Use of phosphodiesterase 10 inhibitor for the treatment of tourette syndrome

Abstract

To provide novel treatments for various symptoms of TS including tics and neurobehavioral disorders.SOLUTION: Provided is a method of treating Tourette Syndrome in a subject in need thereof by administering to the subject compositions comprising a PDE10 inhibitor of Formula (I). Also disclosed are crystalline solid forms of the compound of Formula (I) and uses thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 63 / 035,310, filed June 5, 2020, and U.S. Patent Application No. 63 / 160,302, filed March 12, 2021, the contents of each of which are incorporated by reference herein in their entirety. [Background technology]

[0002] background Tourette syndrome (TS) is a neurological disorder characterized by tics, which are involuntary vocalizations or repetitive, purposeless movements. It is estimated that as many as 200,000 Americans suffer from the most severe form of TS, and as many as 1 in 100 Americans experience milder, less complex TS symptoms, which may include chronic motor or vocal tics (NIH Handbook on Tourette Syndrome (2012)). The prevalence of TS is estimated to be 0.3% among children aged 6 to 17 in the United States, although it has been suggested that this may be an underestimate (Cohen S, et al. Neurosci Biobehav Rev. 37(6): 997-1007 (2013)).

[0003] Currently, no medications are available that are helpful for all patients with TS. While neuroleptics (i.e., antipsychotics) have been effective in treating tics in some patients, these medications have significant side effects and do not completely eliminate tic symptoms. Furthermore, treating neurobehavioral disorders associated with TS, such as ADHD, can be complicated because some medications used to treat ADHD are contraindicated in patients with TS (see Ritalin prescribing information) (2013).

[0004] Thus, there is an unmet need to develop novel treatments for the various symptoms of TS, including tics and neurobehavioral disorders. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] NIH Handbook on Tourette Syndrome (2012) [Non-patent document 2] Cohen S, et al. Neurosci Biobehav Rev. 37(6): 997-1007 (2013) Summary of the Invention

[0006] overview In one aspect, administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof. wherein the therapeutic agent comprises a compound of Formula I: Provided herein is a method for treating Tourette's syndrome, the compound of TIFF2025183391000001.tif33128.

[0007] In certain embodiments, the subject has a total tic score of at least 22 on the Yale Global Tic Severity Scale.

[0008] In another aspect, administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof. wherein the subject has a total tic score of at least 22 on the Yale Global Tic Severity Scale, and the therapeutic agent is a compound represented by Formula I: Provided herein is a method for treating Tourette's syndrome, the compound of TIFF2025183391000002.tif39128.

[0009] In certain embodiments, the subject has been previously administered another treatment for Tourette's syndrome.In certain embodiments, the previously administered another treatment for Tourette's syndrome is administered pimozide, haloperidol or aripiprazole.In certain embodiments, the previously administered another treatment for Tourette's syndrome is administered psychostimulants (for example, methylphenidate, dextroamphetamine or lisdexamfetamine) or alpha 2 adrenergic receptor antagonists (for example, atipamezole, efaroxane or idazoxan).

[0010] 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 about 2.5 mg to about 5 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally. In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as a single unit dose.

[0011] In certain embodiments, the compound of formula I is administered in free base form. In certain embodiments, the compound of formula I is administered in the form of a pharmaceutically acceptable salt.

[0012] In another aspect, administering to a subject in need thereof a composition containing a therapeutically effective amount of a phosphodiesterase 10 (PDE10) inhibitor or a pharmaceutically acceptable salt thereof. wherein the PDE10 therapeutic agent is a compound of Formula I: Provided herein is a method for treating Tourette's syndrome, the compound of TIFF2025183391000003.tif39128.

[0013] In certain embodiments, the subject has attention deficit hyperactivity disorder (ADHD). In certain embodiments, the subject does not have ADHD. In certain embodiments, the subject has obsessive-compulsive disorder (OCD). In certain embodiments, the subject does not have OCD.

[0014] Formula I: Further within the scope of the present invention are solid forms of the compound of TIFF2025183391000004.tif39128, wherein the solid form is a crystalline solid of the free base of the compound of Formula I, and the crystalline solid has a melting point by differential scanning calorimetry (DSC) of about 210-214°C (e.g., about 210°C, about 211°C, about 212°C, about 213°C, or about 214°C).

[0015] In some embodiments, the solid form described above is a crystalline solid of the free base of Formula I having an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0016] In some embodiments, the solid form described above is a crystalline solid of the free base of Formula I having a DSC diagram substantially as shown in FIG.

[0017] The present invention provides In need thereof, a compound of formula I: administering a composition comprising a therapeutically effective amount of a crystalline solid of the free base of the compound of TIFF2025183391000005.tif40128. wherein the crystalline solid has a melting point by DSC of about 210-214°C.

[0018] In some embodiments, the methods described above include producing a crystalline solid of the free base of Formula I having an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0019] In some embodiments, the methods described above include producing a crystalline solid of the free base of Formula I having a DSC diagram substantially as shown in FIG. [Brief explanation of the drawings]

[0020] [Figure 1] FIG. 1 shows an exemplary XRPD pattern of a crystalline solid of the free base of the compound of Formula I. [Figure 2]FIG. 2 shows an exemplary DSC curve for a crystalline solid of the free base of the compound of Formula I. DETAILED DESCRIPTION OF THE INVENTION

[0021] Detailed Description As generally described herein, the present disclosure provides methods of treating Tourette's syndrome in a subject in need thereof. The present disclosure also describes a crystalline form of the free base of the compound of Formula I and uses thereof.

[0022] definition To facilitate understanding of the present invention, several terms and phrases are defined below.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention belongs. Abbreviations used herein have their conventional meanings 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.

[0024] 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.

[0025] In this application, when an element or component is said to be 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.

[0026] 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.

[0027] 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.

[0028] The term "and / or" is used in this disclosure to mean either "and" or "or" unless otherwise indicated.

[0029] 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.

[0030] The use of the terms "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.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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 shall prevail.

[0035] As used herein, a "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.

[0036] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of a federal or state government or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0037] As used herein, "pharmaceutically acceptable salt" refers to any salt of an acidic or basic group that may be present in a compound of the present invention (e.g., a compound of Formula (I)), which is compatible with pharmaceutical administration.

[0038] As known to those skilled in the art, "salts" of compounds may be derived from inorganic or organic acids and bases. 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, although not pharmaceutically acceptable in themselves, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0039] 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.

[0040] 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, 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 1~4and 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).

[0041] 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.

[0042] 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 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 invention. For examples of excipients, see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0043] "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.

[0044] 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.

[0045] 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, or subcutaneous administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), 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.

[0046] "Co-administered" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional treatments (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 alone or simultaneously to a subject. 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).

[0047] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is suffering from a specified disease, disorder, or condition, which 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").

[0048] As used herein, the phrase "therapeutically effective amount" means an amount of a composition (e.g., a composition described herein) or a compound of Formula I or a pharmaceutically acceptable salt thereof effective to produce some desired therapeutic effect in a subject.

[0049] Tourette's syndrome is described in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5, 2013) as a disorder characterized by the presence of both multiple motor tics and one or more vocal tics, with symptoms persisting for at least one year. Tics are sudden, rapid, repetitive, non-rhythmic movements or vocalizations. Symptoms usually appear before the age of 18. As used herein, the term "Tourette's syndrome" includes "persistent (chronic) motor tic disorder," "persistent (chronic) vocal tic disorder," "provisional tic disorder," and "tic disorder." Patients with Tourette's syndrome may have both motor and vocal tic symptoms present for at least one year. However, patients with "tic disorder" may have only motor tics or only vocal tics. Patients with "persistent (chronic) motor tic disorder" may have only motor tics. Patients with "persistent (chronic) vocal tic disorder" may have only vocal tics. Patients with "provisional tic disorder" may have had symptoms for less than a year.

[0050] Patients with TS may also have inattention, hyperactivity, anxiety, mood, and sleep disorders. Currently, TS may be diagnosed using one or more rating scales. An exemplary rating scale is the Yale Generalized Tic Severity Scale, described in Storch et al., Psychol Assess., 2005, 17(4):486-91.

[0051] compound The compound of Formula I, shown below, is a phosphodiesterase 10 (PDE10) inhibitor, also known as 1-methyl-4-(morpholine-4-carbonyl)-N-(2-phenyl[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide. TIFF2025183391000006.tif33128

[0052] Methods for chemically synthesizing compounds of Formula I (including Example 1 provided herein below) are described in US Pat. No. 8,349,824, which is incorporated by reference in its entirety.

[0053] In various embodiments, the pharmaceutically acceptable salts of the compounds of Formula I can be salts of the compounds of Formula I with physiologically compatible mineral acids such as hydrochloric acid, sulfuric acid, sulfurous acid, or phosphoric acid, or with organic acids 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.

[0054] The present invention relates to formula I: Also encompassed are solid forms of the compound of TIFF2025183391000007.tif40128, wherein the solid form is a crystalline solid of the free base of the compound of Formula I, wherein the crystalline solid has a melting point by differential scanning calorimetry (DSC) of about 210-214°C (e.g., about 210°C, about 211°C, about 212°C, about 213°C, or about 214°C).

[0055] In some embodiments, the solid form described above is a crystalline solid of the free base of Formula I having an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0056] In some embodiments, the solid form described above is a crystalline solid of the free base of Formula I having a DSC diagram substantially as shown in FIG.

[0057] Pharmaceutical Compositions In one aspect, provided herein is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for the treatment of Tourette's syndrome in a subject in need thereof. It should be understood that the compounds of Formula I described herein include crystalline solids of the free base of the compounds of Formula I described herein.

[0058] 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 1 mg to about 10 mg, from about 1.5 mg to about 10 mg, from about 2 mg to about 10 mg, from about 2.5 mg to about 10 mg, from about 3 mg to about 10 mg, from about 3.5 mg to about 10 mg, from about 4 mg to about 10 mg, from about 4.5 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. g, approx. 1 mg ~ approx. 5 mg, approx. 1 mg ~ approx. 4.5 mg, approx. 1 mg ~ approx. 4 mg, approx. 1 mg ~ approx. 3.5 mg, approx. 1 mg ~ approx. 3 mg, approx. 1 mg ~ approx. 2.5 mg, approx. Approximately 7 mg, approximately 1.5 mg to approximately 6 mg, approximately 1.5 mg to approximately 5 mg, approximately 1.5 mg to approximately 4.5 mg, approximately 1.5 mg to approximately 4 mg, approximately 1.5 mg to approximately 3.5 mg, approximately 1.5 mg to approximately 3 mg, approximately 1.5 mg to approximately 2.5 mg, approximately 1.5 mg to approximately 2 mg, approximately 2 mg to approximately 9 mg, approximately 2 mg Approximately 8 mg, approximately 2 mg to approximately 7 mg, approximately 2 mg to approximately 6 mg, approximately 2 mg to approximately 5 mg, approximately 2 mg to approximately 4.5 mg, approximately 2 mg to approximately 4 mg, approximately 2 mg to approximately 3.5 mg, approximately 2 mg to approximately 3 mg, approximately 2 mg to approximately 2.5 mg, approximately 2.5 mg to approximately 9 mg, approximately 2.5 mg to approximately 8 mg, approximately 2.5 mg ~about 7mg, about 2.5mg to about 6mg, about 2.5mg to about 5mg, about 2.5mg to about 4.5mg, about 2.5mg to about 4mg, about 2.5mg to about 3.5mg, about 2.5mg to about 3mg, about 3mg to about 9mg, about 3mg to about 8mg, about 3mg to about 7mg, about 3mg to 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.The amount of the compound of Formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein may be from about 5 mg to about 5 mg, from about 5 mg to about 9 mg, from about 5 mg to about 8 mg, from about 5 mg to about 7 mg, from about 5 mg to about 6 mg, from about 6 mg to about 9 mg, from about 6 mg to about 8 mg, from about 6 mg to about 7 mg, from about 7 mg to about 9 mg, from about 7 mg to about 8 mg, or from about 8 mg to about 9 mg. In certain embodiments, the amount of the compound of Formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein may be from about 2.5 mg to about 5 mg.

[0059] 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 0.5 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. 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 2.5 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 5 mg.

[0060] In another aspect, provided herein is a pharmaceutical composition comprising about 2.5 mg to about 5 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for the treatment of Tourette's syndrome in a subject in need thereof. In another aspect, provided herein is a pharmaceutical composition comprising about 5 mg to about 15 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for the treatment of Tourette's syndrome in a subject in need thereof.

[0061] In another aspect, provided herein is a pharmaceutical composition comprising about 2.5 mg to about 5 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for the treatment of Tourette's syndrome in a subject in need thereof, the subject having a total tic score of at least 22 on the Yale Global Tic Severity Scale.

[0062] In various embodiments, for the effective treatment of Tourette's syndrome in a subject in need thereof (the subject having a total tic score of at least 22 on the Yale Global Tic Severity Scale), the compound of Formula I or a pharmaceutically acceptable salt thereof in a pharmaceutical composition may be administered in a daily amount of about 1 mg to about 20 mg, about 2 mg to about 19 mg, about 3 mg to about 18 mg, about 4 mg to about 17 mg, about 5 mg to about 16 mg, about 5 mg to about 15 mg, about 6 mg to about 14 mg, about 7 mg to about 13 mg, about 8 mg to about 12 mg, about 9 mg to about 11 mg, or about 9 mg to about 10 mg. In certain embodiments, the daily dosage amount may be about 2.5 mg to about 5 mg. In certain embodiments, the daily dosage amount may be about 5 mg to about 15 mg.

[0063] In various embodiments, for the effective treatment of Tourette's syndrome in a subject in need thereof (the subject having a total tic score of at least 22 on the Yale Global Tic Severity Scale), the compound of Formula I or a pharmaceutically acceptable salt thereof in a pharmaceutical composition is administered in an amount of 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, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 6 It may be administered in a daily dose of about 5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, about 20 mg, or about 20.5 mg. In certain embodiments, the daily dosage may be about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, or about 5 mg. In certain embodiments, the daily dosage may be about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

[0064] In various embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the free base form of the compound of Formula I.

[0065] 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.

[0066] The pharmaceutical compositions provided herein can be administered by various routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration. In certain embodiments, the pharmaceutical compositions disclosed herein are administered orally.

[0067] 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.

[0068] The pharmaceutical compositions provided herein can 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 desired therapeutic effect in association with suitable pharmaceutical excipients.In various embodiments, the pharmaceutical dosage forms described herein can be administered as a single unit dose.Typical unit dosage forms include pre-measured and pre-filled ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc., for solid compositions.

[0069] In various embodiments, the pharmaceutical compositions provided herein are administered to patients in solid dosage forms. In certain embodiments, the solid dosage form is a capsule. In certain embodiments, the solid dosage form is a tablet.

[0070] In various embodiments, the pharmaceutical compositions provided herein include a compound of Formula I as the sole active agent, or in combination with other active agents.

[0071] 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.

[0072] Methods of Use and Treatment In one aspect, provided herein is a method of treating Tourette's syndrome in a subject in need thereof.

[0073] In various aspects, administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof. wherein the therapeutic agent comprises a compound of Formula I: Provided herein is a method for treating Tourette's syndrome in a subject in need thereof, the compound of TIFF2025183391000008.tif42128.

[0074] In certain embodiments, the subject has a total tic score on the Yale Global Tic Severity Scale of at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25. In certain embodiments, the subject has a total tic score on the Yale Global Tic Severity Scale of at least 22.

[0075] In some embodiments, administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof. wherein the subject has a total tic score of at least 22 on the Yale Global Tic Severity Scale, and the therapeutic agent is a compound represented by Formula I: Provided herein is a method of treating Tourette's syndrome in a subject in need thereof, the compound of TIFF2025183391000009.tif42128.

[0076] In various embodiments, the subject has been previously administered another treatment for Tourette's syndrome.In certain embodiments, the previous administration of another treatment for Tourette's syndrome is administration of pimozide, haloperidol or aripiprazole.In certain embodiments, the previous administration of another treatment for Tourette's syndrome is administration of psychostimulants (for example, methylphenidate, dextroamphetamine or lisdexamfetamine) or alpha 2 adrenergic receptor antagonists (for example, atipamezole, efaroxan or idazoxan).In certain embodiments, the previous administration of another treatment for Tourette's syndrome is administration of pimozide, haloperidol, aripiprazole, methylphenidate, dextroamphetamine, lisdexamfetamine, atipamezole, efaroxan or idazoxan.

[0077] In various embodiments, administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof comprises administering a composition having an amount of a compound described herein (supra).

[0078] In various embodiments, the composition comprises a compound of Formula I or a pharmaceutically acceptable salt thereof as the only active agent.

[0079] In various embodiments, the compositions comprise a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with another active agent. In certain embodiments, the remaining active agent is olanzapine or risperidone.

[0080] In various embodiments, the composition comprises an inactive agent selected from the group consisting of mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silicon dioxide, and sodium stearyl fumarate.

[0081] In various embodiments, the administering step comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof in a capsule.

[0082] In various embodiments, the capsule shell is composed of gelatin, titanium dioxide, red iron oxide, and yellow iron oxide.

[0083] In various embodiments, the capsules described above contain from about 1 mg to about 10 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0084] In various embodiments, the capsule contains from about 2.5 mg to about 5 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0085] In various embodiments, the administering step comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 2.5 mg to about 5 mg.

[0086] In various embodiments, the administering step comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 5 mg to about 15 mg.

[0087] In various embodiments, 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 20 mg.

[0088] In various embodiments, the administering step comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

[0089] In various embodiments, the administering step comprises administering 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, about 10 ... In some embodiments, the administering step comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 0.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, or about 20 mg. In some embodiments, the administering step comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 2.5 mg. In some embodiments, the administering step comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 5 mg. In various embodiments, the administering step comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof in an immediate release formulation.

[0090] In various embodiments, the administering step comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof in a sustained release formulation.

[0091] In various embodiments, the administering step maintains effectiveness throughout the day.

[0092] In various embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once, twice, three times, four times, or five times daily. In various embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily.

[0093] In various embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally.

[0094] In various embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered as a unit dose.

[0095] In various embodiments, the compound of formula I is administered in free base form.

[0096] In various embodiments, the compound of formula I is administered in the form of a pharmaceutically acceptable salt.In certain embodiments, the pharmaceutically acceptable salt of the compound of formula I can be the salt of the compound of formula (I) with physiologically compatible mineral acids such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid, or with organic acids 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.In certain embodiments, the compound of formula I is administered in crystalline form.

[0097] In various aspects, administering to a subject in need thereof a composition containing a therapeutically effective amount of a phosphodiesterase 10 (PDE10) inhibitor or a pharmaceutically acceptable salt thereof. wherein the PDE10 inhibitor is a compound of formula I: Provided herein is a method of treating Tourette's syndrome in a subject in need thereof, the compound of TIFF2025183391000010.tif42128.

[0098] In various embodiments, the TS subject has also been diagnosed with one or more diseases, disorders, or conditions selected from the group consisting of attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), oppositional defiant disorder (ODD), conduct disorder, anxiety disorder, autism, mood disorder, phobia, and depression. In various embodiments, the TS subject does not have ADHD, OCD, ODD, conduct disorder, anxiety disorder, autism, mood disorder, phobia, or depression. In certain embodiments, the subject has ADHD. In certain embodiments, the subject does not have ADHD. In certain embodiments, the subject has OCD. In certain embodiments, the subject does not have OCD.

[0099] In various embodiments, the compound of Formula I is administered as a monotherapy.

[0100] In various embodiments, the methods provided herein further comprise administering to the subject a therapeutically effective amount of a second therapeutic agent.

[0101] Without further elaboration, it is believed that one skilled in the art can, based on the preceding 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 whatsoever. [Example]

[0102] 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 provided herein, and are not to be construed as limiting the scope thereof in any way.

[0103] Example 1: Synthesis of 1-methyl-4-(morpholine-4-carbonyl)-N-(2-phenyl[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (compound of formula I) [see U.S. Pat. No. 8,349,824]. 1-Methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid methyl ester Step A - 1,2-diamino-4-bromo-pyridinium 2,4,6-trimethyl-benzenesulfonate: To a cooled suspension of O-(mesitylsulfonyl)hydroxylamine (11.22 g, 52.1 mmol, 1 eq.) in dichloromethane (130 mL) was added 4-bromopyridin-2-amine (9.3 g, 52.1 mmol, 1 eq.) in portions (exothermic reaction, some cooling required), resulting in a white suspension. After 1 h, the white suspension was diluted with diethyl ether (120 mL). The white solid was collected by filtration, washed with diethyl ether, and dried to give 1,2-diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate (16.74 g, 82.7%) as white crystals. mp.: 176-180 °C. MS: m / z = 188.2, 190.2 (M+H+).

[0104] Step B - 7-Bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine: 1,2-Diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate (15.6 g, 40.2 mmole) in pyridine (106 mL) was heated with benzoyl chloride (9.4 mL, 80 mmole) at 100 °C overnight to give a reddish-brown solution, which turned into a brown suspension after 2 hours. The reaction mixture was concentrated in vacuo, and the residue was triturated with saturated aqueous ammonium chloride (300 mL) for 2.5 hours while neutralizing to pH 6-7 with saturated aqueous sodium bicarbonate. The solid was collected by filtration, washed with water (40 mL), and dried to give 7-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (6.78 g, 61.6%) as an off-white solid. mp: 189-191 °C. MS: m / z = 276.1, 274.2 (M+H+).

[0105] Step C - (2-phenyl-[1,2,4]triazolol[1,5-a]pyridin-7-yl)-carbamic acid tert-butyl ester: To a nitrogen-purged suspension of 7-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (9 g, 32.8 mmol) in dioxane (180 mL) was added sequentially tert-butyl carbamate (4.71 g, 39.4 mmol), tris(dibenzylidene-acetone)dipalladium(0) (601 mg, 657 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (760 mg, 1.31 mmol), and cesium carbonate (15 g, 46 mmol). The brown mixture was then stirred under a nitrogen atmosphere at 100 °C for 22 h. The solvent was removed in vacuo, and the brown residue was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with water (3 × 120 mL) and brine and dried over magnesium sulfate. The solution was concentrated in vacuo to approximately 80 mL: crystallization. The suspension was stirred in an ice bath for 10 minutes, and the solid was collected by filtration, washed with a small amount of cold ethyl acetate, and dried to give (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-carbamic acid tert-butyl ester (7.09 g) as an off-white solid. The mother liquor was evaporated, and the residue (4.79 g) was loaded onto silica (16 g). The product was isolated by chromatography on a 120 g silica cartridge (eluent heptane / ethyl acetate 10-50%, 45 min) to give a second crop of 1.748 g of a white solid. mp.: 200-201 °C. dec. MS: m / z = 311.3 (M+H+). Overall yield: 86.7%.

[0106] Step D - 2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine: A suspension of (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-carbamic acid tert-butyl ester (8.5 g, 27.4 mmol) in hydrochloric acid (6N in diethyl ether, 175 ml) was stirred overnight at room temperature. With cooling, the suspension was diluted with water (approximately 2 L) and ethyl acetate. The aqueous layer was washed once with ethyl acetate, made alkaline with 32% aqueous sodium hydroxide, and extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and the solvent was removed in vacuo to give 2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine (5.52 g, 95.9%) as a pale pink solid. mp.: 212-213 °C. MS: m / z = 211.2 (M+H + ).

[0107] Step E - 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid methyl ester: A solution of 2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine (1.534 g, 7.3 mmol), 4-(methoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (1.61 g, 8.76 mmol), propylphosphonic anhydride (50% in ethyl acetate, 10.7 ml, 18.2 mmol) and diisopropylethylamine (5.1 ml, 29.2 mmol) in tetrahydrofuran (54 ml) was stirred at 70° C. for 1.25 hours to give a white suspension. The cooled suspension was poured into saturated aqueous sodium bicarbonate (200 ml) and stirred at room temperature for 15 minutes. The solid was collected by filtration, washed with water, and dried to give 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid methyl ester (2.596 g, 94.5%) as a white solid. mp.: 243-7°C. MS: m / z = 377.2 (M+H). + ).

[0108] 1-Methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid A white suspension of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid methyl ester (2.37 g, 6.3 mmol) and lithium hydroxide monohydrate (291 mg, 6.93 mmol) in methanol (100 mL) and water (20 mL) was stirred at 70 °C for 1.25 h, yielding a colorless solution after 20 min. The methanol was removed in vacuo, the residue was diluted with water, and the cooled solution was neutralized with 2N aqueous hydrochloric acid (3.46 mL, 6.03 mmol). The solid was collected by filtration and dried to give 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (2.21 g, 97%) as a white solid. mp.: >300℃. MS: m / z = 361.1 (M+H+).

[0109] 1-Methyl-4-(morpholine-4-carbonyl)-N-(2-phenyl[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide A mixture of 1-methyl-5-(2-phenyl-[1,2,4]-triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), morpholine (240 μL, 2.76 mmol), and propylphosphonic anhydride (50% in ethyl acetate, 407 μL, 690 μmol) in tetrahydrofuran (7 mL) was stirred at 70° C. for 3 hours. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was separated, dried over magnesium sulfate, and the solvent was evaporated. The residue (76 mg of white foam) was triturated with diethyl ether and ethyl acetate to give 1-methyl-4-(morpholine-4-carbonyl)-N-(2-phenyl-[1,2,4]triazolo[1.5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (53 mg, 44.5%) as a white solid. mp.: 203-207 °C. MS: m / Z=432.4 (M+H").

[0110] Example 2: Study of the efficacy of compounds of formula I for the treatment of subjects with Tourette's syndrome Research goals Primary Efficacy Objective: To evaluate the efficacy of once-daily administration of the compound of Formula I (2.5 mg to 5 mg) compared to placebo for 12 weeks in adolescent and adult patients with Tourette Syndrome (TS) in a double-blind fashion. The primary endpoint is the change in Yale Generalized Tic Severity Scale (YGTTS) from baseline to week 12 (or endpoint).

[0111] Secondary Objectives: 1. Percent change in YGTSS Total Tic Score (TTS) from baseline to Week 12 (or endpoint); efficacy will be assessed by the subject's percent change in TTS on the YGTSS from randomization to the last visit (Week 12). 2. Response rate on the investigator-scored Tourette Syndrome Clinical Global Impression (TS-CGI) change scale; response rate (percentage of patients scoring 1 or 2) will be assessed on the TS-CGI change scale at week 12 (or endpoint) relative to baseline. 3. Patient Global Impression of Change (PGIC) response rate; patient-reported response (percentage of patients scoring 1 or 2) will be reported at week 12 (or endpoint). 4. Partial response rate on investigator-scored TS-CGI improvement scale: Partial response rate (percentage of patients scoring 3) will be assessed by the TS-CGI improvement scale from baseline to week 12 (or endpoint). 5. Change in TS-CGI Severity Scale score from baseline to week 12 (or endpoint); this is assessed by change in TS-CGI Severity Scale score from baseline to week 12 (or endpoint).

[0112] Study design This was a multicenter, randomized, double-blind, placebo-controlled study in patients with evidence of inadequate efficacy of current treatment.

[0113] Patients who were diagnosed with TS, signed informed consent, met the study eligibility criteria, and agreed to participate in the study entered a screening period of up to 30 days.

[0114] Eligible patients were randomized via an interactive voice / web response system to receive one of two treatments: 1. Treatment A: 2.5 mg or 5 mg dose of the compound of Formula I 2. Treatment B: Placebo

[0115] At the end of the screening period, patients who continued to meet all inclusion criteria were randomized to receive double-blind treatment.

[0116] Research stage The total study duration was up to 16 weeks. 1. Screening and stabilization phase: 4 weeks 2. Randomization phase: 12 weeks

[0117] Number of patients A total of 90 patients were randomly assigned to treatment. An estimated 120 patients were screened and 90 eligible patients were randomly assigned.

[0118] Target population Patients met the following study inclusion criteria: 1. Able and willing to provide written informed consent and comply with study procedures; 2. Fluent in the language of the investigator, study staff, and informed consent; 3. Age range: 11 to 50 years; 4. The subject meets current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria for TS and requires pharmacotherapy; 5. Subject's YGTSS TTS ≥ 22 at the baseline visit; and 6. For female patients, agree to use two adequate methods of contraception, including at least one barrier method and at least one method with a failure rate of less than 1% per year, from the start of screening until 90 days after the last dose of study drug.

[0119] Patients who met any of the following criteria were excluded from participation in the study: 1. Women with a positive pregnancy test result or who are pregnant or breastfeeding; 2. Subjects with secondary tic symptoms with tardive tics, Huntington's chorea, neuroacanthocytosis, mental retardation, or autism; 3. Subjects with comorbid conditions requiring medication, such as attention-deficit / attention-deficit hyperactivity disorder, obsessive-compulsive disorder, or oppositional defiant disorder (patients are eligible to participate in this study if the investigator determines that they do not require medication for any of the above conditions at the time of this study); 4. Subjects with low intelligence; 5. Subjects currently diagnosed with bipolar disorder, psychotic disorder, schizophrenia, or depression; 6. Subjects who have experienced an epileptic seizure episode in the past year; 7. Subjects with a history of severe traumatic brain injury or stroke; 8. Subjects with any unstable medical condition or current illness (e.g., congenital heart disease, arrhythmia, or cancer) that, in the investigator's judgment, would be at risk for serious adverse events during the study or would interfere with the evaluation of safety and efficacy; 9. Subjects who require both pharmacotherapy and cognitive behavioral therapy (CBT, including habit reversal therapy, cognitive therapy, relaxation training, etc.) during the study period; or 10.Subject has participated in any investigational clinical trial within the past month.

[0120] Efficacy endpoints The primary outcome was change in the Yale Generalized Tic Severity Scale (YGTTS) from baseline to week 12 (or endpoint).

[0121] The secondary efficacy endpoints for this study were: 1. Percent Change in YGTSS TTS from Baseline to Week 12 (or Endpoint); Efficacy will be assessed by the percent change in the subject's Total Tic Score (TTS) on the Yale Global Tic Severity Scale (YGTSS) from randomization to the last visit (Week 12). 2. Response rate on the TS-CGI improvement scale: Response rate (percentage of patients scoring 1 or 2) will be assessed by the TS-CGI improvement scale from baseline to week 12 (or endpoint). 3. Patient Global Impression of Change (PGIC) response rate; patient-reported response (percentage of patients scoring 1 or 2) will be reported at week 12 (or endpoint). 4. Partial remission rate on TS-CGI improvement: The partial remission rate (percentage of patients with a score of 3) will be assessed by the TS-CGI improvement scale from baseline to week 12 (or endpoint). 5. Change in TS-CGI Severity Scale score from baseline to week 12 (or endpoint); efficacy will be assessed by change in TS-CGI Severity Scale score from baseline to week 12 (or endpoint).

[0122] Safety evaluation items Safety endpoints for this study were: 1. Incidence, nature and severity of adverse events 2. Laboratory test results, vital sign assessment, and ECG parameters Evaluation Schedule

[0123] (Table 1) Evaluation schedule TIFF2025183391000011.tif120149

[0124] Example 3: Safety and Efficacy Study of Compounds of Formula I for the Treatment of Subjects with Tourette's Syndrome Provided below is an open-label, Phase IIa, multicenter, 12-week prospective study to evaluate the safety and efficacy of the compound of Formula I at a daily dose range of 5 mg to 15 mg in adult male patients with Tourette's syndrome (TS).

[0125] Goals and Endpoints The primary and secondary objectives and endpoints are listed in Table 2 below.

[0126] (Table 2) Primary and secondary objectives and endpoints TIFF2025183391000012.tif204161

[0127] Study design This was an open-label, multicenter, Phase IIa study to identify the optimal dose of the compound of Formula I that produced an anti-tic response as scored by the Tourette Syndrome Clinical Global Impression Index-Change (TS-CGI-C) at 12 weeks or post-treatment in adult male patients with TS. Response was defined as ratings of "slightly improved," "much improved," and "very much improved."

[0128] A total of 10 patients were enrolled in the study. Adult male patients with evidence of inadequate efficacy of current treatment were enrolled in the study.

[0129] Prospective patients underwent a screening study. Eligible patients were assigned a starting dose of 5 mg once daily. Treatment continued for a maximum of 12 weeks or until unacceptable intolerance occurred or the patient withdrew consent. Dose escalation was permitted at the investigator's discretion in 2.5 mg increments up to a maximum of 15 mg once daily. If intolerance occurred at any given dose during the study, the daily dose of the compound was reduced by 2.5 mg increments.

[0130] Screening tests, clinical efficacy and safety tests, and patient-reported endpoints were conducted according to the Schedule of Actions (SoA) (Table 3 below).

[0131] (Table 3) Test schedule TIFF2025183391000013.tif22298 1 Patients failed to complete the 12-week treatment period or discontinued the study 2 Conducted by telephone at investigator discretion. Dose may be increased or decreased in 2.5 mg increments based on investigator assessment. 3 Conducted from week 1 to the end of week 11 at the discretion and judgment of the researcher 4 Visit

[0132] Response to treatment was scored by the Tourette Syndrome Clinical Global Impression-Change (TS-CGI-C) at week 12 or the end of treatment. Response was defined as a rating of "slightly improved," "much improved," or "very much improved." Secondary efficacy assessments included the total tic score (TTS) on the Yale Global Tic Severity Scale (YGTSS) and disease severity as scored by the Tourette Syndrome Clinical Global Impression-Change Severity Scale (TS-CGI-S). Safety was assessed by physical examination, vital signs, ECG, laboratory assessments, adverse events, and monitoring of serious adverse events. Patient-reported outcomes were assessed by the Clinical Global Impression-Change (PGI-C) and Medication Satisfaction Questionnaire (MSQ).

[0133] research treatment Study treatment was defined as any investigational intervention, commercially available product, placebo, or medical device intended to be administered to patients according to a study protocol.

[0134] The study treatments administered are shown in Table 4 below.

[0135] (Table 4) Study treatment TIFF2025183391000014.tif30166

[0136] Preparation / Handling / Storage / Accountability: The clinical formulation of the compound of Formula I is a reddish-brown, hard gelatin capsule for oral administration. The capsule fill consists of the compound of Formula I and the inactive ingredients mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silicon dioxide, and sodium stearyl fumarate.

[0137] The capsule shell is composed of gelatin, titanium dioxide, red iron oxide, and yellow iron oxide. All excipients used in the formulation are compendial (Ph. Eur. and / or USP / NF) grade.

[0138] Hard gelatin capsules containing 2.5 mg and 5 mg of the compound of Formula I are available. The compound capsules are stored under the recommended storage conditions: Store at 15-25°C and protect from light and moisture.

[0139] Example 4: Crystalline forms of the compound of formula I Preparation of Crystalline Forms: The amorphous form of the compound of Formula I was stirred in water or a mixture of 50% water in methanol at 65°C for 3 days to obtain the crystalline form of the free base of the compound of Formula I. The crystalline form is thermodynamically stable at least between 20°C and 60°C. The XRPD and DSC graphs were substantially as shown in Figures 1 and 2. XRPD patterns may be obtained according to protocols known in the art.

[0140] Melting point: Maximum melting point peak (T m ) was determined using DSC, which was performed using a Mettler-Toledo DSC 821e equipped with a sample robot TSO 801RO. 2-5 mg of sample was placed in a 40 μL AL crucible with an AL perforated lid, and the sample was heated from 25 °C to 300 °C at a rate of 10 °C / min. The temperatures of the crystalline melting peak start, peak onset, peak maximum, and peak end were collected. DSC determined the T of the crystalline form. m This indicates that the temperature was 213.16℃.

[0141] Solubility: The crystalline form exhibited very low solubility in aqueous solutions at pH >3 (<0.004 mg / mL). The solubilities in simulated gastric fluid (SGF), fasting simulated intestinal fluid (FaSSIF), and fed simulated intestinal fluid (FeSSIF) were 0.019 mg / mL, 0.006 mg / mL, and 0.022 mg / mL, respectively. Solubility increased 50-100-fold in the presence of surfactants (e.g., Tween-80, sodium dodecyl sulfate, dioctyl sulfosuccinate, or Pluronic F68) and cyclodextrins, but remained somewhat low. Overall, the crystalline form exhibited low solubility not only in aqueous systems at ambient temperature (22°C) but also in most organic solvents tested (<50 mg / mL).

[0142] Stability: Preliminary forced degradation studies of the free base crystalline form of the compound of Formula I under acidic, basic, oxidative, and photolytic stress conditions were conducted to investigate the viability of the crystalline form under various stress conditions. The solubility of the compound of Formula I in the standard solvent ethanol was low, so ethanol was replaced with N-methyl-2-pyrrolidone (NMP).

[0143] Specified amounts (0.2-0.8 mg) of the crystalline form of the free base of the compound of Formula I were weighed into 1.8 mL HPLC vials and stored open (75% RH) or closed (ambient) at the temperatures and times indicated. After incubation, the compounds were dissolved in 1-1.5 mL of NMP to a final concentration of 0.2-0.5 mg / mL and subjected to UPLC analysis (254 nm). The results are substantially as shown in Table 5 below. The data indicate that the crystalline form was stable in the solid state (<0.5% decomposition products) at various temperatures, e.g., 40-60°C for at least 4 weeks.

[0144] Table 5. Preliminary solid-state stability TIFF2025183391000015.tif53128

[0145] The crystalline form of the free base of the compound of Formula I was stable in the solid state at 80°C and in solution at room temperature between pH 3 and pH 7 for up to 8 days. Decomposition was observed at higher or lower pH. The crystalline form was stable in the solid state after exposure to light. In solution, it was stable to sunlight, with time-dependent, moderate to unstable stability in Suntest. It was also stable to oxidation for 1 day but showed some sensitivity with prolonged exposure. The crystalline form was compatible with nearly all excipients, but drug recovery in the CompaS assay was highly dependent on the solvent used for extraction.

[0146] In the suspension vehicle (0.5% HPC / 1% Tween 80) used in PK, PD, and Tox studies, the crystalline form was also stable at room temperature for up to 5 weeks, with only slight particle growth and no hydrate formation. For parenteral administration, a 30% kleptose formulation (1.5 mg / ml, physiological osmolality, pH 6.2) was developed with stability for at least 4 weeks at 40°C.

[0147] INCORPORATION BY REFERENCE This application references various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. Furthermore, any particular aspect of the present disclosure that is encompassed by the prior art may be expressly excluded from any one or more claims. Such aspects may be excluded even if the exclusion is not explicitly set forth herein because such aspects are deemed to be known to those of ordinary skill in the art. Any particular aspect of the disclosure may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0148] equivalent The invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are therefore considered in all respects to be illustrative rather than limiting on the invention described herein. The scope of the invention is accordingly indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof. wherein the therapeutic agent comprises a compound of Formula I: A method for treating Tourette's syndrome, comprising administering to a subject a compound of formula (I) or (II).

2. 10. The method of claim 1, wherein the subject has a total tic score of at least 22 on the Yale Global Tic Severity Scale at the start of treatment.

3. administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof. wherein the subject has a total tic score of at least 22 on the Yale Global Tic Severity Scale at the start of treatment, and the therapeutic agent is a compound represented by Formula I: A method for treating Tourette's syndrome, comprising administering to a subject a compound of formula (I) or (II).

4. 4. The method of any one of claims 1 to 3, wherein the subject has previously been administered another treatment for Tourette's syndrome.

5. 5. The method of claim 4, wherein the prior administration of another treatment for Tourette's syndrome is administration of pimozide, haloperidol, aripiprazole, methylphenidate, dextroamphetamine, lisdexamfetamine, atipamezole, efaroxan, or idazoxan.

6. 6. The method of claim 5, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof once daily.

7. 6. The method of claim 5, wherein the administering step comprises orally administering the compound of formula I or a pharmaceutically acceptable salt thereof.

8. 6. The method of claim 5, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof as a single unit dose.

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

10. 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.

11. administering to a subject in need thereof a composition containing a therapeutically effective amount of a phosphodiesterase 10 (PDE10) inhibitor or a pharmaceutically acceptable salt thereof. wherein the PDE10 inhibitor is a compound of formula I: A method for treating Tourette's syndrome, comprising administering to a subject a compound of formula (I) or (II).

12. 12. The method of any one of claims 1 to 11, wherein the composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof as the only active agent.

13. 12. The method of any one of claims 1 to 11, wherein the composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof in combination with another active agent.

14. 14. The method of claim 13, wherein the remaining active agent is olanzapine or risperidone.

15. 15. The method of any one of claims 1-14, wherein the composition comprises an inactive agent selected from the group consisting of mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silicon dioxide, and sodium stearyl fumarate.

16. 16. The method of any one of claims 1 to 15, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof in a capsule.

17. 17. The method of claim 16, wherein the capsule shell is comprised of gelatin, titanium dioxide, red iron oxide, and yellow iron oxide.

18. 17. The method of claim 16, wherein the capsule comprises about 1 mg to about 10 mg of the compound of formula I or a pharmaceutically acceptable salt thereof.

19. 19. The method of claim 18, wherein the capsule comprises about 2.5 mg to about 5 mg of the compound of formula I or a pharmaceutically acceptable salt thereof.

20. 20. The method of any one of claims 1-19, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 2.5 mg to about 5 mg.

21. 20. The method of any one of claims 1-19, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 5 mg to about 15 mg.

22. 22. The method of claim 21, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

23. 23. The method of any one of claims 1-22, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof in an immediate release formulation.

24. 23. The method of any one of claims 1-22, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof in a sustained release formulation.

25. 25. The method of any one of claims 1 to 24, wherein the administering step maintains effectiveness throughout the day.

26. 26. The method of any one of claims 1 to 25, wherein the subject has attention deficit hyperactivity disorder (ADHD).

27. 26. The method of any one of claims 1 to 25, wherein the subject does not have ADHD.

28. 26. The method of any one of claims 1 to 25, wherein the subject has obsessive-compulsive disorder (OCD).

29. 26. The method of any one of claims 1-25, wherein the subject does not have OCD.

30. administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof. wherein the subject has a total tic score of at least 22 on the Yale Global Tic Severity Scale at the start of treatment, and the therapeutic agent is a compound represented by 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 5 mg to about 15 mg.

31. Formula I: a solid form of the compound of formula I, which is a crystalline solid of the free base of the compound of formula I wherein the crystalline solid has a melting point onset of about 210-214°C as determined by differential scanning calorimetry (DSC).

32. 32. The solid form of claim 31, wherein the crystalline solid has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1.

33. 32. The solid form of claim 31, wherein the crystalline solid has a DSC curve substantially as shown in Figure 2.

34. 34. The solid form of any one of claims 31-33, wherein the crystalline solid is present in the capsule in an amount of from about 1 mg to about 10 mg.

35. In need thereof, a compound of formula I: administering a composition comprising a therapeutically effective amount of a crystalline solid of the free base of the compound of wherein the crystalline solid has an onset of melting point of about 210-214°C as determined by DSC.

36. 36. The method of claim 35, wherein the crystalline solid has an XRPD pattern substantially as shown in Figure 1.

37. 36. The method of claim 35, wherein the crystalline solid has a DSC curve substantially as shown in Figure 2.

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