WO2025248485A1

WO2025248485A1 - Pharmaceutical compositions and methods of use thereof

Info

Publication number: WO2025248485A1
Application number: PCT/IB2025/055562
Authority: WO
Inventors: Debra MAZAIK; Clare MEDENDORP; Vivek Kadambi; Jessica CHRISTO; Sean Kim; Nicholas Lydon; George Demetri; Ben AUSPITZ
Original assignee: IDRx Inc
Current assignee: IDRx Inc
Priority date: 2024-05-31
Filing date: 2025-05-29
Publication date: 2025-12-04
Anticipated expiration: 2026-11-30

Abstract

The present disclosure relates to pharmaceutical compositions and methods for treating conditions associated with aberrant KIT activity (e.g., cancer). The pharmaceutical compositions and methods described herein generally comprise a compound of Formula I.

Description

PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE THEREOF

FIELD

[0001] The present disclosure relates to pharmaceutical compositions and methods for treating conditions associated with aberrant KIT activity (e.g., cancer).

BACKGROUND

[0002] The enzyme KIT (also called CD 117) is a receptor tyrosine kinase expressed on a wide variety of cell types. The KIT molecule contains a long extracellular domain, a transmembrane segment, and an intracellular portion. The ligand for KIT is stem cell factor (SCF), whose binding to the extracellular domain of KIT induces receptor dimerization, kinase domain activation and activation of downstream signaling pathways. KIT plays an important role in the occurrence of diseases, such as cancer, and mutations in KIT are found in several cancers (e.g., GIST).

[0003] Current therapies are inadequate for treatment of GIST that has become resistant to inhibitors of the primary activating KIT mutations. Accordingly, there is a need for therapies targeting resistant KIT mutations.

SUMMARY OF THE INVENTION

[0004] Described herein, in part, are pharmaceutical compositions (e.g., capsules and tablets) comprising a compound of Formula I:

Formula I, or a pharmaceutically acceptable salt thereof.

[0005] The compound of Formula I as described herein is also referred to as “Compound 1” or

“M4205.”

[0006] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound of Formula I:

Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] In some embodiments, the pharmaceutical composition is prepared in an oral dosage form. [0008] In some embodiments, the oral dosage form is a capsule.

[0009] In some embodiments, the size of the capsule is 0. In some embodiments, the size of the capsule is 00.

[0010] In some embodiments, the pharmaceutical composition comprises about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 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 110 mg, about 120 mg, about 140 mg, about

160 mg, about 180 mg, or about 200 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the pharmaceutical composition comprises about 400 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the pharmaceutically acceptable excipient is a glidant. In some embodiments, the glidant is silicon dioxide. In some embodiments, the glidant is colloidal silicon dioxide.

[0013] In some embodiments, the pharmaceutical composition comprises about 99% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and about 1% of colloidal silicon dioxide based on the total weight of the pharmaceutically acceptable composition.

[0014] In some embodiments, the pharmaceutical composition comprises about 99% w/w of the compound of Formula I and about 1% of colloidal silicon dioxide based on the total weight of the pharmaceutically acceptable composition.

[0015] In some embodiments, the pharmaceutical composition comprises about 400 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 400 mg of the compound of Formula I and colloidal silicon dioxide.

[0016] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising:

(a) an intragranular blend comprising a compound of Formula I:

Formula I, or a pharmaceutically acceptable salt thereof; and

(b) an extragranular blend.

[0017] In some embodiments, the pharmaceutical composition is prepared in an oral dosage form. [0018] In some embodiments, the oral dosage form is a tablet.

[0019] In some embodiments, the intragranular blend comprises about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about

38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 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 110 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg or about 500 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the intragranular blend comprises about 20 mg, about 22 mg, about 24 mg, about

26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about

40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 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 110 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the intragranular blend comprises about 100 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the intragranular blend comprises about 200 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the intragranular blend comprises about 250 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the intragranular blend comprises about 300 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the intragranular blend comprises about 500 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof [0021] In some embodiments, the intragranular blend comprises about 22.5% w/w to about 27.5% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 25.0% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition.

[0022] In some embodiments, the intragranular blend comprises a first diluent. In some embodiments, the first diluent is a sugar. In some embodiments, the first diluent is mannitol, lactose, sorbitol, lactitol, erythritol, sucrose, fructose, glucose, agarose, maltose, isomalt, or polydextrose, or a combination thereof. In some embodiments, the intragranular blend comprises about 38.7% w/w to about 47.3% w/w of the first diluent based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 43.0% w/w of the first diluent based on the total weight of the pharmaceutically acceptable composition.

[0023] In some embodiments, the intragranular blend comprises a second diluent. In some embodiments, the second diluent is a cellulose. In some embodiments, the second diluent is a microcrystalline cellulose. In some embodiments, the second diluent is a silicified microcrystalline cellulose. In some embodiments, the intragranular blend comprises about 9.0% w/w to about 11.0% w/w of the second diluent based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 10.0% w/w of the second diluent based on the total weight of the pharmaceutically acceptable composition.

[0024] In some embodiments, the intragranular blend comprises a first disintegrant. In some embodiments, the first disintegrant is sodium starch glycolate. In some embodiments, the intragranular blend comprises about 3.6% w/w to about 4.4% w/w of the first disintegrant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 4.0% w/w of the first disintegrant based on the total weight of the pharmaceutically acceptable composition. [0025] In some embodiments, the intragranular blend comprises a first surfactant. In some embodiments, the first surfactant is a poloxamer. In some embodiments, the intragranular blend comprises about 2.25% w/w to about 2.75% w/w of the first surfactant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 2.5% w/w of the first surfactant based on the total weight of the pharmaceutically acceptable composition.

[0026] In some embodiments, the intragranular blend comprises a first lubricant. In some embodiments, the first lubricant is magnesium stearate. In some embodiments, the intragranular blend comprises about 0.45% w/w to about 0.55% w/w of the first lubricant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 0.5% w/w of the first lubricant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the extragranular blend comprises a third diluent. In some embodiments, the third diluent is a microcrystalline cellulose.

[0027] In some embodiments, the third diluent is a silicified microcrystalline cellulose. In some embodiments, the extragranular blend comprises about 2.7% w/w to about 3.3% w/w of the third diluent based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the extragranular blend comprises about 3.0% w/w of the third diluent based on the total weight of the pharmaceutically acceptable composition.

[0028] In some embodiments, the extragranular blend comprises a second disintegrant. In some embodiments, the second disintegrant is sodium starch glycolate. In some embodiments, the extragranular blend comprises about 3.6% w/w to about 4.4% w/w of the second disintegrant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the extragranular blend comprises about 4.0% w/w of the second disintegrant based on the total weight of the pharmaceutically acceptable composition.

[0029] In some embodiments, the extragranular blend comprises a second surfactant. In some embodiments, the second surfactant is a poloxamer. In some embodiments, the extragranular blend comprises about 6.75% w/w to about 8.25% w/w of the second surfactant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the extragranular blend comprises about 7.5% w/w of the second surfactant based on the total weight of the pharmaceutically acceptable composition. [0030] In some embodiments, the extragranular blend comprises a second lubricant. In some embodiments, the second lubricant is magnesium stearate. In some embodiments, the extragranular blend comprises about 0.45% w/w to about 0.55% w/w of the second lubricant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the extragranular blend comprises about 0.5% w/w of the second lubricant based on the total weight of the pharmaceutically acceptable composition.

[0031] In some embodiments, the pharmaceutical composition comprises a film coating. Film coatings can be composed of hydrophilic polymer materials, such as hydroxypropylmethyl cellulose (HPMC), methyl cellulose, hydroxethyl cellulose (HEC), hydroxypropyl cellulose (HPC), poly(vinylalcohol-co-ethylene glycol) and other water soluble polymers. Suitable polymeric coatings include those containing polyvinyl alcohol.

[0032] In some embodiments, the film coating is Opadry® QX. As used herein, Opadry® QX means a film coating for a tablet that comprises polyethylene glycol/macrogol polyvinyl alcohol graft copolymer, talc, titanium dioxide, glyceryl mono and dicaprylocaprate (glyceryl monocaprylocaprate type 1), polyvinyl alcohol and coloring such as iron oxide.

[0033] In some embodiments, the pharmaceutical composition comprises:

(a) an intragranular blend comprising:

(a-i) about 20% to 40% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof;

(a-ii) about 30% to 50% w/w of at least one diluent;

(a-iii) about 2% to 6% w/w of at least one disintegrant;

(a-iv) about 2% to 6% w/w of at least one surfactant; and

(a-vi) about 0.1% to 1.0% of at least one lubricant; and

(b) an extragranular blend comprising:

(b-i) about 2% to 4% w/w of at least one diluent;

(b-ii) about 2.5% to 5.5% w/wof at least one disintegrant;

(b-iii) about 5% to 10% w/w/ of at least one surfactant; and based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the pharmaceutical composition comprises:

(a) an intragranular blend comprising: (a-i) about 20 to 40% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof;

(a-ii) about 30 to 50% w/w of mannitol;

(a-iii) about 5 to 15% w/w of silicified microcrystalline cellulose;

(a-iv) about 2 to 6% w/w of sodium starch glycolate;

(a-v) about 1 to 4% w/w of poloxamer; and

(a-vi) about 0.1 to 1% of magnesium stearate; and

(b) an extragranular blend comprising:

(b-i) about 2 to 4% w/w of silicified microcrystalline cellulose;

(b-ii) about 2 to 5 % of sodium starch glycolate; and

(b-iii) about 5 to 10 % poloxamer; based on the total weight of the pharmaceutically acceptable composition.

[0034] In some embodiments, the pharmaceutical composition comprises:

(a) an intragranular blend comprising:

(a-i) about 25.0% w/w of the compound of Formula I;

(a-ii) about 43.0% w/w of mannitol;

(a-iii) about 10.0% w/w of silicified microcrystalline cellulose;

(a-iv) about 4.0% w/w of sodium starch glycolate;

(a-v) about 2.5% w/w of poloxamer; and

(a-vi) about 0.5% of magnesium stearate; and

(b) an extragranular blend comprising:

(b-i) about 3.0% w/w of silicified microcrystalline cellulose;

(b-ii) about 4.0% of sodium starch glycolate;

(b-iii) about 7.5% poloxamer; and

(b-iv) about 0.5% poloxamer, based on the total weight of the pharmaceutically acceptable composition.

[0035] In some embodiments, the pharmaceutical composition comprises:

(a) an intragranular blend comprising:

(a-i) about 25.0% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof;

(a-ii) about 43.0% w/w of mannitol; (a-iii) about 10.0% w/w of silicified microcrystalline cellulose;

(a-iv) about 4.0% w/w of sodium starch glycolate;

(a-v) about 2.5% w/w of poloxamer; and

(a-vi) about 0.5% of magnesium stearate;

(b) an extragranular blend comprising:

(b-i) about 3.0% w/w of silicified microcrystalline cellulose;

(b-ii) about 4.0% of sodium starch glycolate;

(b-iii) about 7.5% poloxamer; and

(b-iv) about 0.5% poloxamer; and

(c) about 4% w/w of a film coating (such as Opadry® QX), based on the total weight of the pharmaceutically acceptable composition.

[0036] In some embodiments, the pharmaceutical composition comprises:

(a) an intragranular blend comprising:

(a-i) about 25.0% w/w of the compound of Formula I;

(a-ii) about 43.0% w/w of mannitol;

(a-iii) about 10.0% w/w of silicified microcrystalline cellulose;

(a-iv) about 4.0% w/w of sodium starch glycolate;

(a-v) about 2.5% w/w of poloxamer; and

(a-vi) about 0.5% of magnesium stearate;

(b) an extragranular blend comprising:

(b-i) about 3.0% w/w of silicified microcrystalline cellulose;

(b-ii) about 4.0% of sodium starch glycolate;

(b-iii) about 7.5% poloxamer; and

(b-iv) about 0.5% poloxamer; and

[0037] Disclosed herein, in some embodiments, is a method of treating cancer in a subject in need thereof, comprising administering to the subject any of the pharmaceutical compositions described herein.

[0038] In some embodiments, the method comprises administering an effective amount of the pharmaceutical composition. [0039] In some embodiments, the compound of Formula I is dosed at about 20 mg to about 200 mg per administration. In some embodiments, the compound of Formula I is dosed at about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 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 110 mg, about 120 mg, about

140 mg, about 160 mg, about 180 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg or about 500 mg per administration. In some embodiments, the compound of Formula I is dosed at about 20 mg to about 200 mg per administration. In some embodiments, the compound of Formula I is dosed at about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 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 110 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg per administration.

[0040] In some embodiments, the pharmaceutical composition is administered to the subject once daily. In some embodiments, the pharmaceutical composition is administered to the subject twice daily. In some embodiments, the pharmaceutical composition is administered to the subject three times daily. In some embodiments, the pharmaceutical composition is administered to the subject four times daily.

[0041] In some embodiments, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 350 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 450 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 550 mg, about 560 mg, about 580 mg, about 600 mg, about 620 mg, about 640 mg, about 650 mg, about 660 mg, about 680 mg, about 700 mg, about 720 mg, about 740 mg, about 750 mg, about 760 mg, about 780 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, or about 1200 mg of the compound of Formula I is administered to the subject daily. In some embodiments, about 120 mg, about 240 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, or about 1200 mg of the compound of Formula I is administered to the subject daily. In some embodiments, about 120 mg, about 240 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, or about 1200 mg of the compound of Formula I is administered to the subject daily. In some embodiments, about 300 mg of the compound of Formula I is administered to the subject daily. In some embodiments, about 500 mg of the compound of Formula I is administered to the subject daily.

[0042] In some embodiments, the subject is resistant or has acquired resistance to one or more anti-cancer therapies. In some embodiments, each of the anti-cancer therapies is administering an anti-cancer agent. In some embodiments, the anti-cancer agent is a KIT inhibitor. In some embodiments, each of the anti-cancer agents is independently selected from: imatinib, sunitinib, regorafenib, ripretinib, NB003, and THE-630, and combinations thereof.

[0043] In some embodiments, the subject is receiving an anti-cancer therapy. In some embodiments, the anti-cancer therapy is administering an anti-cancer agent. In some embodiments, the anti-cancer agent is a KIT inhibitor. In some embodiments, the anti-cancer agent is selected from: imatinib, sunitinib, regorafenib, ripretinib, NB003, and THE-630, and combinations thereof. [0044] In some embodiments, the subject is in a fasting state. In some embodiments, the pharmaceutical composition is administered with food. In some embodiments, the pharmaceutical composition is administered about 30 minutes to about 1 hour after food.

[0045] In some embodiments, the cancer is selected from: gastrointestinal stromal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumor, pancreatic cancer, and mediastinal B-cell lymphoma. In some embodiments, the cancer is gastrointestinal stromal tumor (GIST).

[0046] In some embodiments, the GIST is characterized by a tumor with one or more KIT mutations. In some embodiments, the tumor has a primary activating KIT mutation. In some embodiments, the GIST is characterized by a tumor with one or more KIT mutations, each independently selected from an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, an exon 14 KIT mutation, and an exon 17 KIT mutation, and combinations thereof. In some embodiments, each of the one or more KIT mutations is independently selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, K642E, V654A, and N655K, and combinations thereof. In some embodiments, the tumor has an exon 9 KIT mutation. In some embodiments, the tumor has an exon 11 KIT mutation. In some embodiments, the tumor has an exon 13 KIT mutation. In some embodiments, the exon 13 KIT mutation is selected from K642E, V654A and N655K, and combinations thereof. In some embodiments, the tumor has an exon 14 KIT mutation. In some embodiments, the exon 14 KIT mutation is T670I. In some embodiments, the tumor has an exon 17 KIT mutation. In some embodiments, the exon 17 KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D.

[0047] In some embodiments, the tumor is resistant or has acquired resistance to an anti-cancer therapy. In some embodiments, the anti-cancer therapy is administering an anti-cancer agent. In some embodiments, the anti-cancer agent is a KIT inhibitor. In some embodiments, the anti-cancer agent is selected from: imatinib, sunitinib, regorafenib, and ripretinib, and pharmaceutical salts thereof, and combinations thereof. In some embodiments, the tumor resistant or has acquired resistance to one or more anti-cancer therapies. In some embodiments, each of the anti-cancer therapies is administering an anti-cancer agent. In some embodiments, the anti-cancer agent is a KIT inhibitor. In some embodiments, each of the anti-cancer agents is independently selected from: imatinib, sunitinib, regorafenib, ripretinib, NB003, and THE-630, and combinations thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0048] FIG. 1 illustrates the dose escalation as described in Example 1.

[0049] FIG. 2 illustrates the phase lb cohorts as described in Example 1.

[0050] FIG. 3 is a table describing the patient and tumor characteristics observed in the study described in Example 1.

[0051] FIG. 4 is a table describing the treatment related adverse events observed in the study described in Example 1.

[0052] FIG. 5 is a table describing the Grade 3 and above treatment related adverse events observed in the study described in Example 1.

[0053] FIG. 6 is a graph illustrating the plasma concentration of Compound 1 at 120 mg, 240 mg, 400 mg, 600 mg, 800 mg (400 mg BID), and 1200 mg (600 mg BID).

[0054] FIG. 7 is a table describing the tumor response observed in the study described in Example 1.

[0055] FIG. 8 illustrates the change in tumor mass observed for Patient A as described in Example 1. [0056] FIG. 9 illustrates the change in tumor mass observed for Patient B as described in Example 1.

[0057] FIG. 10 illustrates the observed PK between 300 mg tablet and 400 mg capsule in patients with GIST.

DETAILED DESCRIPTION

[0058] As generally described herein, the present disclosure features methods and compositions useful for treating a KIT-dependent disorders or diseases, such as cancer.

[0059] Described herein are pharmaceutical compositions comprising a compound of Formula I:

Formula I, also referred to herein as “Compound 1” and “M4205,” or a pharmaceutically acceptable salt thereof, methods of their use and administration, and methods for their preparation.

Definitions

[0060] The following definitions apply to the terms as used to describe the present disclosure, unless otherwise indicated or apparent from context. Unless explicitly indicated otherwise, or apparent from context, the terms below do not exclude the meaning that the term has acquired in the art to which it pertains. The definitions below are provided to facilitate the description of the disclosure, but they are not intended to limit the scope of the disclosure.

[0061] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

[0062] The terms “a,” “an,” and “the” refer to one or to more than one, unless context indicates otherwise. Similarly, the term “or” is intended to include “and”, unless context indicates otherwise. [0063] As used herein, the term “AUC” refers to area under the curve. [0064] As used herein, the term “Cmax” refers to maximum plasma concentration.

[0065] As used herein, the term “PK” refers to pharmacokinetics.

[0066] As used herein, the terms “about” and “approximately” refer to a value that is within 10% above or below the value being described. For example, the term “about 5 mg” indicates a range of from 4.5 mg to 5.5 mg.

[0067] The terms “disease,” “disorder,” and “condition” are used interchangeably herein.

[0068] The term “effective amount” means an amount when administered to the subject or patient which results in beneficial or desired results, including clinical results (e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control). For example, a therapeutically effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg to about 5 grams per day). The precise amount of compound or pharmaceutically acceptable salt thereof administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease or condition, and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, e.g, when administered in combination with an anti-cancer or antiviral agent, an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57^th ed., 2003).

[0069] As used herein, a “malignant disease” refers to a disease in which abnormal cells divide without control and can invade nearby tissues. Malignant cells can also spread to other parts of the body through the blood or lymph system. Examples of malignant diseases are carcinoma, sarcoma, leukemia, and lymphoma. Cancer is a malignant disease. Systemic mastocytosis is a malignant disease. Indolent systemic mastocytosis is a malignant disease.

[0070] Examples of cancer include, but are not limited to, gastrointestinal stomal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumors, pancreatic cancer and mediastinal B-cell lymphoma.

[0071] As used herein, an “inhibitor” refers to a compound or a pharmaceutically acceptable salt thereof that inhibits a protein, e.g., an enzyme such that a reduction in activity of the protein can be observed, e.g., by biochemical assay. In certain embodiments, an inhibitor has an IC50 of less than 1 mM, less than 500 nM, less than 250 nM, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, and less than 1 nM.

[0072] The term “KIT” refers to a human tyrosine kinase that may be referred to as mast/stem cell growth factor receptor (SCFR), proto-oncogene c-KIT, tyrosine-protein kinase Kit or CD117.

[0073] The term “KIT mutation”, as used herein, refers to a KIT gene, cDNA, mRNA, or protein whose sequence differs from the KIT gene sequence of human reference genome hgl9, or the corresponding cDNA, mRNA, or protein. In some embodiments, when discussing KIT mutations in a nucleotide sequence that encodes a KIT polypeptide, mutations are described in terms of the change that is produced in the sequence of the polypeptide that is encoded by the nucleotide. In some embodiments, the KIT mutation is V654A, N655K or K642E in exon 13. As used herein, the term “an exon 9 KIT mutation” refers to a mutation in exon 9 of KIT. As used herein, the term “an exon 11 KIT mutation” refers to a mutation in exon 11 of KIT. As used herein, the term “an exon 13 KIT mutation” refers to a mutation in exon 13 of KIT. As used herein, the term “an exon

17 KIT mutation” refers to a mutation in exon 17 of KIT. As used herein, the term “an exon 18 KIT mutation” refers to a mutation in exon 18 of KIT. A829P is a mutation at the very start of exon 18 KIT but, in some embodiments, A829P is referred to as an “exon 17” KIT mutation. In some embodiments, the KIT mutation is N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y and D823D in exon 17. In some embodiments, the KIT mutation is A829P in exon

18 or in exon 17.

[0074] As used herein, a “selective KIT inhibitor” refers to a compound or a pharmaceutically acceptable salt thereof that selectively inhibits KIT protein kinase over another protein kinase and exhibits at least a 2-fold selectivity for a KIT protein kinase over another kinase. For example, a selective KIT inhibitor exhibits at least a 10-fold selectivity; at least a 15-fold selectivity; at least a 20-fold selectivity; at least a 30-fold selectivity; at least a 40-fold selectivity; at least a 50-fold selectivity; at least a 60-fold selectivity; at least a 70-fold selectivity; at least a 80-fold selectivity; at least a 90-fold selectivity; at least a 100-fold selectivity, at least a 125-fold selectivity, at least a 150-fold selectivity, at least a 175-fold selectivity, or at least a 200-fold selectivity for a KIT kinase over another kinase. In some embodiments, a selective KIT inhibitor exhibits at least a 150-fold selectivity over another kinase, e.g., VEGFR2 (vascular endothelial growth factor receptor 2), SRC (Non-receptor protein tyrosine kinase), and FLT3 (Fms-Like Tyrosine kinase 3). See for example, Evans et al. (2017). In some embodiments, selectivity for a KIT kinase over another kinase is measured in a cellular assay (e.g., a cellular assay as provided herein). In other embodiments, selectivity for a KIT kinase or over another kinase is measured in a biochemical assay (e.g., a biochemical assay provided in Evans, et al. (2017)).

[0075] As used herein, the term “BID” refers to twice a day.

[0076] As used herein, the term “QD” refers to once a day.

[0077] As used herein, the term “pharmaceutical composition” refers to a formulation (e.g., medicinal formulation) that contains at least one active ingredient (e.g., compound of Formula I, or a pharmaceutically acceptable salt thereof) as well as one or more excipients to enable the active ingredient suitable for the method of administration. The pharmaceutical composition of the present disclosure includes pharmaceutically acceptable components that are compatible with compounds disclosed herein (e.g., compound of Formula I, and pharmaceutically acceptable salts thereof).

[0078] As used herein, the term “pharmaceutically acceptable” refers to compounds, compositions, dosage forms, or materials which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive allergic response, irritation, toxicity, or other problem or complication, commensurate with a reasonable benefit/risk ratio. In some embodiments, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0079] As used herein, the term “pharmaceutically acceptable excipient” refers to a substance or material other than the compounds disclosed herein (e.g., compound of Formula I, and pharmaceutically acceptable salts thereof) that is included in the compositions disclosed herein. Excipients are generally nontoxic to the subject and compatible with the other ingredients of the composition. Excipients include, but are not limited to, adjusting agents, adjuvants, antiadherents, antimicrobial agents, antioxidants, binders, buffers, carriers, coatings, compression aids, diluents, disintegrants, dispersing agents, dyes, emollients, emulsifiers, encapsulating materials, fillers, flavors, fragrances, glidants, lubricants, preservatives, salts, solvents, sorbents, stabilizers, surfactants, suspending agents, and sweeteners. For example, a pharmaceutically acceptable excipient may be a vehicle capable of suspending or dissolving a compound disclosed herein. Exemplary excipients are found, e.g., in Remington’s Pharmaceutical Sciences, 15^th Ed., Mack Publ. Co., Easton, PA (1975).

[0080] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive allergic response, irritation, toxicity, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The term “pharmaceutically acceptable salt” is meant to include salts of the compounds disclosed herein that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds. When compounds contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. When compounds contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Certain compounds contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Exemplary pharmaceutically acceptable salts are found, e.g., in Berge, etal. (J. Pharm. Set. 1977, 66(1), 1; and Gould, P.L., Int. J. Pharmaceutics 1986, 33, 201-217, each of which is hereby incorporated by reference in its entirety.

[0081] A “subject” or “patient” is a mammal in need of medical treatment, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). In one aspect, the patient is a human. In one aspect, the patient is an adult human.

[0082] As used herein, the term “treat” or “treating” a disease or disorder refers to alleviating, ameliorating, delaying, inhibiting, preventing, reversing, slowing down, or stopping the aggravation, deterioration, onset, or progression of the disease or disorder, or a condition or symptom associated with the disease or disorder. In some embodiments, treatment slows the progression of the disease (e.g., cancer), improves the subject's outcome, or eliminates the disease, or symptoms thereof. In some embodiments, treatment of a disease (e.g., cancer) in a subject alleviates or ameliorates one or more symptoms or conditions associated with the disease (e.g., cancer). In some embodiments, treatment of a disease (e.g., cancer) in a subject diminishes the extent of the disease. In some embodiments, treatment of a disease (e.g., cancer) in a subject stabilizes (i.e., not worsening) the state of the disease (e.g., cancer). In some embodiments, treatment of a disease (e.g., cancer) in a subject prevents the spread of the disease (e.g., cancer). In some embodiments, treatment of a disease (e.g., cancer) in a subject delays or slows the progress of the disease (e.g., cancer), as compared to the state or the condition of the disease (e.g., cancer) in the absence of the treatment.

Compounds

[0083] The present disclosure relates, in part, to pharmaceutical compositions comprising a compound of Formula I:

Formula I, also referred to herein as “Compound 1” or “M4205,” or a pharmaceutically acceptable salt thereof.

[0084] Compounds described herein, including the compound of Formula I, can be administered as a free acid, a zwitterion or as a salt. Compounds disclosed herein, including the compound of Formula I, are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. A “pharmaceutically acceptable derivative or prodrug” means any pharmaceutically acceptable salt or other derivative of a compound disclosed herein which, upon administration to a subject, is capable of providing (directly or indirectly) a compound disclosed herein. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds disclosed herein when such compounds are administered to a subject (e.g., by allowing an orally administered compound to be more readily absorbed into the blood), or which enhance delivery of the compounds to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Preferred prodrugs include derivatives where a group which enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein.

[0085] Structures that differ only in the presence of one or more isotopically enriched atoms are contemplated within the scope of the compounds disclosed herein. The term “isotope” refers to an atom having the same atomic number but different mass number, resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium (i.e., ³H) and deuterium (i.e., ²H or D). Exemplary isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, ⁿC, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶C1, ¹²³I, and ¹²⁵I. Isotopically labeled compounds can generally be prepared by following procedures analogous to those described herein for the presently disclosed compounds, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0086] The compounds described herein (e.g., compound of Formula I) may also be represented in multiple tautomeric forms. In such instances, the scope of the compounds disclosed herein includes all tautomeric forms of the compounds described herein.

Methods of Synthesizing Compounds

[0087] The compounds described herein can be synthesized by conventional methods using commercially available starting materials and reagents. For example, a compound of Formula I may be synthesized according to the synthetic methods described in WO 2021/013864, which is incorporated herein by its entirety, or methods described herein.

[0088] Compounds described herein can be purified using various techniques in the art of synthetic organic chemistry, including, but not limited to one or more chromatographic methods (e.g., column chromatography or HPLC) and one or more purification methods that is not chromatography (e.g., recrystallization, slurrying, or trituration), and combinations thereof.

Pharmaceutical Compositions

[0089] Disclosed herein, in some embodiments, are pharmaceutical compositions comprising a compound of Formula I:

or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the pharmaceutical composition comprises about 20 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 22 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 24 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 25 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 26 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 28 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 30 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 32 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 34 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 36 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 38 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 40 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 42 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 44 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 46 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 48 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 50 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 55 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 60 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 65 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 70 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 75 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 80 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 85 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 90 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 110 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 120 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 130 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 140 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 150 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 160 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 170 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 180 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 190 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 200 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 220 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 240 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 250 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 260 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 280 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 300 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 320 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 340 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 360 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 380 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 400 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 420 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 440 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 460 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 480 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 500 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 525 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 550 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 575 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 600 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 625 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 650 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 675 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 700 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 725 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 750 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 775 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 800 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 825 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 850 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 875 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 900 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 925 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 950 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 975 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1000 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1100 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1200 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1300 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1400 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1500 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1600 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1700 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1800 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1900 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 2000 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the pharmaceutical composition comprises about 98% w/wto about 99.9% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the pharmaceutical composition comprises about 98.5% w/w to about 99.5% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition.

[0092] In some embodiments, the pharmaceutical composition comprises about 98% w/w, about 98.1% w/w, about 98.2% w/w, about 98.3% w/w, about 98.4% w/w, about 98.5% w/w, about 98.6% w/w, about 98.7% w/w, about 98.8% w/w, about 98.9% w/w, about 99% w/w, about 99.1% w/w, about 99.2% w/w, about 99.3% w/w, about 99.4% w/w, about 99.5% w/w, about 99.6% w/w, about 99.7% w/w, about 99.8% w/w, about 99.9% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition.

[0093] In some embodiments, the pharmaceutical composition comprises about 98.5% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the pharmaceutical composition comprises about 98.6% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the pharmaceutical composition comprises about 98.7% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the pharmaceutical composition comprises about 98.8% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the pharmaceutical composition comprises about 98.9% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the pharmaceutical composition comprises about 99% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the pharmaceutical composition comprises about 99.1% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the pharmaceutical composition comprises about 99.2% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the pharmaceutical composition comprises about 99.3% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the pharmaceutical composition comprises about 99.4% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the pharmaceutical composition comprises about 99.5% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. [0094] In some embodiments, the pharmaceutical composition is prepared in an oral dosage form. In some embodiments, the oral dosage form is a capsule. In some embodiments, the size of the capsule is 0. In some embodiments, the size of the capsule is 00. As defined herein, a 0 capsule has an overall length of about 21.7 mm and volume capacity of 0.67 mL. As defined herein, a 00 capsule has an overall length of about 23.3 mm and volume capacity of about 0.95 mL.

[0095] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient.

[0096] In some embodiments, the pharmaceutically acceptable excipient is a glidant. Examples of glidants include, but are not limited to, colloidal silicon dioxide, talc, kaolin, and bentonite, and combinations thereof. In some embodiments, the glidant is silicon dioxide. In some embodiments, the glidant is colloidal silicon dioxide. In some embodiments, the glidant comprises colloidal silicon dioxide. In some embodiments, the glidant consists substantially of colloidal silicon dioxide. In some embodiments, the colloidal silicon dioxide is prepared through a process involving flame hydrolysis of silicon tetrachloride in an oxy-hydrogen flame and is referred to as “fumed silica” or “untreated fumed silica” (e.g., Aerosil® 200, CAB-O-SIL® M-5P).

[0097] In some embodiments, the pharmaceutical composition comprises about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, or about 1.5% w/w of pharmaceutically acceptable excipient, based on the total weight of the pharmaceutically acceptable composition.

[0098] In some embodiments, the pharmaceutical composition is prepared in an oral dosage form. In some embodiments, the oral dosage form is a tablet.

[0099] In some embodiments, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients can be present in either the intragranular blend or the extragranular blend of the pharmaceutical composition. In some embodiments, one or more pharmaceutically acceptable excipients are present in both the intragranular blend and the extragranular blend.

[0100] In some embodiments, the pharmaceutical composition comprises: (a) an intragranular blend comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof; and (b) an extragranular blend. [0101] In some embodiments, the intragranular blend comprises about 20% w/w to about 30% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 21% w/w to about 29% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 22% w/w to about 28% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 22.5% w/w to about 27.5% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 23% w/w to about 27% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 24% w/w to about 26% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 24.5% w/w to about 25.5% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition.

[0102] In some embodiments, the intragranular blend comprises about 20% w/w, about 20.2% w/w, about 20.4% w/w, about 20.6% w/w, about 20.8% w/w, about 21% w/w, about 21.2% w/w, about 21.4% w/w, about 21.6% w/w, about 21.8% w/w, about 22% w/w, about 22.2% w/w, about 22.4% w/w, about 22.6% w/w, about 22.8% w/w, about 23% w/w, about 23.2% w/w, about 23.4% w/w, about 23.6% w/w, about 23.8% w/w, about 24% w/w, about 24.2% w/w, about 24.4% w/w, about 24.6% w/w, about 24.8% w/w, about 25% w/w, about 25.2% w/w, about 25.4% w/w, about 25.6% w/w, about 25.8% w/w, about 26% w/w, about 26.2% w/w, about 26.4% w/w, about 26.6% w/w, about 26.8% w/w, about 27% w/w, about 27.2% w/w, about 27.4% w/w, about 27.6% w/w, about 27.8% w/w, about 28% w/w, about 28.2% w/w, about 28.4% w/w, about 28.6% w/w, about 28.8% w/w, about 29% w/w, about 29.2% w/w, about 29.4% w/w, about 29.6% w/w, about 29.8% w/w, or about 30% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. [0103] In some embodiments, the intragranular blend comprises about 23% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 23.2% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 23.4% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 23.6% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 23.8% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 24% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 24.2% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 24.4% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 24.6% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 24.8% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 25% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 25.2% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 25.4% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 25.6% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 25.8% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 26% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 26.2% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 26.4% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 26.6% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 26.8% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition, n some embodiments, the intragranular blend comprises about 27% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition.

[0104] In some embodiments, the intragranular blend comprises a first diluent. In some embodiments, the first diluent is a sugar.

[0105] In some embodiments, the first diluent is mannitol, lactose, sorbitol, lactitol, erythritol, sucrose, fructose, glucose, agarose, maltose, isomalt, or polydextrose, or a combination thereof.

[0106] In some embodiments, the intragranular blend comprises about 38.7% w/w to about 47.3% w/w of the first diluent based on the total weight of the pharmaceutically acceptable composition. [0107] In some embodiments, the intragranular blend comprises about 38% w/w, about 38.2% w/w, about 38.4% w/w, about 38.6% w/w, about 38.8% w/w, about 39% w/w, about 39.2% w/w, about 39.4% w/w, about 39.6% w/w, about 39.8% w/w, about 40% w/w, about 40.2% w/w, about 40.4% w/w, about 40.6% w/w, about 40.8% w/w, about 41% w/w, about 41.2% w/w, about 41.4% w/w, about 41.6% w/w, about 41.8% w/w, about 42% w/w, about 42.2% w/w, about 42.4% w/w, about 42.6% w/w, about 42.8% w/w, about 43% w/w, about 43.2% w/w, about 43.4% w/w, about 43.6% w/w, about 43.8% w/w, about 44% w/w, about 44.2% w/w, about 44.4% w/w, about 44.6% w/w, about 44.8% w/w, about 45% w/w, about 45.2% w/w, about 45.4% w/w, about 45.6% w/w, about 45.8% w/w, about 46% w/w, about 46.2% w/w, about 46.4% w/w, about 46.6% w/w, about 46.8% w/w, about 47% w/w, about 47.2% w/w, about 47.4% w/w, about 47.6% w/w, about 47.8% w/w, or about 48% w/w of the first diluent based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 43.0% w/w of the first diluent based on the total weight of the pharmaceutically acceptable composition. [0108] In some embodiments, the intragranular blend comprises a second diluent. In some embodiments, the second diluent is a cellulose.

[0109] In some embodiments, the second diluent is a microcrystalline cellulose. In some embodiments, the second diluent is a silicified microcrystalline cellulose. Examples of microcrystalline cellulose include, but are not limited to, Avicel®. The microcrystalline cellulose filler can be of different grades (e.g., microcrystalline cellulose PH 101, PH 102, or a mixture thereof). In some embodiments, a diluent (e.g., the second diluent) used in the intragranular blend comprises microcrystalline cellulose of a different grade than a diluent used in the extragranular blend.

[0110] In some embodiments, the intragranular blend comprises about 9.0% w/w to about 11.0% w/w of the second diluent based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 8% w/w, about 8.2% w/w, about 8.4% w/w, about 8.6% w/w, about 8.8% w/w, about 9% w/w, about 9.2% w/w, about 9.4% w/w, about 9.6% w/w, about 9.8% w/w, about 10% w/w, about 10.2% w/w, about 10.4% w/w, about 10.6% w/w, about 10.8% w/w, about 11% w/w, about 11.2% w/w, about 11.4% w/w, about 11.6% w/w, about 11.8% w/w, or about 12% w/w of the second diluent based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 10.0% w/w of the second diluent based on the total weight of the pharmaceutically acceptable composition.

[0111] In some embodiments, the intragranular blend comprises a first disintegrant. In some embodiments, the first disintegrant is sodium starch glycolate.

[0112] In some embodiments, the intragranular blend comprises about 3.6% w/w to about 4.4% w/w of the first disintegrant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 3% w/w, about 3.2% w/w, about 3.4% w/w, about 3.6% w/w, about 3.8% w/w, about 4% w/w, about 4.2% w/w, about 4.4% w/w, about 4.6% w/w, about 4.8% w/w, or about 5% w/w of the first disintegrant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 4.0% w/w of the first disintegrant based on the total weight of the pharmaceutically acceptable composition.

[0113] In some embodiments, the intragranular blend comprises a first surfactant. In some embodiments, the first surfactant is a poloxamer. In some embodiments, the intragranular blend comprises about 2.25% w/w to about 2.75% w/w of the first surfactant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 2% w/w, about 2.05% w/w, about 2.1% w/w, about 2.15% w/w, about 2.2% w/w, about 2.25% w/w, about 2.3% w/w, about 2.35% w/w, about 2.4% w/w, about 2.45% w/w, about 2.5% w/w, about 2.55% w/w, about 2.6% w/w, about 2.65% w/w, about 2.7% w/w, about 2.75% w/w, about 2.8% w/w, about 2.85% w/w, about 2.9% w/w, about 2.95% w/w, or about 3% w/w of the first disintegrant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 2.5% w/w of the first surfactant based on the total weight of the pharmaceutically acceptable composition.

[0114] In some embodiments, the intragranular blend comprises a first lubricant. Examples of lubricants include, but are not limited to, sodium stearyl fumarate, magnesium stearate, stearic acid, and glyceryl behenate, and combinations thereof.

[0115] In some embodiments, the first lubricant is magnesium stearate. In some embodiments, the first lubricant comprises magnesium stearate. In some embodiments, the first lubricant consists substantially of magnesium stearate.

[0116] In some embodiments, the intragranular blend comprises about 0.45% w/w to about 0.55% w/w of the first lubricant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 0.4% w/w, about 0.41% w/w, about 0.42% w/w, about 0.43% w/w, about 0.44% w/w, about 0.45% w/w, about 0.46% w/w, about 0.47% w/w, about 0.48% w/w, about 0.49% w/w, about 0.5% w/w, about 0.51% w/w, about 0.52% w/w, about 0.53% w/w, about 0.54% w/w, about 0.55% w/w, about 0.56% w/w, about 0.56% w/w, about 0.57% w/w, about 0.58% w/w, about 0.59% w/w, or about 0.6% w/w of the first lubricant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the intragranular blend comprises about 0.5% w/w of the first lubricant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the extragranular blend comprises a third diluent. In some embodiments, the third diluent is a microcrystalline cellulose. [0117] In some embodiments, the third diluent is a silicified microcrystalline cellulose. In some embodiments, the extragranular blend comprises about 2.7% w/w to about 3.3% w/w of the third diluent based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the extragranular blend comprises about 2% w/w, about 2.4% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, or about 4% w/w of the third diluent based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the extragranular blend comprises about 3.0% w/w of the third diluent based on the total weight of the pharmaceutically acceptable composition.

[0118] In some embodiments, the extragranular blend comprises a second disintegrant. In some embodiments, the second disintegrant is sodium starch glycolate. In some embodiments, the extragranular blend comprises about 3.6% w/w to about 4.4% w/w of the second disintegrant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the extragranular blend comprises about 3% w/w, about 3.2% w/w, about 3.4% w/w, about 3.6% w/w, about 3.8% w/w, about 4% w/w, about 4.2% w/w, about 4.4% w/w, about 4.6% w/w, about 4.8% w/w, or about 5% w/w of the second disintegrant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the extragranular blend comprises about 4.0% w/w of the second disintegrant based on the total weight of the pharmaceutically acceptable composition.

[0119] In some embodiments, the extragranular blend comprises a second surfactant. In some embodiments, the second surfactant is a poloxamer. In some embodiments, the extragranular blend comprises about 6.75% w/w to about 8.25% w/w of the second surfactant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the extragranular blend comprises about 6.5% w/w, about 6.55% w/w, about 6.6% w/w, about 6.65% w/w, about 6.7% w/w, about 6.75% w/w, about 6.8% w/w, about 6.85% w/w, about 6.9% w/w, about 7% w/w, about 7.05% w/w, about 7.1% w/w, about 7.15% w/w, about 7.2% w/w, about 7.25% w/w, about 7.3% w/w, about 7.35% w/w, about 7.4% w/w, about 7.45% w/w, about 7.5% w/w, about 7.6% w/w, about 7.65% w/w, about 7.7% w/w, about 7.75% w/w, about 7.78% w/w, about 7.85% w/w, about 7.9% w/w, about 8% w/w, 8.05% w/w, about 8.1% w/w, about 8.15% w/w, about 8.2% w/w, about 8.25% w/w, about 8.3% w/w, about 8.35% w/w, about 8.4% w/w, about 8.45% w/w, or about 8.5% w/w of the second disintegrant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the extragranular blend comprises about 7.5% w/w of the second surfactant based on the total weight of the pharmaceutically acceptable composition.

[0120] In some embodiments, the extragranular blend comprises a second lubricant. In some embodiments, the second lubricant is magnesium stearate. In some embodiments, the extragranular blend comprises about 0.45% w/w to about 0.55% w/w of the second lubricant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the extragranular blend comprises about 0.4% w/w, about 0.41% w/w, about 0.42% w/w, about 0.43% w/w, about 0.44% w/w, about 0.45% w/w, about 0.46% w/w, about 0.47% w/w, about 0.48% w/w, about 0.49% w/w, about 0.5% w/w, about 0.51% w/w, about 0.52% w/w, about 0.53% w/w, about 0.54% w/w, about 0.55% w/w, about 0.56% w/w, about 0.56% w/w, about 0.57% w/w, about 0.58% w/w, about 0.59% w/w, or about 0.6% w/w of the second lubricant based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the extragranular blend comprises about 0.5% w/w of the second lubricant based on the total weight of the pharmaceutically acceptable composition.

[0121] In some embodiments, the pharmaceutical composition comprises a film coating. In some embodiments, the film coating is Opadry® QX. In some embodiments, the pharmaceutical composition comprises about 3.6% w/w to about 4.4% w/w of the film coating based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the pharmaceutical composition comprises about 3% w/w, about 3.2% w/w, about 3.4% w/w, about 3.6% w/w, about 3.8% w/w, about 4% w/w, about 4.2% w/w, about 4.4% w/w, about 4.6% w/w, about 4.8% w/w, or about 5% w/w of the film coating based on the total weight of the pharmaceutically acceptable composition. In some embodiments, the pharmaceutical composition comprises about 4.0% w/w of the film coating based on the total weight of the pharmaceutically acceptable composition.

[0122] In some embodiments, the pharmaceutical composition comprises (a) an intragranular blend comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof; and (b) an extragranular blend, wherein the intragranular blend the compound of Formula I, or a pharmaceutically acceptable salt thereof, and wherein the intragranular blend comprises a first diluent. In some embodiments, the pharmaceutical composition comprises (a) an intragranular blend comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof; and (b) an extragranular blend, wherein the intragranular blend the compound of Formula I, or a pharmaceutically acceptable salt thereof, and wherein the intragranular blend comprises a first diluent and a second diluent. In some embodiments, the pharmaceutical composition comprises (a) an intragranular blend comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof; and (b) an extragranular blend, wherein the intragranular blend the compound of Formula I, or a pharmaceutically acceptable salt thereof, and wherein the intragranular blend comprises a first diluent, a second diluent, and a first disintegrant. In some embodiments, the pharmaceutical composition comprises (a) an intragranular blend comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof; and (b) an extragranular blend, wherein the intragranular blend the compound of Formula I, or a pharmaceutically acceptable salt thereof, and wherein the intragranular blend comprises a first diluent, a second diluent, a first disintegrant and a first surfactant. In some embodiments, the pharmaceutical composition comprises (a) an intragranular blend comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof; and (b) an extragranular blend, wherein the intragranular blend the compound of Formula I, or a pharmaceutically acceptable salt thereof, and wherein the intragranular blend comprises a first diluent, a second diluent, a first disintegrant, a first surfactant, and a first lubricant. In some embodiments, the pharmaceutical composition comprises (a) an intragranular blend comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof; and (b) an extragranular blend, wherein the intragranular blend the compound of Formula I, or a pharmaceutically acceptable salt thereof, and wherein the intragranular blend comprises a first diluent, a second diluent, a first disintegrant, a first surfactant, a first lubricant, and wherein the extragranular blend comprises a third diluent. In some embodiments, the pharmaceutical composition comprises (a) an intragranular blend comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof; and (b) an extragranular blend, wherein the intragranular blend the compound of Formula I, or a pharmaceutically acceptable salt thereof, and wherein the intragranular blend comprises a first diluent, a second diluent, a first disintegrant, a first surfactant, a first lubricant, and wherein the extragranular blend comprises a third diluent and a second disintegrant. In some embodiments, the pharmaceutical composition comprises (a) an intragranular blend comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof; and (b) an extragranular blend, wherein the intragranular blend the compound of Formula I, or a pharmaceutically acceptable salt thereof, and wherein the intragranular blend comprises a first diluent, a second diluent, a first disintegrant, a first surfactant, a first lubricant, and wherein the extragranular blend comprises a third diluent, a second disintegrant and a second surfactant, and optionally a film coating.

In one embodiment, the pharmaceutical composition comprises (a) an intragranular blend comprising:

(i) about 20% w/w to about 30% w/w a compound of Formula I, or a pharmaceutically acceptable salt thereof based on the total weight of the pharmaceutically acceptable composition; and

(ii) about 38.7% w/w to about 47.3% w/w of a first diluent based on the total weight of the pharmaceutically acceptable composition; and/or

(iii) about 9.0% w/w to about 11.0% w/w of a second diluent based on the total weight of the pharmaceutically acceptable composition; and/or

(iv) about 3.6% w/w to about 4.4% w/w of a first disintegrant based on the total weight of the pharmaceutically acceptable composition; and/or

(v) about 2.25% w/w to about 2.75% w/w of a first surfactant based on the total weight of the pharmaceutically acceptable composition; and/or

(vi) about 0.45% w/w to about 0.55% w/w of a first lubricant based on the total weight of the pharmaceutically acceptable composition; and

(b) optionally an extragranular blend comprising:

(i) about 2.7% w/w to about 3.3% w/w of a third diluent based on the total weight of the pharmaceutically acceptable composition; and/or

(ii) about 3.6% w/w to about 4.4% w/w of a second disintegrant based on the total weight of the pharmaceutically acceptable composition; and/or

(iii) about 6.75% w/w to about 8.25% w/w of a second surfactant based on the total weight of the pharmaceutically acceptable composition; and/or

(iv) about 0.45% w/w to about 0.55% w/w of a second lubricant based on the total weight of the pharmaceutically acceptable composition; and

(c) optionally, a film coating. In one embodiment, the pharmaceutical composition comprises (a) an intragranular blend comprising:

(i) about 20% w/w to about 30% w/w a compound of Formula I, or a pharmaceutically acceptable salt thereof based on the total weight of the pharmaceutically acceptable composition ; and

(b) an extragranular blend; and optionally (c) a film coating.

(i) about 20% w/w to about 30% w/w a compound of Formula I, or a pharmaceutically acceptable salt thereof based on the total weight of the pharmaceutically acceptable composition;

(ii) about 38.7% w/w to about 47.3% w/w of a first diluent based on the total weight of the pharmaceutically acceptable composition; and

(b) an extragranular blend; and optionally (c) a film coating.

(ii) about 38.7% w/w to about 47.3% w/w of a first diluent based on the total weight of the pharmaceutically acceptable composition;

(iii) about 9.0% w/w to about 11.0% w/w of a second diluent based on the total weight of the pharmaceutically acceptable composition; and

(b) an extragranular blend; and optionally (c) a film coating.

(ii) about 38.7% w/w to about 47.3% w/w of a first diluent based on the total weight of the pharmaceutically acceptable composition; (iii) about 9.0% w/w to about 11.0% w/w of a second diluent based on the total weight of the pharmaceutically acceptable composition;

(iv) about 3.6% w/w to about 4.4% w/w of a first disintegrant based on the total weight of the pharmaceutically acceptable composition; and

(b) an extragranular blend; and optionally (c) a film coating.

(iii) about 9.0% w/w to about 11.0% w/w of a second diluent based on the total weight of the pharmaceutically acceptable composition;

(iv) about 3.6% w/w to about 4.4% w/w of a first disintegrant based on the total weight of the pharmaceutically acceptable composition;

(v) about 2.25% w/w to about 2.75% w/w of a first surfactant based on the total weight of the pharmaceutically acceptable composition; and

(b) an extragranular blend; and optionally (c) a film coating.

(iv) about 3.6% w/w to about 4.4% w/w of a first disintegrant based on the total weight of the pharmaceutically acceptable composition; (v) about 2.25% w/w to about 2.75% w/w of a first surfactant based on the total weight of the pharmaceutically acceptable composition;

(vi) and about 0.45% w/w to about 0.55% w/w of a first lubricant based on the total weight of the pharmaceutically acceptable composition; and

(b) an extragranular blend; and optionally, (c) a film coating.

(v) about 2.25% w/w to about 2.75% w/w of a first surfactant based on the total weight of the pharmaceutically acceptable composition;

(b) an extragranular blend comprising:

(i) about 2.7% w/w to about 3.3% w/w of a third diluent based on the total weight of the pharmaceutically acceptable composition; and

(c) optionally, a film coating.

(b) an extragranular blend comprising:

(ii) about 3.6% w/w to about 4.4% w/w of a second disintegrant based on the total weight of the pharmaceutically acceptable composition; and

(c) optionally, a film coating.

(b) an extragranular blend comprising: (i) about 2.7% w/w to about 3.3% w/w of a third diluent based on the total weight of the pharmaceutically acceptable composition;

(iii) about 6.75% w/w to about 8.25% w/w of a second surfactant based on the total weight of the pharmaceutically acceptable composition; and

(c) optionally, a film coating.

(b) an extragranular blend comprising:

(i) about 2.7% w/w to about 3.3% w/w of a third diluent based on the total weight of the pharmaceutically acceptable composition;

(ii) about 3.6% w/w to about 4.4% w/w of a second disintegrant based on the total weight of the pharmaceutically acceptable composition;

(iv) about 0.45% w/w to about 0.55% w/w of a second lubricant based on the total weight of the pharmaceutically acceptable composition; and (c) optionally, a film coating.

In one embodiment, the pharmaceutical composition is a tablet comprising (a) an intragranular blend comprising:

(b) an extragranular blend comprising:

(c) optionally, a film coating.

Dosage Forms

[0123] In some embodiments, provided are dosage forms comprising a pharmaceutical composition described herein.

[0124] In some embodiments, provided are dosage forms intended for oral administration comprising a pharmaceutical composition described herein. [0125] In some embodiments, the dosage form is selected from the group consisting of a powder, a sachet, a stickpack, a capsule, a minitab, and a tablet.

[0126] In some embodiments, the dosage form is a capsule. In some embodiments, the dosage form is a tablet.

Methods of Treatment

[0127] Disclosed herein is a method of treating a disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof (for example, a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof of the present invention). Also disclosed herein is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof (for example, a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof of the present invention) for use in therapy, for example for use in treating a disease. Also disclosed herein is the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease, for example wherein said medicament is to be administered as a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, of the present invention.

[0128] In some embodiments, the disease is characterized by a KIT mutation (e.g., an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, and exon 14 KIT mutation, or an exon 17 KIT mutation, or a combination thereof). In some embodiments, the disease is a malignant disease. In some embodiments, the disease is a cancer. In some embodiments, the cancer is adjuvant. Examples of malignant diseases or cancers treatable by compounds of the disclosure include gastrointestinal stromal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumors, pancreatic cancer, and mediastinal B-cell lymphoma.

[0129] In some embodiments, the malignant disease or cancer is selected from: gastrointestinal stromal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumors, pancreatic cancer, and mediastinal B-cell lymphoma. In some embodiments, the malignant disease or cancer is gastrointestinal stromal tumor (GIST). [0130] Pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, is contemplated to be useful in treating cancers including, but not limited to, gastrointestinal stromal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumor, pancreatic cancer, and mediastinal B-cell lymphoma.

[0131] In some embodiments, the subject received an anti-cancer therapy for the malignant disease or cancer. In some embodiments, the malignant disease or cancer progressed after the anti-cancer therapy. In some embodiments, the subject is receiving an anti-cancer therapy for the malignant disease or cancer. In some embodiments, the malignant disease or cancer progressed after the anticancer therapy. In some embodiments, the subject is resistant or has acquired resistance to an anticancer therapy.

[0132] In some embodiments, the anti-cancer therapy is administering an anti-cancer agent. In some embodiments, the anti-cancer agent is a KIT inhibitor. In some embodiments, each of the anti-cancer agents is independently selected from: imatinib, sunitinib, regorafenib, ripretinib, AZD3229, BLU-263, alvocidib, anlotinib, avapritinib, axitinib, bezuclastinib, binimetinib, cabozantinib, crenolanib, dasatinib, everolimus, famitinib, larotrectinib, nilotinib, olaratumab, pazopanib, pexidartinib, ponatinib, ribocliclib, sorafenib, and vandetanib, and pharmaceutically acceptable salts thereof, and combinations thereof. In some embodiments, the anti-cancer agent is selected from: imatinib, sunitinib, regorafenib, ripretinib, NB003, and THE-630, and combinations thereof.

[0133] In some embodiments, the subject received one or more anti-cancer therapies for the malignant disease or cancer. In some embodiments, the malignant disease or cancer progressed after the one or more anti-cancer therapies. In some embodiments, the subject is receiving one or more anti-cancer therapies for the malignant disease or cancer. In some embodiments, the malignant disease or cancer progressed after the one or more anti-cancer therapies. In some embodiments, the subject is resistant or has acquired resistance to one or more anti-cancer therapies.

[0134] In some embodiments, each of the anti-cancer therapies is administering an anti-cancer agent. In some embodiments, each of the anti-cancer agents is a KIT inhibitor. In some embodiments, each of the anti-cancer agents is independently selected from: imatinib, sunitinib, regorafenib, ripretinib, AZD3229, BLU-263, alvocidib, anlotinib, avapritinib, axitinib, bezuclastinib, binimetinib, cabozantinib, crenolanib, dasatinib, everolimus, famitinib, larotrectinib, nilotinib, olaratumab, pazopanib, pexidartinib, ponatinib, ribocliclib, sorafenib, and vandetanib, and pharmaceutically acceptable salts thereof, and combinations thereof. In some embodiments, each of the anti-cancer agents is independently selected from: imatinib, sunitinib, regorafenib, ripretinib, NB003, and THE-630, and combinations thereof.

[0135] In some embodiments, the malignant disease or cancer is characterized by a primary activating KIT mutation. A “primary activating mutation” is an initial mutation that converts or contributes to the conversion of a normal cell to a cancer cell (i.e., a primary activating mutation is responsible for initiating tumorigenesis and/or driving the cancer). In some embodiments, the primary activating KIT mutation is an exon 9 KIT mutation or an exon 11 KIT mutation, or a combination thereof. In some embodiments, the primary activating KIT mutation is an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, or an exon 17 KIT mutation, or a combination thereof. In some embodiments, the primary activating KIT mutation is an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, an exon 14 KIT mutation, or an exon 17 KIT mutation, or a combination thereof. In some embodiments, the primary activating KIT mutation is selected from an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, an exon 14 KIT mutation, and an exon 17 KIT mutation. In some embodiments, the primary activating KIT mutation is selected from an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, and an exon 17 KIT mutation.

[0136] In some embodiments, the primary activating KIT mutation is an exon 17 KIT mutation, (e.g., an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y and D823D). In one embodiment, the exon 17 KIT mutation is D816V. In some embodiments, the primary activating mutation is A829P. A829P is a mutation at the very start of exon 18 KIT but is commonly referred to as an ’’exon 17” mutation. In some embodiments, the primary activating KIT mutation is an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D and A829P. In some embodiments, the primary activating KIT mutation is an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y and D823D. In some embodiments, the primary activating KIT mutation is an exon 13 KIT mutation, e.g., an exon 13 KIT mutation such as V654A, N655K or K642E. [0137] In some embodiments, the tumor is resistant or has acquired resistance to an anti-cancer therapy. For example, the tumor is or has acquired mutation resistance to the anti-cancer therapy because a mutation is present in the tumor that renders the tumor resistant or refractory to the anticancer therapy (e.g., administering an anti-cancer agent). For example, the tumor may have become mutation resistant to a Primary KIT Inhibitor. In some embodiments, the tumor has a mutation that is resistant to an exon 9 KIT inhibitor or an exon 11 KIT inhibitor, or a combination thereof. In some embodiments, the tumor has a mutation that is resistant to an exon 9 KIT inhibitor, an exon 11 KIT inhibitor, an exon 13 KIT mutation, an exon 17 KIT mutation, or an exon 14 KIT mutation, or a combination thereof. In some embodiments, the prior agent is imatinib and the mutation is an imatinib-resistant mutation. In one embodiment, the tumor has a mutation that is resistant to a prior agent. In one embodiment, the mutation that is resistant to the prior agent is selected from an exon 13 KIT mutation, an exon 17 KIT mutation, an exon 18 KIT mutation, and an exon 14 KIT mutation, and combinations thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 13 KIT mutation, e.g., an exon 13 KIT mutation selected from V654A, N655K and K642E, and combinations thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 13 KIT mutation, e.g., an exon 13 KIT mutation selected from V654A, N655K, and a combination thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 17 KIT mutation, e.g., an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D and a combination thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 17 KIT mutation, e.g., an exon 17 KIT mutation, e.g., an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y and D823D, and combinations thereof. In some embodiments, the exon 17 KIT mutation is A829P. In some embodiments, the exon 18 KIT mutation is A829P. In some embodiments, the mutation that is resistant to the prior agent is an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, A829P, and a combination thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 17 KIT mutation, e.g., an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D and A829P, and combinations thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 14 KIT mutation, e.g., an exon 14 KIT mutation such as N680K. In some embodiments, the tumor is or has become resistant to the prior agent has one or more mutations.

[0138] In some embodiments, administering an effective amount of a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, comprises administering to the subject a pharmaceutical composition comprising about 20 mg to about 200 mg (e.g., about 20 mg, about 22 mg, about 24 mg, about 25 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about

42 mg, about 44 mg, about 46 mg, about 48 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 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg) of the compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, administering an effective amount of a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, comprises administering to the subject a pharmaceutical composition comprising about 250mg, 300mg or 500mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, administering an effective amount of a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, comprises administering to the subject one or more (for example, one two, three, four of five) pharmaceutical composition(s) comprising about 20 mg to about 200 mg (e.g., about 20 mg, about 22 mg, about

24 mg, about 25 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 32 mg, about

34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about

48 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 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg) of the compound of Formula I, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is dosed at about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about

90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg per administration. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof is dosed at about 100 mg per administration. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof is dosed at about 200 mg per administration.

[0141] In some embodiments, the compound of Formula I is dosed at about 300 mg per administration. In some embodiments, the compound of Formula I is dosed at about 400 mg per administration.

[0142] In some embodiments, the compound of Formula I is dosed at about 500 mg per administration.

[0143] In some embodiments, the pharmaceutical composition is administered to the subject once daily. In some embodiments, the pharmaceutical composition is administered to the subject twice daily. In such embodiments, the pharmaceutical composition may be administered to the subject twice daily at the same time, or twice daily at different times. In some embodiments, the pharmaceutical composition is administered to the subject three times daily. In such embodiments, the pharmaceutical composition may be administered to the subject three times daily at the same time, or three times daily at two or three different times. In some embodiments, the pharmaceutical composition is administered to the subject four times daily. In such embodiments, the pharmaceutical composition may be administered to the subject four times daily at the same time, or four times daily at two, three or four different times.

[0144] In some embodiments, the compound of Formula I is dosed at about 120 mg to about 1200 mg (e.g., 120 mg to about 1200 mg (e.g., about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1100 mg, or about 1200 mg) per day.

[0145] In some embodiments, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 350 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 450 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 550 mg, about 560 mg, about 580 mg, about 600 mg, about 620 mg, about 640 mg, about 650 mg, about 660 mg, about 680 mg, about 700 mg, about 720 mg, about 740 mg, about 750 mg, about 760 mg, about 780 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, or about 1200 mg of the compound of Formula I is administered to the subject daily. In some embodiments, about 120 mg, about 240 mg, about 300 mg, about 400 mg, about 500mg, about 600 mg, about 800 mg, or about 1200 mg of the compound of Formula I is administered to the subject daily. In some embodiments, about 120 mg, about 240 mg, about 300 mg, about 400 mg, about 600 mg, about 800 mg, or about 1200 mg of the compound of Formula I is administered to the subject daily. In some embodiments, about 300 mg of the compound of Formula I is administered to the subject daily. In some embodiments, about 500 mg of the compound of Formula I is administered to the subject daily.

EXAMPLES

[0146] The disclosure is further illustrated by the following examples, which serve as exemplary modes of making and practicing the methods and compositions of the disclosure. The scope of the disclosure is not to be construed as limited to specific embodiments described in these examples, which are illustrative only.

Example 1. Phase lb Study of Compound 1

[0147] This example describes the first clinical trial of Compound 1. The study is designed to evaluate the safety, tolerability, PK, and preliminary antitumor activity of Compound 1 in adult participants with advanced (metastatic and/or surgically unresectable) GIST.

[0148] Study: This is a Phase 1/lb open- label, first-in-human FIH study of Compound 1, an orally administered small molecule tyrosine kinase inhibitor. Eligible participants will have metastatic and/or surgically unresectable GIST. The study consists of 2 parts. Phase 1 comprises dose escalation to assess clinical and pharmacologic profile and safety/tolerability after failure of at least prior imatinib and support choice of the recommended phase lb dose(s) and schedule(s) (RPlbDs)). Phase lb expansion will enroll separate cohorts of participants defined by numbers of lines of prior GIST therapy at the selected RPlbD(s) to assess the preliminary antitumor effect of Compound 1 and further characterize the safety profile of Compound 1 at the RPlbD(s).

[0149] Phase 1: 1. Male or female participants >18 years of age

2. Histologically or cytologically confirmed metastatic and/or surgically unresectable GIST

3. Documented progression on imatinib (Phase 1)

4. Documented pathogenic mutation in KIT OR any PDGFRA mutation other than exon 18 mutations, determined through local testing

5. At least one measurable lesion by mRECIST vl .1 for participants with GIST

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

7. Resolution of any toxicities from prior treatment(s) to < Grade 1 by NCI CTCAE v5.0 criteria, or have resolved to baseline, at the time of first dose of study drug.

8. Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions.

[0150] Additional for Phase lb Exploratory Cohorts:

1. For Cohort 1, progressed on imatinib only (second line therapy) and refused or are ineligible for other standard of care (SOC) therapies.

2. For Cohort 2, progressed on both imatinib and sunitinib (third line therapy) or progressed on imatinib, sunitinib, and an additional agent (i.e., regorafenib or ripretinib) (fourth line therapy) or progressed on imatinib, sunitinib, regorafenib, and ripretininb (fifth line or greater therapy).

3. For Cohort 3, treatment naive (first line therapy) and refused or are ineligible for other standard of care (SOC) therapies.

4. For Cohort 4, met the same criteria as Cohort 2 (third line or greater) and have also had prior treatment with investigational agents NB003 or THE-630 or a line of therapy of bezuclastinib plus sunitinib combination.

[0151] Exclusion Criteria:

1. Any prior exposure to the following investigational agents NB003 or THE-630 or bezuclastinib plus sunitinib combination (except for participants treated in Cohort 4 of Phase lb).

2. GIST with no documented mutation in both KIT and PDGFRA genes.

3. Any prior primary CNS malignancy or known untreated or active central nervous system metastases. 4. Has an active uncontrolled infection, including, but not limited to, the requirement for intravenous antibiotics.

5. Has significant, uncontrolled, or active cardiovascular disease.

[0152] Study Design:

• Metastatic and/or unresectable GIST

• Pathogenic mutations in KIT or non-exon 18 PDGFRA

• Progression on imatinib (phase 1)

• ECOG PS 0-1

[0153] Endpoints included: safety/tolerability, PK, and anti-tumor activity (investigator-assessed). Phase 1 dose escalation design is shown in FIG. 1. To date, 73 patients (all with A'/'/'-mutant GIST) were enrolled in the Phase 1 portion, and doses up to 1200 mg have been cleared by the Safety Review Committee. Phase lb cohorts are described in FIG. 2.

[0154] Results: Patient and tumor characteristics for 73 patients are shown in FIG. 3. Treatment related adverse events (TRAEs) are shown in FIG. 4. Notably, 45% of patients had only Grade 1 or no TRAE. Diarrhea and nausea/vomiting generally tended to begin in the first week of treatment and were managed with anti-diarrheal or anti-emetic therapy.

[0155] Grade > 3 treatment related AEs (adverse events) were uncommon (see FIG. 5). Doselimiting toxicity (DLTs) were observed in 3 of the 73 patients, and maximum tolerated dose (MTD) was not reached.

• Grade 3 syncope (600 mg QD): patient experienced a single syncopal event, rechallenged at 400 mg QD and remains on treatment > 11 months as of the data cutoff, with a confirmed PR; patient reported similar toxicities when taking sunitinib.

• Grade 3 vomiting (400 mg BID): patient rechallenged at 400 mg QD and remains on treatment >8 months as of the data cutoff, with a confirmed PR.

• Drug interrupted for >7 days (in Cycle 1) due to Grade 2 nausea, diarrhea and Grade 1 vomiting (600 mg BID): patient rechallenged at 400 mg BID and remains on treatment for >3 months as of the data cutoff, with stable disease.

There were no treatment-related Grade 5 AEs.

[0156] Half-life: Compound 1 exhibited half-life of about 160-220 hours. High volume of distribution (Vd) indicated potentially high tissue/tumor penetration, compared to plasma levels. There was also a 5-8 fold accumulation in Cmax and AUC from single dose to steady state. Additionally, dose-dependent increase was observed in steady state exposure from 120 to 800 mg/day (FIG. 6). In a bioavailability study in healthy volunteers, tablet formulation of Compound 1 exhibited similar PK profile to capsules and provided 1.35X higher plasma exposure by dose. [0157] Activity: Anti-tumor activity was observed with Compound 1 (see FIG. 7). Most patients had a decrease in tumor diameter, and PRs were observed in patients with baseline mutations in exons 9, 11, 13 and 17. Median duration of treatment was 16 weeks (range: 1-90). Clinical benefit rate (SD for >16 weeks or confirmed PR) in patients with adequate follow up was observed for 33 of 47 overall (70%). Clinical Benefit Rate evaluable population is defined as all patients with an evaluable assessment at >16 weeks or confirmed PR or progression anytime; 400 mg and 800 mg capsule equivalent dose levels include 10 patients treated with 300 mg QD tablets and 5 patients treated with 600 QD mg tablets, respectively; PR, partial response; SD, stable disease.

[0158] ctDNA: Reduction in ctDNA was observed across clinically relevant KIT activating and resistance mutations. 37 patients had a KIT mutation in ctDNA at baseline and at least one on- study sample, analyzed with Guardant360® platform. Mutant allele fraction reductions seen across doses and in most exons represented, including consistently in exon 13 (particularly V654A) and exon 17 mutations. Samples for ctDNA analysis are obtained at C1D1, C1D15, C2D1, C3D1, every 6 cycles thereafter, at End-of-Treatment and at 30-day Follow-Up after last dose. Of baseline samples tested by 15 April 2024, 41/53 had at least one KIT mutation detected in ctDNA. Treated patients with detectable KIT mutations in ctDNA at baseline and at least one postbaseline assessment (N=37) are included in this analysis. Best response for each mutation detected at baseline is represented, and individual patients may be represented more than once. Postbaseline, if a mutation was below the lower limit of quantitation (LLQ), mutant allele frequency value was set to 0% (MAF, mutant allele fraction).

[0159] Patient A: 60 yr old male (400 mg QD), 6th Line (prior imatinib, sunitinib, regorafenib, cabozantinib, and regorafenib rechallenge) with no objective response to prior therapy (FIG. 8).

• Substantial tumor reduction in a 6^th line patient with KIT exon 9 mutation

• Exon 9/17 mutations in ctDNA at baseline, undetectable by C2D1

• PR by end of Cycle 1

• Tolerating drug, with grade 2 treatment-related anemia and neutropenia, remains on treatment >10 months

[0160] Patient B: 59 yr old female (400 mg BID), prior imatinib only (FIG. 9). • FDG-PET and mRECIST response in 2^nd line patient with KIT exon 11 and 13 (V654A) mutations

• Exon 11/13 mutations in ctDNA at baseline, undetectable by C2D1

• Dose reduced to 400 mg QD due to vomiting in Cycle 1

• PR at Cycle 5

• Remains on treatment >8 months tolerating 400 mg QD

[0161] Conclusions: Compound 1 seems to be a selective KIT inhibitor with potent activity against activating mutations and across clinically relevant resistance mutations, particularly in exons 9, 11, 13 and 17. Compound 1 demonstrated linear PK from 120 mg to 800 mg/day and exhibits a favorable safety profile with manageable AEs. Compound 1 also demonstrated clinical activity in patients with advanced GIST following resistance to prior TKIs.

Example 2. Tablet versus Capsule: PK in Patients with GIST

[0162] Based on an HV study, tablet exposure was 35% greater versus capsule exposure, e.g., a 300 mg tablet was equivalent to a 400 mg capsule (see FIG. 10).

Example 3. Capsule composition

[0163] Capsules comprising a compound of Formula I were prepared containing 20 mg or 100 mg. The below Table 1 summarizes the formulations of such capsules.

Table 1 ^aAssuming an average capsule weight of 96 mg for the size 0 and 118 mg for the size 00

Example 4. Tablet compositions

[0164] Tablets comprising a compound of Formula I were prepared containing 25 mg, 50mg or 100 mg. The below Table 2 summarizes the formulations of such capsules.

INCORPORATION BY REFERENCE

[0165] All publications and patents mentioned herein are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

EQUIVALENTS

[0166] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0167] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described herein. Such equivalents are intended to be within the scope of the following claims.

EMBODIMENTS OF THE INVENTION

Embodiments:

1. A pharmaceutical composition comprising a compound of Formula I:

2. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition is prepared in an oral dosage form.

3. The pharmaceutical composition of embodiment 2, wherein the oral dosage form is a capsule.

4. The pharmaceutical composition of embodiment 3, wherein the size of the capsule is 0.

5. The pharmaceutical composition of embodiment 3, wherein the size of the capsule is 00.

6. The pharmaceutical composition of any one of embodiments 1-5, wherein the pharmaceutical composition comprises about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 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 110 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof

7. The pharmaceutical composition of any one of embodiments 1-6, wherein the pharmaceutical composition comprises about 400 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof. 8. The pharmaceutical composition of any one of embodiments 1-7, wherein the pharmaceutical composition comprises about 98.5% w/w to about 99.5% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition.

9. The pharmaceutical composition of any one of embodiments 1-8, wherein the pharmaceutically acceptable excipient is a glidant.

10. The pharmaceutical composition of embodiment 9, wherein the glidant is silicon dioxide.

11. The pharmaceutical composition of embodiment 9 or 10, wherein the glidant is colloidal silicon dioxide.

12. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition comprises about 99% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and about 1% of colloidal silicon dioxide based on the total weight of the pharmaceutically acceptable composition.

13. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition comprises about 99% w/w of the compound of Formula I and about 1% of colloidal silicon dioxide based on the total weight of the pharmaceutically acceptable composition.

14. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition comprises about 400 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and colloidal silicon dioxide.

15. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition comprises about 400 mg of the compound of Formula I and colloidal silicon dioxide.

16. A pharmaceutical composition comprising:

(a) an intragranular blend comprising a compound of Formula I:

Formula I, or a pharmaceutically acceptable salt thereof; and

(b) an extragranular blend.

17. The pharmaceutical composition of embodiment 16, wherein the pharmaceutical composition is prepared in an oral dosage form.

18. The pharmaceutical composition of embodiment 17, wherein the oral dosage form is a tablet.

19. The pharmaceutical composition of any one of embodiments 16-18, wherein the intragranular blend comprises about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 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 110 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition of any one of embodiments 16-18, wherein the intragranular blend comprises about 300 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof.

21. The pharmaceutical composition of any one of embodiments 16-20, wherein the intragranular blend comprises about 22.5% w/w to about 27.5% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition.

22. The pharmaceutical composition of any one of embodiments 16-21, wherein the intragranular blend comprises about 25.0% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition.

23. The pharmaceutical composition of any one of embodiments 16-22, wherein the intragranular blend comprises a first diluent.

24. The pharmaceutical composition of embodiment 23, wherein the first diluent is a sugar.

25. The pharmaceutical composition of embodiment 23 or 24, wherein the first diluent is mannitol, lactose, sorbitol, lactitol, erythritol, sucrose, fructose, glucose, agarose, maltose, isomalt, or poly dextrose, or a combination thereof.

26. The pharmaceutical composition of any one of embodiments 23-25, wherein the intragranular blend comprises about 38.7% w/w to about 47.3% w/w of the first diluent based on the total weight of the pharmaceutically acceptable composition.

27. The pharmaceutical composition of any one of embodiments 23-25, wherein the intragranular blend comprises about 43.0% w/w of the first diluent based on the total weight of the pharmaceutically acceptable composition.

28. The pharmaceutical composition of any one of embodiments 16-27, wherein the intragranular blend comprises a second diluent.

29. The pharmaceutical composition of embodiment 28, wherein the second diluent is a cellulose.

30. The pharmaceutical composition of embodiment 28 or 29, wherein the second diluent is a microcrystalline cellulose.

31. The pharmaceutical composition of embodiment 28 or 29, wherein the second diluent is a silicified microcrystalline cellulose.

32. The pharmaceutical composition of any one of embodiments 16-31, wherein the intragranular blend comprises about 9.0% w/w to about 11.0% w/w of the second diluent based on the total weight of the pharmaceutically acceptable composition. 33. The pharmaceutical composition of any one of embodiments 16-32, wherein the intragranular blend comprises about 10.0% w/w of the second diluent based on the total weight of the pharmaceutically acceptable composition.

34. The pharmaceutical composition of any one of embodiments 16-33, wherein the intragranular blend comprises a first disintegrant.

35. The pharmaceutical composition of embodiment 34, wherein the first disintegrant is sodium starch glycolate.

36. The pharmaceutical composition of any one of embodiments 16-35, wherein the intragranular blend comprises about 3.6% w/w to about 4.4% w/w of the first disintegrant based on the total weight of the pharmaceutically acceptable composition.

37. The pharmaceutical composition of any one of embodiments 16-32, wherein the intragranular blend comprises about 4.0% w/w of the first disintegrant based on the total weight of the pharmaceutically acceptable composition.

38. The pharmaceutical composition of any one of embodiments 16-37, wherein the intragranular blend comprises a first surfactant.

39. The pharmaceutical composition of embodiment 38, wherein the first surfactant is a poloxamer.

40. The pharmaceutical composition of any one of embodiments 16-39, wherein the intragranular blend comprises about 2.25% w/w to about 2.75% w/w of the first surfactant based on the total weight of the pharmaceutically acceptable composition.

41. The pharmaceutical composition of any one of embodiments 16-40, wherein the intragranular blend comprises about 2.5% w/w of the first surfactant based on the total weight of the pharmaceutically acceptable composition.

42. The pharmaceutical composition of any one of embodiments 16-41, wherein the intragranular blend comprises a first lubricant.

43. The pharmaceutical composition of embodiment 42, wherein the first lubricant is magnesium stearate. 44. The pharmaceutical composition of any one of embodiments 16-43, wherein the intragranular blend comprises about 0.45% w/w to about 0.55% w/w of the first lubricant based on the total weight of the pharmaceutically acceptable composition.

45. The pharmaceutical composition of any one of embodiments 16-44, wherein the intragranular blend comprises about 0.5% w/w of the first lubricant based on the total weight of the pharmaceutically acceptable composition.

46. The pharmaceutical composition of any one of embodiments 16-45, wherein the extragranular blend comprises a third diluent.

47. The pharmaceutical composition of embodiment 46, wherein the third diluent is a microcrystalline cellulose.

48. The pharmaceutical composition of embodiment 46, wherein the third diluent is a silicified microcrystalline cellulose.

49. The pharmaceutical composition of any one of embodiments 16-48, wherein the extragranular blend comprises about 2.7% w/w to about 3.3% w/w of the third diluent based on the total weight of the pharmaceutically acceptable composition.

50. The pharmaceutical composition of any one of embodiments 16-49, wherein the extragranular blend comprises about 3.0% w/w of the third diluent based on the total weight of the pharmaceutically acceptable composition.

51. The pharmaceutical composition of any one of embodiments 16-50, wherein the extragranular blend comprises a second disintegrant.

52. The pharmaceutical composition of embodiment 52, wherein the second disintegrant is sodium starch glycolate.

53. The pharmaceutical composition of any one of embodiments 16-52, wherein the extragranular blend comprises about 3.6% w/w to about 4.4% w/w of the second disintegrant based on the total weight of the pharmaceutically acceptable composition.

54. The pharmaceutical composition of any one of embodiments 16-53, wherein the extragranular blend comprises about 4.0% w/w of the second disintegrant based on the total weight of the pharmaceutically acceptable composition. 55. The pharmaceutical composition of any one of embodiments 16-56, wherein the extragranular blend comprises a second surfactant.

56. The pharmaceutical composition of embodiment 55, wherein the second surfactant is a poloxamer.

57. The pharmaceutical composition of any one of embodiments 16-56, wherein the extragranular blend comprises about 6.75% w/w to about 8.25% w/w of the second surfactant based on the total weight of the pharmaceutically acceptable composition.

58. The pharmaceutical composition of any one of embodiments 16-57, wherein the extragranular blend comprises about 7.5% w/w of the second surfactant based on the total weight of the pharmaceutically acceptable composition.

59. The pharmaceutical composition of any one of embodiments 16-58, wherein the extragranular blend comprises a second lubricant.

60. The pharmaceutical composition of embodiment 59, wherein the second lubricant is magnesium stearate.

61. The pharmaceutical composition of any one of embodiments 16-60, wherein the extragranular blend comprises about 0.45% w/w to about 0.55% w/w of the second lubricant based on the total weight of the pharmaceutically acceptable composition.

62. The pharmaceutical composition of any one of embodiments 16-62, wherein the extragranular blend comprises about 0.5% w/w of the second lubricant based on the total weight of the pharmaceutically acceptable composition.

63. The pharmaceutical composition of any one of embodiments 16-62, wherein the pharmaceutical composition comprises a film coating.

64. The pharmaceutical composition of embodiment 63, wherein the film coating is Opadry® QX.

65. The pharmaceutical composition of embodiment 16, wherein the pharmaceutical composition comprises:

(a) an intragranular blend comprising: (a-i) about 25.0% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof;

(a-ii) about 43.0% w/w of mannitol;

(a-iii) about 10.0% w/w of silicified microcrystalline cellulose;

(a-iv) about 4.0% w/w of sodium starch glycolate;

(a-v) about 2.5% w/w of poloxamer; and

(a-vi) about 0.5% of magnesium stearate; and

(b) an extragranular blend comprising:

(b-i) about 3.0% w/w of silicified microcrystalline cellulose;

(b-ii) about 4.0% of sodium starch glycolate;

(b-iii) about 7.5% poloxamer; and

66. The pharmaceutical composition of embodiment 16, wherein the pharmaceutical composition comprises:

(a) an intragranular blend comprising:

(a-i) about 25.0% w/w of the compound of Formula I;

(a-ii) about 43.0% w/w of mannitol;

(a-iii) about 10.0% w/w of silicified microcrystalline cellulose;

(a-iv) about 4.0% w/w of sodium starch glycolate;

(a-v) about 2.5% w/w of poloxamer; and

(a-vi) about 0.5% of magnesium stearate; and

(b) an extragranular blend comprising:

(b-i) about 3.0% w/w of silicified microcrystalline cellulose;

(b-ii) about 4.0% of sodium starch glycolate;

(b-iii) about 7.5% poloxamer; and

67. The pharmaceutical composition of embodiment 16, wherein the pharmaceutical composition comprises:

(a-ii) about 43.0% w/w of mannitol;

(a-iii) about 10.0% w/w of silicified microcrystalline cellulose;

(a-iv) about 4.0% w/w of sodium starch glycolate;

(a-v) about 2.5% w/w of poloxamer; and

(a-vi) about 0.5% of magnesium stearate;

(b) an extragranular blend comprising:

(b-i) about 3.0% w/w of silicified microcrystalline cellulose;

(b-ii) about 4.0% of sodium starch glycolate;

(b-iii) about 7.5% poloxamer; and

(b-iv) about 0.5% poloxamer; and

(c) about 4% w/w of Opadry® QX, based on the total weight of the pharmaceutically acceptable composition.

68. The pharmaceutical composition of embodiment 16, wherein the pharmaceutical composition comprises:

(a) an intragranular blend comprising:

(a-i) about 25.0% w/w of the compound of Formula I;

(a-ii) about 43.0% w/w of mannitol;

(a-iii) about 10.0% w/w of silicified microcrystalline cellulose;

(a-iv) about 4.0% w/w of sodium starch glycolate;

(a-v) about 2.5% w/w of poloxamer; and

(a-vi) about 0.5% of magnesium stearate;

(b) an extragranular blend comprising:

(b-i) about 3.0% w/w of silicified microcrystalline cellulose;

(b-ii) about 4.0% of sodium starch glycolate;

(b-iii) about 7.5% poloxamer; and

(b-iv) about 0.5% poloxamer; and

(c) about 4% w/w of Opadry® QX, based on the total weight of the pharmaceutically acceptable composition. 69. A method of treating cancer in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of any one of embodiments 1-68.

70. The method of embodiment 69, wherein the method comprises administering an effective amount of the pharmaceutical composition.

71. The method of embodiment 69 or 70, wherein the compound of Formula I is dosed at about 20 mg to about 200 mg per administration.

72. The method of any one of embodiments 69-71, wherein the compound of

Formula I is dosed at about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about

44 mg, about 46 mg, about 48 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

110 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg per administration.

73. The method of any one of embodiments 69-72, wherein the pharmaceutical composition is administered to the subject once daily.

74. The method of any one of embodiments 69-72, wherein the pharmaceutical composition is administered to the subject twice daily.

75. The method of any one of embodiments 69-72, wherein the pharmaceutical composition is administered to the subject three times daily.

76. The method of any one of embodiments 69-72, wherein the pharmaceutical composition is administered to the subject four times daily

77. The method of any one of embodiments 69-76, wherein about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 350 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 450 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 550 mg, about 560 mg, about 580 mg, about 600 mg, about 620 mg, about 640 mg, about 650 mg, about 660 mg, about 680 mg, about 700 mg, about 720 mg, about 740 mg, about 750 mg, about 760 mg, about 780 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, or about 1200 mg of the compound of Formula I is administered to the subject daily.

78. The method of any one of embodiments 69-77, wherein about 120 mg, about 240 mg, about 300 mg, about 400 mg, about 600 mg, about 800 mg, or about 1200 mg of the compound of Formula I is administered to the subject daily.

79. The method of any one of embodiments 69-78, wherein the subject is resistant or has acquired resistance to one or more anti-cancer therapies.

80. The method of embodiment 79, wherein each of the anti-cancer therapies is administering an anti-cancer agent.

81. The method of embodiment 80, wherein the anti-cancer agent is a KIT inhibitor.

82. The method of embodiment 81, wherein each of the anti-cancer agents is independently selected from: imatinib, sunitinib, regorafenib, ripretinib, NB003, and THE-630, and combinations thereof.

83. The method of any one of embodiments 69-82, wherein the subject is receiving an anti-cancer therapy.

84. The method of embodiment 83, wherein the anti-cancer therapy is administering an anti-cancer agent.

85. The method of embodiment 84, wherein the anti-cancer agent is a KIT inhibitor.

86. The method of embodiment 84 or 85, wherein the anti-cancer agent is selected from: imatinib, sunitinib, regorafenib, ripretinib, NB003, and THE-630, and combinations thereof.

87. The method of any one of embodiments 69-86, wherein subject is in a fasting state.

88. The method of any one of embodiments 69-86, wherein the pharmaceutical composition is administered with food.

89. The method of any one of embodiments 69-86, wherein the pharmaceutical composition is administered about 30 minutes to about 1 hour after food. 90. The method of any one of embodiments 69-89, wherein the cancer is selected from: gastrointestinal stromal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumor, pancreatic cancer, and mediastinal B-cell lymphoma.

91. The method of any one of embodiments 69-90, wherein the cancer is gastrointestinal stromal tumor (GIST).

92. The method of embodiment 90 or 91, wherein the GIST is characterized by a tumor with one or more KIT mutations.

93. The method of embodiment 92, wherein the tumor has a primary activating KIT mutation.

94. The method of embodiment 92 or 93, wherein the GIST is characterized by a tumor with one or more KIT mutations, each independently selected from an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, an exon 14 KIT mutation, and an exon 17 KIT mutation, and combinations thereof.

95. The method of embodiment 95, wherein each of the one or more KIT mutations is independently selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, K642E, V654A, and N655K, and combinations thereof.

96. The method of embodiment 95, wherein the tumor has an exon 9 KIT mutation.

97. The method of embodiment 95, wherein the tumor has an exon 11 KIT mutation.

98. The method of embodiment 95, wherein the tumor has an exon 13 KIT mutation.

99. The method of embodiment 98, wherein the exon 13 KIT mutation is selected from K642E, V654A and N655K, and combinations thereof.

100. The method of embodiment 95, wherein the tumor has an exon 14 KIT mutation.

101. The method of embodiment 100, wherein the exon 14 KIT mutation is T670I.

102. The method of embodiment 95, wherein the tumor has an exon 17 KIT mutation.

103. The method of embodiment 102, wherein the exon 17 KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D. 104. The method of any one of embodiments 92-103, wherein the tumor is resistant or has acquired resistance to an anti-cancer therapy.

105. The method of embodiment 105, wherein the anti-cancer therapy is administering an anti-cancer agent.

106. The method of embodiment 105, wherein the anti-cancer agent is a KIT inhibitor.

107. The method of embodiment 105, wherein the anti-cancer agent is selected from: imatinib, sunitinib, regorafenib, and ripretinib, and pharmaceutical salts thereof, and combinations thereof.

108. The method of any one of embodiments 92-107, wherein the tumor resistant or has acquired resistance to one or more anti-cancer therapies.

109. The method of embodiment 108, wherein each of the anti-cancer therapies is administering an anti-cancer agent.

110. The method of embodiment 109, wherein the anti-cancer agent is a KIT inhibitor.

111. The method of embodiment 109 or 110, wherein each of the anti-cancer agents is independently selected from: imatinib, sunitinib, regorafenib, ripretinib, NB003, and THE-630, and combinations thereof.

Claims

CLAIMS Claims:

1. A pharmaceutical composition comprising a compound of Formula I: or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

2. A pharmaceutical composition according to claim 1 wherein the composition comprises:

(a) an intragranular blend comprising a compound of Formula I: or a pharmaceutically acceptable salt thereof; and

(b) an extragranular blend.

3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition is an oral dosage form and is a tablet.

4. The pharmaceutical composition of any one of claims 1-3, wherein the intragranular blend comprises about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 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 110 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof; or wherein the intragranular blend comprises about 100 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof; or wherein the intragranular blend comprises about 200 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof; or wherein the intragranular blend comprises about 300 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof; or wherein the intragranular blend comprises about 400 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof; or wherein the intragranular blend comprises about 500 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition of any one of claims 1-4, wherein the intragranular blend comprises about 22.5% w/w to about 27.5% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition; optionally wherein the intragranular blend comprises about 25.0% w/w of the compound of Formula I, or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutically acceptable composition.

6. The pharmaceutical composition of any one of claims 1-5, wherein the intragranular blend comprises a first diluent.

7. The pharmaceutical composition of claim 6, wherein the first diluent is a sugar; optionally wherein the first diluent is mannitol, lactose, sorbitol, lactitol, erythritol, sucrose, fructose, glucose, agarose, maltose, isomalt, or polydextrose, or a combination thereof.

8. The pharmaceutical composition of any one of claims 1-7, wherein the intragranular blend comprises about 38.7% w/w to about 47.3% w/w of the first diluent based on the total weight of the pharmaceutically acceptable composition; optionally wherein the intragranular blend comprises about 43.0% w/w of the first diluent based on the total weight of the pharmaceutically acceptable composition.

9. The pharmaceutical composition of any one of claims 1-8, wherein the intragranular blend comprises a second diluent.

10. The pharmaceutical composition of claim 9, wherein the second diluent is a cellulose; optionally wherein the second diluent is a microcrystalline cellulose or a silicified microcrystalline cellulose.

11. The pharmaceutical composition of claim 9 or 10, wherein the intragranular blend comprises about 9.0% w/w to about 11.0% w/w of the second diluent based on the total weight of the pharmaceutically acceptable composition; optionally wherein the intragranular blend comprises about 10.0% w/w of the second diluent based on the total weight of the pharmaceutically acceptable composition.

12. The pharmaceutical composition of any one of claims 1-11, wherein the intragranular blend comprises a first disintegrant; optionally wherein the first disintegrant is sodium starch glycolate.

13. The pharmaceutical composition of claim 12, wherein the intragranular blend comprises about 3.6% w/w to about 4.4% w/w of the first disintegrant based on the total weight of the pharmaceutically acceptable composition; optionally wherein the intragranular blend comprises about 4.0% w/w of the first disintegrant based on the total weight of the pharmaceutically acceptable composition.

14. The pharmaceutical composition of any one of claims 1-13, wherein the intragranular blend comprises a first surfactant; optionally wherein the first surfactant is a poloxamer.

15. The pharmaceutical composition of claim 14, wherein the intragranular blend comprises about 2.25% w/w to about 2.75% w/w of the first surfactant based on the total weight of the pharmaceutically acceptable composition; optionally wherein the intragranular blend comprises about 2.5% w/w of the first surfactant based on the total weight of the pharmaceutically acceptable composition.

16. The pharmaceutical composition of any one of claims 1-15, wherein the intragranular blend comprises a first lubricant; optionally wherein the first lubricant is magnesium stearate.

17. The pharmaceutical composition of claim 16, wherein the intragranular blend comprises about 0.45% w/w to about 0.55% w/w of the first lubricant based on the total weight of the pharmaceutically acceptable composition; optionally wherein the intragranular blend comprises about 0.5% w/w of the first lubricant based on the total weight of the pharmaceutically acceptable composition.

18. The pharmaceutical composition of any one of claims 1-17, wherein the extragranular blend comprises a third diluent; optionally wherein the third diluent is a microcrystalline cellulose or a silicified microcrystalline cellulose.

19. The pharmaceutical composition of claim 18, wherein the extragranular blend comprises about 2.7% w/w to about 3.3% w/w of the third diluent based on the total weight of the pharmaceutically acceptable composition; optionally wherein the extragranular blend comprises about 3.0% w/w of the third diluent based on the total weight of the pharmaceutically acceptable composition.

20. The pharmaceutical composition of any one of claims 1-19, wherein the extragranular blend comprises a second disintegrant; optionally wherein the second disintegrant is sodium starch glycolate.

21. The pharmaceutical composition of claim 20, wherein the extragranular blend comprises about 3.6% w/w to about 4.4% w/w of the second disintegrant based on the total weight of the pharmaceutically acceptable composition; optionally wherein the extragranular blend comprises about 4.0% w/w of the second disintegrant based on the total weight of the pharmaceutically acceptable composition.

22. The pharmaceutical composition of any one of claims 1-21, wherein the extragranular blend comprises a second surfactant; optionally wherein the second surfactant is a poloxamer.

23. The pharmaceutical composition of claim 22, wherein the extragranular blend comprises about 6.75% w/w to about 8.25% w/w of the second surfactant based on the total weight of the pharmaceutically acceptable composition; optionally wherein the extragranular blend comprises about 7.5% w/w of the second surfactant based on the total weight of the pharmaceutically acceptable composition.

24. The pharmaceutical composition of any one of claims 1-23, wherein the extragranular blend comprises a second lubricant; optionally wherein the second lubricant is magnesium stearate.

25. The pharmaceutical composition of claim 24, wherein the extragranular blend comprises about 0.45% w/w to about 0.55% w/w of the second lubricant based on the total weight of the pharmaceutically acceptable composition; optionally wherein the extragranular blend comprises about 0.5% w/w of the second lubricant based on the total weight of the pharmaceutically acceptable composition.

26. The pharmaceutical composition of any one of claims 1-25, wherein the pharmaceutical composition comprises a film coating.

27. The pharmaceutical composition of claim 1-26, wherein the pharmaceutical composition comprises:

(a) an intragranular blend comprising:

(a-ii) about 43.0% w/w of mannitol;

(a-iii) about 10.0% w/w of silicified microcrystalline cellulose;

(a-iv) about 4.0% w/w of sodium starch glycolate;

(a-v) about 2.5% w/w of poloxamer; and

(a-vi) about 0.5% of magnesium stearate; and

(b) an extragranular blend comprising:

(b-i) about 3.0% w/w of silicified microcrystalline cellulose;

(b-ii) about 4.0% of sodium starch glycolate;

(b-iii) about 7.5% poloxamer; and

(b-iv) about 0.5% poloxamer, based on the total weight of the pharmaceutically acceptable composition; or wherein the pharmaceutical composition comprises:

(a) an intragranular blend comprising:

(a-i) about 25.0% w/w of the compound of Formula I;

(a-iv) about 4.0% w/w of sodium starch glycolate;

(a-v) about 2.5% w/w of poloxamer; and

(a-vi) about 0.5% of magnesium stearate; and

(b) an extragranular blend comprising:

(b-i) about 3.0% w/w of silicified microcrystalline cellulose;

(b-ii) about 4.0% of sodium starch glycolate;

(b-iii) about 7.5% poloxamer; and

(a) an intragranular blend comprising:

(a-ii) about 43.0% w/w of mannitol;

(a-iii) about 10.0% w/w of silicified microcrystalline cellulose;

(a-iv) about 4.0% w/w of sodium starch glycolate;

(a-v) about 2.5% w/w of poloxamer; and

(a-vi) about 0.5% of magnesium stearate;

(b) an extragranular blend comprising:

(b-i) about 3.0% w/w of silicified microcrystalline cellulose;

(b-ii) about 4.0% of sodium starch glycolate;

(b-iii) about 7.5% poloxamer; and

(b-iv) about 0.5% poloxamer; and

(c) about 4% w/w of a film coating, based on the total weight of the pharmaceutically acceptable composition; or wherein the pharmaceutical composition comprises:

(a) an intragranular blend comprising:

(a-i) about 25.0% w/w of the compound of Formula I;

(a-ii) about 43.0% w/w of mannitol;

(a-iii) about 10.0% w/w of silicified microcrystalline cellulose; (a-iv) about 4.0% w/w of sodium starch glycolate;

(a-v) about 2.5% w/w of poloxamer; and

(a-vi) about 0.5% of magnesium stearate;

(b) an extragranular blend comprising:

(b-i) about 3.0% w/w of silicified microcrystalline cellulose;

(b-ii) about 4.0% of sodium starch glycolate;

(b-iii) about 7.5% poloxamer; and

(b-iv) about 0.5% poloxamer; and

(c) about 4% w/w of a film coating, based on the total weight of the pharmaceutically acceptable composition.

28. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition of any one of claims 1-27.

29. Use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer in a subject in need thereof wherein said medicament is to be administered as the pharmaceutical composition of any one of claims 1-27.

30. A pharmaceutical composition according to any one of claims 1-27 for use in the treatment of cancer in a subject in need thereof.

31. The method of claim 28, use of claim 29 or pharmaceutical composition for use according to claim 30, wherein the compound of Formula I is dosed at about 20 mg to about 200 mg per administration; or wherein the compound of Formula I is dosed at about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 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 110 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg per administration.

32. The method of claim 28, use of claim 29 or pharmaceutical composition for use according to claim 30, wherein the pharmaceutical composition is administered to the subject once daily; or wherein the pharmaceutical composition is administered to the subject twice daily; or wherein the pharmaceutical composition is administered to the subject three times daily; or wherein the pharmaceutical composition is administered to the subject four times daily.

33. The method of claim 28, use of claim 29 or pharmaceutical composition for use according to claim 30, wherein about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 350 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 450 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 550 mg, about 560 mg, about 580 mg, about 600 mg, about 620 mg, about 640 mg, about 650 mg, about 660 mg, about 680 mg, about 700 mg, about 720 mg, about 740 mg, about 750 mg, about 760 mg, about 780 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, or about 1200 mg of the compound of Formula I is administered to the subject daily.

34. The method of claim 28, use of claim 29 or pharmaceutical composition for use according to claim 30, wherein about 120 mg, about 240 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, or about 1200 mg of the compound of Formula I is administered to the subject daily.

35. The method of claim 28, use of claim 29 or pharmaceutical composition for use according to claim 30, wherein the subject is resistant or has acquired resistance to one or more anti-cancer therapies; or wherein the subject is the subject is receiving an anti-cancer therapy.

36. The method, use or pharmaceutical composition for use according to claim 35, wherein the one or more anti-cancer therapies or anti-cancer therapy is a KIT inhibitor; or wherein the one or more anti-cancer therapies or anti-cancer therapy is independently selected from: imatinib, sunitinib, regorafenib, ripretinib, NB003, and THE-630, and combinations thereof.

37. The method, use or pharmaceutical composition for use according to any one of claims 28-36, wherein the cancer is selected from: gastrointestinal stromal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumor, pancreatic cancer, and mediastinal B-cell lymphoma.

38. The method, use or pharmaceutical composition for use according to any one of claims 28-37, wherein the cancer is gastrointestinal stromal tumor (GIST); optionally wherein the GIST is characterized by a tumor with one or more KIT mutations.

39. The method, use or pharmaceutical composition for use according to any one of claims 28-36, wherein the GIST is characterized by a tumor with one or more KIT mutations, each independently selected from an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, an exon 14 KIT mutation, and an exon 17 KIT mutation, and combinations thereof; optionally wherein each of the one or more KIT mutations is independently selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, K642E, V654A, and N655K, and combinations thereof.

40. The method, use or pharmaceutical composition for use according to claim 38, wherein the GIST is characterized by having an exon 13 KIT mutation selected from K642E, V654A and N655K, and combinations thereof; or wherein the GIST is characterized by having an the exon 14 KIT mutation which is T670I; or wherein the GIST is characterized by having an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D.