Methods of treatment of tuberous sclerosis complex

Abstract

To provide novel methods of treatment of tuberous sclerosis complex (TSC).SOLUTION: Provided herein are methods of treating tuberous sclerosis complex in a subject in need thereof by administering to the subject a composition comprising an mGlu5 negative allosteric modulator (NAM) having the structure of Formula (I).SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 63 / 035,313, filed June 5, 2020, the contents of which are incorporated herein by reference in their entirety.

[0002] Field The present disclosure relates to the field of medicine and to the treatment of medical conditions associated with tuberous sclerosis. More specifically, the present disclosure relates to the use of a composition comprising 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine or a pharmaceutically acceptable salt thereof in the treatment or amelioration of medical conditions associated with tuberous sclerosis. [Background technology]

[0003] background Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the growth of numerous noncancerous tumors in many parts of the body, including the skin, brain, kidneys, and other organs. TSC can cause developmental problems and, in some cases, lead to significant health challenges. TSC is typically caused by mutations in the TSC1 or TSC2 genes, which encode the hamartin and tuberin proteins, respectively. Mutations in TSC2 account for the majority of cases and tend to cause more severe symptoms.

[0004] There is currently no cure for TSC. While medications such as antiepileptic drugs can help treat certain types of disorders associated with TSC (e.g., seizures), some of these medications have significant side effects that limit their medical use.

[0005] Therefore, there is an unmet medical need to develop novel methods for treating TSC without significant side effects. Summary of the Invention

[0006] overview In one aspect, In need thereof, a compound of formula I: administering a composition containing a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; Provided herein are methods for treating a medical condition associated with tuberous sclerosis complex (TSC), comprising:

[0007] In some embodiments, treating employs a composition comprising a crystalline anhydrous form of the monosulfate salt of the compound of Formula I (Form A), which has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1. Specifically, Form A has a 2θ (two-theta) pattern of Cu Kα Crystalline Form A is characterized by the following X-ray powder diffraction peaks obtained by differential scanning calorimetry (DSC) analysis: 9.8±0.2°, 13.4±0.2°, 14.2±0.2°, 18.1±0.2°, 18.9±0.2°, 19.6±0.2°, 22.6±0.2°, 22.9±0.2°, 25.7±0.2°, 27.1±0.2°, and 29.9±0.2°. m is typically about 180 to 190°C.

[0008] In some embodiments, treating employs a composition comprising the crystalline monohydrate form of the monosulfate salt of the compound of Formula I (Form B), which Form B has an XRPD pattern substantially as shown in Figure 2. Crystalline Form B exhibits a T m is typically around 60-70°C.

[0009] In some embodiments, treating employs a composition comprising a crystalline hemihydrate form of the hemisulfate salt of the compound of Formula I (Form C), which has an XRPD pattern substantially as shown in Figure 3. Crystalline Form C exhibits a T m is typically around 90-100°C.

[0010] In some embodiments, the composition used is a tablet formulation, such as a controlled release tablet formulation, as defined herein, or a matrix pellet formulation, such as a controlled release matrix pellet formulation, which may be encapsulated.

[0011] In some embodiments, treating uses a composition comprising a pharmaceutically acceptable salt of a compound of Formula I, wherein the salt is 90% by weight or more (e.g., 95% by weight or more or 99% by weight or more) in crystalline Form A, based on the total weight of the salt present in the composition.

[0012] The present disclosure provides compounds of formula I: 1. A solid pharmaceutical composition comprising a solid form of a compound of TIFF2025122066000002.tif33128, The solid form has a 2θ (two theta) Kα The following XRPD peaks are obtained by the line: 9.8±0.2°, 13.4±0.2°, 14.2±0.2°, 18.1±0.2°, 18.9±0.2°, 19.6±0.2°, 22.6±0.2°, 22.9±0.2°, 25.7±0.2°, 27.1±0.2°, and 29.9±0.2° and having a median particle size (Dv50) of about 100 μm or less; the solid pharmaceutical composition is in the form of a matrix pellet; Also included are solid pharmaceutical compositions. In some embodiments, the solid form has a particle size of 47 μm or less (e.g., about 25 μm or less, or about 10 μm or less).

[0013] In some embodiments, the pharmaceutical composition has a Cu 2θ (two theta) Kα Form A monosulfate salt characterized by the following XRPD peaks obtained by lines: 9.8±0.2°, 13.4±0.2°, 14.2±0.2°, 18.1±0.2°, 18.9±0.2°, 19.6±0.2°, 22.6±0.2°, 22.9±0.2°, 25.7±0.2°, 27.1±0.2°, and 29.9±0.2°.

[0014] In some embodiments, the pharmaceutical composition comprises Form A of the monosulfate salt, characterized by an XRPD pattern substantially as shown in FIG.

[0015] The present disclosure provides compounds of formula I: 1. A method for preparing matrix pellets comprising the crystalline anhydrous form of the monosulfate salt of the compound of TIFF2025122066000003.tif27128 (Form A), comprising: granulating Form A of the monosulfate salt and one or more polymers with purified water to form a mixture; extruding, spheronizing, drying and sieving the mixture to obtain a solid; and mixing said solid with other pharmaceutical excipients to obtain matrix pellets. Also included is a method comprising:

[0016] In some embodiments, the method of preparation further comprises filling the matrix pellets into a capsule to form a matrix pellet capsule. In some embodiments, the one or more polymers are selected from the group consisting of cellulose, such as microcrystalline cellulose, methacrylic acid copolymer, and hypromellose. In some embodiments, the remaining pharmaceutical excipient is talc.

[0017] In another aspect, the method comprises administering to a subject in need thereof a composition comprising a therapeutically effective amount of an mGlu5 negative allosteric modulator (NAM) or a pharmaceutically acceptable salt thereof, wherein the mGlu5 NAM has Formula I: Provided herein is a method for treating TSC, the compound of TIFF2025122066000004.tif33128.

[0018] The details of one or more embodiments of the disclosure are set forth in the description below. Other features, objects, and advantages of the disclosure will become apparent from the following drawings, description, and appended claims. [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 shows an exemplary XRPD pattern of the crystalline anhydrous form of the monosulfate salt of the compound of Formula I (Form A). [Figure 2] FIG. 2 shows an exemplary XRPD pattern of the crystalline monohydrate form of the monosulfate salt of the compound of Formula I (Form B). [Figure 3] FIG. 3 shows an exemplary XRPD pattern of the crystalline hemihydrate form of the hemisulfate salt of the compound of Formula I (Form C). DETAILED DESCRIPTION OF THE INVENTION

[0020] Detailed Description As generally described herein, the present disclosure provides methods of treating a medical condition associated with tuberous sclerosis complex (TSC) in a subject in need thereof. The present disclosure also describes treating a medical condition associated with TSC by using a particular crystalline form of a pharmaceutically acceptable salt of the compound of Formula I. Additionally, the present disclosure provides a solid form of a crystalline anhydrous form of the monosulfate salt of the compound of Formula I (Form A) having a particle size (Dv50) of about 100 μm or less (e.g., less than 47 μm, or 10 μm or less).

[0021] definition To facilitate understanding of the present invention, several terms and phrases are defined below.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those usually understood by those skilled in the art to which this invention belongs. Unless otherwise defined, all abbreviations used herein have their conventional meaning in the chemical and biological fields. The chemical structures and formulas described herein are constructed according to the standard rules of chemical valence known in the chemical field.

[0023] Throughout the description, when compositions are described as having, including, or comprising particular ingredients, or when processes and methods are described as having, including, or comprising particular steps, it is further contemplated that there are compositions of the invention that consist essentially of or consist of the recited ingredients, and that there are processes and methods of the invention that consist essentially of or consist of the recited processing steps.

[0024] When an application refers to an element or component as being included in and / or selected from a list of stated elements or components, it should be understood that the element or component can be any one of the stated elements or components, or the element or component can be selected from a group consisting of two or more of the stated elements or components.

[0025] Furthermore, it should be understood that the elements and / or features of the compositions or methods described herein, whether express or implied herein, can be combined in various ways without departing from the spirit and scope of the present invention. For example, when a particular compound is referred to, that compound can be used in various embodiments of the compositions of the present invention and / or in the methods of the present invention, unless the context indicates otherwise. In other words, although embodiments have been described and illustrated herein in a manner that allows a clear and concise application to be written and drawn, it is intended and will be recognized that the embodiments may be combined or separated in various ways without departing from the present teachings and invention. For example, it will be recognized that all features described and illustrated herein may be applicable to all aspects of the invention described and illustrated herein.

[0026] As used in this disclosure, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context requires otherwise. By way of example, "an element" means one element or more than one element.

[0027] The term "and / or" is used in this disclosure to mean either "and" or "or" unless otherwise indicated.

[0028] The phrase "at least one of" should be understood to include each of the listed objects that follow it individually, and various combinations of two or more of the listed objects, unless the context and usage dictate otherwise. The phrase "and / or" in connection with more than two listed objects should be understood to have the same meaning, unless the context dictates otherwise.

[0029] The use of the terms "comprise," "comprises," "comprising," "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing," including grammatical equivalents thereof, should generally be understood to be open-ended and open-ended, e.g., not excluding additional, unrecited elements or steps, unless otherwise specifically recited or understood from the context.

[0030] When the term "about" is used before a quantitative value, the present invention also includes the specific quantitative value itself, unless otherwise specifically stated. As used herein, the term "about" refers to a ±10% variation from the nominal value, unless otherwise indicated or inferred from the context.

[0031] At various places herein, variables or parameters are disclosed in groups or ranges. The description is specifically intended to include every individual subcombination of the members of such groups and ranges. For example, integers in the range of 0 to 40 are specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and integers in the range of 1 to 20 are specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0032] Any examples or use of exemplary language herein, such as "such as" or "including," are intended solely to better describe the invention and do not pose a limitation on the scope of the invention unless otherwise recited in the appended claims. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0033] As a general matter, percentages of compositions specified are by weight unless otherwise specified. Furthermore, if a variable is not accompanied by a definition, the preceding definition of the variable will prevail.

[0034] As used herein, a "composition" or "pharmaceutical composition" or "pharmaceutical formulation" refers to a combination of an active agent with an inert or active excipient or carrier that makes the composition particularly suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0035] "Pharmaceutically acceptable" refers to compounds, molecular entities, compositions, materials and / or dosage forms that do not produce adverse, allergic, or other unintended reactions when administered to animals or humans, as appropriate, and / or that are approved or approvable by a federal or state government regulatory agency or a corresponding agency in a country other than the United States, or that are listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, and more particularly in humans.

[0036] As used herein, "pharmaceutically acceptable salt" refers to any salt of an acidic or basic group which may be present in a compound of the present invention (e.g., a compound of Formula I), which is compatible with pharmaceutical administration.

[0037] Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0038] Examples of bases are alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and bases where W is C 1~4 Alkyl group of formula NW4 + and the like.

[0039] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, monosulfate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include Na + , K. + , Ca 2+ , NH4 + , and NW4 + (Where W is C 1~4 and the anion of a compound of the present invention combined with a suitable cation such as a cation group (which may be an alkyl group).

[0040] For therapeutic use, salts of the compounds of the invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0041] As used herein, "pharmaceutically acceptable excipient" refers to a substance that aids in the administration and / or absorption of an active agent to a subject and can be included in the compositions of the present invention without causing significant adverse toxic effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions such as phosphate-buffered saline, emulsions (e.g., oil / water or water / oil emulsions), lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and dyes. Such preparations are sterilized and, if desired, may be mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents that do not adversely react with the compounds of the present invention. For examples of excipients, see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0042] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly)) and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0043] As used herein, "solid dosage form" means a pharmaceutical dose in solid form, for example, tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalants, and chewables.

[0044] As used herein, "administering" refers to oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or subcutaneous administration to a subject, or implantation of a sustained-release device, e.g., a mini-osmotic pump. Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous injection, transdermal patches, and the like.

[0045] "Co-administered" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutic agents (e.g., anti-cancer agents, chemotherapeutic agents, or treatments for neurodegenerative diseases). The compound of Formula I or a pharmaceutically acceptable salt thereof can be administered to a patient alone or simultaneously. Co-administration includes simultaneous or sequential administration of compounds individually or in combination (multiple compounds or agents). Thus, if desired, the preparation can also be combined with other active substances (e.g., to reduce metabolic degradation).

[0046] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" include actions taken while a subject is suffering from a specified disease, disorder, or condition that reduce the severity of the disease, disorder, or condition or slow or delay the progression of the disease, disorder, or condition (e.g., "therapeutic treatment"). As used herein, "treat," "treating," and "treatment" can include any effect that results in the improvement of a condition, disease, disorder, etc., or one or more symptoms thereof, e.g., alleviating, reducing, modulating, ameliorating, or eliminating. Treating can be curing, improving, or at least partially ameliorating a disorder.

[0047] As used herein, the phrase "therapeutically effective amount" refers to the amount of a compound (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof that produces the biological or medical response of a tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or other clinician. The compounds described in this disclosure or their pharmaceutically acceptable salts may be administered in therapeutically effective amounts to treat diseases. A therapeutically effective amount of a compound or its pharmaceutically acceptable salt may be the amount necessary to achieve the desired therapeutic and / or prophylactic effect, such as an amount that results in the alleviation of symptoms of a disease such as TSC.

[0048] Tuberous sclerosis complex (TSC) is a rare, multisystem, genetic disorder that causes benign tumors to grow in the brain and other vital organs, such as the kidneys, heart, eyes, lungs, and skin. TSC usually affects the central nervous system, resulting in a combination of symptoms, including seizures, developmental delay, behavioral disorders, skin abnormalities, and kidney disease. See, e.g., https: / / www.ninds.nih.gov / Disorders / Patient-Caregiver-Education / Fact-Sheets / Tuberous-Sclerosis-Fact-Sheet.

[0049] compound Formula I shown below: The compound of TIFF2025122066000005.tif27128 is an mGlu5 negative allosteric modulator (NAM), also known as 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine.

[0050] Methods for chemically synthesizing compounds of Formula I (including Example 1 provided herein) are described in US Pat. No. 7,332,510, which is incorporated by reference in its entirety.

[0051] The compounds of Formula I described herein should be understood to include crystalline solid forms of either the free base or pharmaceutically acceptable salts of the compounds of Formula I described herein.

[0052] In certain embodiments, the pharmaceutically acceptable salt of the compound of Formula I can be a salt of the compound of Formula I with a physiologically compatible mineral acid such as hydrochloric acid, sulfuric acid, sulfurous acid, or phosphoric acid, or with an organic acid such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, or salicylic acid. Exemplary pharmaceutically acceptable salts of the compound of Formula I are monosulfate or hemisulfate salts.

[0053] In certain embodiments, the pharmaceutically acceptable salt of the compound of Formula I is a monosulfate or hemisulfate salt, respectively, in hydrate or anhydrous form (e.g., anhydrous, hemihydrate, or monohydrate).

[0054] In certain embodiments, the pharmaceutically acceptable salt of the compound of Formula I is in crystalline or amorphous form.

[0055] In some embodiments, the compound is a crystalline anhydrous form of the monosulfate salt of the compound of Formula I (Form A) having an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1. In some embodiments, Form A has a 2θ (two-theta) pattern of Cu Kα The crystalline form A is characterized by at least three peaks selected from the following X-ray powder diffraction peaks obtained by DSC analysis: 9.8±0.2°, 13.4±0.2°, 14.2±0.2°, 18.1±0.2°, 18.9±0.2°, 19.6±0.2°, 22.6±0.2°, 22.9±0.2°, 25.7±0.2°, 27.1±0.2°, and 29.9±0.2°. The crystalline form A has a T mis typically about 180-190° C. In some embodiments, Form A has peaks of 3068, 2730, 2618, 2236, 2213, 1628, 1587, 1569, 1518, 1384, 1374, 1295, 1236, 1168, 1157, 1116, 1064, 1019, 902, 855, 786, and 674 cm -1 (±3cm -1 ) is characterized by an infrared spectrum with a sharp band at

[0056] In some embodiments, the compound is a crystalline monohydrate form of the monosulfate salt of the compound of Formula I (Form B), having an XRPD pattern substantially as shown in Figure 2. Crystalline Form B has a T m is typically around 60-70°C.

[0057] In some embodiments, the compound is a crystalline hemihydrate form of the hemisulfate salt of the compound of Formula I (Form C), having an XRPD pattern substantially as shown in Figure 3. Crystalline Form C has a T m is typically around 90-100°C.

[0058] Pharmaceutical Compositions In one aspect, the present disclosure relates to a composition, such as a pharmaceutical composition, comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for the treatment of TSC in a subject in need thereof. In various embodiments, the composition is a solid pharmaceutical composition.

[0059] In various embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein is from about 0.01 mg to about 30 mg, from about 0.05 mg to about 20 mg, from about 0.1 mg to about 10 mg, from about 0.5 mg to about 10 mg, from about 1 mg to about 10 mg, from about 2 mg to about 10 mg, from about 3 mg to about 10 mg, from about 4 mg to about 10 mg, from about 5 mg to about 10 mg, from about 6 mg to about 10 mg, from about 7 mg to about 10 mg, from about 8 mg to about 10 mg, from about 9 mg to about 10 mg, from about 1 mg to about 9 mg, from about 1 mg to about 8 mg, from about 1 mg to about 7 mg, from about 1 mg to about 6 mg, mg, about 1 mg to about 5 mg, about 1 mg to about 4.5 mg, about 1 mg to about 4 mg, about 1 mg to about 3.5 mg, about 1 mg to about 3 mg, about 1 mg to about 2.5 mg, about 1 mg to about 2 mg, about 1 mg to about 1.5 mg, about 1.5 mg to about 9 mg, about 1.5 mg to about 8 mg, about 1.5 mg ~7mg, 1.5mg~6mg, 1.5mg~5mg, 1.5mg~4.5mg, 1.5mg~4mg, 1.5mg~3.5mg, 1.5mg~3mg, 1.5mg~2.5mg, 1.5mg~2mg, 2mg~9mg, 2mg ~Approx. 8mg, approx. 2mg ~ approx. 7mg, approx. 2mg ~ approx. 6mg, approx. 2mg ~ approx. 5mg, approx. 2mg ~ approx. 4.5mg, approx. 2mg ~ approx. 4mg, approx. 2mg ~ approx. 3.5mg, approx. g ~ about 7mg, about 2.5mg - about 6mg, about 2.5mg - about 5mg, about 2.5mg - about 4.5mg, about 2.5mg - about 4mg, about 2.5mg - about 3.5mg, about 2.5mg - about 3mg, about 3mg - about 9mg, about 3mg - about 8mg, about 3mg - about 7mg, about 3mg - about 6mg , about 3 mg to about 5 mg, about 3 mg to about 4.5 mg, about 3 mg to about 4 mg, about 3 mg to about 3.5 mg, about 3.5 mg to about 9 mg, about 3.5 mg to about 8 mg, about 3.5 mg to about 7 mg, about 3.5 mg to about 6 mg, about 3.5 mg to about 5 mg, about 3.5 mg to about 4.5 mg, about 3. 5mg to about 4mg, about 4mg to about 9mg, about 4mg to about 8mg, about 4mg to about 7mg, about 4mg to about 6mg, about 4mg to about 5mg, about 4mg to about 4.5mg, about 4.5mg to about 9mg, about 4.5mg to about 8mg, about 4.5mg to about 7mg, about 4.5mg to about 6mg, about 4.It may be 5 mg to about 5 mg, about 5 mg to about 9 mg, about 5 mg to about 8 mg, about 5 mg to about 7 mg, about 5 mg to about 6 mg, about 6 mg to about 9 mg, about 6 mg to about 8 mg, about 6 mg to about 7 mg, about 7 mg to about 9 mg, about 7 mg to about 8 mg, or about 8 mg to about 9 mg.

[0060] In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be from about 0.1 mg to about 1.5 mg.

[0061] In various embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein can be about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

[0062] In certain embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein can be from about 0.1 mg to about 0.2 mg (e.g., about 0.13 mg).

[0063] In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be from about 0.2 mg to about 0.3 mg (e.g., about 0.26 mg).

[0064] In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be from about 0.6 mg to about 0.7 mg (e.g., about 0.65 mg).

[0065] In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be from about 1.2 mg to about 1.4 mg (eg, about 1.3 mg).

[0066] In certain embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein can be about 1 mg to about 4 mg. In certain embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein can be about 1 mg to about 3 mg. In certain embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein can be about 1.5 mg to about 4.5 mg. In certain embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein can be about 1.5 mg to about 3.5 mg. In certain embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein can be about 3.5 mg, about 3.0 mg, about 2.5 mg, about 2.0 mg, about 1.5 mg, or about 1.0 mg. In certain embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein can be about 5.0 mg, about 4.5 mg, about 4.0 mg, about 3.5 mg, about 3.0 mg, about 2.5 mg, about 2.0 mg, about 1.5 mg, about 1.0 mg, or about 0.5 mg.

[0067] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.01% to about 20%, about 0.05% to about 15%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.1% to about 1%, or about 0.1% to about 0.5% by weight, based on the total weight of the composition.

[0068] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.05% to about 15% by weight.

[0069] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.1% to about 0.5% by weight.

[0070] In various embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I. In some embodiments, the pharmaceutically acceptable salt of a compound of Formula I can be a salt of a compound of Formula I with a physiologically compatible mineral acid, such as hydrochloric acid, sulfuric acid, sulfurous acid, or phosphoric acid, or with an organic acid, such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, or salicylic acid.

[0071] In certain embodiments, the pharmaceutically acceptable salt of the compound of Formula I is a monosulfate or hemisulfate salt, respectively, in hydrate or anhydrous form (e.g., anhydrous, hemihydrate, or monohydrate).

[0072] In certain embodiments, the pharmaceutically acceptable salt of the compound of Formula I is in crystalline or amorphous form.

[0073] In certain embodiments, the pharmaceutical compositions described herein comprise a crystalline anhydrous form of the monosulfate salt of the compound of Formula I (Form A), having an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1. Crystalline Form A has a T m is typically about 180 to 190°C (e.g., 180±1°C, 182±1°C, 184±1°C, 186±1°C, 188±1°C, or 190±1°C).

[0074] In some embodiments, the pharmaceutical compositions described herein comprise a crystalline monohydrate form of the monosulfate salt of the compound of Formula I (Form B), having an XRPD pattern substantially as shown in Figure 2. Crystalline Form B has a T m is typically about 60 to 70°C (e.g., 60±1°C, 62±1°C, 64±1°C, 66±1°C, 68±1°C, or 70±1°C).

[0075] In some embodiments, the pharmaceutical compositions described herein comprise a crystalline hemihydrate form of the hemisulfate salt of the compound of Formula I (Form C), having an XRPD pattern substantially as shown in Figure 3. Crystalline Form C has a T m is typically about 90 to 100°C (e.g., 90±1°C, 92±1°C, 94±1°C, 96±1°C, 98±1°C, or 100±1°C).

[0076] In certain embodiments, the pharmaceutical compositions described herein comprise at least one of the following: 2730, 2592, 2219, 1633, 1586, 1570, 1513, 1375, 1343, 1293, 1226, 1157, 1130, 1084, 1040, 986, 903, 848, 788, 712, and 670 cm -1 (±3cm -1 ) in the infrared spectrum, and the amorphous form of the monosulfate salt of the compound of formula I.

[0077] In some embodiments, the pharmaceutical composition is a tablet formulation, such as a controlled-release tablet formulation, or a matrix pellet formulation, such as a controlled-release matrix pellet formulation that can be encapsulated.As used herein, " controlled-release formulation" or " controlled-release dosage form" refers to a mechanism that delivers drug after its administration later (delayed-release dosage form) or for a prolonged period (extended-release dosage form) (as opposed to immediate-release dosage form).See Perrie et al., Pharmaceutics: Drug Delivery and Targeting (2nd), 2012, 7-13.

[0078] In certain embodiments, the pharmaceutical composition is a encapsulated controlled-release matrix pellet formulation in which the compound of Formula I or a pharmaceutically acceptable salt thereof is present in an amount of about 0.05 mg to about 20 mg (e.g., about 0.1 mg to about 0.2 mg, about 0.2 mg to about 0.3 mg, about 0.6 mg to about 0.7 mg, or about 1.2 mg to about 1.4 mg).

[0079] In certain embodiments, the pharmaceutical composition is a controlled-release pellet formulation encapsulated in an capsule, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.01% to about 20% by weight (e.g., about 0.05% to about 15% by weight, about 0.1% to about 1% by weight, or about 0.1% to about 0.5% by weight) based on the total weight of the composition.

[0080] In certain embodiments, the pharmaceutical compositions described herein comprise a crystalline anhydrous form of the monosulfate salt of the compound of Formula I (Form A), having an XRPD pattern substantially as shown in Figure 1; and Form A of the monosulfate salt is present in the composition in an amount of from about 0.05 mg to about 20 mg (e.g., from about 0.1 mg to about 0.2 mg, from about 0.2 mg to about 0.3 mg, from about 0.6 mg to about 0.7 mg, or from about 1.2 mg to about 1.4 mg).

[0081] In certain embodiments, the pharmaceutical compositions described herein comprise a crystalline anhydrous form of the monosulfate salt of the compound of Formula I (Form A), having an XRPD pattern substantially as shown in Figure 1; and Form A of the monosulfate salt is present in the composition in an amount of about 0.01% to about 20% by weight (e.g., about 0.05% to about 15% by weight, about 0.1% to about 1% by weight, or about 0.1% to about 0.5% by weight), based on the total weight of the composition.

[0082] As described herein, the present disclosure includes a solid pharmaceutical composition comprising a solid form of the compound of Formula I, i.e., a crystalline anhydrous form of the monosulfate salt of the compound of Formula I (Form A); the composition is in the form of matrix pellets, and the solid form has an average particle size (Dv50) of about 100 μm or less. Dv50 can be determined by LA-950 laser diffraction. See https: / / static.horiba.com / fileadmin / Horiba / Products / Scientific / Particle_Characterization / Downloads / Technical_Notes / TN159_LA-950_Laser_Diffraction_Technique.pdf.

[0083] In various embodiments, the pharmaceutical composition comprises matrix pellets in a solid form having a particle size of less than 47 μm, less than 45 μm, less than 40 μm, less than 35 μm, less than 30 μm, less than 25 μm, less than 20 μm, less than 15 μm, less than 10 μm, or less than 5 μm. In certain embodiments, the solid form has a particle size of about 10 μm or less (e.g., about 10 μm, about 9 μm, about 8 μm, about 7 μm, about 6 μm, about 5 μm, about 4 μm, about 3 μm, about 2 μm, or about 1 μm).

[0084] In certain embodiments, the solid form has a particle size of less than 47 μm and Form A monosulfate is present in the composition in an amount of 1% or less by weight based on the total weight of the composition.

[0085] In certain embodiments, the solid form has a particle size of about 10 μm or less (e.g., about 3.3 μm), and Form A monosulfate is present in the composition in an amount of 0.5 wt % or less (e.g., 0.1 wt %) based on the total weight of the composition.

[0086] In certain embodiments, the pharmaceutical composition comprises pharmaceutical excipients including polymers, binders, disintegrants, lubricants, or glidants.

[0087] In certain embodiments, the polymer is a matrix-forming polymer (e.g., microcrystalline cellulose), a pH-responsive polymer (e.g., methacrylic acid copolymer), or a binder (e.g., hypromellose). In certain embodiments, the polymer is one or more polymers selected from the group consisting of cellulose, such as microcrystalline cellulose, methacrylic acid copolymer, and hypromellose. In certain embodiments, the lubricant is talc.

[0088] The pharmaceutical compositions provided herein can be administered to a subject by various routes, including but not limited to oral administration, administration as a suppository, topical contact, parenteral administration (e.g., intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial), intralesional administration, intrathecal administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or implantation of a sustained-release device, such as a mini-osmotic pump. In certain embodiments, the pharmaceutical compositions disclosed herein are administered orally.

[0089] The pharmaceutical compositions provided herein may also be administered chronically ("long-term administration"). Long-term administration refers to the administration of a compound or its pharmaceutical composition for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely, for example, for the lifetime of the subject. In certain embodiments, long-term administration is intended to maintain a constant concentration of the compound in the blood, for example, within the therapeutic window for a long period of time.

[0090] The pharmaceutical compositions provided herein may be provided in unit dosage form to facilitate accurate dosing.The term "unit dosage form" refers to a physically separate unit suitable as a single dose for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect in association with suitable pharmaceutical excipients.In various embodiments, the pharmaceutical dosage forms described herein can be administered as unit doses.Typical unit dosage forms include pre-measured and pre-filled ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc., for solid compositions.

[0091] In certain embodiments, the pharmaceutical compositions provided herein are administered to patients in solid dosage form.In certain embodiments, the solid dosage form is a capsule (for example, a capsule-encapsulated controlled-release pellet formulation).In certain embodiments, the solid dosage form is a tablet (for example, a controlled-release tablet formulation).

[0092] In certain embodiments, the pharmaceutical compositions provided herein comprise a compound of Formula I as the sole active agent, or in combination with other active agents.

[0093] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to all types of animals. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to various animals are well understood, and veterinary pharmacologists of ordinary skill can design and / or implement such modifications with no more than routine experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005.

[0094] Methods of Use and Treatment In one aspect, provided herein is a method of treating a medical condition associated with tuberous sclerosis complex (TSC) in a subject (eg, a human) in need thereof.

[0095] In various embodiments, a subject in need thereof is administered a compound of Formula I: Provided herein are methods for treating a medical condition associated with TSC in a subject in need thereof, comprising administering a composition comprising a therapeutically effective amount of a compound, TIFF2025122066000006.tif27128, or a pharmaceutically acceptable salt thereof.

[0096] In certain embodiments, the method comprises administering to a subject in need thereof a composition comprising a therapeutically effective amount of an mGlu5 negative allosteric modulator (NAM) or a pharmaceutically acceptable salt thereof, wherein the mGlu5 NAM has the formula I: Provided herein are methods for treating tuberous sclerosis complex, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is a compound of Formula I (TIFF2025122066000007.tif37128), and the administering step comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of about 1.5 mg to about 3.5 mg once daily. In some embodiments, the subject weighs at least 40 kg. In some embodiments, the subject weighs less than 40 kg.

[0097] In certain embodiments, the method comprises administering to a subject in need thereof a composition comprising a therapeutically effective amount of an mGlu5 negative allosteric modulator (NAM) or a pharmaceutically acceptable salt thereof, wherein the mGlu5 NAM has the formula I: Provided herein are methods for treating tuberous sclerosis complex, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is a compound of Formula I (TIFF2025122066000008.tif37128), and the administering step comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of about 1.0 mg to about 3.0 mg once daily. In some embodiments, the subject weighs at least 40 kg. In some embodiments, the subject weighs less than 40 kg.

[0098] In various embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to the subject about 0.05 mg to about 20 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg) of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0099] In certain embodiments, the step of administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to a subject in need thereof about 0.1 mg to about 1.5 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0100] In certain embodiments, the step of administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof in a dose of about 0.1 mg to about 4 mg (e.g., about 0.1 mg to about 3.8 mg, about 0.1 mg to about 3.6 mg, about 0.1 mg to about 3.4 mg, about 0.1 mg to about 3.2 mg, about 0.1 mg to about 3.0 mg, about 0.1 mg to about 2.8 mg, about 0.1 to about 2.6 mg, about 0.1 mg to about 2.4 mg, about 0.1 mg to about 2.2 mg). , about 0.1 mg to about 2.0 mg, about 0.1 mg to about 1.8 mg, about 0.1 mg to about 1.6 mg, about 0.1 mg to about 1.4 mg, about 0.1 mg to about 1.2 mg, about 0.1 mg to about 1.0 mg, about 0.1 mg to about 0.8 mg, about 0.1 mg to about 0.6 mg, about 0.1 mg to about 0.4 mg, about 0.1 mg to about 0.2 mg, about 0.2 mg to about 4 mg, about 0.2 mg to about 3.5 mg, about 0.5 mg to about 3.5 mg, about 0.5 mg to about 4 mg, or about 1 mg to about 4 mg). In certain embodiments, administration is once daily.

[0101] In certain embodiments, the step of administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to a subject in need thereof about 0.1 mg to about 3 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, or about 3.0 mg) of a compound of Formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, administration is once daily.

[0102] In certain embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof comprises administering between about 0.1 mg and about 3.5 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, or about 1.4 mg) of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof. g, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, or about 3.5 mg). In certain embodiments, administration is once daily.

[0103] In certain embodiments, the step of administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to a subject in need thereof about 1.0 mg to about 5.0 mg (e.g., about 1.0 mg to about 4.9 mg, about 1.0 mg to about 4.8 mg, about 1.0 mg to about 4.7 mg, about 1.0 mg to about 4.6 mg, about 1.0 mg to about 4.5 mg, about 1.0 mg to about 4.4 mg, about 1.0 mg to about 4.3 mg, about 1.0 mg to about 4.2 mg, about 1.0 mg to about 4.1 mg, about 1.0 mg to about 4.0 mg, about 1.0 mg to about 3.9 mg, about 1.0 mg to about 3.8 mg, about 1.0 mg to about 3.7 mg, and about 1.0 mg to about 3.6 mg) of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0104] In certain embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to a subject in need thereof about 1.0 mg to about 3.0 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to a subject in need thereof about 0.5 mg to about 3.0 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to a subject in need thereof about 1.0 mg to about 3.5 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to a subject in need thereof about 1.0 mg to about 4 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In various embodiments, administration is once daily.

[0105] In certain embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to a subject in need thereof about 1.5 mg to about 3.5 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, administration is once daily. In certain embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to a subject in need thereof about 1.5 mg to about 4.0 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, administration is once daily. In certain embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to a subject in need thereof about 1.5 mg to about 4.5 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to a subject in need thereof about 1.0 mg to about 3.5 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to a subject in need thereof about 0.5 mg to about 3.5 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In various embodiments, administration is once daily.

[0106] In certain embodiments, the step of administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to a subject in need thereof about 3.5 mg, about 3.0 mg, about 2.5 mg, about 2.0 mg, about 1.5 mg, or about 1.0 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, the administration is once daily. In certain embodiments, the step of administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to a subject in need thereof about 6.0 mg, 5.5 mg, 5.0 mg, 4.5 mg, 4.0 mg, 3.5 mg, about 3.0 mg, about 2.5 mg, about 2.0 mg, about 1.5 mg, about 1.0 mg, or about 0.5 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, the administration is once daily.

[0107] In certain embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering about 3 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof once daily to a subject in need thereof. In some embodiments, the subject has a body weight of less than 40 kg. In certain embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering about 3.5 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof once daily to a subject in need thereof. In some embodiments, the subject has a body weight of less than 40 kg. In certain embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering about 4.0 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof once daily to a subject in need thereof.

[0108] In some embodiments, the subject weighs less than about 40 kg. In some embodiments, the subject weighs about 40 kg or more (e.g., about 40 kg, about 45 kg, about 50 kg, about 55 kg, about 60 kg, about 65 kg, about 70 kg, about 75 kg, about 80 kg, about 85 kg, about 90 kg, about 95 kg, about 100 kg, about 105 kg, about 110 kg, about 115 kg, about 120 kg, about 125 kg, about 130 kg, about 135 kg, about 140 kg, about 145 kg). In some embodiments, the subject weighs at least about 40 kg (e.g., about 38 kg, about 36 kg, about 34 kg, about 32 kg, about 30 kg, about 28 kg, about 26 kg, about 24 kg, about 22 kg, about 20 kg, about 18 kg, about 16 kg, about 14 kg, about 12 kg, about 10 kg, about 8 kg, about 6 kg, about 4 kg, about 2 kg). In some embodiments, the subject weighs between about 1 kg and about 40 kg (e.g., between about 5 kg and about 40 kg, between about 10 kg and about 40 kg, between about 15 kg and about 40 kg, between about 20 kg and about 40 kg, between about 25 kg and about 40 kg, between about 30 kg and about 40 kg, or between about 35 kg and about 40 kg). In embodiments, the subject weighs between about 41 kg and about 100 kg (about 40 kg to about 100 kg, about 45 kg to about 100 kg, about 50 kg to about 100 kg, about 55 kg to about 100 kg, about 60 kg to about 100 kg, about 40 kg to about 45 kg, about 40 kg to about 50 kg, about 40 kg to about 55 kg, about 40 kg to about 60 kg, about 40 kg to about 65 kg, about 40 kg to about 70 kg, about 40 kg to about 80 kg, about 40 kg to about 90 kg). In some embodiments, the subject weighs at least about 35 kg, about 30 kg, about 25 kg, about 20 kg, about 15 kg, about 10 kg, or about 5 kg.

[0109] In certain embodiments, provided herein are methods of administering the free base form of the compound of Formula I for the treatment of a medical condition associated with TSC in a subject in need thereof.

[0110] In certain aspects, provided herein are methods of administering a pharmaceutically acceptable salt of a compound of Formula I for the treatment of a medical condition associated with TSC in a subject in need thereof.

[0111] In certain embodiments, treating comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof once, twice, three times, four times, or five times daily. In certain embodiments, treating comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof once daily.

[0112] In certain embodiments, treating comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject by various routes, including, but not limited to, oral administration, administration as a suppository, topical contact, parenteral administration (e.g., intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial), intralesional administration, intrathecal administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or implantation of a sustained-release device, e.g., a mini-osmotic pump.

[0113] In certain embodiments, treating comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof by oral administration.

[0114] In certain embodiments, treating comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof as a single unit dose.

[0115] In certain embodiments, treating comprises administering a compound of formula I as a free base form.

[0116] In certain embodiments, treating comprises administering a compound of Formula I in the form of its pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt of a compound of Formula I can be a salt of a compound of Formula I with a physiologically compatible mineral acid, such as hydrochloric acid, sulfuric acid, sulfurous acid, or phosphoric acid, or with an organic acid, such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, or salicylic acid.

[0117] In certain embodiments, as described above, the treatment involves administering a compound of Formula I in a sulfate salt form (e.g., a monosulfate or hemisulfate salt) in a crystalline form (e.g., Form A, Form B, or Form C).

[0118] In various embodiments, the method includes administering to a subject in need thereof a composition comprising a therapeutically effective amount of an mGlu5 negative allosteric modulator (NAM) or a pharmaceutically acceptable salt thereof, wherein the mGlu5 NAM has the formula I: Provided herein are methods for treating medical conditions associated with TSC, the compounds of TIFF2025122066000009.tif27128.

[0119] In certain embodiments, treating comprises administering a compound of formula I as monotherapy.

[0120] In certain aspects, the methods provided herein further comprise administering to the subject a therapeutically effective amount of another therapeutic agent.

[0121] As described above, the present invention relates to the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for treating a medical condition (e.g., a disease or disorder) associated with TSC. In certain embodiments, the medical condition associated with TSC is a TSC-associated neuropsychiatric disorder, a TSC-associated tumor, or a cardiac arrhythmia.

[0122] In certain embodiments, the medical condition associated with TSC is a TSC-associated neuropsychiatric disorder selected from the group consisting of autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), anxiety disorder, and depressive disorder.

[0123] In certain embodiments, the medical condition associated with TSC is a TSC-associated tumor selected from the group consisting of subependymal giant cell astrocytoma (SEGA), angiomyolipoma (ALM), renal cell carcinoma, oncocytoma, lymphangioleiomyomatosis (LAM), cardiac rhabdomyoma, nail fibroma, oral fibroma, retinal lesions, retinal hamartoma, and pancreatic neuroendocrine nephropathy.

[0124] In certain embodiments, the medical condition associated with TSC is selected from the group consisting of seizures, intellectual disability, developmental delay, behavioral disorders, skin disorders, lung disease, kidney disease, and heart disease.

[0125] In certain aspects, the therapeutic effect of the treatment is (a) reduced incidence of seizures; (b) a reduction in tumor size in the brain, eye, heart, kidney, skin, or lung; (c) inhibition of tumor growth in the brain, eye, heart, kidney, skin, or lung; or (d) Improvement of cognitive function is determined by.

[0126] In some embodiments, the efficacy of the compound is determined by change in caregiver global impression. In some embodiments, the efficacy of the compound is determined by the Sheehan Disability Scale. In some embodiments, the efficacy of the compound is determined by patient self-recorded seizure counts.

[0127] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following specific examples are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way. All publications cited herein are incorporated by reference in their entirety. [Example]

[0128] The following examples are provided to provide a more complete understanding of the disclosure described herein. The examples described herein are presented to illustrate the compounds, pharmaceutical compositions, and methods described herein, and are not to be construed as limiting the scope thereof in any way.

[0129] Example 1: Synthesis of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (compound of Formula I, supra) [see U.S. Pat. No. 7,332,510]. 2-Chloro-4-[1-(4-fluorophenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine (200 mg, 0.6 mmol) was dissolved in 10 mL of tetrahydrofuran (THF) and cooled to -75 °C. Lithium diisopropylamide (0.45 mL, 0.91 mmol) was added, and the mixture was stirred at -75 °C for 15 minutes. Iodomethane (0.05 mL, 0.85 mmol) was added, and stirring was continued at -75 °C for 2 hours. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with water and ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The crude product was purified by flash chromatography on silica gel (heptane / ethyl acetate 90:10 to 20:80 gradient) and recrystallized from ethyl acetate. The title compound was obtained as a white solid. MS: m / z = 326.5 (M+H+).

[0130] Example 2: Preparation of polymorphs of salts of compounds of formula I [see US Pat. No. 8,063,076]. Monosulfate Form A: 61.0 g of 2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine was dissolved in 610 mL of 2-propanol. The solution was filtered, and the filter was rinsed with 31 mL of 2-propanol. A mixture of 30 mL of water and 18.91 g of sulfuric acid (97%) was added dropwise to the combined solution. The solution was cooled to 0-5°C. Seeding was performed at 58°C, if necessary. The solid residue was filtered, washed with 2-propanol (0-5°C), and dried at 50°C and less than 1 mbar for 18 hours to give the monosulfate salt of the compound of Formula I in a yield of 69.1 g (87.1%). Seed crystals of Form A can be prepared by cooling and crystallizing a hot solution of 250 mg of the monosulfate salt in 10 mL of 2-propanol. After cooling to 0° C., the solid residue could be filtered and dried under vacuum at 50° C. to obtain Form A of the monosulfate salt, which was confirmed by an XRPD pattern substantially as shown in FIG. 1.

[0131] Form B Monosulfate: 300 mg of Form A monosulfate of the compound of Formula I was dissolved in 3 mL of 2-propanol and 1 mL of water at 60° C. to produce a clear solution. The clear solution was seeded with Form B monosulfate and sealed at room temperature (e.g., about 25° C.). After 3 days, single crystals had formed. Seed crystals can be prepared by forming a saturated slurry of Form A monosulfate of the compound of Formula I in 2-propanol and water (3:1 v / v) at room temperature. The slurry was stirred at room temperature for about 3 weeks. The solid was filtered through a glass 35 filter to obtain crystalline Form B monosulfate, which was confirmed by the XRPD pattern substantially as shown in FIG. 2.

[0132] Form C Hemisulfate: 128 g of water was mixed with 41 g of Form A monosulfate of compound of Formula I. The slurry was stirred at room temperature for 2-16 hours. After all of the Form A monosulfate was converted to the hemisulfate, the resulting crystals were collected by filtration and rinsed with water. The wet cake thus obtained was dried in a vacuum oven at 40°C for 48 hours to obtain Form C hemisulfate in 93% yield. Form C hemisulfate was confirmed by the XRPD pattern substantially as shown in Figure 3.

[0133] Amorphous Monosulfate: 0.53 g of the monosulfate salt of the compound of formula I was dissolved in 10 mL of methanol at about 65°C. After complete evaporation of the solvent under vacuum, the solid (foam) was further dried at about 50°C and 5-20 mbar for 18 hours. Analysis (XRPD and DSC) revealed that an amorphous form of the compound of formula I was obtained. The amorphous monosulfate salt exhibited peaks of 2730, 2592, 2219, 1633, 1586, 1570, 1513, 1375, 1343, 1293, 1226, 1157, 1130, 1084, 1040, 986, 903, 848, 788, 712, and 670 cm -1 (±3cm -1 The amorphous form was characterized by an infrared spectrum with a band at 100°C. The glass transition temperature (T g ) varied significantly depending on the solvent content and was observed at approximately 42°C for wet samples (sealed pans) and at approximately 77°C for in situ dried samples (pans with perforated lids).

[0134] Example 3: Form A monosulfate controlled release matrix pellet capsules Two different matrix pellet compositions were prepared according to the formulations shown in Table 1 below. The matrix pellets thus obtained were filled into capsules to obtain matrix pellet capsules. The process included high-shear wet granulation of Form A monosulfate, microcrystalline cellulose, methacrylic acid copolymer, and hypromellose with purified water to form a mixture; then extruding, spheronizing, fluid-bed drying, and sieving the mixture to obtain a solid material; and subsequently mixing the solid material with talc, an external pharmaceutical excipient, to obtain matrix pellets; and then filling the matrix pellets into capsules to obtain matrix pellet capsules. More specifically, the granulation, extrusion, spheronization, drying, sieving, and mixing steps were performed as follows, respectively: 1. Form A monosulfate salt and approximately 15% of the required amount of microcrystalline cellulose were weighed into a suitable container. The contents were mixed using a tubular blender or equivalent at 40±10 rpm for 30 minutes. 2. All other excipients: methacrylic acid copolymer, hypromellose, and remaining microcrystalline cellulose were weighed out. 3. All materials from step 2 followed by the mixture from step 1 were transferred to a high shear granulator. All ingredients were mixed for 2 minutes using the impeller and chopper at the following speeds: Impeller: 300±100 rpm and Chopper: 1500±500 rpm. 4. The powder mixture from step 3 was granulated in a high shear granulator by spraying purified water (approximately 83% of the batch size) onto the powder mixture while continuously mixing the contents using an impeller at 300±100 rpm and a chopper at 1500±500 rpm for 20 minutes. The power consumption at the granulation endpoint was recorded. 5. The wet granules were fed at a uniform rate and extruded from the extruder using a screen #1.0 mm and a speed setting of approximately 40±5 rpm. 6. Approximately 700 g of the extrudate from step 5 was transferred to a spheronizer using a #1 graded plate. The contents were spheronized for 5±1 minutes at a speed of approximately 0.6 (approximately 1000 rpm). 7. The spheronized material from step 6 was collected and dried in a fluidized bed dryer with an inlet temperature of 60±10°C until the moisture content of the pellets was less than 0.8% as measured using a halogen moisture meter or equivalent instrument set at 90°C. 8. The dried pellets from step 7 were screened through size #10 and #40 screens, and the pellet fraction between the #10 and #40 screens was collected. 9. The weight of the pellets from step 8 was used to adjust the amount of talc and weigh out. 10. The pellets from step 9 were placed in a bin blender or equivalent device and the talc was added and mixed for 5 minutes at 20±5 rpm. 11. The pellets from step 10 were filled into hard gelatin capsules. 12. The filled capsules from step 11 were stored in a sealed fiber drum in a double polyethylene lined bag with two silica gel bags between the polyethylene bags at a temperature not to exceed 25°C.

[0135] (Table 1) Matrix pellet formulation TIFF2025122066000010.tif71161*In the paragraph below, * represents a 0.1 mg dose and # represents a 1.0 mg dose.

[0136] The content uniformity of the matrix pellets was found to vary depending on the median particle size (Dv50) and the amount of monosulfate salt of Form A ("API"). Specifically, three API variants were produced at two different doses (0.1 mg and 1.0 mg API), achieved by jet milling and pin milling to median particle sizes (Dv50) of 3.3 μm (jet mill), 10 μm (pin mill), and 47 μm (pin mill), respectively. At the 1.0 mg API dose, matrix pellets prepared with APIs having Dv50s of 3.3 μm, 10 μm, and 47 μm exhibited USP Dosage Unit Uniformity (UDU) Acceptance Values (AV) of 2.2, 6.3, and 3.4, respectively, all meeting the UDU acceptance criteria (AV<15). At a dose of 0.1 mg API, matrix pellets prepared with an API Dv50 of 47 μm had an AV of 20.9, failing to meet the UDU acceptance criteria, whereas unexpectedly, matrix pellets prepared with API Dv50s of 3.3 μm and 10 μm met the UDU acceptance criteria with AVs of 6.0 and 10.3, respectively. API particle sizes (Dv50) below 10 μm (e.g., 3.3-10 μm) have been shown to provide acceptable manufacturing process and formulation performance (e.g., content uniformity, pellet size distribution, and dissolution) for matrix pellet formulations and are therefore more suitable for pharmaceutical development.

[0137] Example 4: Study of Compounds of Formula I for the Treatment of Subjects with Tuberous Sclerosis Complex (TSC) As shown in Table 2 and described below, a Phase 2B, multicenter, 30-week, prospective, crossover, double-blind, randomized, placebo-controlled trial will be conducted to evaluate the efficacy and safety of 1.0 mg to 3.0 mg or 1.5 mg to 3.5 mg daily of the compound of Formula I ("CF-I") adjunctive to ongoing epilepsy treatment in 55 patients with TSC who have an inadequate response to current antiseizure therapy. Specifically, the study will be conducted in patients with TSC who, despite optimal treatment with antiseizure therapy, have persistent focal or generalized seizures of at least one type, including absence, astatic (atonic, tonic, tonic-clonic, or myoclonic), for at least six months prior to study enrollment.

[0138] Vasingulant is administered according to two weight categories (<40 kg and ≥40 kg). The initial dose of vasingulant is 1.0 mg once daily for patients weighing <40 kg and 1.5 mg once daily for patients weighing ≥40 kg. The maximum dose of vasingulant is 3.0 mg once daily for patients weighing <40 kg and 3.5 mg once daily for patients weighing ≥40 kg. The dose of vasingulant is then blindly increased by 0.5 mg at weekly intervals based on individual tolerability. Once the dose-titration phase is complete, patients continue to receive the same dose of vasingulant throughout the maintenance phase.

[0139] Table 2. Study Protocol - Objectives and Endpoints TIFF2025122066000011.tif108161TIFF2025122066000012.tif211161

[0140] Begin accrual of patients aged 12-18 years. After at least 8 patients complete Period 2, the Data and Safety Monitoring Board (DSMB) will review safety data. Based on the endpoints of this review, the remaining 5-11 year old patient group will be randomized to treatment.

[0141] Part A: Part A includes four periods. Period 1 is a 4-week stabilization period (baseline). During this period, patients receive a placebo and are monitored to ensure stability on previous antiepileptic medications and to accurately record seizure frequency and duration. Period 2 is a 12-week double-blind treatment period (study weeks 5–16). During this period, patients are randomly assigned to receive vasingulant or placebo. Period 3 is a 2-week washout period (study weeks 17 and 18), during which patients receive a placebo. Period 4 is a 12-week double-blind treatment period (study weeks 19–30). During this period, patients who initially received placebo will be assigned to receive vasingulant, and patients who initially received vasingulant will receive placebo.

[0142] Basinglant or matching placebo will be administered once daily (preferably in the morning) with food for 12 weeks during Periods 2 and 4 (Weeks 5-16 and 19-30, respectively). Each of these two periods will have an initial 5-week dose-escalation phase followed by a 7-week maintenance phase. At each dose-escalation step, the investigator will conduct an overall assessment of the safety and tolerability of the current dose. Dose escalation will occur only if the current dose is deemed well tolerated and the patient and their caregiver agree. If toleration is inadequate, the patient may continue on the same dose or have the dose reduced by 0.5 mg at the investigator's discretion.

[0143] Patients receiving placebo will undergo sham dose escalation based on the same criteria to maintain blinding. On study day 211, patients who complete study periods 1-4 and tolerate the study drug will be offered entry into the 52-week OLE study (Part B).

[0144] Part B: Part B involves a 52-week OLE in which all patients receive vasopressin. All OLE study participants will resume vasopressin at the lowest weight-appropriate dose, which will be titrated to the maximum individually tolerated dose and maintained at that dose until the end of the study.

[0145] Seizure frequency during study periods 1-4 and the 52-week OLE period will be monitored and recorded using patient / caregiver diaries and, if available at study initiation, a wearable device that detects and records potential focal and generalized tonic-clonic seizures.

[0146] Other Aspects All features disclosed herein may be combined in any combination. Each feature disclosed herein may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is merely an example of a general series of equivalent or similar functions.

[0147] Furthermore, from the above description, those skilled in the art can easily ascertain the essential features of the present invention, and can make various changes and modifications to the invention to adapt it to various uses and conditions without departing from the spirit and scope thereof. Accordingly, other embodiments are within the scope of the claims.

Claims

1. In need thereof, a compound of formula I: or a pharmaceutically acceptable salt thereof.

1. A method of treating a medical condition associated with tuberous sclerosis complex (TSC), comprising:

2. 10. The method of claim 1, wherein the administering step comprises administering the compound of formula I in its free base form.

3. 10. The method of claim 1, wherein the administering step comprises administering a compound of formula I in the form of a pharmaceutically acceptable salt thereof.

4. 4. The method of claim 3, wherein the pharmaceutically acceptable salt is a monosulfate or hemisulfate salt.

5. 5. The method of claim 4, wherein the pharmaceutically acceptable salt is in a crystalline or amorphous form.

6. Pharmaceutically acceptable salts include the crystalline anhydrous form of the monosulfate salt of the compound of Formula I (Form A), which has a 2θ (two-theta) resolution of Cu. Kα The following X-ray powder diffraction peaks are obtained by the 9.8±0.2°, 13.4±0.2°, 14.2±0.2°, 18.1±0.2°, 18.9±0.2°, 19.6±0.2°, 22.6±0.2°, 22.9±0.2°, 25.7±0.2°, 27.1±0.2°, and 29.9±0.2° 6. The method of claim 5, characterized by at least three peaks selected from:

7. Form A is Cu at 2θ (two theta). Kα The following X-ray powder diffraction peaks are obtained by the 9.8±0.2°, 13.4±0.2°, 14.2±0.2°, 18.1±0.2°, 18.9±0.2°, 19.6±0.2°, 22.6±0.2°, 22.9±0.2°, 25.7±0.2°, 27.1±0.2°, and 29.9±0.2° 7. The method of claim 6, wherein:

8. Form A has an X-ray powder diffraction (XRPD) pattern substantially as shown below:

8. The method of claim 6 or 7, comprising:

9. Pharmaceutically acceptable salts include a crystalline monohydrate form of the monosulfate salt of the compound of Formula I (Form B), wherein Form B has an XRPD pattern substantially as shown below:

6. The method of claim 5, comprising:

10. Pharmaceutically acceptable salts include those having the following structures: 2730, 2592, 2219, 1633, 1586, 1570, 1513, 1375, 1343, 1293, 1226, 1157, 1130, 1084, 1040, 986, 903, 848, 788, 712, and 670 cm -1 (±3cm -1 6. The method of claim 5, comprising an amorphous form of the monosulfate salt of the compound of formula I, characterized by an infrared spectrum having a band at

11. Pharmaceutically acceptable salts include a crystalline hemihydrate form of the hemisulfate salt of the compound of Formula I (Form C), wherein Form C has an XRPD pattern substantially as shown below:

6. The method of claim 5, comprising:

12. 12. The method of any one of claims 1 to 11, wherein the composition is an encapsulated immediate release formulation, a controlled release tablet formulation, or an encapsulated controlled release pellet formulation.

13. 13. The method of claim 12, wherein the composition is a controlled-release pellet formulation encapsulated in an capsule, and the compound of formula I or a pharmaceutically acceptable salt thereof is present in an amount of about 0.05 mg to about 20 mg.

14. 14. The method of any one of claims 1 to 13, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.01% to about 20% by weight, based on the total weight of the composition.

15. 15. The method of claim 14, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.05% to about 15% by weight, based on the total weight of the composition.

16. 13. The method of claim 12, wherein the composition is a controlled-release pellet formulation encapsulated in an capsule, and wherein the monosulfate salt of Form A of the compound of Formula I is present in the composition in an amount of about 0.05 mg to about 20 mg.

17. 17. The method of claim 16, wherein Form A of the monosulfate salt is present in the composition in an amount of about 0.01% to about 20% by weight, based on the total weight of the composition.

18. 18. The method of claim 17, wherein Form A of the monosulfate salt is present in the composition in an amount of about 0.05% to about 15% by weight, based on the total weight of the composition.

19. The composition is an immediate release formulation encapsulated in an encapsulated formulation comprising:

19. The method of any one of claims 1 to 18, comprising:

20. The composition is an immediate release formulation encapsulated in an encapsulated formulation comprising:

19. The method of any one of claims 1 to 18, comprising:

21. The composition is an immediate release formulation encapsulated in an encapsulated formulation comprising:

19. The method of any one of claims 1 to 18, comprising:

22. The composition is an immediate release formulation encapsulated in an encapsulated formulation comprising:

19. The method of any one of claims 1 to 18, comprising:

23. The composition is a controlled release pellet formulation encapsulated in an encapsulated capsule, and the composition has the following properties as shown in the table below:

19. The method of any one of claims 1 to 18, comprising a formulation selected from the group consisting of formulation 1, formulation 2, formulation 3, and formulation 4 shown in

24. 7. The method of claim 6, wherein the pharmaceutically acceptable salt is 90% or more by weight of crystalline Form A, based on the total weight of the salt present in the composition.

25. 25. The method of claim 24, wherein the pharmaceutically acceptable salt is 95% or more by weight of crystalline Form A, based on the total weight of the salt present in the composition.

26. 26. The method of claim 25, wherein the pharmaceutically acceptable salt is 99% or more by weight of crystalline Form A, based on the total weight of the salt present in the composition.

27. 27. The method of any one of claims 1-26, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof once daily.

28. 28. The method of any one of claims 1-27, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 0.1 mg to about 3.5 mg.

29. 29. The method of any one of claims 1-28, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 0.1 mg to about 3 mg.

30. 30. The method of any one of claims 1-29, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 1.5 mg to about 3.5 mg.

31. 31. The method of any one of claims 1-30, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 1 mg to about 3 mg.

32. 32. The method of any one of claims 1-31, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 3.5 mg, about 3.0 mg, about 2.5 mg, about 2.0 mg, about 1.5 mg, or about 1.0 mg.

33. 33. The method of any one of claims 1-32, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 3.5 mg.

34. 34. The method of any one of claims 1-33, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 3 mg.

35. 35. The method of any one of claims 1-34, wherein the administering step comprises orally administering the compound of formula I or a pharmaceutically acceptable salt thereof.

36. 36. The method of any one of claims 1-35, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof as a single unit dose.

37. 37. The method of any one of claims 1 to 36, wherein the subject has a body weight of at least 40 kg.

38. 37. The method of any one of claims 1 to 36, wherein the subject has a body weight of less than 40 kg.

39. 39. The method of any one of claims 1-38, wherein the medical condition associated with TSC is a TSC-associated neuropsychiatric disorder, a TSC-associated tumor, or a cardiac arrhythmia.

40. 40. The method of claim 39, wherein the medical condition associated with TSC is a TSC-associated neuropsychiatric disorder selected from the group consisting of autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), anxiety disorder, and depressive disorder.

41. 40. The method of claim 39, wherein the medical condition associated with TSC is a TSC-associated tumor selected from the group consisting of subependymal giant cell astrocytoma (SEGA), angiomyolipoma (ALM), renal cell carcinoma, oncocytoma, lymphangioleiomyomatosis (LAM), cardiac rhabdomyoma, nail fibroma, oral fibroma, retinal lesion, retinal hamartoma, and pancreatic neuroendocrine nephropathy.

42. 42. The method of any one of claims 1-41, wherein the medical condition associated with TSC is selected from the group consisting of seizures, intellectual disability, developmental delay, behavioral disorders, skin abnormalities, lung disease, kidney disease, and heart disease.

43. The therapeutic effect of the treatment (a) a reduction in the occurrence or frequency of seizures; (b) a reduction in tumor size in the brain, eye, heart, kidney, skin, or lung; (c) inhibiting tumor growth in the brain, eye, heart, kidney, skin, or lung; or (d) Improvement of cognitive function The method of any one of claims 1 to 42, wherein the method is determined by

44. Pharmaceutical excipients and compounds of formula I: and a solid form of the compound of The solid form has a 2θ (two theta) Kα The following XRPD peaks are obtained by the line: 9.8±0.2°, 13.4±0.2°, 14.2±0.2°, 18.1±0.2°, 18.9±0.2°, 19.6±0.2°, 22.6±0.2°, 22.9±0.2°, 25.7±0.2°, 27.1±0.2°, and 29.9±0.2° and having a particle size (Dv50) of about 100 μm or less; the solid pharmaceutical composition is in the form of a matrix pellet; Solid pharmaceutical compositions.

45. 45. The pharmaceutical composition of claim 44, wherein the solid form has a particle size of less than 47 μm.

46. 45. The pharmaceutical composition of claim 44, wherein the solid form has a particle size of about 25 μm or less.

47. 45. The pharmaceutical composition of claim 44, wherein the solid form has a particle size of about 10 μm or less.

48. 48. The pharmaceutical composition of any one of claims 44-47, wherein Form A of the monosulfate salt is present in the composition in an amount of 1% by weight or less, based on the total weight of the composition.

49. 49. The pharmaceutical composition of claim 48, wherein Form A of the monosulfate salt is present in the composition in an amount of 0.5% by weight or less, based on the total weight of the composition.

50. 50. The pharmaceutical composition of any one of claims 44-49, wherein the pharmaceutical excipient comprises one or more of a polymer, a binder, a disintegrant, a lubricant, and a glidant.

51. 51. The pharmaceutical composition of claim 50, wherein the polymer is one or more polymers selected from the group consisting of cellulose, methacrylic acid copolymer, and hypromellose.

52. Form A of the monosulfate salt exhibits Cu at 2θ (two theta). Kα The following XRPD peaks are obtained by the line: 9.8±0.2°, 13.4±0.2°, 14.2±0.2°, 18.1±0.2°, 18.9±0.2°, 19.6±0.2°, 22.6±0.2°, 22.9±0.2°, 25.7±0.2°, 27.1±0.2°, and 29.9±0.2° 52. The pharmaceutical composition according to any one of claims 44 to 51, characterized in that

53. Form A of the monosulfate salt has an XRPD pattern substantially as shown below:

53. The pharmaceutical composition of any one of claims 44 to 52, comprising:

54. Formula I, which comprises the steps of: A method for preparing matrix pellets comprising the crystalline anhydrous form (Form A) of the monosulfate salt of a compound of: granulating Form A Monosulfate Salt and one or more polymers with purified water to form a mixture; extruding, spheronizing, drying and sieving the mixture to obtain a solid; and Mixing the solid with other pharmaceutical excipients to obtain matrix pellets.

55. 55. The method of claim 54, further comprising filling the matrix pellets into a capsule to form a matrix pellet capsule.

56. 56. The method of claim 54 or 55, wherein Form A of the Monosulfate Salt has a particle size (Dv50) of less than about 100 μm.

57. 57. The method of any one of claims 54-56, wherein Form A of the Monosulfate Salt has a particle size (Dv50) of less than 47 μm.

58. 57. The method of any one of claims 54-56, wherein Form A of the Monosulfate Salt has a particle size (Dv50) of about 10 μm or less.

59. 59. The method of any one of claims 54-58, wherein the one or more polymers are selected from the group consisting of cellulose, methacrylic acid copolymer, and hypromellose.

60. 60. The method of any one of claims 54-59, wherein the remaining pharmaceutical excipients comprise talc.

61. Administering to a subject in need thereof the pharmaceutical composition of any one of claims 44 to 53.

1. A method for treating tuberous sclerosis, comprising:

62. administering to a subject in need thereof a composition comprising a therapeutically effective amount of an mGlu5 negative allosteric modulator (NAM) or a pharmaceutically acceptable salt thereof. wherein the mGlu5 NAM has formula I: A method for treating tuberous sclerosis, comprising administering to said patient a compound of formula (I) or (II).

63. administering to a subject in need thereof a composition comprising a therapeutically effective amount of an mGlu5 negative allosteric modulator (NAM) or a pharmaceutically acceptable salt thereof. wherein the mGlu5 NAM has formula I: wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 1.5 mg to about 3.5 mg.

64. 64. The method of claim 63, wherein the subject has a body weight of at least 40 kg.

65. administering to a subject in need thereof a composition comprising a therapeutically effective amount of an mGlu5 negative allosteric modulator (NAM) or a pharmaceutically acceptable salt thereof. wherein the mGlu5 NAM has formula I: wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 1.0 mg to about 3.0 mg.

66. 66. The method of claim 65, wherein the subject has a body weight of less than 40 kg.

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