Pharmaceutical composition comprising PKC inhibitor

Abstract

Provided herein is a pharmaceutical composition comprising a PKC inhibitor for use in the treatment of cancer, such as uveal melanoma.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 520,857, filed August 21, 2023. The contents of this application are incorporated herein by reference in their entirety. Background Technology

[0003] Uveal melanoma (UM) is the most common primary malignant tumor of the eye in adults. UM is an ocular cancer located in the uvea and is traditionally classified as originating from the iris, choroid, and ciliary body, but can also be classified as category I (low risk of metastasis) and category II (high risk of metastasis). Because there is no lymphatic pathway to the uvea, metastasis occurs through local extension and / or hematogenous dissemination. The most common site of metastasis for uveal melanoma is the liver; the liver is the first site of metastasis in 80%–90% of patients with ocular melanoma. Other common sites of metastasis include the lungs, bones, and directly beneath the skin (subcutaneous tissue). Approximately 50% of patients will develop metastases within 15 years of treatment for the primary tumor, and the liver will be involved in 90% of these cases.

[0004] International application PCT / IB2015 / 055951 (WO 2016 / 020864) discloses a number of potent and selective PKC inhibitors, including 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazin-2-carboxamide. This compound may be used to treat certain cancers, including uveal melanoma.

[0005] This article provides an improved pharmaceutical composition comprising 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazin-2-carboxamide. Summary of the Invention

[0006] An improved pharmaceutical composition having the following structure is desired: 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazin-2-carboxamide (“Compound 1”). .

[0007] Therefore, in one aspect, this document provides a pharmaceutical composition comprising a superdisintegrant, a binder, a lubricant, a filler, and compound 1 or a pharmaceutically acceptable salt thereof. This document also provides a method of treating a subject with cancer, comprising administering to the subject a therapeutically effective amount of the disclosed pharmaceutical composition. In some embodiments, the cancer is uveal melanoma. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer carries a GNAQ mutation. In some embodiments, the cancer carries a GNA11 mutation. Attached Figure Description

[0008] Figure 1 The XRPD diffraction pattern of the crystalline form of compound 1 is shown.

[0009] Figure 2 The DSC thermogram of the crystalline form of compound 1 is shown.

[0010] Figure 3 The manufacturing process of a tablet containing compound 1 is shown. Detailed Implementation

[0011] This article provides pharmaceutical compositions comprising a PKC inhibitor or a pharmaceutically acceptable salt thereof. Such compositions may be used to treat cancers such as uveal melanoma, including metastatic uveal melanoma.

[0012] definition

[0013] The definitions of the various terms used herein are listed below. These definitions apply to terms used throughout this specification and claims, unless otherwise limited individually or as part of a larger group in specific instances.

[0014] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Typically, the nomenclature used herein, as well as laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry, are those well-known and commonly used in the art.

[0015] As used herein, the articles “a” and “an” refer to one (or a kind) or more than one (or a kind) (i.e., at least one (or a kind)) grammatical object. For example, “an element” means one element or more elements. Furthermore, the use of the term “including” and other formations (such as “include,” “includes,” and “included”) is not restrictive.

[0016] As used herein, the term “about” will be understood by those skilled in the art and will vary to some extent depending on the context of its use. As used herein, when referring to measurable values ​​such as quantity, duration of time, etc., the term “about” is intended to cover variations of ±10% from the specified value, including ±5%, ±1%, and ±0.1%, if such variations are appropriate for performing the disclosed method. For example, a dose of about 300 mg can be understood to mean that the dose can vary between 270 mg and 330 mg.

[0017] As used in the specification and claims, the term "comprising" may include embodiments "consisting of" and "substantially composed of". As used herein, the terms "comprising", "including", "having", "having", "may", "containing", and variations thereof are intended to require the presence of a specified ingredient / step and allow for the presence of other ingredients / steps as open transitional phrases, terms, or words. However, such a description should be interpreted as also describing the composition or method as consisting of the compounds listed as "of" and "substantially composed of", allowing only the specified compounds and any pharmaceutically acceptable carriers to be present, and excluding other compounds.

[0018] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed in range format herein. It should be understood that such range format is used for convenience and brevity and should therefore be interpreted flexibly to include not only the values ​​explicitly listed as limits of the range, but also all individual values ​​or subranges contained within the range, as if each value and subrange were explicitly listed. For example, the dose range of “200 mg to approximately 600 mg” should be interpreted to include not only the explicitly listed concentrations of approximately 200 mg to approximately 600 mg, but also individual doses (e.g., 250 mg, 400 mg, 550 mg) and subranges (e.g., 250 mg to 450 mg) within the indicated range. To further illustrate, a tumor size reduction of “30%–50%” should be interpreted to include not only the explicitly listed concentrations of approximately 30% to approximately 50%, but also individual percentages (e.g., 35%, 40%, 50%) and subranges (e.g., 35%–45%) within the indicated range. The term “about” can include ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, ±9%, or ±10% of the modified numerical value. Additionally, the phrase “about 'x' to 'y'” includes “about 'x' to about 'y'”.

[0019] As used in this article, “metastasis” or “metastatic” refers to the spread of cancer from its primary site to other locations in the body. Cancer cells can detach from the primary tumor, infiltrate lymphatic vessels and blood vessels, circulate through the bloodstream, and grow in distant lesions in normal tissues elsewhere in the body (metastasis). Metastasis can be local or distant. Metastasis is a continuous process that depends on tumor cells detaching from the primary tumor, spreading through the bloodstream, and stopping at a distant site. At the new site, the cells establish a blood supply and can grow to form a life-threatening mass. Both stimulatory and inhibitory molecular pathways within the tumor cells regulate this behavior, and the interactions between tumor cells and host cells in distant sites are also significant.

[0020] As used herein, the term “treating” (or “treatment”) refers to suppressing a disease; for example, suppressing the disease, illness, or symptom of an individual who is experiencing or exhibiting the pathology or symptomology of a disease, illness, or symptom (i.e., preventing further development of the pathology and / or symptomology), or improving a disease; for example, improving the disease, illness, or symptom of an individual who is experiencing or exhibiting the pathology or symptomology of a disease, illness, or symptom (i.e., reversing the pathology and / or symptomology), such as reducing the severity of the disease.

[0021] As used herein, the term "prevent" means the absence of the development of a symptom or disease (if the development of said symptom or disease has not yet occurred), or the absence of further development of the symptom or disease (if said symptom or disease has already developed). The ability to treat and prevent some or all of the symptoms associated with the symptom or disease is also considered.

[0022] As used herein, the terms “patient,” “individual,” or “subject” refer to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets, such as sheep, cattle, pigs, dogs, cats, and marine mammals. Preferably, the patient, subject, or individual is a human.

[0023] As used herein, the terms "effective amount," "pharmaceutical effective amount," and "therapeutic effective amount" refer to an amount of an agent that is non-toxic but sufficient to provide the desired biological outcome. This outcome may be the reduction or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. The appropriate therapeutic amount in any individual case can be determined by a person skilled in the art using routine laboratory methods. The agent is administered to the subject alone or as part of a pharmaceutical composition and in a single dose or as part of a series of doses.

[0024] As used herein, the term “pharmaceutically acceptable” means that a material (such as a carrier or diluent) does not eliminate the biological activity or properties of a compound and is relatively non-toxic, i.e., can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any of the components of a composition containing it.

[0025] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a disclosed compound in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and so on. Pharmaceutically acceptable salts described herein include, for example, conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts discussed herein can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, such salts are prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both; non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typically used. The phrase "pharmaceutically acceptable salt" is not limited to a single salt or a 1:1 salt. For example, "pharmaceutically acceptable salt" also includes disalts, such as dihydrochlorides. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0026] As used herein, the term "composition" or "pharmaceutical composition" refers to at least one compound or a pharmaceutically acceptable salt thereof and a mixture of one or more pharmaceutically acceptable carriers. Pharmaceutical compositions facilitate administration to a patient or subject. Various techniques for administering compounds exist in the art, including but not limited to intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0027] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting a compound useful to a patient and enabling the compound to perform its intended function. Typically, such constructs carry or transport from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable," meaning it is compatible with other components of the formulation, including the compounds disclosed herein, and is harmless to the patient. Examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic, compatible substances used in pharmaceutical preparations.

[0028] As used herein, "pharmaceuticalally acceptable carrier" also includes any and all coatings, antimicrobial and antifungal agents, and absorption delayers that are compatible with the activity of the compounds disclosed herein and are physiologically acceptable to patients. Complementary active compounds may also be incorporated into the composition. "Pharmaceuticalally acceptable carrier" may also include pharmaceutically acceptable salts of the compounds disclosed herein. Other additional components that may be included in the pharmaceutical composition are known in the art and described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0029] As used herein, the term "superdisintegrant" refers to a substance that promotes disintegration and reduces disintegration time. Non-limiting examples include crospovidone, xanthan gum, chitin, gellan gum, sodium starch glycolate, crospovidone carboxymethyl cellulose, and microcrystalline cellulose. In one embodiment, the superdisintegrant is crospovidone.

[0030] As used herein, the term "binder" refers to a chemical compound that has adhesive properties to promote cohesion. Binders are typically polymeric materials included in pharmaceutical compositions to allow for increased viable bond formation upon exposure to high forces, thereby producing a compact with sufficient mechanical strength, such as a tablet. Non-limiting examples include hydroxypropylcellulose, methylcellulose [MC], povidone [PVP], starch, gelatin, resins, and hydroxypropylcellulose. In one embodiment, the binder is ultra-low viscosity hydroxypropylcellulose.

[0031] The term "lubricant" is used herein to refer to an additive that reduces friction to prevent tablet breakage or damage. Non-limiting examples include magnesium stearate, calcium stearate, stearic acid, talc, sodium stearoyl fumarate, carrageenan, glyceryl behenate, and sodium lauryl sulfate. In one embodiment, the lubricant is magnesium stearate.

[0032] As used herein, the term "filler" refers to an inactive substance used to make an active pharmaceutical ingredient (such as compound 1) easier to measure. Non-limiting examples include microcrystalline cellulose, lactose, mannitol, pregelatinized starch, titanium dioxide, glycerol, and dextrin. In one embodiment, the filler is microcrystalline cellulose.

[0033] As used herein, the term “tablet fragility” refers to the tendency of a tablet to lose component particles due to wear, friction or mechanical impact.

[0034] Unless otherwise stated, dosage (for compound 1) is expressed as free base equivalent.

[0035] Pharmaceutical Composition

[0036] In one aspect, this article provides a pharmaceutical composition comprising: a superdisintegrant; a binder; a lubricant; and a filler; And compound 1: (1)

[0038] Or its pharmaceutically acceptable salt.

[0039] In one embodiment, the pharmaceutical composition comprises about 1-5% w / w of a superdisintegrant. In another embodiment, the pharmaceutical composition comprises about 3-7% w / w of a binder. In yet another embodiment, the pharmaceutical composition comprises about 0.25-3% w / w of a lubricant. In yet another embodiment, the pharmaceutical composition comprises about 0.05-3% w / w of a lubricant. In still another embodiment, the pharmaceutical composition comprises about 15-35% w / w of a filler. In one embodiment, the pharmaceutical composition comprises about 45-85% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0040] In another embodiment, the pharmaceutical composition comprises: Approximately 2-4% w / w of superdisintegrant; Approximately 4-6% w / w of binder; Approximately 20-30% w / w of filler; Approximately 0.5-3% w / w of lubricant; and Approximately 50-80% w / w of compound 1 or its pharmaceutically acceptable salt.

[0041] In another embodiment, the pharmaceutical composition comprises: Approximately 2-4% w / w of superdisintegrant; Approximately 4-6% w / w of binder; Approximately 20-30% w / w of filler; Lubricant of approximately 0.25-2% w / w; and Approximately 50-80% w / w of compound 1 or its pharmaceutically acceptable salt.

[0042] In another embodiment, the pharmaceutical composition comprises: 2-4% w / w superdisintegrant; 4-6% w / w binder; 20-30% w / w filler; 0.5-3% w / w lubricant; and 50-80% w / w of compound 1 or its pharmaceutically acceptable salt.

[0043] In yet another embodiment, the pharmaceutical composition comprises: Approximately 3% w / w of superdisintegrant; Approximately 5% w / w of adhesive; Approximately 24% w / w of filler; Approximately 1% w / w of lubricant; and Approximately 67% w / w of compound 1 or its pharmaceutically acceptable salt.

[0044] In yet another embodiment, the pharmaceutical composition comprises: 3% w / w super disintegrant; 5% w / w adhesive; 24% w / w filler; 1% w / w lubricant; and 67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0045] In yet another embodiment, the pharmaceutical composition comprises: Approximately 3% w / w of superdisintegrant; Approximately 5% w / w of adhesive; Approximately 25% w / w of filler; Approximately 0.50% w / w of lubricant; and Approximately 67% w / w of compound 1 or its pharmaceutically acceptable salt.

[0046] In yet another embodiment, the pharmaceutical composition comprises: Approximately 3% w / w of superdisintegrant; Approximately 5% w / w of adhesive; Approximately 24.33% w / w of filler; Approximately 1% w / w of lubricant; and Approximately 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0047] In yet another embodiment, the pharmaceutical composition comprises: Approximately 3% w / w of superdisintegrant; Approximately 5% w / w of adhesive; Approximately 24.83% w / w of filler; Approximately 0.50% w / w of lubricant; and Approximately 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0048] In yet another embodiment, the pharmaceutical composition comprises: 3% w / w super disintegrant; 5% w / w binder; 24.83% w / w filler; 0.50% w / w lubricant; and 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0049] In yet another embodiment, the pharmaceutical composition comprises: 3% w / w super disintegrant; 5% w / w binder; 24.83% w / w filler; 0.50% w / w lubricant; and Compound 1, 66.67% w / w.

[0050] In yet another embodiment, the pharmaceutical composition comprises: 3% w / w super disintegrant; 5% w / w binder; 24.33% w / w filler; 1% w / w lubricant; and 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0051] In one embodiment, the superdisintegrant is crospovidone. In another embodiment, the binder is hydroxypropyl cellulose. In yet another embodiment, the lubricant is magnesium stearate. In still another embodiment, the filler is microcrystalline cellulose.

[0052] In one embodiment, the pharmaceutical composition comprises: Cross-linked polyvinylpyrrolidone; Hydroxypropyl cellulose; Microcrystalline cellulose; Magnesium stearate; and Compound 1 or a pharmaceutically acceptable salt thereof.

[0053] In one embodiment, the pharmaceutical composition comprises: Cross-linked polyvinylpyrrolidone; Hydroxypropyl cellulose; Microcrystalline cellulose; Magnesium stearate; and Compound 1.

[0054] In yet another embodiment, the pharmaceutical composition comprises: Approximately 2-4% w / w crosslinked polyvinylpyrrolidone; Approximately 4-6% w / w hydroxypropyl cellulose; Approximately 20-30% w / w microcrystalline cellulose; Approximately 0.5-3% w / w magnesium stearate; and Approximately 50-80% w / w of compound 1 or its pharmaceutically acceptable salt.

[0055] In yet another embodiment, the pharmaceutical composition comprises: 2-4% w / w crospovidone; 4-6% w / w hydroxypropyl cellulose; 20-30% w / w microcrystalline cellulose; 0.5-3% w / w magnesium stearate; and 50-80% w / w of compound 1 or its pharmaceutically acceptable salt.

[0056] In another embodiment, the pharmaceutical composition comprises: Approximately 3% w / w cross-linked polyvinylpyrrolidone; Approximately 5% w / w hydroxypropyl cellulose; Approximately 24% w / w microcrystalline cellulose; Approximately 1% w / w magnesium stearate; and Approximately 67% w / w of compound 1 or its pharmaceutically acceptable salt.

[0057] In another embodiment, the pharmaceutical composition comprises: 3% w / w crosslinked polyvinylpyrrolidone; 5% w / w hydroxypropyl cellulose; 24% w / w microcrystalline cellulose; 1% w / w magnesium stearate; and 67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0058] In another embodiment, the pharmaceutical composition comprises: Approximately 3% w / w cross-linked polyvinylpyrrolidone; Approximately 5% w / w hydroxypropyl cellulose; Approximately 24.33% w / w microcrystalline cellulose; Approximately 1% w / w magnesium stearate; and Approximately 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0059] In another embodiment, the pharmaceutical composition comprises: 3% w / w crosslinked polyvinylpyrrolidone; 5% w / w hydroxypropyl cellulose; 24.33% w / w microcrystalline cellulose; 1% w / w magnesium stearate; and 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0060] In yet another embodiment, the pharmaceutical composition comprises: Approximately 2-4% w / w crosslinked polyvinylpyrrolidone; Approximately 4-6% w / w ultra-low viscosity hydroxypropyl cellulose; Approximately 20-30% w / w microcrystalline cellulose; Approximately 0.5-3% w / w magnesium stearate; and Approximately 50-80% w / w of compound 1 or its pharmaceutically acceptable salt.

[0061] In yet another embodiment, the pharmaceutical composition comprises: Approximately 2-4% w / w crosslinked polyvinylpyrrolidone; Approximately 4-6% w / w ultra-low viscosity hydroxypropyl cellulose; Approximately 20-30% w / w microcrystalline cellulose; Approximately 0.25-2% w / w magnesium stearate; and Approximately 50-80% w / w of compound 1 or its pharmaceutically acceptable salt.

[0062] In yet another embodiment, the pharmaceutical composition comprises: 2-4% w / w crospovidone; 4-6% w / w ultra-low viscosity hydroxypropyl cellulose; 20-30% w / w microcrystalline cellulose; 0.5-3% w / w magnesium stearate; and 50-80% w / w of compound 1 or its pharmaceutically acceptable salt.

[0063] In another embodiment, the pharmaceutical composition comprises: Approximately 3% w / w cross-linked polyvinylpyrrolidone; Approximately 5% w / w ultra-low viscosity hydroxypropyl cellulose; Approximately 24% w / w microcrystalline cellulose; Approximately 1% w / w magnesium stearate; and Approximately 67% w / w of compound 1 or its pharmaceutically acceptable salt.

[0064] In another embodiment, the pharmaceutical composition comprises: Approximately 3% w / w cross-linked polyvinylpyrrolidone; Approximately 5% w / w ultra-low viscosity hydroxypropyl cellulose; Approximately 25% w / w microcrystalline cellulose; Approximately 0.50% w / w magnesium stearate; and Approximately 67% w / w of compound 1 or its pharmaceutically acceptable salt.

[0065] In another embodiment, the pharmaceutical composition comprises: 3% w / w crosslinked polyvinylpyrrolidone; 5% w / w ultra-low viscosity hydroxypropyl cellulose; 24% w / w microcrystalline cellulose; 1% w / w magnesium stearate; and 67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0066] In another embodiment, the pharmaceutical composition comprises: Approximately 3% w / w cross-linked polyvinylpyrrolidone; Approximately 5% w / w ultra-low viscosity hydroxypropyl cellulose; Approximately 24.83% w / w microcrystalline cellulose; Approximately 0.50% w / w magnesium stearate; and Approximately 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0067] In another embodiment, the pharmaceutical composition comprises: 3% w / w crosslinked polyvinylpyrrolidone; 5% w / w ultra-low viscosity hydroxypropyl cellulose; 24.83% w / w microcrystalline cellulose; 0.50% w / w magnesium stearate; and 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0068] In another embodiment, the pharmaceutical composition comprises: Approximately 3% w / w cross-linked polyvinylpyrrolidone; Approximately 5% w / w hydroxypropyl cellulose; Approximately 24.83% w / w microcrystalline cellulose; Approximately 0.50% w / w magnesium stearate; and Approximately 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0069] In another embodiment, the pharmaceutical composition comprises: 3% w / w crosslinked polyvinylpyrrolidone; 5% w / w hydroxypropyl cellulose; 24.83% w / w microcrystalline cellulose; 0.50% w / w magnesium stearate; and 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0070] In another embodiment, the pharmaceutical composition comprises: Approximately 3% w / w cross-linked polyvinylpyrrolidone; Approximately 5% w / w hydroxypropyl cellulose; Approximately 24.83% w / w microcrystalline cellulose; Approximately 0.50% w / w magnesium stearate; and Compound 1, 66.67% w / w.

[0071] In another embodiment, the pharmaceutical composition comprises: 3% w / w crosslinked polyvinylpyrrolidone; 5% w / w hydroxypropyl cellulose; 24.83% w / w microcrystalline cellulose; 0.50% w / w magnesium stearate; and Compound 1, 66.67% w / w.

[0072] In another embodiment, the pharmaceutical composition comprises: Approximately 3% w / w cross-linked polyvinylpyrrolidone; Approximately 5% w / w ultra-low viscosity hydroxypropyl cellulose; Approximately 24.83% w / w microcrystalline cellulose; Approximately 0.50% w / w magnesium stearate; and Compound 1, approximately 66.67% w / w.

[0073] In another embodiment, the pharmaceutical composition comprises: 3% w / w crosslinked polyvinylpyrrolidone; 5% w / w ultra-low viscosity hydroxypropyl cellulose; 24.83% w / w microcrystalline cellulose; 0.50% w / w magnesium stearate; and Compound 1, 66.67% w / w.

[0074] In another embodiment, the pharmaceutical composition comprises: Approximately 3% w / w cross-linked polyvinylpyrrolidone; Approximately 5% w / w ultra-low viscosity hydroxypropyl cellulose; Approximately 24.33% w / w microcrystalline cellulose; Approximately 1% w / w magnesium stearate; and Approximately 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0075] In another embodiment, the pharmaceutical composition comprises: 3% w / w crosslinked polyvinylpyrrolidone; 5% w / w ultra-low viscosity hydroxypropyl cellulose; 24.33% w / w microcrystalline cellulose; 1% w / w magnesium stearate; and 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0076] In yet another embodiment, the pharmaceutical composition comprises compound 1.

[0077] In another embodiment, the pharmaceutical composition is in tablet form. In another embodiment, the tablet is an immediate-release form. In one embodiment, the tablet is film-coated. In one embodiment, the film is Opadry® Yellow.

[0078] In one embodiment, the pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof is in capsule form. In one embodiment, the capsule is a hard gelatin capsule. In one embodiment, the capsule is an immediate-release form.

[0079] In one embodiment, the pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof is in capsule form, wherein the capsule comprises gelatin. In one embodiment, the pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof is in capsule form, wherein the capsule comprises titanium dioxide (E171). In one embodiment, the pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof is in capsule form, wherein the capsule comprises gelatin and titanium dioxide (E171). In one embodiment, the capsule is a hard gelatin capsule having a No. 0 capsule shell comprising gelatin and titanium dioxide. In one embodiment, the capsule is a hard gelatin capsule having a No. 1 capsule shell comprising gelatin and titanium dioxide. In one embodiment, the capsule is a hard gelatin capsule having a No. 2 capsule shell comprising gelatin and titanium dioxide.

[0080] In one embodiment, the pharmaceutical composition comprises about 25 mg to 400 mg of free base equivalent of compound 1. In another embodiment, the pharmaceutical composition comprises 25 mg of free base equivalent of compound 1. In yet another embodiment, the pharmaceutical composition comprises 100 mg of free base equivalent of compound 1. In yet another embodiment, the pharmaceutical composition comprises 200 mg of free base equivalent of compound 1. In still another embodiment, the pharmaceutical composition comprises 300 mg of free base equivalent of compound 1.

[0081] In one embodiment, the compound 1, 100 mg IR (immediate-release) tablet is a round coated tablet. In one embodiment, the compound 1, 300 mg IR tablet is a yellow, oval coated tablet. In one embodiment, the compound 1, 100 mg IR tablet has an indentation on one side. In one embodiment, the compound 1, 300 mg IR tablet has an indentation on one side. In one embodiment, the compound 1, 100 mg IR tablet is coated with Opadry. ® Yellow (20A120007) coating. In one embodiment, compound 1, 300 mg IR tablets are coated with Opadry. ® Yellow (20A120007) coating.

[0082] In one embodiment, the pharmaceutical composition is administered orally, i.e., it is formulated for oral administration to a subject.

[0083] In one embodiment, the pharmaceutical composition comprises a coating of 1-5% w / w, 2-4% w / w, or 3% w / w, such as Opadry. ® Yellow. In one embodiment, w / w is in addition to the total percentage of the uncoated components of the pharmaceutical composition.

[0084] In one embodiment, the pharmaceutical composition comprises compound 1 in crystalline form.

[0085] Characterization of crystalline form

[0086] In some embodiments, the crystalline forms described herein can be identified based on characteristic peaks in X-ray powder diffraction (XRPD) analysis. X-ray powder diffraction is a scientific technique for structural characterization of powders, crystallites, or other solid materials using X-rays, neutrons, or electron diffraction. Descriptions of methods for obtaining certain XRPD diffraction patterns associated with the crystalline forms provided herein can be found in the examples below. In one embodiment, the X-ray powder diffraction data provided herein are obtained using Cu, K-α1 radiation.

[0087] In one aspect, this paper provides a crystalline form of 3-amino-N-[3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl]-6-[3-(trifluoromethyl)pyridin-2-yl]pyrazin-2-carboxamide (compound 1), wherein the crystalline form is characterized by XRPD diffraction patterns having peaks at angles (±0.2°) of 8.3, 15.0, and 16.6, expressed as °-2θ.

[0088] In one embodiment, the crystalline form of compound 1 is characterized by an XRPD diffraction pattern having peaks at angles (±0.2°) of 8.3, 15.0, 16.6, and 25.0, expressed as °-2θ.

[0089] In one embodiment, the crystalline form of compound 1 is characterized by an XRPD diffraction pattern with peaks at angles (±0.2°) of 8.3, 15.0, 16.6, 25.0, and 23.1, expressed as °-2θ.

[0090] In one embodiment, the crystalline form of compound 1 is characterized by XRPD diffraction patterns with peaks at angles (±0.2°) of 8.3, 15.0, 16.6, and 11.8, expressed as °-2θ.

[0091] In another embodiment, the crystalline form of compound 1 is characterized by an XRPD diffraction pattern with peaks at angles (±0.2°) of 8.3, 15.0, 16.6, 25.0, 23.1, 11.8 and 22.4, expressed as °-2θ.

[0092] In yet another embodiment, the crystalline form of compound 1 is characterized by an XRPD diffraction pattern with peaks at angles (±0.2°) of 8.3, 15.0, 16.6, 25.0, 23.1, 11.8, 22.4 and 23.7, expressed in °-2θ.

[0093] In yet another embodiment, the crystalline form of compound 1 is characterized by an XRPD diffraction pattern having peaks at angles (±0.2°) of 8.3, 15.0, 16.6, 25.0, 23.1, 11.8, 22.4, 23.7 and 24.8, expressed in °-2θ.

[0094] In yet another embodiment, the crystalline form of compound 1 is characterized by an XRPD diffraction pattern with peaks at angles (±0.2°) of 8.3, 15.0, 16.6, 25.0, 23.1, 11.8, 22.4 and 23.7, expressed in °-2θ.

[0095] In yet another embodiment, the crystalline form of compound 1 is characterized by an XRPD diffraction pattern containing at least three or at least four peaks, expressed in °-2θ, at angles (±0.2°) of 8.3, 15.0, 16.6, 25.0, 23.1, 11.8, 22.4 and 23.7.

[0096] In yet another embodiment, the crystalline form of compound 1 is characterized by: Figure 1 The XRPD diffraction pattern depicted in the image.

[0097] In another embodiment, the crystalline form of compound 1 is characterized by an XRPD diffraction pattern having peaks at angles listed in Table 19, expressed in °-2θ.

[0098] Table 19.

[0099] In one embodiment, the crystalline form of compound 1 has a DSC thermogram, characterized by an endothermic onset temperature of about 245.5°C.

[0100] Treatment

[0101] In one aspect, this document also provides a method for treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of the disclosed pharmaceutical composition.

[0102] In one embodiment, the cancer is melanoma. In one embodiment, the cancer is uveal melanoma. In another embodiment, the cancer is a solid tumor. In another embodiment, the cancer is metastatic uveal melanoma. In one embodiment, the cancer is cutaneous melanoma. In one embodiment, the cancer is mucosal melanoma. In another embodiment, the subject has an intraocular tumor. In another embodiment, the intraocular tumor is malignant. In another embodiment, the intraocular tumor is not malignant. In yet another embodiment, the cancer carries a GNAQ mutation. In still another embodiment, the cancer carries a GNA11 mutation.

[0103] In another embodiment, uveal melanoma is a solid tumor carrying a GNAQ or GNA11 mutation. In one embodiment, the patient has another non-ocular tumor. In another embodiment, the non-ocular tumor is metastatic.

[0104] In another implementation, the cancer is selected from the group consisting of: melanoma, uveal melanoma, lymphoma, diffuse large B-cell lymphoma (DLBCL), ibrutinib-resistant cancer, papillary carcinoma, thyroid cancer, ovarian cancer, colon cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), hematologic malignancies, chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia.

[0105] On the other hand, this article provides a method for treating uveal melanoma (including uveal melanoma carrying GNAQ or GNA11 mutations) in a subject of need, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of this disclosure to reduce or prevent tumor growth in the subject.

[0106] In another aspect, this document provides a method for treating a subject in need of lymphoma (including diffuse large B-cell lymphoma (DLBCL)) comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of this disclosure.

[0107] Exemplary time lengths associated with the course of treatment are approximately five years, approximately four years, approximately three years, approximately two years, approximately one year, approximately 11 months, approximately 10 months, approximately nine months, approximately eight months, approximately seven months, approximately six months, approximately five months, approximately four months, approximately three months, approximately two months, or approximately one month.

[0108] An exemplary time length associated with the course of a treatment is approximately five years; or any days, weeks, months, or years therein; for example, a treatment cycle may include 5 months and an additional number of weeks and / or days, or a year and an additional number of months, weeks, and / or days, etc.

[0109] In some implementations, compound 1 or a pharmaceutically acceptable salt thereof is administered continuously (i.e., treatment continues until termination).

[0110] The UM to be treated may include one or more of a number of mutations, including substitution mutations, insertion mutations, and / or deletions in GNAQ or GNA11 mutations. In some respects, GNAQ or GNA11 mutations are gain-of-function mutations. In some respects, GNAQ or GNA11 mutations activate the PKC signaling pathway. In various respects, GNAQ or GNA11 mutations may be a substitution of glutamine (Q209) at codon 209 and / or a substitution of arginine (R183) at codon 183. GNAQ or GNA11 mutations may be substitutions other than glutamine (Q209) at codon 209, substitutions other than arginine (R183) at codon 183, or substitutions other than both. In some respects, the GNAQ mutation is one of Q209P, Q209L, Q209H, Q209K, or Q209Y, or the GNA11 mutation is one of Q209P, Q209L, Q209K, or Q209H. In other respects, the GNAQ mutation can be R183Q, or the GNA11 mutation can be R183C or R183H. In other examples, the GNAQ or GNA11 mutation is located at one or more of R256, L279, R166, A168, R210, R213, R166, A231, A342, D333, G171, R147, R73, T47, E191, E221, R149, T175, T379, T85, A86, E163, D195, E319, E191, E280, E49, P293, R300, R338, R60, D155, D205, D321, I226, R37, or V240. In other examples, UM may contain one or more of the Q209P, Q209L, Q209H, Q209K, Q209Y, or R183Q mutations in GNAQ, or UM may contain one or more of the Q209P, Q209L, Q209H, or Q209K mutations in GNA11. Further examples of mutations in GNAQ or GNA11 are described in WO 2020 / 146355, which is incorporated herein by reference in its entirety.

[0111] Exemplary time lengths associated with the treatment process disclosed herein include: approximately one week; approximately two weeks; approximately three weeks; approximately four weeks; approximately five weeks; approximately six weeks; approximately seven weeks; approximately eight weeks; approximately nine weeks; approximately ten weeks; approximately eleven weeks; approximately twelve weeks; approximately thirteen weeks; approximately fourteen weeks; approximately fifteen weeks; approximately sixteen weeks; approximately seventeen weeks; approximately eighteen weeks; approximately nineteen weeks; approximately twenty weeks; approximately twenty-one weeks; approximately twenty-two weeks; approximately twenty-three weeks; approximately twenty-four weeks; approximately four months; approximately seven months; approximately eight months; approximately nine months; approximately ten months; Approximately eleven months; approximately twelve months; approximately thirteen months; approximately fourteen months; approximately fifteen months; approximately sixteen months; approximately seventeen months; approximately eighteen months; approximately nineteen months; approximately twenty months; approximately twenty-one months; approximately twenty-two months; approximately twenty-three months; approximately twenty-four months; approximately thirty months; approximately three years; approximately four years and approximately five years, etc.; or any days, weeks, months or years in between; for example, a treatment cycle may include five months and an additional number of weeks and / or days, or a year and an additional number of months, weeks and / or days, etc.

[0112] In one embodiment of these methods, the method involves administering a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof to a subject requiring treatment (including subjects identified as requiring treatment) (including, but not limited to, a human or animal).

[0113] Application / Dosage / Formulation

[0114] The actual dose level of the active ingredient in a pharmaceutical composition can be varied to obtain an amount of the active ingredient that effectively achieves the desired therapeutic response for a particular patient, composition, and administration mode without being toxic to the patient.

[0115] In particular, the selected dose level will depend on a variety of factors, including the activity of the specific compound used, the timing of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health status and medical history of the patient being treated, and similar factors well known in the medical field.

[0116] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can begin administering the pharmaceutical composition at a level lower than required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0117] In certain embodiments, it is particularly advantageous to formulate the compound in unitary dosage form for ease of administration and uniform dosage. As used herein, unitary dosage form refers to a physically discrete unit suitable as a single dose to a patient to be treated; each unit contains a predetermined amount of the disclosed compound bound to the desired drug medium in a manner calculated to produce the desired therapeutic effect. The unitary dosage form is determined by and directly depends on (a) the unique properties of the disclosed compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations in the field of coagulating / formulating such a disclosed compound for the treatment of a patient's pain, depressive disorder, or drug addiction.

[0118] In one embodiment, the compound provided herein is formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical composition provided herein comprises a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier.

[0119] The optimal proportions, individual doses, and combined doses and concentrations of pharmaceutical compounds that produce efficacy without toxicity are determined based on the kinetics of the utilization of the active ingredient against the target site and using methods known to those skilled in the art.

[0120] One embodiment provides a method of treating cancer in a subject in need, comprising administering the pharmaceutical composition disclosed herein to the subject at a dose of compound 1 (measured as free base) of about 50 mg BID to about 400 mg BID for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks. In one embodiment of these methods, the pharmaceutical composition is administered at a dose of compound 1 (measured as free base) of about 100 mg BID, about 200 mg BID, or about 300 mg BID for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks.

[0121] Routes of administration for any of the compositions discussed herein include oral, nasal, rectal, vaginal, parenteral, buccal, sublingual, or topical. The compounds can be formulated for administration via any suitable route, such as oral or parenteral, including transdermal, transmucosal (e.g., sublingual, translingual, (trans)buccal, (trans)urethral, ​​vaginal (e.g., vaginal and perivallary), (internal)nasal, and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration. In one embodiment, oral administration is preferred.

[0122] Suitable compositions and dosage forms include, for example, tablets, capsules, pouches, pills, gel caps, lozenges, dispersants, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pills, pastes, lozenges, creams, ointments, lotions, tablets, suppositories, liquid sprays for nasal or oral administration, dry powder or nebulized formulations for inhalation, and compositions and formulations for intravesical administration. It should be understood that formulations and compositions are not limited to the specific formulations and compositions described herein.

[0123] For oral applications, tablets, sugar-coated pills, liquids, drops, suppositories or capsules, capsules, and gel caps are particularly suitable. Compositions intended for oral use can be prepared according to any method known in the art, and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrants such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or may be coated using known techniques for aesthetic purposes or to delay the release of the active ingredient. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0124] For parenteral administration, the disclosed compounds may be formulated for injection or infusion, such as intravenous, intramuscular, or subcutaneous injection or infusion, or for administration by bolus dose or continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous media may be used, optionally containing other formulations such as suspending agents, stabilizers, or dispersants.

[0125] Reagent test kit

[0126] In one aspect, this disclosure provides a kit for treating uveal melanoma comprising the pharmaceutical composition of this disclosure. In some embodiments, the kit further comprises packaging and instructions for use. In yet another embodiment, the uveal melanoma is metastatic uveal melanoma. In still another embodiment, the metastatic uveal melanoma is a solid tumor carrying a GNAQ or GNA11 mutation.

[0127] In some embodiments, the kit contains a pharmaceutical product comprising a pharmaceutical composition of the present disclosure.

[0128] In another embodiment, a pharmaceutical kit is provided. The kit includes a sealed container approved for storing a pharmaceutical composition containing one of the aforementioned pharmaceutical compositions. In some embodiments, the sealed container minimizes contact between air and the ingredients, such as a vacuum bottle. In other embodiments, the sealed container is a sealed tube. The kit should include instructions for use of the composition and information about the composition.

[0129] The kits described herein contain prescription information, such as prescription information for patients or healthcare providers, or as a label on a packaged pharmaceutical preparation. Prescription information may include, for example, information regarding the efficacy, dosage and administration, contraindications, and adverse reactions of the pharmaceutical preparation.

[0130] The kits provided herein are designed to maintain the conditions necessary for properly maintaining the components contained therein (e.g., refrigeration or freezing). The kits may include labels or instructions for use, including identification information for the components and instructions for use (e.g., dosing parameters, clinical pharmacology of the active ingredient, including mechanism of action, pharmacokinetics and pharmacodynamics, adverse reactions, contraindications, etc.).

[0131] The components of the kit can be packaged in individual containers, and all different containers can be contained in a single package. Labels or instructions may include manufacturer information such as batch number and expiration date. Labels or instructions may be integrated into the physical structure containing the components, contained separately within the physical structure, or affixed to components of the kit (e.g., ampoules, syringes, or vials).

[0132] Non-limiting exemplary implementations: In the following further embodiments 1 to 78, this disclosure includes: 1. Embodiment 1 is a pharmaceutical composition comprising a superdisintegrant; a binder; a lubricant; a filler; and compound 1 or a pharmaceutically acceptable salt thereof.

[0133] 2. Embodiment 2 is a pharmaceutical composition as described in Embodiment 1, wherein the pharmaceutical composition comprises about 1-5% w / w of a superdisintegrant.

[0134] 3. Embodiment 3 is a pharmaceutical composition as described in Embodiment 1 or 2, wherein the pharmaceutical composition comprises about 3-7% w / w of a binder.

[0135] 4. Embodiment 4 is a pharmaceutical composition as described in any one of Embodiments 1 to 3, wherein the pharmaceutical composition comprises about 0.25-3% w / w of a lubricant.

[0136] 5. Embodiment 5 is a pharmaceutical composition as described in any one of Embodiments 1 to 3, wherein the pharmaceutical composition comprises about 0.05-3% w / w of a lubricant.

[0137] 6. Embodiment 6 is a pharmaceutical composition as described in any one of Embodiments 1 to 5, wherein the pharmaceutical composition comprises about 15-35% w / w of a filler.

[0138] 7. Embodiment 7 is a pharmaceutical composition as described in any one of Embodiments 1 to 6, wherein the pharmaceutical composition comprises about 45-85% w / w of Compound 1 or a pharmaceutically acceptable salt thereof.

[0139] 7A. Embodiment 7A is a pharmaceutical composition as described in any one of Embodiments 1 to 7, comprising: Approximately 2-4% w / w of superdisintegrant; Approximately 4-6% w / w of binder; Approximately 20-30% w / w of filler; Approximately 0.5-3% w / w of lubricant; and Approximately 50-80% w / w of compound 1 or its pharmaceutically acceptable salt.

[0140] 8. Embodiment 8 is a pharmaceutical composition as described in any one of Embodiments 1 to 7, comprising: Approximately 2-4% w / w of superdisintegrant; Approximately 4-6% w / w of binder; Approximately 20-30% w / w of filler; Lubricant of approximately 0.25-2% w / w; and Approximately 50-80% w / w of compound 1 or its pharmaceutically acceptable salt.

[0141] 9. Embodiment 9 is a pharmaceutical composition as described in any one of Embodiments 1 to 7, comprising: 2-4% w / w superdisintegrant; 4-6% w / w binder; 20-30% w / w filler; 0.5-3% w / w lubricant; and 50-80% w / w of compound 1 or its pharmaceutically acceptable salt.

[0142] 10. Embodiment 10 is a pharmaceutical composition as described in any one of Embodiments 1 to 9, comprising: 2-4% w / w superdisintegrant; 4-6% w / w binder; 20-30% w / w filler; 0.25-2% w / w lubricant; and 50-80% w / w of compound 1 or its pharmaceutically acceptable salt.

[0143] 11. Embodiment 11 is a pharmaceutical composition as described in any one of Embodiments 1 to 10, comprising: Approximately 3% w / w of superdisintegrant; Approximately 5% w / w of adhesive; Approximately 24% w / w of filler; Approximately 1% w / w of lubricant; and Approximately 67% w / w of compound 1 or its pharmaceutically acceptable salt.

[0144] 12. Embodiment 12 is a pharmaceutical composition as described in any one of Embodiments 1 to 10, comprising: Approximately 3% w / w of superdisintegrant; Approximately 5% w / w of adhesive; Approximately 25% w / w of filler; Approximately 0.50% w / w of lubricant; and Approximately 67% w / w of compound 1 or its pharmaceutically acceptable salt.

[0145] 13. Embodiment 13 is a pharmaceutical composition as described in any one of Embodiments 1 to 10, comprising: Approximately 3% w / w of superdisintegrant; Approximately 5% w / w of adhesive; Approximately 24.33% w / w of filler; Approximately 1% w / w of lubricant; and Approximately 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0146] 14. Embodiment 14 is a pharmaceutical composition as described in any one of Embodiments 1 to 10, comprising: Approximately 3% w / w of superdisintegrant; Approximately 5% w / w of adhesive; Approximately 24.83% w / w of filler; Approximately 0.50% w / w of lubricant; and Approximately 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0147] 15. Embodiment 15 is a pharmaceutical composition as described in any one of Embodiments 1 to 10 and 13, comprising: 3% w / w super disintegrant; 5% w / w binder; 24.33% w / w filler; 1% w / w lubricant; and 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0148] 16. Embodiment 16 is a pharmaceutical composition as described in any one of embodiments 1 to 10, 12 and 14, comprising: 3% w / w super disintegrant; 5% w / w binder; 24.83% w / w filler; 0.50% w / w lubricant; and 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0149] 17. Embodiment 17 is a pharmaceutical composition as described in any one of Embodiments 1 to 16, wherein the superdisintegrant is crospovidone.

[0150] 18. Embodiment 18 is a pharmaceutical composition as described in any one of Embodiments 1 to 17, wherein the binder is hydroxypropyl cellulose.

[0151] 19. Embodiment 19 is a pharmaceutical composition as described in Embodiment 18, wherein the hydroxypropyl cellulose is ultra-low viscosity hydroxypropyl cellulose.

[0152] 20. Embodiment 20 is a pharmaceutical composition as described in any one of Embodiments 1 to 19, wherein the filler is microcrystalline cellulose.

[0153] 21. Embodiment 21 is a pharmaceutical composition as described in any one of Embodiments 1 to 20, wherein the lubricant is magnesium stearate.

[0154] 22. Embodiment 22 is a pharmaceutical composition as described in any one of embodiments 1 to 10 and 17 to 21, comprising: Approximately 2-4% w / w crosslinked polyvinylpyrrolidone; Approximately 4-6% w / w ultra-low viscosity hydroxypropyl cellulose; Approximately 20-30% w / w microcrystalline cellulose; Approximately 0.5-3% w / w magnesium stearate; and Approximately 50-80% w / w of compound 1 or its pharmaceutically acceptable salt.

[0155] 23. Embodiment 23 is a pharmaceutical composition as described in any one of embodiments 1 to 10 and 17 to 22, comprising: Approximately 2-4% w / w crosslinked polyvinylpyrrolidone; Approximately 4-6% w / w ultra-low viscosity hydroxypropyl cellulose; Approximately 20-30% w / w microcrystalline cellulose; Approximately 0.25-2% w / w magnesium stearate; and Approximately 50-80% w / w of compound 1 or its pharmaceutically acceptable salt.

[0156] 24. Embodiment 24 is a pharmaceutical composition as described in any one of embodiments 1 to 10 and 17 to 23, comprising: Approximately 3% w / w cross-linked polyvinylpyrrolidone; Approximately 5% w / w ultra-low viscosity hydroxypropyl cellulose; Approximately 24% w / w microcrystalline cellulose; Approximately 1% w / w magnesium stearate; and Approximately 67% w / w of compound 1 or its pharmaceutically acceptable salt.

[0157] 25. Embodiment 25 is a pharmaceutical composition as described in any one of embodiments 1 to 10 and 17 to 24, comprising: 3% w / w crosslinked polyvinylpyrrolidone; 5% w / w ultra-low viscosity hydroxypropyl cellulose; 24% w / w microcrystalline cellulose; 1% w / w magnesium stearate; and 67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0158] 26. Embodiment 26 is a pharmaceutical composition as described in any one of embodiments 1 to 10 and 17 to 23, comprising: Approximately 3% w / w cross-linked polyvinylpyrrolidone; Approximately 5% w / w ultra-low viscosity hydroxypropyl cellulose; Approximately 24.33% w / w microcrystalline cellulose; Approximately 1% w / w magnesium stearate; and Approximately 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0159] 27. Embodiment 27 is a pharmaceutical composition as described in any one of embodiments 1 to 10 and 17 to 23 and 26, comprising: 3% w / w crosslinked polyvinylpyrrolidone; 5% w / w ultra-low viscosity hydroxypropyl cellulose; 24.33% w / w microcrystalline cellulose; 1% w / w magnesium stearate; and 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0160] 28. Embodiment 28 is a pharmaceutical composition as described in any one of embodiments 1 to 10, 12 and 17 to 23, comprising: Approximately 3% w / w cross-linked polyvinylpyrrolidone; Approximately 5% w / w ultra-low viscosity hydroxypropyl cellulose; Approximately 25% w / w microcrystalline cellulose; Approximately 0.50% w / w magnesium stearate; and Approximately 67% w / w of compound 1 or its pharmaceutically acceptable salt.

[0161] 29. Embodiment 29 is a pharmaceutical composition as described in any one of embodiments 1 to 10, 12, 17 to 23 and 28, comprising: 3% w / w crosslinked polyvinylpyrrolidone; 5% w / w ultra-low viscosity hydroxypropyl cellulose; 25% w / w microcrystalline cellulose; 0.50% w / w magnesium stearate; and 67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0162] 30. Embodiment 30 is a pharmaceutical composition as described in any one of embodiments 1 to 10, 14, 17 to 23 and 28, comprising: Approximately 3% w / w cross-linked polyvinylpyrrolidone; Approximately 5% w / w ultra-low viscosity hydroxypropyl cellulose; Approximately 24.83% w / w microcrystalline cellulose; Approximately 0.50% w / w magnesium stearate; and Approximately 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0163] 31. Embodiment 31 is a pharmaceutical composition as described in any one of embodiments 1 to 10, 14 and 16 to 23 and 30, comprising: 3% w / w crosslinked polyvinylpyrrolidone; 5% w / w ultra-low viscosity hydroxypropyl cellulose; 24.83% w / w microcrystalline cellulose; 0.50% w / w magnesium stearate; and 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

[0164] 32. Embodiment 32 is a pharmaceutical composition as described in any one of Embodiments 1 to 31, wherein the pharmaceutical composition comprises compound 1.

[0165] 33. Embodiment 33 is a pharmaceutical composition as described in any one of Embodiments 1 to 32, wherein compound 1 is in crystalline form.

[0166] 34. Embodiment 34 is a pharmaceutical composition as described in any one of Embodiments 1 to 33, wherein the pharmaceutical composition is in tablet form.

[0167] 35. Embodiment 35 is a pharmaceutical composition as described in Embodiment 34, wherein the tablet is an immediate-release form.

[0168] 36. Embodiment 36 is a pharmaceutical composition as described in Embodiment 34 or 35, wherein the tablet is film-coated.

[0169] 37. Embodiment 37 is a pharmaceutical composition as described in Embodiment 36, wherein the membrane is Opadry® Yellow.

[0170] 38. Embodiment 38 is a pharmaceutical composition as described in Embodiment 36, wherein the membrane is Opadry® AMB.

[0171] 39. Embodiment 39 is a pharmaceutical composition as described in any one of Embodiments 1 to 38, wherein the tablet has a disintegration time of less than 10 minutes.

[0172] 40. Embodiment 40 is a pharmaceutical composition as described in any one of Embodiments 1 to 39, wherein the tablet has a friability of less than 0.5% w / w.

[0173] 41. Embodiment 41 is a pharmaceutical composition as described in any one of Embodiments 1 to 39, wherein the tablet has a friability of 0.5% w / w.

[0174] 42. Embodiment 42 is a pharmaceutical composition as described in any one of Embodiments 1 to 39, wherein the friability of the tablet is less than or equal to 1.0% w / w.

[0175] 43. Embodiment 43 is a pharmaceutical composition as described in any one of Embodiments 1 to 42, wherein the dissolution rate of the tablet is greater than 80% at 15 minutes.

[0176] 44. Embodiment 44 is a pharmaceutical composition as described in any one of Embodiments 1 to 43, wherein the dissolution rate of the tablet is greater than 85% at 15 minutes.

[0177] 45. Embodiment 45 is a pharmaceutical composition as described in any one of Embodiments 1 to 44, wherein the dissolution rate of the tablet is greater than 90% at 15 minutes.

[0178] 46. ​​Embodiment 46 is a pharmaceutical composition as described in any one of Embodiments 1 to 45, wherein the dissolution rate of the tablet is greater than 95% at 15 minutes.

[0179] 47. Embodiment 47 is a pharmaceutical composition as described in any one of Embodiments 1 to 46, wherein the pharmaceutical composition comprises about 25 mg to 400 mg of free base equivalent of compound 1.

[0180] 48. Embodiment 48 is a pharmaceutical composition as described in any one of Embodiments 1 to 47, wherein the pharmaceutical composition comprises about 100 mg of free base equivalent of compound 1.

[0181] 49. Embodiment 49 is a pharmaceutical composition as described in any one of Embodiments 1 to 47, wherein the pharmaceutical composition comprises about 200 mg of free base equivalent of compound 1.

[0182] 50. Embodiment 50 is a pharmaceutical composition as described in any one of Embodiments 1 to 47, wherein the pharmaceutical composition comprises about 300 mg of free base equivalent of compound 1.

[0183] 51. Embodiment 51 is a pharmaceutical composition as described in any one of Embodiments 1 to 50, wherein the pharmaceutical composition is administered orally.

[0184] 52. Embodiment 52 is a pharmaceutical composition as described in any one of Embodiments 1 to 51, wherein the compound 1 is in crystalline form, characterized by having an XRPD diffraction pattern with peaks at angles (±0.2°) of 8.3, 15.0, and 16.6, expressed as °-2θ.

[0185] 53. Embodiment 53 is a pharmaceutical composition as described in any one of Embodiments 1 to 52, wherein the compound 1 is in crystalline form, characterized by having an XRPD diffraction pattern with peaks at angles (±0.2°) of 8.3, 15.0, 16.6, 25.0, and 23.1, expressed in °-2θ.

[0186] 54. Embodiment 54 is a pharmaceutical composition as described in any one of Embodiments 1 to 53, wherein the compound 1 is in crystalline form, characterized by having an XRPD diffraction pattern of peaks at angles (±0.2°) of 8.3, 15.0, 16.6, 25.0, 23.1, 11.8 and 22.4, expressed in °-2θ.

[0187] 55. Embodiment 55 is a pharmaceutical composition as described in any one of Embodiments 1 to 54, wherein the compound 1 is in crystalline form, characterized by having an XRPD diffraction pattern with peaks at angles (±0.2°) of 8.3, 15.0, 16.6, 25.0, 23.1, 11.8, 22.4 and 23.7, expressed in °-2θ.

[0188] 56. Embodiment 56 is a pharmaceutical composition as described in any one of Embodiments 1 to 51, wherein the compound 1 is in crystalline form, characterized by comprising an XRPD diffraction pattern of at least three or at least four peaks, expressed in °-2θ, at an angle (±0.2°) selected from the group consisting of about 8.3, 15.0, 16.6, 25.0, 23.1, 11.8, 22.4 and 23.7.

[0189] 57. Embodiment 57 is a pharmaceutical composition as described in any one of Embodiments 1 to 56, wherein said compound 1 is in crystalline form, characterized in that... Figure 1 The XRPD diffraction pattern depicted in the image.

[0190] 58. Embodiment 58 is a pharmaceutical composition as described in any one of Embodiments 1 to 57, wherein the compound 1 is in crystalline form and is characterized by having an endothermic DSC thermal analysis chromatogram with an initial temperature of about 245.5°C.

[0191] 59. Embodiment 59 is a method of treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described in any one of Embodiments 1 to 58.

[0192] 60. Implementation scheme 60 is the method as described in implementation scheme 59, wherein the cancer is uveal melanoma.

[0193] 61. Implementation method 61 is the method as described in implementation method 59 or 60, wherein the cancer is a solid tumor.

[0194] 62. Embodiment 62 is a method as described in any one of Embodiments 59 to 61, wherein the cancer is metastatic uveal melanoma.

[0195] 63. Implementation scheme 63 is a method as described in any one of implementation schemes 59 to 62, wherein the subject has an intraocular tumor.

[0196] 64. Implementation scheme 64 is the method as described in implementation scheme 63, wherein the intraocular tumor is not malignant.

[0197] 65. Implementation scheme 65 is the method as described in implementation scheme 63, wherein the intraocular tumor is malignant.

[0198] 66. Implementation scheme 66 is the method as described in implementation scheme 59, wherein the cancer is skin melanoma.

[0199] 67. Implementation scheme 67 is the method as described in implementation scheme 59, wherein the cancer is mucosal melanoma.

[0200] 68. Embodiment 68 is a method as described in any one of embodiments 59 to 67, wherein the cancer carries a GNAQ mutation.

[0201] 69. Embodiment 69 is a method as described in any one of Embodiments 59 to 68, wherein the cancer carries a GNA11 mutation.

[0202] 70. Embodiment 70 is a method as described in any one of Embodiments 1 to 69, wherein the pharmaceutical composition is administered at a dose of about 50 mg BID to about 400 mg BID of Compound 1 (measured as free base) for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks.

[0203] 71. Embodiment 71 is a method as described in any one of Embodiments 1 to 70, wherein the pharmaceutical composition is administered at a dose of compound 1 (measured as free base) of about 100 mg BID, about 200 mg BID, or about 300 mg BID for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks.

[0204] 72. Embodiment 72 is a pharmaceutical composition as described in any one of Embodiments 1 to 58, used in a therapy.

[0205] 73. Embodiment 73 is a pharmaceutical composition as described in any one of Embodiments 1 to 58, used in the treatment of cancer.

[0206] 74. Embodiment 74 is the use as described in Embodiment 73, wherein the cancer is melanoma.

[0207] 75. Embodiment 75 is the use as described in Embodiment 73, wherein the cancer is uveal melanoma.

[0208] 76. Embodiment 76 is the use as described in Embodiment 73, wherein the cancer is metastatic uveal melanoma.

[0209] 77. Embodiment 77 is the use as described in Embodiment 73, wherein the cancer is skin melanoma.

[0210] 78. Embodiment 78 is the use as described in Embodiment 73, wherein the cancer is mucosal melanoma.

[0211] Those skilled in the art will recognize or be able to determine numerous equivalents of the particular procedures, embodiments, claims, and examples described herein using only conventional experiments. Such equivalents are considered to be within the scope of this disclosure and are covered by the appended claims. For example, it should be understood that modifications to reaction conditions, including but not limited to reaction time, reaction size / volume, and experimental reagents such as solvents, catalysts, pressure, atmospheric conditions (e.g., nitrogen atmosphere), and reducing / oxidizing agents, using art-recognized alternatives and employing only conventional experiments, are all within the scope of this application.

[0212] It should be understood that wherever values ​​and ranges are provided herein, all values ​​and ranges covered by such values ​​and ranges are intended to be covered within the scope of this disclosure. Furthermore, all values ​​falling within these ranges, as well as the upper or lower limits of the ranges of values, are also covered by this application.

[0213] The following embodiments further illustrate various aspects of this disclosure. However, they in no way limit the teachings of this disclosure as set forth.

[0214] Example

[0215] The pharmaceutical compositions disclosed herein are further illustrated by the following examples, which should not be construed as further limitations. Unless otherwise stated, practice of this disclosure will employ conventional techniques of organic synthesis and pharmaceutical formulation within the scope of the art.

[0216] The methods for preparing compound 1, the crystalline form of compound 1, and the bioactivity of compound 1 can be found in at least / WO 2016 / 020864, ​​the contents of which are incorporated herein by reference in their entirety. Compound 1 is referred to as Example 9 in WO 2016 / 020864 and shows IC50 values ​​of 1.9 nM and 0.4 nM for PKCα and PKCθ, respectively. 50 Values ​​(Table 2).

[0217] The crystalline form of compound 1 was determined using a Bruker D8 advance X-ray diffractometer or equivalent.

[0218] Example 1. Development of Pharmaceutical Compositions

[0219] In one aspect, the pharmaceutical composition comprising compound 1 is an immediate-release (IR) tablet for oral administration, comprising compound 1 provided in two dose strengths, 100 mg and 300 mg, referred to herein as: Compound 1, 100 mg IR tablets Compound 1, 300 mg IR tablets Compound 1, 100 mg IR tablets are yellow, round, uncoated tablets, and Compound 1, 300 mg IR tablets are yellow, oval, uncoated tablets. In one embodiment, Compound 1, 100 mg IR tablets are round, coated tablets. In one embodiment, Compound 1, 300 mg IR tablets are yellow, oval, coated tablets. In one embodiment, Compound 1, 100 mg IR tablets have a depression on one side. In one embodiment, Compound 1, 300 mg IR tablets have a depression on one side. In one embodiment, Compound 1, 100 mg IR tablets are coated with Opadry. ® Yellow (20A120007) coating. In one embodiment, compound 1, 300 mg IR tablets are coated with Opadry. ® Yellow (20A120007) coating. Compound 1 in crystalline form is used in the following compositions.

[0220] Composition of Compound 1 IR Tablet

[0221] The quantitative composition of Compound 1 IR tablets is presented in Table 1. Compound 1, 100 mg IR tablets and Compound 1, 300 mg IR tablets are dose-proportional.

[0222] Table 1: Quantitative composition of Compound 1 IR tablets

[0223] In one embodiment, the quantitative composition of the Compound 1 IR tablet is as per Table 1A. The Compound 1, 100 mg IR tablet and the Compound 1, 300 mg IR tablet are dose-proportional.

[0224] Table 1A: Quantitative composition of Compound 1 IR tablets

[0225] Screening of superdisintegrants demonstrated that crospovidone was a better disintegrant than crospovidone sodium carboxymethyl cellulose (CCNa). Tablets made of crospovidone sodium showed a significant increase in disintegration time during storage; while tablets made of crospovidone showed no change in disintegration time during storage. Additional feasibility batches were conducted to evaluate the effect of various binders at different levels on disintegration time. Ultrafine hydroxypropyl cellulose (HPCEXF), low viscosity hydroxypropyl methyl cellulose (Methocel E5 Premium LV), and ultralow viscosity hydroxypropyl cellulose (HPC-SL) were evaluated (see AAPS PharmSciTech March 2013;14(1):151-9). Based on disintegration time and processability, HPC-SL was selected as the binder of choice for Compound 1 IR tablets.

[0226] Additional feasibility batches were conducted to evaluate the effects of various surfactants (such as sodium lauryl sulfate (SLS) and poloxamer (Kolliphor P 407)) on the release of Compound 1, and no significant difference in dissolution was found between tablets containing and without surfactants. Therefore, it was determined that surfactants are not required as wetting agents in Compound 1 tablets.

[0227] Further feasibility batches were conducted to assess the effects of granulation fluid level, compound 1 particle size, and compression force on tablet dissolution.

[0228] Based on feasibility batches, it was determined that compound 1 with smaller particle size resulted in better tablet properties and a more robust manufacturing process.

[0229] Example 2. Manufacturing of 100 mg and 300 mg tablets of Compound 1

[0230] To develop the manufacturing process for Compound 1 IR tablets, high-shear wet granulation was chosen. This choice was based on the anticipated high effective dose required to develop high-drug-load formulations. Formulation development focused on selecting the most suitable superdisintegrant, binder, and determining whether a wetting agent was needed.

[0231] Manufacturing formulations for preliminary feasibility development, using HPC EXF as a binder, and CCNa

[0232] The first feasibility batch was conducted using a superdisintegrant (CCNa) and a binder (HPC EXF), with the drug loading fixed at approximately 67%, and SLS included as a wetting agent.

[0233] Table 2. Manufacturing formulations of Compound 1 tablets 300 mg initial feasibility batch, CCNa, and HPC EXF. Granulation fluid (%) dry mix weight

[0234] Manufacturing process for preliminary feasibility development, using HPC EXF as a binder, CCNa

[0235] Granulation: Compound 1, croscarmellose sodium, hydroxypropyl cellulose (EXF), and sodium lauryl sulfate (SLS) were co-sieved through a 20-mesh sieve. The sieved material was loaded into a 1 L RMG bowl and dry-mixed for 0.5 min. Purified water was added to the mixture at a constant rate using a peristaltic pump, and granulation was performed using the parameters listed in Table 3 below.

[0236] Drying and sieving: The wet granules were placed in a disc dryer with an inlet temperature of 60°C for 30 minutes. The semi-dried granules were then ground using a comul FZB-150 mill through a 1.2 mm sieve. The semi-dried granules were further dried until the desired LOD was achieved. The drying parameters are listed in Table 4.

[0237] Table 3: Wet granulation parameters for initial feasibility batches, CCNa, and HPC EXF

[0238] Blending: Microcrystalline cellulose PH102 and cross-linked sodium carboxymethyl cellulose were sieved together through a 30-mesh sieve and then blended with the dried granules at 15 rpm for 10 minutes using a 1 L hopper.

[0239] Lubrication: Magnesium stearate was sieved through a 60-mesh sieve and added to the above blend and mixed at 15 rpm for 3 minutes.

[0240] Table 4: Powder flow characteristics and sieving analysis details of initial feasibility batches, CCNa, and HPC EXF

[0241] Compression: The lubricated blend was compressed into tablets with a target weight of 450 mg using a 15.6 × 7.4 mm oval punch.

[0242] Table 5: Compression parameters for 300 mg Compound 1 tablets, initial feasibility batch, CCNa and HPC EXF The disintegration time was found to be satisfactory in the initial stage. However, tablets stored under ambient conditions for 12 days showed [disintegration time issues]. Increased disintegration time, but no change in hardness.

[0243] Observation: Feasibility batches of wet granulation using intragranular and extragranular cross-linked sodium carboxymethyl cellulose (CCNa) were conducted. Storage under ambient conditions resulted in a significant increase in disintegration time. This increase in disintegration time was attributed to the molecular interaction between the drug substance and CCNa. Therefore, the use of croscarmellose sodium was discontinued, and further formulation development efforts focused on evaluating crospovidone and sodium starch glycolate as suitable disintegrants.

[0244] Evaluation of crospovidone and sodium starch glycolate (SSG)

[0245] Two feasibility test batches were performed using alternative superdisintegrants, namely crospovidone (Polyplasdone XL) and sodium starch glycolate (Explotab). Disintegration times for both batches were measured immediately after manufacturing and immediately after storage under ambient conditions.

[0246] Table 6: Manufacturing formulation of Compound 1 tablets (300 mg) (crospovidone compared to SSG) Granulation fluid (%) dry mix weight Granulation: Compound 1, hydroxypropyl cellulose (EXF), sodium lauryl sulfate (SLS), and crospovidone (Polyplasdone XL) / sodium starch glycolate type A (Explotab) were sieved together through a 20-mesh sieve. The sieved material was loaded into 200 mL of Turbula and dry-mixed for 15 minutes. Due to the small batch size, wet granulation was performed manually with sufficient water to produce the desired granules.

[0247] Blending: Microcrystalline cellulose PH102 and crospovidone (Polyplasdone XL) / sodium starch glycolate type A (Explotab) were sieved together through a 30-mesh sieve. The sieved material and the sieved particles were loaded together into a 0.2 L Turbula chamber and blended at 46 rpm for 10 minutes.

[0248] Lubrication: Magnesium stearate was sieved through a 60-mesh sieve and added to the above blend and mixed at 46 rpm for 0.5 minutes.

[0249] Compression: The lubricated blend is compressed into tablets with a target weight of 450 mg using a 16×6.5 mm capsule punch.

[0250] Table 7: Compression parameters of Compound 1 tablets (300 mg), selection of disintegrant type, and comparison of crospovidone with SSG.

[0251] Table 8: Disintegration times of batches with crospovidone and batches with SSG during storage period No disintegration time was observed in the prototypes of crospovidone and sodium starch glycolate after 11 days of environmental storage. change.

[0252] Drug release profiles, disintegrant selection, CCNa compared to crospovidone compared to SSG

[0253] Table 9: Dissolution profiles of Compound 1 tablets (300 mg), batch selection of disintegrant type, CCNa compared to crospovidone compared to SSG.

[0254] in conclusion: Cross-linked polyvinylpyrrolidone The granulation and compression parameters were satisfactory. Rapid disintegration was observed. Drug release in pH 6.8 phosphate buffer was slightly slower compared to drug release in 0.01 M HCl.

[0255] Sodium starch glycolate The granulation and compression parameters were satisfactory. Rapid disintegration was observed. Drug release in pH 6.8 phosphate buffer was similar to that in 0.01 M HCl.

[0256] Both disintegrants exhibited satisfactory disintegration efficiency compared to the original croscarmellose sodium. No changes in disintegration were observed during storage for tablets containing either croscarmellose or SSG.

[0257] Optimization study of disintegrant levels: crospovidone compared to sodium starch glycolate (SSG)

[0258] To optimize the level of superdisintegrant in Compound 1 tablets, batches were produced with 2% intraparticle and 2% extraparticle disintegrants. For Compound 1, the dissolution of tablets is relatively slower than that of 200 mg powder (PIC) in capsules (i.e., 88% drug release within 5 minutes and 98% drug release within 10 minutes). Therefore, a feasibility batch was executed with 4% w / w intraparticle disintegrant and 2% w / w extraparticle disintegrant to obtain a rapid drug release profile.

[0259] Table 10: Manufacturing formulation of Compound 1 tablets (300 mg) (disintegrant level optimized, crospovidone compared to SSG) Granulation fluid (%) dry mix weight

[0260] Manufacturing process, batch optimization of disintegrant levels, cross-linked polyvinylpyrrolidone compared to SSG

[0261] Granulation: Compound 1, hydroxypropyl cellulose (EXF), sodium lauryl sulfate (SLS), and crospovidone (Polyplasdone XL) / sodium starch glycolate type A (Explotab) were co-sieved through a 20-mesh sieve. The sieved material was loaded into a 1 L RMG bowl and dry-mixed for 5 minutes. Purified water was added to the mixture at a constant rate using a peristaltic pump, and granulation was performed using the parameters listed in Table 11 below.

[0262] Drying and sieving: The wet granules were placed in a disc dryer with an inlet temperature of 60°C for 15 minutes. The semi-dried granules were then ground using a Comil FZB-150 mill through a 1.2 mm sieve. The semi-dried granules were further dried until the LOD reached less than 0.5% w / w at 105°C. The drying parameters are listed in Table 11.

[0263] Table 11: Wet granulation parameters for batches optimized with disintegrant levels, crospovidone compared to SSG

[0264] Blending: Microcrystalline cellulose PH102 and crospovidone (Polyplasdone XL) / sodium starch glycolate type A (Explotab) (SSG) were sieved together through a 30-mesh sieve. The sieved material and the sieved particles were loaded together into a 0.2 L Turbula chamber and blended at 46 rpm for 10 minutes.

[0265] Lubrication: Magnesium stearate was sieved through a 60-mesh sieve and added to the above blend and mixed at 46 rpm for 0.3 minutes.

[0266] Compression: The lubricated blend was compressed into tablets with a target weight of 450 mg using a 17×6.7 mm capsule punch.

[0267] Table 12: Dissolution profiles of 300 mg Compound 1 tablets (disintegrant level optimized, crospovidone compared to SSG)

[0268] Conclusion: The prototypes with optimized disintegrant levels (i.e., 4% in-particle and 2% out-of-particle crosslinked povidone / SSG) resulted in satisfactory granulation and tablet properties. For the SSG prototype, no significant difference in drug release was observed between the 2% and 4% in-particle disintegrants. In pH 6.8 phosphate buffer, the 4% in-particle crosslinked povidone prototype showed improved drug release profiles compared to the 2% in-particle crosslinked povidone batch. However, in 0.01M HCl (pH 2.0), the drug release profiles of the 2% and 4% in-particle disintegrant prototypes were similar.

[0269] It was observed that after 20 days of storage at room temperature, the disintegration time of tablets composed of 4% intraparticle and 2% extraparticle SSG increased from an initial disintegration time of 1'54" min to 2'36" min, and then to 8'14" min. Although the change in disintegration time during storage did not affect the dissolution time, it was suspected that the change in the disintegration time of the SSG prototype would lead to a significant change in the dissolution time with prolonged storage. Therefore, the prototype containing SSG was abandoned.

[0270] Drug release profiles from feasible batches with different granulation fluid levels (i.e., 18%, 20%, and 23% w / w water) showed that tablet hardness directly affects drug release and disintegration time. Low-hardness tablets produced using different granulation fluid levels resulted in very rapid drug release profiles (>90% drug release within 10 minutes). Optimal-hardness tablets produced using different granulation fluid levels also resulted in rapid drug release (>90% drug release within 20 minutes). High-hardness tablets produced using different granulation fluid levels resulted in relatively slower drug release profiles compared to other lower hardness levels (>90% drug release only achieved at 60 minutes). However, optimal-hardness tablets produced at different granulation fluid levels resulted in similar drug release. This confirms that tablet hardness has a greater impact on drug release than granulation fluid level. Therefore, determining an appropriate hardness range before manufacturing is crucial.

[0271] Feasibility of using hydroxypropyl cellulose SL (HPC-SL) as a binder for mass production

[0272] Feasibility batches were performed using HPC-SL as a binder to evaluate different concentrations of cross-linked povidone, primarily to identify the optimal disintegrant concentration (2% vs. 3% cross-linked povidone) leading to satisfactory drug release outcomes. Fine-grained compound 1 (particle size detail: D) was used in these feasibility batches. 10 =24.3 µ, D 50 =83.1 µ, D 90 =211 µ), and tablets were compressed with different compression forces to produce tablets with different hardness values ​​(low, optimal, and high). Drug release profiles of tablets compressed at different compression forces were generated.

[0273] Table 13: Manufacturing formulation of Compound 1 tablets 300 mg, HPC-SL as binder, and fine grade Compound 1 (2% compared to 3% crospovidone) Granulation fluid (%) dry mix weight

[0274] Feasibility study of using HPC-SL as a binder and fine compound 1 (2% compared to 3% crosslinked polyvinyl chloride) Subsequent manufacturing processes

[0275] Granulation: Compound 1, microcrystalline cellulose PH102, crospovidone (Polyplasdone XL), and hydroxypropyl cellulose SL were sieved together through a 30-mesh sieve. The sieved material was loaded into a 4 L RMG bowl and dry-mixed for 10 minutes.

[0276] Drying and sieving: The wet granules were placed in a disc dryer with an inlet temperature of 60°C for 20 minutes. The semi-dried granules were then ground using a 1.143 mm sieve through a comul 193 mill. The semi-dried granules were further dried until the LOD reached less than 2.0% w / w at 105°C.

[0277] Table 14: Wet granulation parameters for feasible batches using HPC-SL as a binder and fine compound 1 (2% vs. 3% crosslinked polyvinyl chloride).

[0278] Lubrication: Magnesium stearate was sieved through a 60-mesh sieve and loaded together with the sieved particles into a 0.2 L Turbula box and mixed at 46 rpm for 0.3 minutes.

[0279] Compression: The lubricated granules were compressed into tablets with different hardness levels using a 14×6.5 mm oval punch, with a target weight of 450 mg.

[0280] Observations and Conclusions: For feasible batches with 2% crospovidone, higher disintegration times were observed for high-hardness tablets, and changes in hardness significantly affected tablet disintegration time. The optimal hardness tablets exhibited slower drug release profiles, with complete drug release observed only at 45 minutes.

[0281] For the feasibility batch with 3% crospovidone, the disintegration time was satisfactory for tablets compressed at different hardness levels. The drug release profile of the optimal hardness tablet was similar to that of the high-hardness tablet. Based on the disintegration time and drug release results, it can be concluded that for the feasibility batch with 3% crospovidone, tablet hardness has minimal impact on drug release. Therefore, 5% HPC-SL and 3% crospovidone were selected for further studies.

[0282] Table 15: Production scale-up of Compound 1 tablets (100 mg and 300 mg) (HPC-SL)

[0283] Dry mixing: Compound 1, microcrystalline cellulose PH102, crospovidone (Polyplasdone XL), and hydroxypropyl cellulose SL were co-sieved through a 30-mesh sieve. The sieved material was loaded into a 6 L RMG bowl and dry-mixed for 10 minutes. Purified water was added to the mixture at a constant rate using a peristaltic pump, and granulation was performed.

[0284] Drying: Load the wet particles into a fluidized bed dryer (GPCG 2) with an inlet temperature of 60°C. Continue drying until the LOD reaches less than 2.0% w / w at 105°C.

[0285] Lubrication: Magnesium stearate is sieved through a 60-mesh sieve and loaded together with the sieved particles into a 5 L box mixer and mixed at 15 rpm for 0.3 minutes.

[0286] compression: 100 mg tablets The lubricated granules were compressed into tablets with different hardness levels using a 7 mm circular punch, with a target tablet weight of 150 mg.

[0287] Description of compressed tablets: Yellow, round, uncoated tablets with flat sides.

[0288] 300 mg tablets The lubricated granules were compressed into tablets with different hardness levels using a 14×6.5 mm oval punch, with a target tablet weight of 450 mg.

[0289] Description of compressed tablets: Yellow, oval, uncoated tablets with the letters GP on one side and a flat surface on the other.

[0290] Table 16: Dissolution curves of Compound 1 tablets (100 mg and 300 mg)

[0291] Physical observations during dissolution testing: Dissolution testing with 100 mg and 300 mg tablets at 60 rpm: Slight adhesion was observed at the initial time point for all units, and cone formation was observed at subsequent time points. Dissolution testing with 100 mg and 300 mg tablets at 75 rpm: Very slight adhesion was observed at the initial time point for all units, but cone formation was not observed.

[0292] Table 17: Dissolution profiles of Compound 1 tablets (100 mg and 300 mg, 062G coli screening batch)

[0293] Observation: During granulation, 27% w / w water was used to reach the desired granulation endpoint. Kneading was performed for 60 seconds, and optimal granule quality was found. The wet material was dried in a Retsch dryer (fluidized bed dryer). After complete drying (LOD less than 2%), the granules were divided into two equal portions, and these two portions were co-milled through a 062R sieve and a 062G sieve, respectively. It was found that the compressibility index and particle size distribution of the sieved particles were similar for batches milled using either the 062R or 062G sieve. Therefore, dry milling can be performed using either the 062G or 062R sieve. The compression parameters for 100 mg and 300 mg strengths were found to be satisfactory. The hardness and DT matched the lead prototype, allowing for batch scale-up. No tendency to stick was observed during the compression of 100 mg and 300 mg tablets of Compound 1.

[0294] Conclusions and Summary

[0295] Based on the research findings, the following key parameters were identified and summarized as follows: Compound 1 Particle size Compared to larger compound 1 particle sizes, smaller compound 1 particle sizes result in satisfactory granulation and compression properties. Granulation and compression are reproducible when using smaller compound 1 particle sizes.

[0296] Disintegrant Feasible batches containing croscarmellose sodium and starch glycolate resulted in a significant increase in disintegration time when stored under ambient conditions. Tablets composed of croscarmellose showed no change in disintegration time after storage under both ambient and accelerated conditions for up to six months. Therefore, croscarmellose was selected as the binder for the production of Compound 1 IR tablets. The optimal level of croscarmellose appears to be at least 3%. A 3% disintegrant level was identified for the production of Compound 1 IR tablets.

[0297] adhesive Several binders were investigated. Feasibility studies included prototypes consisting of HPC EXF, povidone, HPMC E5, and HPC-SL. Tablets composed of povidone exhibited good dissolution properties but high friability. Tablets composed of HPMC E5 showed good tablet hardness and friability but variable dissolution values ​​at different hardness levels. Tablets composed of HPC-SL exhibited optimal hardness and friability values, with fairly consistent dissolution values. Studies of the effects of compression force and compound 1 particle size on tablet dissolution profiles showed that the formulation composed of HPC-SL and 3% crosslinked povidone had a sufficiently wide processing window for large-scale production.

[0298] wetting agentSeveral feasibility batches were conducted to assess whether a wetting agent was needed to promote granulation and dissolution. Results from these feasibility batches, produced with or without SLS and poloxamer, indicated that a wetting agent was not required.

[0299] Granulation fluid level A granulation fluid level of approximately 25% w / w and the use of small-particle compound 1 result in satisfactory granulation and compression properties. In one embodiment, the granulation fluid level is 20-30% w / w.

[0300] compression : 100 mg tablets: Target weight = 150.0 mg Punch = 7 mm, round punch, both sides are flat.

[0301] Target time (DT) = approximately less than 8 minutes (limit: <15 minutes)

[0302] 300 mg tablets: Target weight = 450.0 mg Punch: 14×6.5 mm, oval punch with flat sides. Target time (DT) = less than 8 minutes (limit: <15 minutes)

[0303] Dissolution method: Medium: 0.01M HCl, Apparatus: USP II (paddle type), Rotation speed: 75 rpm, Volume: 900 mL.

[0304] In one embodiment, the quantitative composition of compound 1 IR tablets is as shown in Table 18.

[0305] Table 18: Unit formulations of Compound 1 tablets (100 mg and 300 mg) Add 20% w / w purified water as the standard initial amount for granulation, and the final purity should be determined based on the granulation endpoint. The final amount of water.

[0306] The compositions in Table 18A exhibit improved tablet properties, such as reduced sensitivity to tablet properties, such as hardness and disintegration, and therefore dissolution due to excessive lubrication. In one embodiment, the quantitative composition of Compound 1 IR tablets is as per Table 18A.

[0307] Table 18A: Unit formulations of Compound 1 tablets (100 mg and 300 mg)

[0308] In one embodiment, the quantitative composition of compound 1 IR tablets is as shown in Table 18B.

[0309] Table 18B: Unit formulations of coated compound tablets (100 mg and 300 mg)

[0310] Clinical batch manufacturing procedures and process flow diagram

[0311] Grinding of Compound 1 (applicable only when Compound 1 with a higher particle size is used for granulation)

[0312] The comul U5 with a 024R sieve for one cycle was used for compound 1, and then the resulting material was further ground for one cycle using a 006R sieve (the required further grinding was determined based on the PSD of compound 1 being ground).

[0313] dry mix Compound 1, microcrystalline cellulose PH102, crospovidone (Polyplasdone XL), and hydroxypropyl cellulose SL were sieved together through a 30-mesh sieve.

[0314] The sieved material is loaded into a high-shear granulator and dry-mixed for 10 minutes with a slow impeller speed and the shredder turned off.

[0315] Adhesive addition and kneading Purified water is added to the mixture at a slow impeller and shredder speed using a peristaltic pump with a target addition time of approximately 8 minutes.

[0316] Knead for 1 minute at high impeller and shredder speeds.

[0317] dry The wet particles were loaded into a fluidized bed dryer and dried at an inlet temperature of 60°C. The wet particles were then dried until the LOD reached less than 2.0% w / w.

[0318] Dry grinding Dry particles were ground using a Co-mill U5 sieve with a 062G / 062R sieve.

[0319] lubricating Magnesium stearate was sieved through a 60-mesh sieve into granules, and the resulting material was lubricated for 5 minutes. Note: According to Based on the observation results of GMP clinical batches (lubrication phase), the lubrication time was changed from 5 minutes to 3 minutes.

[0320] Powder flow characteristics Bulk density and tapped density tests and sieve analysis were performed.

[0321] compression

[0322] 100 mg tablets: Target weight: 150 mg Punch: 7 mm, round punch with flat sides.

[0323] Average tablet weight (n=10): 1500 ± 5% (1425 mg to 1575 mg) Single tablet weight: 150 ± 7.5% (139 mg to 161 mg) Hardness: Target size approximately 40N Disintegration time: 8 minutes NMT for compressed settings; 12 minutes NMT for in progress settings.

[0324] Friability: For compression settings, NMT 0.5% w / w; for in-process testing, NMT 1.0% w / w.

[0325] 300 mg tablets: Target weight: 450 mg Punch: 14×6.5 mm, oval punch with flat sides.

[0326] Average tablet weight (n=10): 4500 ± 5% (4275 mg to 4725 mg) Single tablet weight: 450 ± 7.5% (417 mg to 483 mg) Hardness: Target value approximately 100N Disintegration time: 8 minutes NMT for compressed settings; 12 minutes NMT for in progress settings.

[0327] Friability: For compression settings, NMT 0.5% w / w; for in-process testing, NMT 1.0% w / w.

[0328] Manufacturing process flow chart shown in Figure 3 middle.

[0329] In one implementation, USP / NF is a quality reference for hydroxypropyl cellulose, microcrystalline cellulose, crospovidone, and magnesium stearate. "USP" refers to the United States Pharmacopeia. "NF" refers to the National Formulary. In one implementation, Ph. Eur. is a quality reference for hydroxypropyl cellulose, microcrystalline cellulose, crospovidone, and magnesium stearate. "Ph. Eur." refers to the European Pharmacopoeia.

[0330] Example 3. Alternative procedure for preparing the crystalline form of compound 1

[0331] Ethanol (714 g), 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazin-2-carboxamide (compound 1) (210 g, 1.00 equivalent) and water (861 g) were added to reactor (R1). The slurry was heated to 55°C for 1 hour to obtain a clear solution, which was then filtered into reactor 2 (R2). R1 ​​was washed with a mixture of ethanol and water (107 g, EtOH / water weight ratio of 0.23:0.28) and then filtered into R2. The solution in R2 was adjusted to 45°C and then cooled to 35°C over 1 hour. 3-Amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazin-2-carboxamide (compound 1, 1.1 g) seed crystals were then added to R2. The resulting slurry in R2 was stirred at 35°C for 5 hours, and then water (1680 g) was added over 8 hours at 35°C. The contents of R2 were cooled to 5°C over 5 hours and then stirred at 5°C for 3 hours. The slurry was then wet-milled until the target particle size distribution (d50 range = 30-65 µm) was achieved. The slurry was filtered, and the resulting solid was washed with water (420 g). The solid was then dried under vacuum at 55 °C for 20 hours to obtain a pale yellow solid, 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazin-2-carboxamide (compound 1) (190.7 g, 99.9% purity, 99.8% by weight, 90.6% yield). MS (ESI, m / z): 473.2024 [M+H] + . 1 H NMR (400 MHz, DMSO-) d6) δ = 10.60 (s, 1H), 8.96 (dd, J = 4.7, 1.0 Hz, 1H), 8.75(s, 1H), 8.40 (dd, J = 8.1, 1.3 Hz, 1H), 8.10 (dd, J = 4.8, 1.6 Hz, 1H), 8.05(br. s, 2H), 7.72 (dd, J = 7.9, 4.8 Hz, 1H), 7.55 (dd, J = 7.9, 1.6 Hz, 1H), 7.14 (dd, J = 7.8, 4.8 Hz, 1H), 2.90 - 2.84 (m, 2H), 2.67 - 2.63 (m, 2H), 1.24 - 1.12 (m, 6H), 0.60 (s, 3H). XRPD: Figure 1 (Using Cu-Kα radiation). DSC: Figure 2 .

[0332] This document describes specific embodiments of the invention, including the best mode known to the inventors for carrying out the invention. Variations of the disclosed embodiments will be apparent to those skilled in the art upon reading the foregoing description, and it is expected that such variations will be appropriately adopted by those skilled in the art. Therefore, the invention is intended to be practiced in a manner different from that specifically described herein, and the invention includes all modifications and equivalents of the subject matter set forth in the appended claims as permitted by applicable law. Furthermore, unless otherwise indicated herein or clearly contradicted by the context, the invention covers any combination of the foregoing elements in all its possible variations.

[0333] All patent applications, patents, and print publications cited herein are incorporated herein in their entirety, except for any definitions, subject matter disclaimers, or denials, and unless the incorporated material is inconsistent with the express disclosure herein, in which case the language of this disclosure shall prevail.

Claims

1. A pharmaceutical composition comprising: Super disintegrant; Adhesive; Lubricant; filler; And compound 1: (1) Or its pharmaceutically acceptable salt.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises about 1-5% w / w of a superdisintegrant.

3. The pharmaceutical composition of any one of claims 1 or 2, wherein the pharmaceutical composition comprises about 3-7% w / w of a binder.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition comprises about 0.25-3% w / w of lubricant.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition comprises about 15-35% w / w of filler.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the pharmaceutical composition comprises about 45-85% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to any one of claims 1 to 6, comprising: Approximately 2-4% w / w of superdisintegrant; Approximately 4-6% w / w of binder; Approximately 20-30% w / w of filler; Lubricant of approximately 0.25-2% w / w; and Approximately 50-80% w / w of compound 1 or its pharmaceutically acceptable salt.

8. The pharmaceutical composition according to any one of claims 1 to 7, comprising: Approximately 3% w / w of superdisintegrant; Approximately 5% w / w of adhesive; Approximately 25% w / w of filler; Approximately 0.50% w / w of lubricant; and Approximately 67% w / w of compound 1 or its pharmaceutically acceptable salt.

9. The pharmaceutical composition according to any one of claims 1 to 7, comprising: 3% w / w superdisintegrant; 5% w / w adhesive; 24.83% w / w filler; 0.50% w / w lubricant; and 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the superdisintegrant is crospovidone.

11. The pharmaceutical composition of any one of claims 1 to 10, wherein the binder is hydroxypropyl cellulose.

12. The pharmaceutical composition of claim 11, wherein the hydroxypropyl cellulose is ultra-low viscosity hydroxypropyl cellulose.

13. The pharmaceutical composition of any one of claims 1 to 12, wherein the filler is microcrystalline cellulose.

14. The pharmaceutical composition of any one of claims 1 to 13, wherein the lubricant is magnesium stearate.

15. The pharmaceutical composition according to any one of claims 1 to 7 and 10 to 13, comprising: Approximately 2-4% w / w crosslinked polyvinylpyrrolidone; Approximately 4-6% w / w ultra-low viscosity hydroxypropyl cellulose; Approximately 20-30% w / w microcrystalline cellulose; Approximately 0.25-2% w / w magnesium stearate; and Approximately 50-80% w / w of compound 1 or its pharmaceutically acceptable salt.

16. The pharmaceutical composition according to any one of claims 1 to 8 and 10 to 15, comprising: Approximately 3% w / w crosslinked polyvinylpyrrolidone; Approximately 5% w / w ultra-low viscosity hydroxypropyl cellulose; Approximately 25% w / w microcrystalline cellulose; Approximately 0.50% w / w magnesium stearate; and Approximately 67% w / w of compound 1 or its pharmaceutically acceptable salt.

17. The pharmaceutical composition according to any one of claims 1 to 7 and 9 to 14, comprising: 3% w / w crosslinked polyvinylpyrrolidone; 5% w / w ultra-low viscosity hydroxypropyl cellulose; 24.83% w / w microcrystalline cellulose; 0.50% w / w magnesium stearate; and 66.67% w / w of compound 1 or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition of any one of claims 1 to 17, wherein the pharmaceutical composition comprises compound 1.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein said compound 1 is in crystalline form.

20. The pharmaceutical composition of claim 19, wherein the compound 1 is in crystalline form, characterized in that it comprises an XRPD diffraction pattern of at least three or at least four peaks, expressed in °-2θ, at angles (±0.2°) selected from the group consisting of about 8.3, 15.0, 16.6, 25.0, 23.1, 11.8, 22.4 and 23.

7.

21. The pharmaceutical composition of claim 19, wherein the compound 1 is in crystalline form, characterized by the XRPD diffraction pattern depicted in FIG1.

22. The pharmaceutical composition of any one of claims 1 to 21, wherein the pharmaceutical composition is in tablet form.

23. The pharmaceutical composition of any one of claims 1 to 22, wherein the tablet is an immediate-release form.

24. The pharmaceutical composition of claim 22 or 23, wherein the tablet is film-coated.

25. The pharmaceutical composition of any one of claims 22 to 24, wherein the tablet has a disintegration time of less than 10 minutes.

26. The pharmaceutical composition of any one of claims 22 to 25, wherein the tablet has a friability of less than 0.5% w / w.

27. The pharmaceutical composition of any one of claims 22 to 26, wherein the dissolution rate of the tablet is greater than 80% at 15 minutes.

28. The pharmaceutical composition of any one of claims 1 to 27, wherein the pharmaceutical composition comprises about 25 mg to 400 mg of free base equivalent of compound 1.

29. The pharmaceutical composition of any one of claims 1 to 28, wherein the pharmaceutical composition comprises 100 mg of free base equivalent of compound 1.

30. The pharmaceutical composition of any one of claims 1 to 28, wherein the pharmaceutical composition comprises 300 mg of free base equivalent of compound 1.

31. The pharmaceutical composition according to any one of claims 1 to 30, wherein the pharmaceutical composition is administered orally.

32. A method of treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition as described in any one of claims 1 to 31.

33. The method of claim 32, wherein the cancer is uveal melanoma.

34. The method of claim 32 or 33, wherein the cancer is metastatic uveal melanoma.

35. The method of any one of claims 32 to 34, wherein the cancer carries a GNAQ mutation.

36. The method of any one of claims 32 to 35, wherein the cancer carries a GNA11 mutation.

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