Methods for the treatment of childhood onset dysfluency disorder

Abstract

Provided herein is a method for treating childhood onset dysfluency disorder (COFD) in a subject by administering to the subject in need thereof a composition comprising PDE10A inhibitor.Also disclosed is a method for treating COFD in a subject by administering to the subject in need thereof a composition comprising the compound of formula I below: TIFF2024505515000051.tif43128

Description

[Background technology]

[0001] background Childhood-onset dysphagia (COFD; also known as stuttering or developmental stuttering or stammering) is a neurodevelopmental speech disorder involving frequent and severe problems with the normal fluency and smoothness of speech. Typically characterized by repeated prolongations, repetitions, or interruptions of sounds, syllables, phrases, or words, COFD can lead to serious secondary effects, including negative self-perceptions and negative perceptions by others, anxiety, and in some cases depression. It affects approximately 5%-10% of preschool children and approximately 1% of adults (RW Sander, et al. American Family Physician, 2019, 100(9): 556-560).

[0002] There are currently no approved pharmacological treatments for COFD. Management of the disorder includes speech and language therapy, psychotherapy, and antipsychotic medications, but with limited success. Antipsychotic medications are often used off-label and are associated with serious side effects.

[0003] Therefore, there is an unmet medical need to develop novel methods that can effectively treat COFD without serious side effects. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] RWSander, et al. American Family Physician, 2019, 100(9): 556-560 Summary of the Invention

[0005] overview In one aspect, the disclosure is directed to a method for treating childhood onset dysfluency disorder (COFD), comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a phosphodiesterase 10A (PDE10A) inhibitor or its pharmacologic acceptable salt.In another aspect, the disclosure is directed to a method for treating childhood onset dysfluency disorder (COFD), comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a phosphodiesterase 10A (PDE10A) inhibitor (e.g., a compound of formula I) or its pharmacologic acceptable salt and a compound of formula III or its pharmacologic acceptable salt.Each of these different aspects can be more specifically described by various embodiments described herein, and the embodiments can be similarly applied to different aspects.

[0006] Examples of PDE10A inhibitors include, but are not limited to, papaverine, PF-02545920 (also known as MP-10), RO5545965, TAK-063, AMG579, and THPP-1. The structures of these PDE10A inhibitors are shown below. TIFF2024505515000002.tif126159

[0007] In certain embodiments, the method comprises administering PDE10A inhibitor or its pharmaceutically acceptable salt once a day.In certain embodiments, the method comprises administering PDE10A inhibitor or its pharmaceutically acceptable salt orally.In certain embodiments, the method comprises administering PDE10A inhibitor or its pharmaceutically acceptable salt as a unit dose.

[0008] In another aspect, the method comprises administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent or a pharma- ceutically acceptable salt thereof, wherein the therapeutic agent has Formula I: Provided herein is a method for treating COFD, the compound of TIFF2024505515000003.tif43128 (also referred to herein as RO5545965).

[0009] In a further aspect, provided herein is a method of treating COFD comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent or a pharma- ceutically acceptable salt thereof, wherein the therapeutic agent is a compound of formula I (i.e., RO5545965) and the free base of the compound or a pharma- ceutically acceptable salt thereof is administered in an amount of about 5 mg to about 15 mg once daily. In certain embodiments, the therapeutic agent is a compound of formula I (i.e., RO5545965) and the free base or a pharma- ceutically acceptable salt thereof is administered in an amount of about 2.5 mg to about 15 mg once daily. In certain embodiments, the therapeutic agent is a compound of formula I (i.e., RO5545965) and the free base or a pharma- ceutically acceptable salt thereof is administered in an amount of about 2.5 mg, about 5.0 mg, about 10 mg, or about 15 mg once daily.

[0010] Yet another aspect of the present invention is a method of treating COFD comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a crystalline solid of the compound of formula I, wherein the crystalline solid has an onset of melting of about 210°C to about 214°C as determined by differential scanning calorimetry (DSC), and the administering step comprises administering to the subject the crystalline solid in an amount of about 5 mg to about 15 mg once a day. In certain embodiments, the therapeutically effective amount of the crystalline solid of the compound of formula I is administered in an amount of about 2.5 mg to about 15 mg once a day. In certain embodiments, the therapeutically effective amount of the crystalline solid of the compound of formula I is administered in an amount of about 2.5 mg, about 5.0 mg, about 10 mg, or about 15 mg once a day.

[0011] In some embodiments, the crystalline solid has an XRPD pattern substantially as shown in Figure 1. In some embodiments, the crystalline solid has a DSC curve substantially as shown in Figure 2.

[0012] For those who need it, Formula III: Compound TIFF2024505515000004.tif35128, and Formula I: Compound TIFF2024505515000005.tif34128, or a pharma- ceutically acceptable salt thereof. Also provided herein is a method of treating childhood onset fluency disorder (COFD) in a subject in need thereof, comprising administering a therapeutically effective amount of

[0013] In certain embodiments, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 2.5 mg to about 5.0 mg once daily, and the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 5.0 mg to about 15 mg once daily.

[0014] Formula III: Compound of compound TIFF2024505515000006.tif35128, and A compound of formula I having an onset melting point of about 210° C. to about 214° C. as determined by DSC: Also provided herein is a crystalline solid of TIFF2024505515000007.tif34128, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 2.5 mg to about 5.0 mg once daily, and the crystalline solid of formula I or a pharma- ceutically acceptable salt thereof is administered at about 5.0 mg to about 15 mg once daily.

[0015] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will become apparent from the accompanying drawings, the description, and the appended claims. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 shows an exemplary XRPD pattern of a crystalline solid of the free base of the compound of Formula I. [Diagram 2] FIG. 2 shows an exemplary DSC curve for a crystalline solid of the free base of the compound of Formula I. [Diagram 3] FIG. 3 shows glucose levels during an oral glucose tolerance test in Sprague-Dawley rats following acute treatment with olanzapine (the compound of formula III) or haloperidol. [Figure 4]FIG. 4 shows insulin levels in Sprague-Dawley rats following an oral glucose challenge (2 g / kg). [Diagram 5] FIG. 5 shows oral glucose tolerance tests and glucose levels in Sprague-Dawley rats following acute treatment with olanzapine (the compound of formula III) or haloperidol. [Figure 6] FIG. 6 shows the body weight and food intake of Sprague-Dawley rats upon treatment with olanzapine (compound of formula III) or RO5545965 (compound of formula I). [Figure 7] FIG. 7 shows oral glucose tolerance tests and glucose levels in Sprague-Dawley rats following subchronic treatment with olanzapine (compound of formula III), RO5545965 (compound of formula I), or a combination of olanzapine (compound of formula III) and a compound of formula I. [Figure 8] FIG. 8 shows insulin levels in Sprague-Dawley rats before an oral glucose tolerance test with olanzapine (compound of formula III), RO5545965 (compound of formula I), and a combination of olanzapine (compound of formula III) and compound of formula I. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Detailed Description As generally described herein, the present disclosure provides a method for treating COFD in a subject in need thereof. The present disclosure also describes the use of the specific PDE10A inhibitor RO5545965 for treating COFD.

[0018] definition To facilitate the understanding of the present invention, several terms and expressions are defined below.

[0019] 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. The abbreviations used herein have their conventional meaning in the chemical and biological arts. The chemical structures and formulas described herein are constructed according to the standard rules of chemical valence known in the chemical arts.

[0020] Throughout the description, where compositions are described as having, including, or comprising particular components, or where 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 components, and that there are processes and methods of the invention that consist essentially of or consist of the recited processing steps.

[0021] In this application, when an element or component is said to be included in and / or selected from a list of described elements or components, it should be understood that the element or component can be any one of the described elements or components, or the element or component can be selected from a group consisting of two or more of the described elements or components.

[0022] Furthermore, it should be understood that the elements and / or features of the compositions or methods described herein, whether express or implied herein, may be combined in various ways without departing from the spirit and scope of the present invention.For example, when a specific compound is mentioned, that compound may be used in various aspects of the compositions of the present invention and / or in the methods of the present invention, unless otherwise interpreted from the context.In other words, although the embodiments have been described and illustrated in this application 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 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.

[0023] The articles "a" and "an" are used in this disclosure, unless the context is inappropriate, to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. As an example, "an element" means one element or more than one element.

[0024] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0025] The phrase "at least one of" should be understood to include each of the listed objects following the phrase individually, and various combinations of two or more of the listed objects, unless otherwise interpreted from context and usage. The phrase "and / or" in connection with three or more listed objects should be understood to have the same meaning, unless otherwise interpreted from context.

[0026] 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.

[0027] 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. For example, the term "about 10 mg" means an amount ranging from 10 mg with a ±10% variation from 10 mg, i.e., 9 mg to 11 mg.

[0028] At various places in this specification, 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, an integer in the range of 0 to 40 is 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 an integer in the range of 1 to 20 is 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.

[0029] The use of any examples or exemplary language herein, such as "such as" or "including," is intended only to better describe the invention and does not pose a limitation on the scope of the invention unless 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.

[0030] As a general matter, percentages of compositions specified are by weight unless otherwise indicated. Further, in the absence of a definition for any variable, the preceding definition of the variable shall prevail.

[0031] 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 in vivo or ex vivo diagnostic or therapeutic use.

[0032] "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 pharmacopoeias for use in animals, or more specifically, in humans.

[0033] As used herein, "pharmaceutically acceptable salt" refers to any salt of acidic or basic groups which may be present in the compounds of the invention (e.g., compounds of Formula (I)), which are compatible with pharmaceutical administration.

[0034] As known to those skilled in the art, the "salt" of a compound 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, are not themselves pharmaceutically acceptable, but may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0035] Examples of bases are alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and 1~4 Formula NW4 is an alkyl + and the like.

[0036] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, 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.

[0037] For therapeutic use, the salts of the compounds of the present disclosure are contemplated as being pharma- ceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may find use, for example, in the preparation or purification of a pharma- ceutically acceptable compound.

[0038] As used herein, "a pharma- ceutically 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 pharma- ceutically acceptable excipients include water, NaCl, normal saline 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, coatings, 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, can be mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, and / or flavorants 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).

[0039] "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.

[0040] As used herein, "solid dosage form" means a pharmaceutical dose in solid form, such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalants and chewables.

[0041] 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 (e.g., buccal, sublingual, nasal, or transdermal) administration, 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 injections, transdermal patches, and the like.

[0042] "Co-administer" means that the compositions described herein are administered simultaneously, immediately before, or immediately after the administration of one or more additional therapies (e.g., dopamine receptor antagonists, antipsychotics, or treatments for neurodevelopmental diseases).The PDE10A inhibitors or their pharmacologic acceptable salts described above can be administered alone or simultaneously to a subject.Co-administration means the 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 dopamine hyperactivity).

[0043] As used herein, the term "administered simultaneously" is not particularly limited and means that the components of the combination therapy are administered substantially simultaneously, for example, as a mixture or in immediate succession. As used herein, the term "administered sequentially" is not particularly limited and means that the components of the combination therapy are not administered simultaneously, but are administered one by one or in groups with a specific time interval.

[0044] As used herein, unless otherwise stated, the terms "treat", "treating" and "treatment" contemplate actions taken during a subject's 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"). A subject is effectively treated if a clinically beneficial result is obtained. This may mean, for example, a complete or significant disappearance of symptoms of the disorder, a reduction in the frequency, severity and / or duration of symptoms, or a delay in the progression of the disorder. Thus, effective treatment may be manifested as a reduction in the number, duration, frequency and / or intensity of repetitions, prolongations, stammers and interruptions in speech fluency observed in the subject.

[0045] As used herein, the phrase "therapeutically effective amount" refers to an amount of a composition (e.g., a composition described herein) or a compound of Formula I or a pharma- ceutically acceptable salt thereof effective to produce some desired therapeutic effect in a subject.

[0046] Childhood-onset fluency disorder (COFD), also known as stuttering, stammering, or dysphemia, is a communication disorder characterized by involuntary repetition and prolongation of sounds, syllables, words, or phrases, or involuntary silences or blocks during which the stutterer is unable to produce speech. In certain embodiments, administration of a composition (e.g., a composition described herein) improves the symptoms of COFD.

[0047] In certain embodiments, one or more compounds disclosed herein are useful for treating speech and language disorders, including expressive language disorder, mixed receptive-expressive language disorder, phonological disorder, and communication disorder not otherwise specified (DSM-IV).

[0048] The term "stuttering" encompasses a wide range of severity, from a mostly superficial, barely noticeable impediment to severe symptoms that virtually prevent oral communication. Nearly 70 million people worldwide stutter, of whom four-fifths are men. Lifelong sufferers typically experience a significant worsening of symptoms when they reach their seventh and eighth decades.

[0049] The impact of COFD on a person's activities and mental state can be profound. This can include fear of having to pronounce certain vowels or consonants, fear that the stuttering will be revealed in social situations, self-imposed isolation, anxiety, stress, shame, low self-esteem, potential target of bullying (especially in children), having to paraphrase and rearrange words in sentences to hide the stuttering, or a feeling of "not being in control" when speaking. Symptoms of COFD begin between the ages of 2 and 7, with 80-90% of cases beginning by age 6. Mild stuttering is common in children who are beginning to speak, but if this behavior persists over time and causes distress to the child, it becomes a fluency disorder.

[0050] Phosphodiesterase inhibitors Phosphodiesterases are a diverse family of enzymes that hydrolyze cyclic nucleotides and thus play an important role in regulating intracellular levels of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). In certain embodiments, compounds of the present disclosure block the enzyme phosphodiesterase, thereby preventing the activation of one or more intracellular second messengers.

[0051] compound As described in the Summary section above, a PDE10A inhibitor that may be used in the methods of the present invention may be one of the following compounds, or a pharma- ceutically acceptable salt thereof. TIFF2024505515000008.tif126158

[0052] The synthesis of the PDE10A inhibitors listed above can follow procedures known in the art.For example, the method of chemically synthesizing the compound RO5545965 (including Example 1 provided herein below) is described in US Patent No. 8,349,824, which is incorporated by reference in its entirety.

[0053] The compound of formula I shown below is a phosphodiesterase 10A (PDE10A) inhibitor, also known as RO5545965, which has the chemical name 1-methyl-4-(morpholine-4-carbonyl)-N-(2-phenyl[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide.

[0054] The structure of the compound of formula 1: TIFF2024505515000009.tif33128 The term "compound of formula I" may also be referred to as "compound 1" or "RO554965."

[0055] In various embodiments, the pharma- ceutically 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.

[0056] The compound of formula III shown below is also known as Olanzapine or ZYPREXA, which has the chemical name 10H-thieno[2,3-b][1,5]benzodiazepine, 2-methyl-4-(4-methyl-1-piperazinyl)-, or 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine and the CAS number 132539-06-1.

[0057] The structure of the compound of formula III: TIFF2024505515000010.tif35128 The term "compound of formula III" may also be referred to as "compound 3" or "olanzapine."

[0058] In various embodiments, the pharma- ceutically acceptable salt of the compound of formula III can be a salt of the compound of formula III 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.

[0059] The present disclosure includes administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent or a pharma- ceutically acceptable salt thereof, wherein the therapeutic agent has Formula I: The compound of TIFF2024505515000011.tif43128 (also known as RO5545965) is included in the methods for treating COFD.

[0060] In certain embodiments, the compound is administered in an amount of about 1 mg to about 17 mg once per day. In certain embodiments, the compound is administered in an amount of about 2.5 mg to about 15 mg once per day. In some embodiments, the compound is administered in an amount of about 5 mg to about 15 mg once per day. In certain embodiments, the therapeutic agent is the free base of the compound of Formula I (i.e., RO5545965) or a pharma- ceutically acceptable salt thereof, and is administered in an amount of about 2.0 mg, about 2.5 mg, about 5.0 mg, about 10 mg, or about 15 mg once per day.

[0061] The present disclosure provides to a subject in need thereof a compound comprising a compound of formula I: Also included are methods of treating COFD, comprising administering a composition containing a therapeutically effective amount of a crystalline solid of the compound of TIFF2024505515000012.tif40128, wherein the crystalline solid has an onset of melting of about 210°C to about 214°C (e.g., about 210°C, about 211°C, about 212°C, about 213°C, or about 214°C) as determined by differential scanning calorimetry (DSC), and the administering step comprises administering the crystalline solid in an amount of about 5 mg to about 15 mg once daily.

[0062] The present disclosure provides to a subject in need thereof a compound comprising a compound of formula I: Also included are methods of treating COFD, comprising administering a composition containing a therapeutically effective amount of a crystalline solid of the compound of TIFF2024505515000013.tif40128, wherein the crystalline solid has an onset of melting of about 210°C to about 214°C (e.g., about 210°C, about 211°C, about 212°C, about 213°C, or about 214°C) as determined by differential scanning calorimetry (DSC), and the administering step comprises administering the crystalline solid in an amount of about 2.5 mg to about 15 mg once daily.

[0063] For those who need it, Formula III: Compound TIFF2024505515000014.tif35128, and Formula I: Compound TIFF2024505515000015.tif33128, or a pharma- ceutically acceptable salt thereof. Also provided herein is a method of treating childhood onset fluency disorder (COFD) in a subject in need thereof, comprising administering a therapeutically effective amount of

[0064] In certain embodiments, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 2.5 mg to about 5.0 mg once daily, and the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 5.0 mg to about 15 mg once daily.

[0065] Formula III: Compound of compound TIFF2024505515000016.tif35128, and having an onset melting point of about 210° C. to about 214° C. as determined by DSC, Formula I: TIFF2024505515000017.tif34128 crystalline solid, or a pharma- ceutically acceptable salt thereof are also provided herein.

[0066] In some embodiments, said crystalline solid of the free base of Formula I has an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0067] In some embodiments, said crystalline solid of the free base of Formula I has a DSC diagram substantially as shown in FIG.

[0068] Pharmaceutical Compositions In one aspect, provided herein is a method of treating COFD using a pharmaceutical composition comprising a PDE10A inhibitor (e.g., the compound of Formula I or RO5545965) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, for the treatment of COFD in a subject in need thereof.

[0069] Typically, the PDE10A inhibitors used in the methods of the invention do not affect insulin resistance.

[0070] In various embodiments, the methods administer a composition comprising a PDE10A inhibitor, or a pharma- ceutically acceptable salt thereof, as the only active agent.

[0071] In various embodiments, the methods involve administering a composition comprising a PDE10A inhibitor, or a pharma- ceutically acceptable salt thereof, in combination with another therapeutically active agent.

[0072] In some embodiments, the other therapeutically active agent is a dopamine receptor antagonist.

[0073] In some embodiments, the other therapeutically active agent is a dopamine receptor D1 (DRD1) antagonist. An exemplary DRD1 antagonist is ecopipam.

[0074] In some embodiments, the other therapeutically active agent is a dopamine receptor D2 (DRD2) antagonist. Exemplary DRD2 antagonists are olanzapine, risperidone, lurasidone, or pimozide.

[0075] In various embodiments, the amount of a PDE10A inhibitor (e.g., the compound of Formula I, also known as RO5545965) or a pharma- ceutically acceptable salt thereof in the pharmaceutical compositions described herein can be from about 1 mg to about 100 mg, from about 2 mg to about 50 mg, from about 3 mg to about 20 mg, from about 5 mg to about 15 mg, from about 5 mg to about 10 mg, or from about 2.5 mg to about 15 mg.

[0076] In certain embodiments, the amount of a PDE10A inhibitor (e.g., a compound of Formula I or RO5545965) or a pharma- ceutical acceptable salt thereof in the pharmaceutical compositions described herein is from about 1.0 mg to about 17 mg, from about 2.0 mg to about 16 mg, from about 2.5 mg to about 15 mg, from about 5.5 mg to about 15 mg, from about 6 mg to about 15 mg, from about 6.5 mg to about 15 mg, from about 7 mg to about 15 mg, from about 7.5 mg to about 15 mg, 5 mg, about 8 mg to about 15 mg, about 8.5 mg to about 15 mg, about 9 mg to about 15 mg, about 9.5 mg to about 15 mg, about 10 mg to about 15 mg, about 10.5 mg to about 15 mg, about 11 mg to about 15 mg, about 11.5 mg to about 15 mg, about 12 mg to about 15 mg, about 12.5 mg to about 15 mg, about 13 mg to about 15 mg, about 13.5 mg to about 15 mg, or about 14 mg to about 15 mg.

[0077] In certain embodiments, the amount of a PDE10A inhibitor (e.g., a compound of Formula I or RO5545965) or a pharma- ceutically acceptable salt thereof in a pharmaceutical composition described herein can be about 5 mg to about 14.5 mg, about 5 mg to about 14 mg, about 5 mg to about 13.5 mg, about 5 mg to about 13 mg, about 5 mg to about 12.5 mg, about 5 mg to about 12 mg, about 5 mg to about 11.5 mg, about 5 mg to about 11 mg, about 5 mg to about 10.5 mg, about 5 mg to about 10 mg, about 5 mg to about 9.5 mg, about 5 mg to about 9 mg, about 5 mg to about 8.5 mg, about 5 mg to about 8 mg, about 5 mg to about 7.5 mg, about 5 mg to about 7 mg, about 5 mg to about 6.5 mg, or about 5 mg to about 6 mg.

[0078] In certain embodiments, the amount of a PDE10A inhibitor (e.g., a compound of Formula I or RO5545965) or a pharma- ceutically acceptable salt thereof in a pharmaceutical composition described herein can be from about 5 mg to about 15 mg (e.g., 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 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, or about 15 mg).

[0079] In some embodiments, the PDE10A inhibitor or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 100 mg once daily.

[0080] In some embodiments, the PDE10A inhibitor or a pharma- ceutically acceptable salt thereof is administered at about 5 mg to about 15 mg once daily.

[0081] In some embodiments, the other therapeutically active agent is administered at about 0.1 mg to about 10 mg once daily.

[0082] In some embodiments, the other therapeutically active agent is administered at about 0.5 mg to about 5 mg once daily.

[0083] In some embodiments, the PDE10A inhibitor or a pharma- ceutically acceptable salt thereof is administered at about 5 mg to about 15 mg once daily, and the dopamine receptor antagonist is administered at about 0.5 mg to about 5 mg once daily.

[0084] In certain embodiments, the PDE10A inhibitor or a pharma- ceutically acceptable salt thereof is administered at about 5 mg to about 15 mg once daily, and the compound of formula III is administered at about 2.5 mg to about 5.0 mg once daily. In certain embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 5 mg to about 15 mg once daily, and the compound of formula III is administered at about 2.5 mg to about 5.0 mg once daily.

[0085] In an embodiment, the amount of the compound of formula III or a pharma- ceutically acceptable salt thereof in the pharmaceutical compositions described herein can be about 2.5 mg to about 5.0 mg (e.g., 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, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg).

[0086] In various embodiments, the amount of the compound of formula I or a pharma- ceutically acceptable salt thereof in the pharmaceutical compositions described herein may be about 1.0 mg to about 17 mg. In various embodiments, the amount of the compound of formula I or a pharma- ceutically acceptable salt thereof in the pharmaceutical compositions described herein may be about 2.5 mg to about 15 mg. In certain embodiments, the amount of the compound of formula I or a pharma- ceutically acceptable salt thereof in the pharmaceutical compositions described herein may be about 2.5 mg. In certain embodiments, the amount of the compound of formula I or a pharma- ceutically acceptable salt thereof in the pharmaceutical compositions described herein may be about 5.0 mg. In certain embodiments, the amount of the compound of formula I or a pharma- ceutically acceptable salt thereof in the pharmaceutical compositions described herein may be about 10 mg. In certain embodiments, the amount of the compound of formula I or a pharma- ceutically acceptable salt thereof in the pharmaceutical compositions described herein may be about 15 mg.

[0087] In certain embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 2.5 mg to about 15 mg once daily.

[0088] In certain embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 2.5 mg once daily.

[0089] In certain embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 5.0 mg once daily.

[0090] In certain embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 10 mg once daily.

[0091] In certain embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 15 mg once daily.

[0092] In various embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the free base form of the compound of formula I.

[0093] In various embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a pharma- ceutically acceptable salt of a compound of formula I. In some embodiments, the pharma- ceutically 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.

[0094] The pharmaceutical compositions provided herein may 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. In certain embodiments, the pharmaceutical compositions disclosed herein are administered orally.

[0095] The pharmaceutical compositions provided herein may be administered chronically ("chronic administration").Chronic administration refers to administration of the compound or its pharmaceutical composition for an extended period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely, such as for the lifetime of the subject.In certain embodiments, chronic administration is intended to maintain the concentration of the compound in the blood constant, such as within the therapeutic window for an extended period of time.

[0096] 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 material calculated to produce a desired therapeutic effect in association with suitable pharmaceutical excipients.In various aspects, the pharmaceutical dosage forms described herein may be administered as unit doses.Exemplary unit dosage forms include pre-measured and pre-filled ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc., in the case of solid compositions.

[0097] In various embodiments, the pharmaceutical compositions provided herein are administered to a patient in a solid dosage form. In certain embodiments, the solid dosage form is a capsule. In certain embodiments, the solid dosage form is a tablet.

[0098] In various embodiments, the pharmaceutical compositions provided herein contain a compound of Formula I as the sole active agent, or in combination with other active agents.

[0099] 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 any type of animal. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and a veterinary pharmacologist of ordinary skill could design and / or perform 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 21 st ed., Lippincott Williams & Wilkins, 2005.

[0100] Methods of Use and Treatment In one aspect, the method comprises administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent or a pharma- ceutically acceptable salt thereof, wherein the therapeutic agent has Formula I: Provided herein is a method for treating COFD in a subject in need thereof, the compound of TIFF2024505515000018.tif43128.

[0101] In various embodiments, the step of administering a therapeutically effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof comprises administering a composition having an amount of the compound as described herein above.

[0102] In various embodiments, the composition comprises a compound of formula I, or a pharma- ceutically acceptable salt thereof, as the only active agent.

[0103] In various embodiments, the composition comprises a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with another active agent, which in certain embodiments is a dopamine receptor antagonist (e.g., a D1 antagonist or a D2 antagonist).

[0104] 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.

[0105] In various embodiments, administering comprises administering the compound of formula I or a pharma- ceutically acceptable salt thereof in a capsule.

[0106] In various embodiments, the capsule shell is comprised of gelatin, titanium dioxide, red iron oxide, and yellow iron oxide.

[0107] In various embodiments, the capsules described above contain the compound of formula I (or RO5545965) or a pharma- ceutically acceptable salt thereof in an amount of about 1 mg to about 100 mg, about 2 mg to about 50 mg, about 3 mg to about 20 mg, or about 5 mg to about 15 mg. In certain embodiments, the capsules described above contain the compound of Formula I (or RO5545965) or a pharma- ceutically acceptable salt thereof in an amount of about 5.5 mg to about 10 mg, about 6 mg to about 10 mg, about 6.5 mg to about 10 mg, about 7 mg to about 10 mg, about 7.5 mg to about 10 mg, about 8 mg to about 10 mg, about 8.5 mg to about 10 mg, about 9 mg to about 10 mg, about 5 mg to about 9.5 mg, about 5 mg to about 9 mg, about 5 mg to about 8.5 mg, about 5 mg to about 8 mg, about 5 mg to about 7.5 mg, about 5 mg to about 7 mg, about 5 mg to about 6.5 mg, or about 5 mg to about 6 mg.

[0108] In certain embodiments, the capsules described above contain the compound of formula I (or RO5545965) or a pharma- ceutically acceptable salt thereof in an amount of about 5 mg to about 15 mg (e.g., 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).

[0109] In various embodiments, the capsule described above contains the compound of formula I (or RO5545965) or a pharma- ceutically acceptable salt thereof in an amount of about 1.0 mg to about 17 mg. In various embodiments, the capsule described above contains the compound of formula I (or RO5545965) or a pharma- ceutically acceptable salt thereof in an amount of about 2.5 mg to about 15 mg. In certain embodiments, the capsule described above contains the compound of formula I (or RO5545965) or a pharma- ceutically acceptable salt thereof in an amount of about 2.5 mg. In certain embodiments, the capsule described above contains the compound of formula I (or RO5545965) or a pharma- ceutically acceptable salt thereof in an amount of about 5.0 mg. In certain embodiments, the capsule described above contains the compound of formula I (or RO5545965) or a pharma- ceutically acceptable salt thereof in an amount of about 10 mg.

[0110] In some embodiments, administering comprises administering the compound of Formula I (or RO5545965) or a pharma- ceutically acceptable salt thereof once daily in an amount of about 5 mg to about 15 mg.

[0111] In some embodiments, administering comprises administering the compound of formula I (or RO5545965) or a pharma- ceutically acceptable salt thereof in an amount of about 2.5 mg to about 15 mg once per day. In some embodiments, administering comprises administering the compound of formula I (or RO5545965) or a pharma- ceutically acceptable salt thereof in an amount of about 2.5 mg once per day. In some embodiments, administering comprises administering the compound of formula I (or RO5545965) or a pharma- ceutically acceptable salt thereof in an amount of about 5.0 mg once per day. In some embodiments, administering comprises administering the compound of formula I (or RO5545965) or a pharma- ceutically acceptable salt thereof in an amount of about 10 mg once per day. In some embodiments, administering comprises administering the compound of formula I (or RO5545965) or a pharma- ceutically acceptable salt thereof in an amount of about 15 mg once per day.

[0112] In various embodiments, administering comprises administering the compound of formula I or a pharma- ceutically acceptable salt thereof in an immediate release formulation.

[0113] In various embodiments, administering comprises administering the compound of Formula I or a pharma- ceutically acceptable salt thereof in a sustained release formulation.

[0114] In various embodiments, the administration remains effective throughout the day.

[0115] In various embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once, twice, three times, four times, or five times per day. In various embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once per day. In certain embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice per day.

[0116] In various embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is administered orally.

[0117] In various embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is administered as a unit dose.

[0118] In various embodiments, the compound of formula I is administered in free base form.

[0119] In various embodiments, the compound of formula I is administered in the form of 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 acid such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid, or with 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.In certain embodiments, the compound of formula I is administered in crystalline form.

[0120] For those who need it, Formula III: Compound TIFF2024505515000019.tif35128, and Formula I: Compound TIFF2024505515000020.tif34128, or a pharma- ceutically acceptable salt thereof. Also provided herein is a method of treating childhood onset fluency disorder (COFD) in a subject in need thereof, comprising administering a therapeutically effective amount of

[0121] In an embodiment, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 500 mg once daily, and the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 500 mg once daily.

[0122] In an embodiment, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 50 mg once daily, and the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 50 mg once daily.

[0123] In an embodiment, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 30 mg once daily, and the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 500 μg to about 20 mg once daily.

[0124] In an embodiment, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 0.1 mg to about 10 mg once daily, and the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 20 mg once daily.

[0125] In an embodiment, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 2.5 mg to about 5.0 mg once daily, and the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 5.0 mg to about 15 mg once daily.

[0126] In an embodiment, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 2.5 mg to about 5.0 mg (e.g., about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg) once daily, and the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 5.0 mg to about 15 mg (e.g., about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg) once daily.

[0127] In an embodiment, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 6.0 mg once daily, and the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 4.0 mg to about 16 mg once daily. In an embodiment, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at 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, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 ... 0.8 mg, about 4.9 mg, about 5.0 mg, and the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 5.0 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 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, or about 15 mg.

[0128] In embodiments, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 1 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5 mg, about 5.5 mg, or about 6 mg once daily, and the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 7.5 mg, about 8.0 mg, about 8.5 mg, about 9.0 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 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, or about 16 mg once daily.

[0129] In an embodiment, the compound of formula I and the compound of formula III, or pharma- ceutically acceptable salts thereof, are administered simultaneously. In an embodiment, the compound of formula I and the compound of formula I, or pharma- ceutically acceptable salts thereof, are administered sequentially.

[0130] In an embodiment, the compound of formula III is present in a single dosage form and the compound of formula I is present in another dosage form. In an embodiment, the compound of formula III, the compound of formula I, or both the compound of formula III and the compound of formula I, or pharma- ceutically acceptable salts thereof, are administered intravenously, intramuscularly, or orally. In an embodiment, the compound of formula III and the compound of formula I are included in a composition, and the composition is in aerosol, inhalable powder, injectable, liquid, solid, capsule, or tablet form. In an embodiment, the composition further comprises an agent selected from the group consisting of mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silicon dioxide, and sodium stearyl fumarate. In an embodiment, the composition further comprises an additive selected from the group consisting of gelatin, titanium dioxide, red iron oxide, and yellow iron oxide.

[0131] For those who need it, Formula III: Compounds of TIFF2024505515000021.tif35128, and Formula I: TIFF2024505515000022.tif34128 crystalline solid, or Pharmaceutically acceptable salts thereof Also provided herein is a method of treating childhood-onset dysfluid syndrome (COFD) in a subject in need thereof, comprising administering a therapeutically effective amount of the crystalline solid having an onset melting point of about 210° C. to about 214° C. as determined by DSC.

[0132] In some embodiments, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 500 mg once a day, and the crystalline solid of formula I or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 500 mg once a day. In some embodiments, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 50 mg once a day, and the crystalline solid of formula I or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 50 mg once a day. In some embodiments, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 30 mg once a day, and the crystalline solid of formula I or a pharma- ceutically acceptable salt thereof is administered at about 500 μg to about 20 mg once a day. In an embodiment, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 2.5 mg to about 5.0 mg once daily, and the crystalline solid of formula I or a pharma- ceutically acceptable salt thereof is administered at about 5.0 mg to about 15 mg once daily. In an embodiment, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 1 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5 mg, about 5.5 mg, or about 6 mg once daily, and the crystalline solid of formula I or a pharma- ceutically acceptable salt thereof is administered at about 4.0 mg, about 4.5 mg, about 5. 0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 7.5 mg, about 8.0 mg, about 8.5 mg, about 9.0 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 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, or about 16 mg.

[0133] In some embodiments, the compound of formula III and the crystalline solid compound of formula I, or a pharma- ceutically acceptable salt thereof, are administered simultaneously. In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, are administered sequentially. In some embodiments, the compound of formula III is present in a single dosage form and the crystalline solid of formula I is present in another dosage form. In some embodiments, the compound of formula III, the crystalline solid of formula I, or both the compound of formula III and the crystalline solid of formula I, or a pharma- ceutically acceptable salt thereof, are administered intravenously, intramuscularly, or orally. In some embodiments, the compound of formula III and the crystalline solid of formula I are included in a composition, and the composition is in aerosol, inhalable powder, injectable, liquid, solid, capsule, or tablet form. In some embodiments, the composition further comprises an agent selected from the group consisting of mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silicon dioxide, and sodium stearyl fumarate. In some embodiments, the composition further comprises an additive selected from the group consisting of gelatin, titanium dioxide, red iron oxide, and yellow iron oxide.

[0134] A subject in need thereof is administered a therapeutically effective amount of Formula III: Compound TIFF2024505515000023.tif35128, and Formula I: Compound TIFF2024505515000024.tif34128, or a pharmaceutically acceptable salt thereof, wherein the compound of formula III or a pharmaceutically acceptable salt thereof is administered at about 2.5 mg to about 5.0 mg once daily, and the compound of formula I or a pharmaceutically acceptable salt thereof is administered at about 5.0 mg to about 15 mg once daily.

[0135] A subject in need thereof is administered a therapeutically effective amount of Formula III: Compound TIFF2024505515000025.tif35128, and Formula I: Crystalline solids in TIFF2024505515000026.tif34128, or a pharmaceutically acceptable salt thereof, wherein the compound of formula III or a pharmaceutically acceptable salt thereof is administered at about 2.5 mg to about 5.0 mg once daily, and the crystalline solid of formula I or a pharmaceutically acceptable salt thereof is administered at about 5.0 mg to about 15 mg once daily.

[0136] 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. EXAMPLES

[0137] The following examples are provided to facilitate a more detailed 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.

[0138] 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. 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) to give 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-bromo-pyridinium 2,4,6-trimethyl-benzenesulfonate (16.74 g, 82.7%) as white crystals. mp.: 176-180 °C. MS: m / z = 188.2, 190.2 (M+H+).

[0139] Step B - 7-Bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine: 1,2-Diamino-4-bromo-pyridinium 2,4,6-trimethyl-benzenesulfonate (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 red-brown solution which became 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 + ).

[0140] Step C - (2-Phenyl-[1,2,4]triazolyl[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) were added successively 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 at 100° C. under nitrogen atmosphere 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 about 80 ml: crystallization. The suspension was stirred in an ice bath for 10 min, the solid was filtered off, 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%.

[0141] 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 at room temperature overnight. With cooling the suspension was diluted with water (ca. 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 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 + ).

[0142] 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 min. 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 + ).

[0143] 2. 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 to give a colourless solution after 20 min. The methanol was removed in vacuo, the residue diluted with water and the cooled aqueous solution neutralised 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+).

[0144] 3. 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 umol) 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").

[0145] Example 2: 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. The XRPD patterns may be obtained according to protocols known in the art.

[0146] Melting point: The maximum melting point peak of the crystalline form (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 40uL 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 was used to determine the T of the crystalline form. m This indicates that the temperature was 213.16°C.

[0147] Solubility: The above crystalline form showed 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. The 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 was still somewhat low. Overall, the crystalline form showed low solubility at ambient temperature (22 °C) not only in aqueous systems but also in most organic solvents tested (<50 mg / mL).

[0148] Stability: Preliminary forced degradation studies of the crystalline form of the free base 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).

[0149] 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 in open (75% RH) or closed (ambient) conditions at the indicated temperatures and times. After incubation, the compound was 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 show that the crystalline form was stable (<0.5% decomposition products) at various temperatures in the solid state, e.g., at 40-60°C for at least 4 weeks.

[0150] Table 5. Preliminary solid state stability TIFF2024505515000027.tif53128

[0151] The crystalline form of the free base of the compound of formula I was stable in the solid state at 80°C and in solutions at room temperature with pH between 3 and 7 for up to 8 days. Decomposition was observed at higher or lower pH. The crystalline form was stable after exposure to light in the solid state. In solution, it was stable to sunlight and, in a time-dependent manner, was of moderate to unstable stability in Suntest. It was also stable to oxidation for 1 day, but showed some sensitivity on sustained exposure. The crystalline form was compatible with almost all excipients, but drug recovery in the CompaS assay was highly dependent on the solvent used for extraction.

[0152] In the suspension vehicle (0.5% HPC / 1% Tween 80) used for PK, PD, and Tox studies, the crystalline form was also stable at room temperature for up to 5 weeks with only minor 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 a stability of at least 4 weeks at 40°C.

[0153] Example 3: Safety and Efficacy Study of Compound of Formula I for the Treatment of Subjects with COFD 1. Research A Provided below is an open-label, Phase IIa, multicenter, 6-week prospective study to evaluate the safety and efficacy of compound of Formula I at a daily dose range of 5 mg to 15 mg in adult male patients with COFD.

[0154] Study design TIFF2024505515000028.tif144162

[0155] 2. Research B Provided below is the study design for a double-blind, placebo-controlled, Phase IIb, multicenter, 6-10 week prospective study to evaluate the efficacy and safety of a compound of formula I (i.e., compound 1, RO5545965), a PDE10A inhibitor, at a daily dose range of 2.5 mg to 15 mg in adult male patients with COFD. The endpoint refers to the first visit after the last dose of study drug.

[0156] Overall Design: After screening to confirm eligibility, on day -7 participants enter a run-in period with various placebos for up to 5 weeks. Beginning at the baseline visit (day 1), participants may be randomized to double-blind, placebo-controlled, parallel-group treatment with either the compound of Formula I or placebo once daily. During the first 3-week treatment period after randomization, participants receive increasing doses of the compound of Formula I or double-blind increasing doses of placebo until they reach the maximum tolerated dose. Participants are then maintained on this dose until they complete the total 10-week treatment period.

[0157] Population: An estimated total of 67 male participants aged 18-50 years who meet DSM-5 criteria for childhood onset dysfluency disorder (COFD) and require pharmacotherapy, have a history of stuttering > 2 years, and have had developmental stuttering by age 8 years, will be enrolled in the study. It is estimated that 60 participants will be randomized to receive either the compound of Formula I or a placebo.

[0158] Objectives and Endpoints: TIFF2024505515000029.tif218149

[0159] Exclusion criteria: Patients were excluded from the study if they met any of the following criteria: Medical Conditions: 1. The stuttering is associated with a known neurological cause, for example, a stroke. 2. Researchers believe that they have a low IQ. 3. The patient has an uncontrolled seizure disorder. 4. Have a history of severe traumatic brain injury or stroke. 5. In the investigator's opinion, the patient is at high risk of suicide. 6. Known positive human immunodeficiency virus test. 7. Known DSM-5 diagnosis of substance abuse or dependence. 8. Have unstable medical disease or clinically significant abnormalities on screening tests / examinations. 9.Has any unstable medical condition or current illness (e.g., congenital heart disease, arrhythmia, or cancer) that, in the opinion of the investigator, places the patient at risk for serious adverse events during the study or is expected to progress during the study, or which would interfere with the evaluation of safety and efficacy. Upfront / concomitant therapy: 10. Has had new behavioral treatment for stuttering initiated within 10 weeks prior to baseline. Prior / concurrent clinical research experience: 11. Participation in another clinical study involving IP administration within the past 30 days. 12. Participant has known hypersensitivity to Compound 1 or any of the product excipients. Diagnostic assessment: 13. Have a positive urine drug test for cocaine or non-prescribed opiates. Other exclusions: 14. Involved in the design and / or conduct of the study (applies to both Noema staff and / or research facility staff). 15. The investigator determines that the participant is unlikely to comply with study procedures, restrictions, and requirements and should not participate in the study. 16. Previously randomly assigned to this study.

[0160] Product Description: TIFF2024505515000030.tif46128

[0161] Dose levels of the compound of formula I will be slowly escalated from a starting dose of 2.5 mg to a maximum dose of 15 mg according to the tolerability demonstrated by the individual participant.

[0162] Example 4: Study of the effect of the compound of formula III (olanzapine) and the compound of formula I (RO5545965) on glucose tolerance (Ogtt) Three consecutive studies were performed to evaluate the effect of olanzapine (the compound of formula III) and the compound of formula I (RO5545965) on glucose tolerance.

[0163] The first objective was to select healthy rats as a predictive model to characterize metabolic side effects caused by olanzapine (compound of formula III). The study was performed in 10-week-old male SD rats fed a chow diet. A glucose challenge was performed 1 h after the last treatment. Glucose loading was performed by oral gavage (2 g / kg body weight) and formulations were prepared in saline. Details of the formulations are shown in Table 1. Blood glucose and plasma insulin were measured at 0 (before challenge), +15, +30, +60 and +120 min. Blood was collected in EDTA-coated tubes and blood samples were kept on ice until centrifugation at 4°C. ELISA for insulin (Mercodia, Uppsala Sweden) and fluorometric analysis for glucose measurement (AccuCheck System) were used for analysis. Data analysis was performed using the software JMP for Windows (Version 5.01, SAS institute Inc., SAS Campus Drive, Cary, NC 27513). Analysis of variance ANOVA (alpha 0.05 and 0.01) followed by Dunnett's test (comparison to control).

[0164] (Table 1) Formulation TIFF2024505515000031.tif33158Vehicle: 0.3% Tween in water.

[0165] Glucose levels during the oral glucose tolerance test are shown in Figure 3, and insulin levels during the oral glucose tolerance test are shown in Figure 4. The study showed that acute treatment of SD rats with olanzapine induced a dose-dependent increase in fasting blood glucose, a dose-dependent glucose intolerance, and a dose-dependent increase in fasting insulin. Overall, the study revealed that olanzapine induced glucose intolerance.

[0166] The second study evaluated the effect of acute treatment with the compound of formula I. The study was performed in chow-fed male SD rats aged 9 weeks. A glucose challenge was performed 1 hour after treatment. Glucose loading was performed by oral gavage (2 g / kg body weight) and the formulations were prepared in saline. Details of the formulations are shown in Table 2. Blood glucose and plasma insulin were measured at 0 (before challenge), +15, +30, +60 and +120 min. Blood was collected in EDTA-coated tubes and blood samples were kept on ice until centrifugation at 4°C. ELISA for insulin (Mercodia, Uppsala Sweden) and fluorimetric analysis for glucose measurement (AccuCheck System) were used for analysis. Data analysis was performed using the software JMP for Windows (Version 5.01, SAS institute Inc., SAS Campus Drive, Cary, NC 27513). Analysis of variance ANOVA (alpha 0.05 and 0.01) followed by Dunnett's test (comparison to control).

[0167] (Table 2) Formulation TIFF2024505515000032.tif30156Vehicle: 0.3% Tween in water.

[0168] Glucose levels during oral glucose tolerance test are shown in Figure 5. The study showed that acute treatment of SD rats with olanzapine induced an increase in fasting blood glucose and glucose intolerance. The details of the formulation are shown in Table 3. The study also showed that acute treatment with the compound of formula I did not induce any changes in glucose tolerance. The third study evaluated the subchronic (8 days) effect of the compound of formula I alone or in combination with olanzapine. The study was performed in 10-week-old male SD rats on chow diet. A glucose challenge was performed 1 hour after treatment. Glucose loading was performed by oral gavage (2 g / kg body weight (water)). Blood glucose was measured by glucometer at 0 (before challenge), +15, +30, +60 and +120 min. Insulin was measured only at time 0. Blood was collected in EDTA-coated tubes and blood samples were kept on ice until centrifugation at 4°C. ELISA for insulin (Mercodia, Uppsala Sweden) and fluorometric assay for glucose measurement (AccuCheck System) were used for the analysis. Data analysis was performed using the software JMP for Windows (Version 5.01, SAS institute Inc., SAS Campus Drive, Cary, NC 27513). Analysis of variance ANOVA (alpha 0.05 and 0.01) followed by Dunnett's test (comparison to control).

[0169] (Table 3) Formulation TIFF2024505515000033.tif25158Vehicle: 0.3% Tween 80 in water.

[0170] Body weight and food intake are shown in FIG. 6, glucose levels during oral glucose tolerance test are shown in FIG. 7, and insulin levels before oral glucose tolerance test are shown in FIG. 8. The study showed that acute treatment of SD rats with olanzapine induced an increase in fasting blood glucose and glucose intolerance, and the effects on glucose and insulin were similar to those reported in two previous studies performed under similar conditions. Repeated treatment with the compound of formula I, when administered in combination with olanzapine, slightly improved glucose intolerance, did not change fasting blood glucose, and reduced fasting insulin compared to olanzapine alone. The study showed that the compound of formula I, alone or in combination, did not induce glucose intolerance in healthy rats. On the contrary, the study showed that the compound of formula I alone induced a slight improvement in glucose intolerance after 8 days of treatment. The study showed the persistence of glucose intolerance induced by olanzapine.

[0171] Example 5: Compositions containing Compound 1 The composition of a 10 mg strength capsule containing the compound of formula I (i.e., Compound 1, RO5545965) is set forth below: The capsule is characterized as being reddish brown, opaque, size 1 hard capsule. TIFF2024505515000034.tif85137 a Purified water (Ph. Eur.) is used for wet granulation; this is substantially removed during processing.

[0172] The composition of a 5 mg strength capsule containing the compound of formula I (i.e., Compound 1, RO5545965) is set forth below: The capsule is characterized as being a reddish-brown, opaque, size 1 hard capsule. TIFF2024505515000035.tif85128 a Purified water (Ph. Eur.) is used for wet granulation; this is substantially removed during processing.

[0173] Provided below are capsules in 2.5 mg strength containing the compound of formula I (i.e., Compound 1, RO5545965). The capsules are characterized as being reddish brown, opaque, size 1 hard capsules. TIFF2024505515000036.tif93133 a Purified water (Ph. Eur.) is used for wet granulation; this is substantially removed during processing.

[0174] INCORPORATION BY REFERENCE This application refers to 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 expressly set forth herein, since such aspects are deemed to be known to those skilled in the art. Any particular aspect of the disclosure may be excluded from any claim for any reason, whether related to the existence of prior art or not.

[0175] 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 therefore 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. A pharmaceutical comprising a phosphodiesterase 10A (PDE10A) inhibitor or a pharma- ceutical acceptable salt thereof for use in a method for treating childhood-onset dysfluency disorder (COFD), comprising: The method comprises administering to a subject the PDE10A inhibitor or a pharma- ceutical acceptable salt thereof. The said medicine.

2. The method according to claim 1, wherein the administering step comprises administering the PDE10A inhibitor or a pharma- ceutically acceptable salt thereof once a day.

3. The pharmaceutical composition according to claim 1 or 2, wherein the administering step comprises orally administering a PDE10A inhibitor or a pharma- ceutically acceptable salt thereof.

4. The method according to any one of claims 1 to 3, wherein the administering step comprises administering the PDE10A inhibitor or a pharma- ceutically acceptable salt thereof as a unit dose.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the PDE10A inhibitor is selected from the group consisting of papaverine, PF-02545920, RO5545965, TAK-063, AMG579, and THPP-1.

6. The pharmaceutical agent according to any one of claims 1 to 5, wherein the PDE10A inhibitor does not affect insulin resistance.

7. A pharmaceutical composition according to any one of claims 1 to 6, comprising a PDE10A inhibitor or a pharma- ceutical acceptable salt thereof as the only active agent.

8. A pharmaceutical agent according to any one of claims 1 to 6, used in combination with another therapeutically active agent.

9. 9. The method of claim 8, wherein the additional therapeutically active agent is a dopamine receptor antagonist.

10. 10. The method of claim 9, wherein the other therapeutically active agent is a dopamine receptor D1 (DRD1) antagonist.

11. The pharmaceutical agent according to claim 10, wherein the DRD1 antagonist is ecopipam.

12. 10. The method of claim 9, wherein the additional therapeutically active agent is a dopamine receptor D2 (DRD2) antagonist.

13. The pharmaceutical agent of claim 12, wherein the DRD2 antagonist is olanzapine, risperidone, lurasidone, or pimozide.

14. The pharmaceutical agent according to any one of claims 1 to 13, wherein in the method, the PDE10A inhibitor or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 100 mg once a day.

15. The pharmaceutical agent according to any one of claims 1 to 14, wherein in the method, the PDE10A inhibitor or a pharma- ceutically acceptable salt thereof is administered at about 2.5 mg to about 15 mg once a day.

16. The pharmaceutical agent according to any one of claims 1 to 15, wherein in the method, the PDE10A inhibitor or a pharma- ceutically acceptable salt thereof is administered at about 5 mg to about 15 mg once a day.

17. A pharmaceutical composition according to any one of claims 8 to 16, wherein in the method, another therapeutically active agent is administered at about 0.1 mg to about 10 mg once a day.

18. A pharmaceutical composition described in any one of claims 8 to 17, wherein in the method, another therapeutically active agent is administered at about 0.5 mg to about 5 mg once a day.

19. A pharmaceutical composition according to any one of claims 8 to 17, wherein in the method, another therapeutically active agent is administered at about 2.5 mg to about 5 mg once a day.

20. The pharmaceutical composition of claim 9, wherein in the method, the PDE10A inhibitor or a pharma- ceutically acceptable salt thereof is administered at about 5 mg to about 15 mg once a day, and the dopamine receptor antagonist is administered at about 0.5 mg to about 5 mg once a day.

21. A compound of formula I: or a pharma- ceutical agent comprising a compound of formula (I) or a pharma- ceutical acceptable salt thereof, the method comprising administering to a subject the compound or a pharma- ceutically acceptable salt thereof; The said medicine.

22. 22. The method of claim 21, wherein the administering step comprises administering to the subject a free base form of the compound of formula I.

23. 22. The method of claim 21, wherein the administering step comprises administering to the subject a pharma- ceutically acceptable salt form of the compound of formula I.

24. The method of any one of claims 21 to 23, wherein the administering step comprises orally administering the compound of formula I or a pharma- ceutically acceptable salt thereof.

25. The method of claim 21, comprising administering to said patient a compound of formula I or a pharma- ceutically acceptable salt thereof as the only active agent.

26. A pharmaceutical agent according to any one of claims 21 to 24, used in combination with another therapeutically active agent.

27. ​​The pharmaceutical composition of any one of claims 21 to 26, comprising 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.

28. The method of any one of claims 21 to 27, wherein the administering step comprises administering the compound of formula I or a pharma- ceutically acceptable salt thereof in a capsule.

29. 29. The pharmaceutical of claim 28, wherein the capsule shell is comprised of gelatin, titanium dioxide, red iron oxide, and yellow iron oxide.

30. 30. The method of claim 29, wherein the capsule comprises from about 1 mg to about 10 mg of the compound of formula I or a pharma- ceutically acceptable salt thereof.

31. 30. The method of claim 29, wherein the capsule comprises from about 2.5 mg to about 15 mg of the compound of formula I or a pharma- ceutically acceptable salt thereof.

32. 30. The method of claim 29, wherein the capsule contains about 2.5 mg, about 5.0 mg, or about 10 mg of the compound of formula I or a pharma- ceutically acceptable salt thereof.

33. The method of any one of claims 21 to 32, wherein the administering step comprises administering the compound of formula I or a pharma- ceutically acceptable salt thereof in an amount of about 5 mg to about 15 mg once daily.

34. The method of any one of claims 21 to 32, wherein the administering step comprises administering the compound of formula I or a pharma- ceutically acceptable salt thereof in an amount of about 2.5 mg to about 15 mg once daily.

35. 33. The method of any one of claims 21 to 32, wherein the administering step comprises administering the compound of formula I or a pharma- ceutically acceptable salt thereof in an amount of about 2.5 mg, about 5.0 mg, about 10 mg, or about 15 mg once daily.

36. A compound of formula I: or a pharma- ceutical agent comprising a compound of formula (I) or a pharma- ceutical acceptable salt thereof, The method comprises administering to the subject a compound of formula I or a pharma- ceutically acceptable salt thereof in an amount of about 5 mg to about 15 mg once daily. The said medicine.

37. A compound of formula I: or a pharma- ceutical agent comprising a compound of formula (I) or a pharma- ceutical acceptable salt thereof, The method comprises administering to the subject a compound of formula I or a pharma- ceutically acceptable salt thereof in an amount of about 2.5 mg to about 15 mg once daily. The said medicine.

38. The method of claim 37, wherein the compound of formula I or a pharma- ceutically acceptable salt thereof is administered in an amount of about 2.5 mg, about 5.0 mg, about 10 mg or about 15 mg once daily.

39. A compound of formula I: A pharmaceutical comprising a crystalline solid of a compound of the crystalline solid has an onset of melting of about 210° C. to about 214° C. as determined by DSC; and the method comprising administering the crystalline solid to a subject in an amount of about 2.5 mg to about 15 mg once daily; The said medicine.

40. 40. The method of claim 39, wherein the administering step comprises administering the crystalline solid in an amount of about 5 mg to about 15 mg once daily.

41. 40. The method of claim 39, wherein the administering step comprises administering the crystalline solid in an amount of about 2.5 mg, about 5.0 mg, about 10 mg, or about 15 mg once daily.

42. The crystalline solid is 40. The pharmaceutical composition of claim 39, having an XRPD pattern substantially as shown in:

43. The crystalline solid is The pharmaceutical composition of claim 39, having a DSC curve substantially as shown in:

44. A pharmaceutical composition described in any one of claims 1 to 43, which results in improvement of one or more symptoms of COFD selected from the group consisting of sound repetition, syllable repetition, word repetition, and speech prolongation, blocking, and struggling behavior.

45. A compound of formula I: or a pharma- ceutical acceptable salt thereof, The method comprises reacting a compound of formula I, or a pharma- ceutically acceptable salt thereof, with a compound of formula III: or a pharma- ceutically acceptable salt thereof, The said medicine.

46. ​​The method of claim 45, wherein the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 500 mg once a day, and the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 500 mg once a day.

47. The method of claim 45, wherein the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 50 mg once a day, and the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 50 mg once a day.

48. The method of claim 45, wherein the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 30 mg once a day, and the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 500 μg to about 20 mg once a day.

49. The method of claim 45, wherein the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 2.5 mg to about 5.0 mg once daily and the compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 5.0 mg to about 15 mg once daily.

50. The method of claim 45, wherein the compound of formula III and the compound of formula I, or pharma- ceutically acceptable salts thereof, are administered simultaneously.

51. The method of claim 45, wherein the compound of formula III and the compound of formula I, or pharma- ceutically acceptable salts thereof, are administered sequentially.

52. 52. The method of claim 51, wherein the compound of formula III or a pharma- ceutically acceptable salt thereof is present in a single dosage form and the compound of formula I or a pharma- ceutically acceptable salt thereof is present in another dosage form.

53. The method of claim 45, wherein the compound of formula III, the compound of formula I, or both the compound of formula III and the compound of formula I, or pharma- ceutically acceptable salts thereof, is administered intravenously, intramuscularly, or orally.

54. 54. The method of any one of claims 45 to 53, wherein the compound of formula III or a pharma- ceutically acceptable salt thereof and the compound of formula I or a pharma- ceutically acceptable salt thereof are comprised in a composition, the composition being in the form of an aerosol, an inhalable powder, an injectable, a liquid, a solid, a capsule or a tablet, and wherein the method comprises administering the composition.

55. 55. The pharmaceutical composition of claim 54, wherein the composition further comprises an agent selected from the group consisting of mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silicon dioxide, and sodium stearyl fumarate.

56. 56. The pharmaceutical of claim 55, wherein the composition further comprises an additive selected from the group consisting of gelatin, titanium dioxide, red iron oxide, and yellow iron oxide.

57. A compound of formula I: A pharmaceutical comprising a crystalline solid of the crystalline solid has an onset of melting of about 210° C. to about 214° C. as determined by DSC; and The method comprises: forming the crystalline solid into a crystalline solid of formula III: or a pharma- ceutically acceptable salt thereof, The said medicine.

58. The crystalline solid is 58. The pharmaceutical composition of claim 57, having an XRPD pattern substantially as shown in:

59. The crystalline solid is The pharmaceutical composition of claim 57, having a DSC curve substantially as shown in:

60. The pharmaceutical agent of any one of claims 57 to 59, wherein in the method, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 500 mg once a day, and the crystalline solid is administered at about 1 mg to about 500 mg once a day.

61. The pharmaceutical agent of any one of claims 57 to 59, wherein in the method, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 50 mg once a day, and the crystalline solid is administered at about 1 mg to about 50 mg once a day.

62. The pharmaceutical agent of any one of claims 57 to 59, wherein in the method, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 1 mg to about 30 mg once daily, and the crystalline solid is administered at about 500 μg to about 20 mg once daily.

63. The pharmaceutical agent of any one of claims 57 to 59, wherein in the method, the compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 2.5 mg to about 5.0 mg once a day, and the crystalline solid is administered at about 5.0 mg to about 15 mg once a day.

64. The method of claim 57, wherein the compound of formula III or a pharma- ceutically acceptable salt thereof and the crystalline solid are administered simultaneously.

65. The method of claim 57, wherein the compound of formula III or a pharma- ceutically acceptable salt thereof and the crystalline solid are administered sequentially.

66. 66. The method of claim 65, wherein the compound of formula III or a pharma- ceutically acceptable salt thereof is present in a single dosage form and the crystalline solid is present in a separate dosage form.

67. The pharmaceutical composition of any one of claims 57 to 66, wherein in the method, the compound of formula III or a pharma- ceutically acceptable salt thereof, the crystalline solid, or both the compound of formula III or a pharma- ceutically acceptable salt thereof and the crystalline solid are administered intravenously, intramuscularly, or orally.

68. 68. The method of any one of claims 57 to 67, wherein the compound of formula III or a pharma- ceutically acceptable salt thereof and said crystalline solid are comprised in a composition, said composition being in aerosol, inhalable powder, injectable, liquid, solid, capsule or tablet form, and wherein said method comprises administering said composition.

69. 69. The pharmaceutical of claim 68, wherein the composition further comprises an agent selected from the group consisting of mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silicon dioxide, and sodium stearyl fumarate.

70. 70. The pharmaceutical of claim 69, wherein the composition further comprises an additive selected from the group consisting of gelatin, titanium dioxide, red iron oxide, and yellow iron oxide.

71. A compound of formula I: or a pharma- ceutical acceptable salt thereof, The method comprises reacting a compound of formula I, or a pharma- ceutically acceptable salt thereof, with a compound of formula III: or a pharma- ceutical acceptable salt thereof, A compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 2.5 mg to about 5.0 mg once daily; and The compound of formula I or a pharma- ceutically acceptable salt thereof is administered at about 5.0 mg to about 15 mg once daily. The said medicine.

72. A compound of formula I: A pharmaceutical comprising a crystalline solid of The method comprises: forming the crystalline solid into a crystalline solid of formula III: or a pharma- ceutical acceptable salt thereof, A compound of formula III or a pharma- ceutically acceptable salt thereof is administered at about 2.5 mg to about 5.0 mg once daily; and the crystalline solid is administered at about 5.0 mg to about 15 mg once daily; The said medicine.

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