AUClast is 9426 h*ng / mL. Cmax of 700 ng / mL was observed at 5.50 hours following the 2 mg / kg POB dose for which AUClast is 9137 h*ng / mL. Cmax of 455 ng / mL was observed at 4.00 hours following the 2 mg / kg POC dose for which AUClast is 5594 h*ng / mL. Cmax of 643 ng / mL was observed at 4.25 hours following the 2 mg / kg POD dose for which AUClast is 8710 h*ng / mL. Cmax of 595 ng / mL was observed at 5.63 hours following the 2 mg / kg POE dose for which AUClast is 7835 h*ng / mL.Table 5.3: Plasma Pharmacokinetic Parameters of Formula (I) Following POA Administration in Male Beagle Dogs at 2 mg / kgTable 5.4: Plasma Pharmacokinetic Parameters of Formula (I) Following POBAdministration in Male Beagle Dogs at 2 mg / kgTable 5.5: Plasma Pharmacokinetic Parameters of Formula (I) after Following POC Administration in Male Beagle Dogs at 2 mg / kgTable 5.6: Plasma Pharmacokinetic Parameters of Formula (I) Following POD Administration in Male Beagle Dogs at 2 mg / kgTable 5.7: Plasma Pharmacokinetic Parameters of Formula (I) Besylate Following POE Administration in Male Beagle Dogs at 2 mg / kgExample 6. - Pharmacokinetic Study #2

[0297] The objective of this study is to determine the plasma pharmacokinetic profiles of Formula (I) in male Beagle dogs after oral administration.Test article

[0298] Test article information is listed in Table 6.1:Table 6.1: Test article informationAnimals

[0299] Male Beagle dogs are 1- 3 years old. The animals are housed in a 12-hour light / 12-hour dark cycle environment.Study design

[0300] Total of four male Beagle dogs are dosed via a design as shown in Table6.2. Formula (I) is administered as PO doses (3 mg / kg for POA, 3 mg / kg for POB, and 10 mg / kg for POD).Table 6.2: Dosing information* Food control: the animals of PO group are fasted overnight, then fed one hour before dosing. For POB, and POD, Oral with 20 mL water chaser Four groups share same four animals. The wash out period is 7 days, f Correction factor of 1.32 is usedSample collection

[0301] For PO (2 mg / kg) administration, blood samples are collected from each animal at 0.00, 0.5, 1, 1.5, 2, 3, 4, 6, 9 and 24 hours post dose.

[0302] Blood samples (1.00 mL) are collected from each animal via peripheral veins. These blood samples are placed into tubes containing K2EDTA, and then centrifuged at 2000 g for 10 minutes at 4°C to produce plasma.

[0303] All samples are stored at -75±15 °C pending analysis.Formulation preparationPreparation of dosing for POA administration (2 mg / kg):

[0304] 112.85 mg of Formula (I) besylate is dissolved in 213.731 mL of" 30%HP- P-CD in sterile water" with vortexing and sonication to obtain a solution with concentration of 0.4 mg / mL.Preparation of dosing for POB administration (2 mg / kg):

[0305] 116.87 mg of Formula (I) besylate is added to 221.345 mL of " 0.5% Methocel A4 / 0.2% Tween 80 suspension vehicle (micronized drug)" with vortexing and sonication to obtain a suspension with concentration of 0.4 mg / mL.Preparation of dosing for POD administration (2 mg / kg):

[0306] Formula (I) free base: 1.25% (w / w); Massester E8120: 63.00% (w / w); Kolliphor HS15: 18.75% (w / w); Vit E TPGS: 15.00% (w / w); Kollidon K30 1.00% (w / w); Ascorbyl Palmitate: 1.00% (w / w).Preparation of standard solutions for LC-MS / MS analysis

[0307] Formula (I) besylate is prepared in DMSO with vortex at 1 mg / mL as a standard stock solution.

[0308] Calibration standard working solutions are prepared at concentrations of 10, 20, 50, 100, 500, 1000, 5000, 10000 and 20000 ng / mL by serial dilution of the standard stock solution with 50% acetonitrile in water. Quality control working solutions at concentrations of 20, 50, 500, 8000 and 16000 ng / mL are prepared by serial dilution of the standard stock solution with 50% acetonitrile in water. These QC samples are prepared on the day of analysis in the same way as calibration standards.Sample treatment

[0309] 5 pL of each calibration standard working solution (10, 20, 50, 100, 500, 1000, 5000, 10000 and 20000 ng / mL) is added to 50 pL of blank Beagle dog plasma to achieve calibration standards of 1-2000 ng / mL (1, 2, 5, 10, 50, 100, 500, 1000 and 2000 ng / mL) in a total volume of 55 pL. Quality Control (QC) samples at 2 ng / mL (low-1), 5 ng / mL (low-2), 50 ng / mL (mid), 800 ng / mL (high-1) and 1600 ng / mL (high-2) in blank plasma are prepared independently from those used for the calibration curves. These QC samples are prepared on the day of analysis in the same way as calibration standards.

[0310] 55 pL of standards, 55 pL of QC samples or 55 pL of unknown samples (50 pL of plasma sample with 5 pL of 50% acetonitrile in water) are mixed with 200 pL of acetonitrile containing IS (50 ng / mL) to precipitate proteins. Then the samples are vortexed for 30 sec. After centrifugation at 4°C, 3900 rpm for 15 min, the supernatant is diluted at aratio of 1 :2 with water (v / v: 1 / 2). 10 pL of diluted supernatant is injected into the LC-MS / MS system for quantitative analysis.LC-MS / MS conditions

[0311] The LC-MS / MS system consists of Degasser DGU-20A5R; LC-30AD; SIL-30 AC; Rack Changer II S; CTO-30 A; CBM-20A and an AB API 5500 LC / MS / MS

[0312] Chromatographic separation is performed on a Waters Xselect HSS T3 2.5pm (50*2.1 mm) at room temperature. The mobile phase is composed of A: 5% acetonitrile (0.1% formic acid) in water; B: 95% acetonitrile (0.1% formic acid) in water. The flow rate is 0.6 mL / min. The injection volume is 10 pL.

[0313] Positive mode electrospray ionization (ESI) is performed on a Turbo V® ion source to obtain protonated ions of Formula (I) and (IS). A multiple reaction monitoring (MRM) method is selected for quantitative analysis. The optimized transitions are 558.90 / 384.80 Da and 564.93 / 388.00 Da for Formula (I) and IS, respectively. The instrument parameters are set as follows: ion spray voltage: 5500 V; curtain gas: 40 psi; nebulizer gas: 50 psi; turbo gas: 50 psi; collision gas: 10 psi; temperature: 450°C. The compound-dependent parameters are listed in Table 6.3.Table 6.3 Compound-dependent parameters on MSData acceptance criteriaAcceptance criteria of standard calibration samples:

[0314] At least 6 samples should be analyzed to obtain a calibration curve.Acceptance of calibration standards requires calculated concentration within 80%-120% of the nominal concentrations, and 75% of the calibration standards should be within the acceptable range.Acceptance criteria of quality control samples:

[0315] At least 3 concentrations of quality control samples (QCs) should be analyzed in a run. Each concentration should include at least 2 individual samples.Acceptance of QCs requires calculated concentration within 80%-120% of the nominal concentration. QCs should be analyzed amongst all unknown samples, and 2 / 3 of the QCs should be within the acceptable range, including at least 1 sample at each concentration level in an analytical run.Acceptance criteria of unknown samples:

[0316] Unknown samples with normal peak shape of analytes and calculated concentration within the calibration range should be accepted. Samples with calculated concentration below LLOQ should be recorded as BLOQ. Samples with calculated concentration above 120% of ULOQ should be diluted with blank matrix and re-assayed. The re-assayed concentration should be multiplied by the dilution factor to obtain the final data. In cases of abnormality, such as equipment malfunction, power outage, sample treatment failure and / or sample injection failure, re-assay should be done in an individual analytical run.Statistical analysis

[0317] Data acquisition is performed by Sciex Analyst 1.8.3 software (AB Sciex, Forster City, CA). All concentration data and pharmacokinetic parameters are reported with 3 significant figures, except ti / 2 and Tmax with one decimal point. BLOQ is set to zero in calculation. Data statistics are performed using Excel 2016 software.RESULTSClinical observationsLinearity

[0318] In this study, a calibration standard is used for the regression of a 1 / x2- weighted calibration curve. The curve is plotted using the peak area ratio of Formula (I) and IS versus the nominal concentration. The accuracy of the accepted standard samples is 81.7%- 110% for plasma samples.Quality control samples

[0319] The accuracy of the accepted QC samples was 95.7%-107% for plasma. The accuracy of quality control samples is within acceptance criteria (80-120%).Pharmacokinetic sample analysis

[0320] The Formula (I) plasma concentration vs. time profiles are shown in Fig. 22.Pharmacokinetic analysis

[0321] Formula (I) plasma concentrations for each animal following PO administration are used to calculate pharmacokinetic parameters by employing noncompartmental analysis (Phoenix TM WinNonlin® 8.3). The linear trapezoidal algorithm is used for AUC calculation. Plasma pharmacokinetic parameters are shown in Tables 6.4- 6.7. In summary, Formula (I) maximum concentration (Cmax) of 685 ng / mL is observed at 3.25 hours following the 2 mg / kg POA dose for which AUClast is 8610 h*ng / mL. Cmax of 609 ng / mL is observed at 4.25 hours following the 2 mg / kg POB dose for which AUClast is 7506 h*ng / mL. Cmax of 618 ng / mL is observed at 2.75 hours following the 2 mg / kg POD dose for which AUClast is 7895 h*ng / mL.Table 6.4: Plasma Pharmacokinetic Parameters of Formula (I) Besylate Following POA Administration in Male Beagle Dogs at 2 mg / kgTable 6.5: Plasma Pharmacokinetic Parameters of Formula (I) Besylate Following POB Administration in Male Beagle Dogs at 2 mg / kgTable 6.7: Plasma Pharmacokinetic Parameters of Formula (I) Lipid-based formulation Following POD Administration in Male Beagle Dogs at 2 mg / kgExample 7 - Cyclodextrin Solutions

[0322] To support the development of the aqueous solution formulations of the disclosure, the solubility of various Formula (I) salts in cyclodextrins was determined.Table 7.1 Formula (I) salts solubility in pH2 30% HPBCD solutionTable 7.2 Formula (I) salts solubility in 30% HPBCD solution

[0323] It was observed that all of the tested salts are poorly soluble in pH 2 solutions. Even 1 mg of salt could not be dissolved in -3 mL of solution.Table 7.3 Formula (I) salts and the free base solubility in pH2 - 10% HPBCD solutionTable 7.4 Formula (I) and the free base solubility in pH2 - 20% HPBCD solution.Table 7.5 Formula (I) salts the free base solubility in pH2 - 30% HPBCD solution.Table 7.6 Formula (I) free base solubility in 10% HPBCD solution (note that this is not pH 2 solution).Table 7.7. Formula (I) free base solubility in 20% HPBCD solution (note that this is not pH 2 solution).Table 7.8 Formula (I) free base solubility in 30% Sulfobutylether-p-cyclodextrin (Captisol®) solution (note that this is not pH 2 solution).Table 7.9 Formula (I) salts and the free base solubility in pH2 - 10% Captisol® solution.Table 7.10 Formula (I) salts and the free base solubility in pH2 - 20% Captisol® solution.Example 8: 10 MG AND 30 MG TABLETS

[0324] Formula (I) Besylate salt is formulated as white to off-white round tablets containing 10 mg or 30 mg of Formula (I) Besylate salt drug substance as free base equivalents. The components and quantitative composition are presented in Table 8.1.Table 8.1 Formula (I) Besylate Tablets CompositionN / A = not applicable; Ph. Eur. = European Pharmacopoeia; NF = National Formulary; USP = United States Pharmacopoeia.a= Equivalent to 10 mg of Formula (I) free base; the actual salt quantity determined using correction factor, CF = % Assay (Anhydrous and Solvent Free) / 100 x (100% - % Water - % Residual Solvent - % Impurities -% Counterion Content). The amount of lactose is adjusted accordingly. b = Equivalent to 30 mg of Formula (I) free base; the actual salt quantity determined using correction factor, CF = % Assay (Anhydrous and Solvent Free) / 100 x (100% - % Water - % Residual Solvent - % Impurities -% Counterion Content). The amount of lactose is adjusted accordingly. c = 3.7% weight gain on coated tablet weight. d = Removed during processing.Table 8.2 Film Coating System Opadry II 85F18422 White CompositionN / A = not applicable; Ph. Eur. = European Pharmacopoeia; NF = National Formulary;USP = United States Pharmacopoeia. a = The w / w% refers to the Opadry II 85F 18422 White coating system.Example 9: Sprinkle Capsules with Minitabs

[0325] The Formula (I) Besylate drug product is formulated in 3 different strengths: as size 0 hard gelatin sprinkle capsules, opaque white body and cap for the 1 mg strength, opaque white body and opaque light blue cap for the 5 mg strength, and Swedish orange opaque body and cap for the 10 mg strength. The sprinkle capsules are filled with 4, 20, and 40 minitablets for the 1 mg, 5 mg, and 10 mg strengths, respectively, each containing Formula (I) Besylate drug substance as free base equivalents.

[0326] The minitablets components, their function, and quality standards are provided in Table 9.1. The composition of the 1 mg sprinkle capsules is provided in Table 9.2, of the 5 mg in Table 9.3, and of the 10 mg in Table 9.4.Table 9.1 Composition of Formula (I) Besylate MinitabletsNA = not applicable; NF = National Formulary; Ph Eur = European Pharmacopoeia; USP = United States Pharmacopeia, a = The actual salt quantity determined using correction factor, CF = % Assay (Anhydrous and Solvent Free) / 100 x (100% - % Water - % Residual Solvent - % Impurities - % Counterion Content). b = 10% weight gain on coated minitablet weight. c = Removed during processing.Table 9.2: Formula (I) Besylate Drug Product Composition - White Opaque Body and Cap, 1 mg StrengthNA = not applicable; NF = National Formulary; Ph Eur = European Pharmacopoeia; USP = United States Pharmacopeia, a = The actual salt quantity determined using correction factor, CF = % Assay (Anhydrous and Solvent Free) / 100 x (100% - % Water - % Residual Solvent - % Impurities - % Counterion Content). b = 10% weight gain on coated minitablet weight. c = Removed during processing.Table 9.3: Formula (I) Besylate Drug Product Composition - White Opaque Body and Blue Opaque Cap, 5 mg StrengthNA = not applicable; NF = National Formulary; Ph Eur = European Pharmacopoeia; USP = United States Pharmacopeia. a = The actual salt quantity determined using correction factor, CF = % Assay (Anhydrous and Solvent Free) / 100 x (100% - % Water - % Residual Solvent - % Impurities - % Counterion Content).b = 10% weight gain on coated minitablet weight. c = Removed during processing.Table 9.4: Formula (I) Besylate Drug Product Composition - Swedish Orange Opaque Body and Cap, 10 mg StrengthNA = not applicable; NF = National Formulary; Ph Eur = European Pharmacopoeia; USP = United States Pharmacopeia, a = The actual salt quantity determined using correction factor, CF = % Assay (Anhydrous andSolvent Free) / 100 x (100% - % Water - % Residual Solvent - % Impurities - % Counterion Content). b = 10% weight gain on coated minitablet weight. c = Removed during processingTable 9.5: Film Coating System Opadry AMB White 88A180040 CompositionGMDCC / GMCC Type 1 = Glyceryl Mono- and Di capryl ocaprate (or glyceryl monocaprylocaprate); NF = National Formulary; Ph Eur = European Pharmacopoeia; USP = United States Pharmacopeia. a = The w / w% refers to the Opadry AMB White 88A180040 coating system.

Claims

What is claimed:

1. A method of treating cancer in a subject in need thereof, comprising orally administering to the subject a pharmaceutical composition comprising: a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

2. The method of claim 1, wherein the pharmaceutical composition is a tablet or a capsule.

3. The method of claim 2, wherein the tablet comprises a pharmaceutically acceptable excipient that is a diluent, a binder, a disintegrant, a glidant, a lubricant, or a surfactant.

4. The method of claim 3, wherein the pharmaceutically acceptable excipient is microcrystalline cellulose, mannitol, croscarmellose sodium, fumed silica, sodium stearyl fumarate, or a mixture thereof.

5. The method of any one of claims 2-4, wherein the tablet further comprise a film coating, such as, a hydroxypropyl methyl cellulose-based coating or a polyvinyl alcohol-based coating.

6. The method of claim 1, wherein the pharmaceutical composition comprises:(a) a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof;(b) a lipid vehicle;(c) an antioxidant; and(d) a crystallization inhibitor.

7. The method of claim 6, wherein the lipid vehicle is Masester E8120, Kolliphor HS15, Kolliphor RH40, Gelucire 44 / 14, Caproyl 90, Vitamin E TPGS, or Maisine CC, or mixtures thereof.

8. The method of claim 6 or 7, wherein the antioxidant is ascorbyl palmitate.

9. The method of claim 6, 7, or 8, wherein the crystallization inhibitor is Kollidon K30 (polyvinylpyrollidone).

10. The method of any one of claims 6-9, wherein the pharmaceutical composition comprises about 1% to about 3% by weight of the compound of Formula (I), or pharmaceutically acceptable salt thereof (on a compound of Formula (I) basis).

11. The method of any one of claims 6-10 wherein the pharmaceutical composition is a liquid suspension.

12. The method of any one of claims 6-10, wherein the pharmaceutical composition is a liquid solution.

13. The method of any one of claims 6-12, wherein the pharmaceutical composition comprises one of:(a) Formula (I) (1.25% wt / wt), Masester E8120 (63.0% wt / wt), Kolliphor HS 15 (18.75% wt / wt), Vitamin E TPGS (15.0% wt / wt), Ascorbyl Palmitate (1.0% wt / wt), and Kollidon K30 (1.0% wt / wt);(b) Formula (I) (1.25% wt / wt), Masester E8120 (54.0% wt / wt), Gelucire 44 / 14 (24.0% wt / wt), Capryol 90 (18.75% wt / wt), Ascorbyl Palmitate (1.0% wt / wt), and Kollidon K30 (1.0% wt / wt);(c) Formula (I) (1.0% wt / wt), Masester E8120 (54.0% wt / wt), and Kolliphor RH40 (20.0% wt / wt), Maisine CC (23.0% wt / wt), Ascorbyl Palmitate (1.0% wt / wt), Kollidon K30 (1.0% wt / wt); or(d) Formula (I) (2.0% wt / wt), Labrasol ALF (55.0% wt / wt), Kolliphor RH40 (26.0% wt / wt), Maisine CC (15.0% wt / wt), Ascorbyl Palmitate (1.0% wt / wt), and Kollidon K30 (1.0% wt / wt).

14. The method of any one of claims 6-13, wherein the total impurities in the pharmaceutical composition increases by less than 1% (HPLC area%) when the pharmaceutical composition is stored at 40°C for two weeks.

15. The method of any one of claims 6-14, wherein addition of the pharmaceutical composition to fasted simulated intestinal fluid (FASSIF) in an amount of 12.5 mg of Formula (I) per 500 mL of media, results in 3- to 5- times more Formula (I) dissolved in the FASSIF than results from adding micronized Formula (I) to FASSIF in an amount of 12.5 mg of Formula (I) per 500 mL of media.

16. The method of claim 1, wherein the pharmaceutical composition is a solution comprising:(a) a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof;(b) a diluent; and(c) a solubilizer.

17. The method of claim 16, wherein the solution comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount (on a Formula (I) basis) of about 1 mg / mL to 20 mg / mL.

18. The method of claim 16 or claim 17, wherein the diluent comprises water.

19. The method of any one of claims 16-18, the solubilizer is a cyclodextrin.

20. The method of claim 19, wherein the cyclodextrin is hydroxy propyl betacyclodextrin.

21. The method of claim 19, wherein the cyclodextrin is sulfobutylether betacyclodextrin.

22. The method of any one of claims 16-21, wherein the solution comprises 10%-40% by weight (w / w) of solubilizer.

23. The method of any one of claims 16-22, wherein the solution further comprises a viscosity modifier.

24. The method of claim 23, wherein the viscosity modifier is 1-5% by weight (w / w) polyvinylpyrrolidone.

25. The method of any one of claims 16-24, wherein the solution further comprises a pH modifier.

26. The method of claim 25, wherein the pH modifier is 0.1 - 5% by weight (w / w) citric acid (on an anhydrous basis).

27. The method of any one of claims 16-26, wherein the solution further comprises a preservative.

28. The method of claim 27, wherein the preservative is 0.1 - 0.5% by weight (w / w) of sodium benzoate, potassium sorbate, or a mixture of sodium benzoate and potassium sorbate.

29. The method of any one of claims 16-28, wherein the solution further comprises a sweetener.

30. The method of claim 29, wherein the sweetener is 0.1 - 0.5% by weight (w / w) of sucralose.

31. The method of any one of claims 16-30, wherein the composition comprises 1-10 mg / mL Formula (I) or a pharmaceutically acceptable salt thereof, 0.1% (w / w) sucralose, 3 % (w / w) polyvinylpyrrolidone, 1% (w / w) citric acid (anhydrous basis), 10-40% (w / w) hydroxy propyl beta-cyclodextrin, 0.1% (w / w) sodium benzoate, 0.1% (w / w) potassium sorbate, and purified water (q.s. to 100% (w / w)).

32. The method of claim 1, wherein the pharmaceutical composition is a capsule comprising:(a) a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof; and (b) a diluent.

33. The method of claim 32, wherein the capsule contains 5 mg - 30 mg (on a Formula (I) free base basis) of Formula (I), or a pharmaceutically acceptable salt thereof.

34. The method of claim 31 or claim 32, wherein the diluent is microcrystalline cellulose.

35. The method of claim 1, wherein the pharmaceutical composition is a tablet comprising:(a) a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof; and(b) a pharmaceutically acceptable excipient.

36. The method of claim 35, wherein the tablet comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 5 mg - about 40 mg (on a Formula (I) basis).

37. The method of claim 35 or claim 36, wherein the tablet comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 7.5% - about 8.0% by weight (on a Formula (I) basis).

38. The method of any one of claims 35-37, wherein the compound of Formula (I), or pharmaceutically acceptable salt thereof, has a volume mean diameter of Xio<l pm; Xso<3 pm; and X90<10 pm.

39. The method of any one of claims 35-38, wherein the compound of Formula (I), or pharmaceutically acceptable salt thereof, has a volume mean diameter of Xio<l pm; Xso<3 pm; and X9o<5 pm.

40. The method of claim 39, wherein the compound of Formula (I), or pharmaceutically acceptable salt thereof, has a volume mean diameter of Xio<O.9 pm; Xso<1.8 pm; and X9O<4.3 pm.

41. The method of any one of claims 35-40, wherein the pharmaceutically acceptable excipient is a diluent / compression aid, a binder, a disintegrant, a glidant, a lubricant, or a surfactant, or a combination thereof.

42. The method of claim 41, wherein the pharmaceutically acceptable excipient is a diluent / compression aid, such as lactose monohydrate, microcrystalline cellulose, mannitol, pregeletanized starch, or mixtures thereof.

43. The method of claim 42, wherein the diluent / compression aid is present in the tablets in an amount of about 80% - about 90% by weight.

44. The method of any one of claims 41-43, wherein the pharmaceutically acceptable excipient is a binder, such as, hydroxypropyl methylcellulose or polyvinylpyrrolidone.

45. The method of any one of claims 41-44, wherein the pharmaceutically acceptable excipient is a disintegrant, such as, croscarmellose sodium or crospovidone.

46. The method of claim 45, wherein the disintegrant is present in the tablets in an amount of 2% - 4% by weight (w / w).

47. The method of any one of claims 41-46, wherein the pharmaceutically acceptable excipient is a glidant, such as, silicon dioxide.

48. The method of claim 47, wherein the glidant is present in the tablet in an amount of about 0.2% - about 0.7% by weight.

49. The method of any one of claims 41-48, wherein the pharmaceutically acceptable excipient is a lubricant, such as magnesium stearate or sodium stearyl fumarate.

50. The method of claim 49, wherein the lubricant is present in the tablet in an amount of about 1% - about 2% by weight.

51. The method of any one of claims 41-50, wherein the pharmaceutically acceptable excipient is a surfactant, such as sodium lauryl sulfate or poly(ethylene glycol)-Z> / oc&- poly(propylene glycol)-Z> / oc& polyethylene glycol.

52. The method of any one of claims 35-51, wherein tablet further comprises a film coating, such as, a hydroxypropyl methyl cellulose-based coating or a polyvinyl alcohol-based coating.

53. The method of claim 52, wherein the film coating adds between 2% - 4% by weight to the uncoated tablet.

54. The method of any one of the preceding claims, wherein the cancer has an activating FGFR3 gene alteration.

55. The method of any one of the preceding claims, wherein the cancer is urothelial cancer, breast cancer, endometrial cancer, lung cancer, ovarian cancer, or bladder cancer.

56. The method of any one of the preceding claims, wherein the cancer is a locally advanced solid tumor.

57. The method of any one of claims 1-56, wherein the cancer is a metastatic solid tumor.

58. The method of any one of claims 54 to 57, wherein the activating FGFR3 gene alteration is a mutation.

59. The method of any one of claims 54 to 58, wherein the activating FGFR3 gene alteration is a fusion.

60. A pharmaceutical composition comprising: a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

61. The pharmaceutical composition of claim 60, in the form of a tablet or a capsule.

62. The pharmaceutical composition of claim 61, wherein the tablet comprises a pharmaceutically acceptable excipient that is a diluent, a binder, a disintegrant, a glidant, a lubricant, or a surfactant.

63. The pharmaceutical composition of claim 62, wherein the pharmaceutically acceptable excipient is microcrystalline cellulose, mannitol, croscarmellose sodium, fumed silica, sodium stearyl fumarate, or a mixture thereof.

64. The method of any one of claims 61-63, wherein the tablet further comprise a film coating, such as, a hydroxypropyl methyl cellulose-based coating or a polyvinyl alcohol-based coating.

65. The pharmaceutical composition of claim 60, wherein the pharmaceutical composition comprises:(a) a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof;a lipid vehicle;an antioxidant; anda crystallization inhibitor.

66. The pharmaceutical composition of claim 65, wherein the lipid vehicle is Masester E8120, Kolliphor HS15, Kolliphor RH40, Gelucire 44 / 14, Caproyl 90, Vitamin E TPGS, or Maisine CC, or mixtures thereof.

67. The pharmaceutical composition of claim 65 or 66, wherein the antioxidant is ascorbyl palmitate.

68. The pharmaceutical composition of claim 65, 66, or 67, wherein the crystallization inhibitor is Kollidon K30 (polyvinylpyrollidone).

69. The pharmaceutical composition of any one of claims 65-68, wherein the pharmaceutical composition comprises about 1% to about 3% by weight of the compound of Formula (I), or pharmaceutically acceptable salt thereof (on a compound of Formula (I) basis).

70. The pharmaceutical composition of any one of claims 65-69, wherein the pharmaceutical composition is a liquid suspension.

71. The pharmaceutical composition of any one of claims 65-70, wherein the pharmaceutical composition is a liquid solution.

72. The pharmaceutical composition of any one of claims 65-71, wherein the pharmaceutical composition comprises one of:(a) Formula (I) (1.25% wt / wt), Masester E8120 (63.0% wt / wt), Kolliphor HS 15 (18.75% wt / wt), Vitamin E TPGS (15.0% wt / wt), Ascorbyl Palmitate (1.0% wt / wt), and Kollidon K30 (1.0% wt / wt);(b) Formula (I) (1.25% wt / wt), Masester E8120 (54.0% wt / wt), Gelucire 44 / 14 (24.0% wt / wt), Capryol 90 (18.75% wt / wt), Ascorbyl Palmitate (1.0% wt / wt), and Kollidon K30 (1.0% wt / wt);(c) Formula (I) (1.0% wt / wt), Masester E8120 (54.0% wt / wt), and Kolliphor RH40 (20.0% wt / wt), Maisine CC (23.0% wt / wt), Ascorbyl Palmitate (1.0% wt / wt), Kollidon K30 (1.0% wt / wt); or(d) Formula (I) (2.0% wt / wt), Labrasol ALF (55.0% wt / wt), Kolliphor RH40 (26.0% wt / wt), Maisine CC (15.0% wt / wt), Ascorbyl Palmitate (1.0% wt / wt), and Kollidon K30 (1.0% wt / wt).

73. The pharmaceutical composition of any one of claims 65-72, wherein the total impurities in the pharmaceutical composition increases by less than 1% (HPLC area%) when the pharmaceutical composition is stored at 40°C for two weeks.

74. The pharmaceutical composition of any one of claims 65-73, wherein addition of the pharmaceutical composition to fasted simulated intestinal fluid (FASSIF) in an amount of 12.5 mg of Formula (I) per 500 mL of media, results in 3- to 5- times more Formula (I) dissolved in the FASSIF than results from adding micronized Formula (I) to FASSIF in an amount of 12.5 mg of Formula (I) per 500 mL of media.

75. The pharmaceutical composition of claim 60, wherein the pharmaceutical composition is a solution comprising:(a) a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof;(b) a diluent; and(c) a solubilizer.

76. The pharmaceutical composition of claim 75, wherein the solution comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount (on a Formula (I) basis) of about 1 mg / mL to 20 mg / mL.

77. The pharmaceutical composition of claim 75 or claim 76, wherein the diluent comprises water.

78. The pharmaceutical composition of any one of claims 75-77, the solubilizer is a cyclodextrin.

79. The pharmaceutical composition of claim 78, wherein the cyclodextrin is hydroxy propyl beta-cyclodextrin.

80. The pharmaceutical composition of claim 78, wherein the cyclodextrin is sulfobutylether beta-cyclodextrin.

81. The pharmaceutical composition of any one of claims 75-80, wherein the solution comprises 10%-40% by weight (w / w) of solubilizer.

82. The pharmaceutical composition of any one of claims 75-80, wherein the solution further comprises a viscosity modifier.

83. The pharmaceutical composition of claim 82, wherein the viscosity modifier is 1-5% by weight (w / w) polyvinylpyrrolidone.

84. The pharmaceutical composition of any one of claims 75-83, wherein the solution further comprises a pH modifier.

85. The pharmaceutical composition of claim 84, wherein the pH modifier is 0.1 - 5% by weight (w / w) citric acid (on an anhydrous basis).

86. The pharmaceutical composition of any one of claims 75-85, wherein the solution further comprises a preservative.

87. The pharmaceutical composition of claim 86, wherein the preservative is 0.1 - 0.5% by weight (w / w) of sodium benzoate, potassium sorbate, or a mixture of sodium benzoate and potassium sorbate.

88. The pharmaceutical composition of any one of claims 75-88, wherein the solution further comprises a sweetener.

89. The pharmaceutical composition of claim 88, wherein the sweetener is 0.1 - 0.5% by weight (w / w) of sucralose.

90. The pharmaceutical composition of any one of claims 75-89, wherein the composition comprises 1-10 mg / mL Formula (I) or a pharmaceutically acceptable salt thereof, 0.1% (w / w) sucralose, 3 % (w / w) polyvinylpyrrolidone, 1% (w / w) citric acid (anhydrous basis), 10-40% (w / w) hydroxy propyl beta-cyclodextrin, 0.1% (w / w) sodium benzoate, 0.1% (w / w) potassium sorbate, and purified water (q.s. to 100% (w / w)).

91. The pharmaceutical composition of claim 60, wherein the pharmaceutical composition is a capsule comprising:(a) a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof; and(b) a diluent.

92. The pharmaceutical composition of claim 91, wherein the capsule contains 5 mg - 30 mg (on a Formula (I) free base basis) of Formula (I), or a pharmaceutically acceptable salt thereof.

93. The pharmaceutical composition of claim 91 or claim 92, wherein the diluent is microcrystalline cellulose.

94. The pharmaceutical composition of claim 62, wherein the pharmaceutical composition is a tablet comprising:(a) a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient.

95. The pharmaceutical composition of claim 94, wherein the tablet comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 5 mg - about 40 mg (on a Formula (I) basis).

96. The pharmaceutical composition of claim 94 or claim 95, wherein the tablet comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 7.5% - about 8.0% by weight (on a Formula (I) basis).

97. The pharmaceutical composition of any one of claims 94-96, wherein the compound of Formula (I), or pharmaceutically acceptable salt thereof, has a volume mean diameter of Xio<l pm; Xso<3 pm; and X90<10 pm.

98. The pharmaceutical composition of any one of claims 94-97, wherein the compound of Formula (I), or pharmaceutically acceptable salt thereof, has a volume mean diameter of Xio<l pm; Xso<3 pm; and X9o<5 pm.

99. The pharmaceutical composition of claim 98, wherein the compound of Formula (I), or pharmaceutically acceptable salt thereof, has a volume mean diameter of Xio<O.9 pm; Xso<1.8 pm; and X9o<4.3 pm.

100. The pharmaceutical composition of any one of claims 94-100, wherein the pharmaceutically acceptable excipient is a diluent / compression aid, a binder, a disintegrant, a glidant, a lubricant, or a surfactant, or a combination thereof.

101. The pharmaceutical composition of claim 100, wherein the pharmaceutically acceptable excipient is a diluent / compression aid, such as lactose monohydrate, microcrystalline cellulose, mannitol, pregeletanized starch, or mixtures thereof.

102. The pharmaceutical composition of claim 101, wherein the diluent / compression aid is present in the tablets in an amount of about 80% - about 90% by weight.

103. The pharmaceutical composition of any one of claims 100-102, wherein the pharmaceutically acceptable excipient is a binder, such as, hydroxypropyl methylcellulose or polyvinylpyrrolidone.

104. The pharmaceutical composition of any one of claims 100-103, wherein the pharmaceutically acceptable excipient is a disintegrant, such as, croscarmellose sodium or crospovidone.

105. The pharmaceutical composition of claim 104, wherein the disintegrant is present in the tablets in an amount of 2% - 4% by weight (w / w).

106. The pharmaceutical composition of any one of claims 100-105, wherein the pharmaceutically acceptable excipient is a glidant, such as, silicon dioxide.

107. The pharmaceutical composition of claim 106, wherein the glidant is present in the tablet in an amount of about 0.2% - about 0.7% by weight.

108. The pharmaceutical composition of any one of claims 100-107, wherein the pharmaceutically acceptable excipient is a lubricant, such as magnesium stearate or sodium stearyl fumarate.

109. The pharmaceutical composition of claim 108, wherein the lubricant is present in the tablet in an amount of about 1% - about 2% by weight.

110. The pharmaceutical composition of any one of claims 100-109, wherein the pharmaceutically acceptable excipient is a surfactant, such as sodium lauryl sulfate or poly(ethylene glycol)-6 / ocA poly(propylene glycol)-Z> / oc& polyethylene glycol.

111. The pharmaceutical composition of any one of claims 94-110, wherein tablet further comprises a film coating, such as, a hydroxypropyl methyl cellulose-based coating or a polyvinyl alcohol-based coating.

112. The pharmaceutical composition of any one of claims 60-111, for use in treating developmental disorders in a subject in need thereof.

113. The pharmaceutical composition of claim 112, wherein the developmental disorders is Achondroplasia (Ach) and related chondrodysplasia syndromes, including Hypochondroplasia (Hch), Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (SADDAN), and Thanatophoric dysplasia (TD).

114. The pharmaceutical composition of any one of claims 60-111, for use in treating cancer.

115. The pharmaceutical composition of claim 114, wherein the cancer has an activating FGFR3 gene alteration.

116. The pharmaceutical composition of claim 115, wherein the cancer is urothelial cancer, breast cancer, endometrial cancer, lung cancer, ovarian cancer, or bladder cancer.

117. The pharmaceutical composition of any one of claims 114-116, wherein the cancer is a locally advanced solid tumor.

118. The pharmaceutical composition of any one of claims 114-117, wherein the cancer is a metastatic solid tumor.

119. The pharmaceutical composition of any one of claims 115 to 118, wherein the activating FGFR3 gene alteration is a mutation.

120. The pharmaceutical composition of claim 115 to 118, wherein the activating FGFR3 gene alteration is a fusion.

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