CN117157077A

CN117157077A - Methods of treating childhood onset fluency disorders

Info

Publication number: CN117157077A
Application number: CN202280026032.1A
Authority: CN
Inventors: G·加里波第
Original assignee: Noema Pharma AG
Current assignee: Noema Pharma AG
Priority date: 2021-01-28
Filing date: 2022-01-28
Publication date: 2023-12-01

Abstract

Provided herein are methods of treating Childhood Onset Fluency Disorders (COFDs) in a subject in need thereof by administering to the subject a composition comprising a PDE10A inhibitor. Also disclosed are methods of treating COFD in a subject in need thereof by administering to the subject a composition comprising a compound of formula I:

Description

Methods of treating childhood onset fluency disorders

background

Childhood onset fluency disorders (COFD; also known as stuttering or developmental stuttering or stuttering) are neuro-developmental speech disorders that involve frequent and serious problems with normal fluency and flow of speech. COFDs typically characterized by repeated prolongation, reverberation, or chunking (bloc) of sounds, syllables, phrases, or words can lead to significant secondary effects including passive self-cognition and passive cognition of others, anxiety, and occasional depression. It affects about 5% to 10% of preschool children and about 1% of adults. (R.W. Sander et al American Family Physician,2019, 100 (9): 556-560).

There is currently no pharmacological treatment approved for COFD. Disorder management includes speech therapy, psychotherapy and antipsychotics, but has limited effectiveness. Antipsychotics are often used superscript (off label) and are associated with serious side effects.

Accordingly, there is an unmet medical need to develop new methods that can effectively treat COFD without serious side effects.

Disclosure of Invention

In one aspect, the present disclosure relates to a method of treating a Childhood Onset Fluency Disorder (COFD), wherein the method comprises administering to a subject in need thereof a composition comprising a therapeutically effective amount of a phosphodiesterase 10A (PDE 10A) inhibitor or a pharmaceutically acceptable salt thereof. In another aspect, a method of treating a Childhood Onset Fluency Disorder (COFD), wherein the method comprises administering to a subject in need thereof a composition comprising a therapeutically effective amount of a phosphodiesterase 10A (PDE 10A) inhibitor (e.g., a compound of formula I) or a pharmaceutically acceptable salt thereof and a compound of formula III or a pharmaceutically acceptable salt thereof. Each of these different aspects may be more specifically described by various embodiments described herein, which may be equally applicable to the different aspects.

Examples of PDE10A inhibitors include, but are not limited to, papaverine, PF-02545920 (also known as MP-10), RO5545965, TAK-063, AMG 579, and THPP-1. The structure of these PDE10A inhibitors is shown below:

PapaverinePF-02545920/>RO5545965/>TAK-063/>AMG 579THPP-1/>

In certain embodiments, the method comprises administering the PDE10A inhibitor, or a pharmaceutically acceptable salt thereof, once daily. In certain embodiments, the method comprises orally administering a PDE10A inhibitor, or a pharmaceutically acceptable salt thereof. In certain embodiments, the method comprises administering the PDE10A inhibitor, or a pharmaceutically acceptable salt thereof, as a unit dose.

In another aspect, provided herein is a method of treating COFD comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent is a compound of formula I (also referred to herein as RO 5545965):

in a further aspect, provided herein is a method of treating COFD comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a therapeutic agent, or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent is a compound of formula I (i.e., RO 5545965), wherein the compound in free base or a pharmaceutically acceptable salt thereof is administered once daily in an amount of about 5mg to about 15 mg. In certain embodiments, the therapeutic agent is a compound of formula I (i.e., RO 5545965) as the free base or a pharmaceutically acceptable salt thereof, administered once daily in an amount of about 2.5mg to about 15 mg. In certain embodiments, the therapeutic agent is a compound of formula I as a free base (i.e., RO 5545965), or a pharmaceutically acceptable salt thereof, administered once daily in an amount of about 2.5mg, about 5.0mg, about 10mg, or about 15 mg.

Still another aspect of the invention is a method of treating COFD comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a crystalline solid of a compound of formula I above, wherein the crystalline solid has a melting point onset of about 210 ℃ to about 214 ℃ as determined by Differential Scanning Calorimetry (DSC), and the administering comprises administering the crystalline solid to the subject once daily in an amount of about 5mg to about 15 mg. In certain embodiments, a therapeutically effective amount of the crystalline solid of the compound of formula I is administered once daily in an amount of about 2.5mg to about 15 mg. In certain embodiments, a therapeutically effective amount of the crystalline solid of the compound of formula I is administered once daily in an amount of about 2.5mg, about 5.0mg, about 10mg, or about 15 mg.

In some embodiments, the crystalline solid set forth above has an XRPD pattern substantially as shown in figure 1. In some embodiments, the crystalline solid set forth above has a DSC curve substantially as shown in figure 2.

Also provided herein are methods of treating a Childhood Onset Fluency Disorder (COFD) in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of:

a compound of formula III:

And

a compound of formula I:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 2.5mg to about 5.0mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 5.0mg to about 15mg once per day.

Also provided herein are compounds of the compounds of formula III:

a crystalline solid of formula I:

wherein the crystalline solid has a melting point onset as determined by DSC from about 210 ℃ to about 214 ℃; or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 2.5mg to about 5.0mg once per day; and the crystalline solid of formula I or a pharmaceutically acceptable salt thereof is administered at about 5.0mg to about 15mg once per day.

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 be apparent from the drawings, the description, and from the claims.

Drawings

Fig. 1 depicts an exemplary XRPD pattern of crystalline solids of the free base of the compound of formula I.

Figure 2 depicts an exemplary DSC curve for the crystalline solid of the free base of the compound of formula I.

Figure 3 depicts glucose levels during oral glucose tolerance testing in Sprague Dawley rats following acute treatment with olanzapine (compound of formula III) or haloperidol.

FIG. 4 depicts insulin levels in Sprague Dawley rats following oral glucose challenge (2 g/kg).

Figure 5 depicts oral glucose tolerance testing and glucose levels in Sprague Dawley rats after acute treatment with olanzapine (compound of formula III) or haloperidol.

Figure 6 depicts body weight and food intake of Sprague Dawley rats during treatment of olanzapine (compound of formula III) or RO5545965 (compound of formula I).

Figure 7 depicts oral glucose tolerance testing and glucose levels in Sprague Dawley rats after sub-chronic treatment with olanzapine (compound of formula III), RO5545965 (compound of formula I) or a combination of olanzapine (compound of formula III) and compound of formula I.

Fig. 8 depicts insulin levels in Sprague Dawley rats prior to oral glucose tolerance testing 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

As generally described herein, the present disclosure provides methods of treating COFD in a subject in need thereof. The present disclosure also describes the use of a specific PDE10A inhibitor RO5545965 for the treatment of COFD.

Definition of the definition

In order to facilitate an understanding of the present invention, a number of terms and phrases are defined below.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Abbreviations used herein have their conventional meaning in the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to standard rules of chemical valence known in the chemical arts.

Throughout this specification, when compositions are described as having, comprising, or containing specific components, or when processes and methods are described as having, comprising, or containing specific steps, it is contemplated that, in addition, there are compositions of the invention consisting essentially of, or consisting of, the recited components, and there are processes and methods in accordance with the invention consisting essentially of, or consisting of, the recited processing steps.

In the present application, when an element or component is said to be included in and/or selected from a list of recited elements or components, it is understood that the element or component may be any one of the recited elements or components, or the element or component may be selected from two or more of the recited elements or components.

Further, it is to be understood that elements and/or features of the compositions or methods described herein may be combined in various ways without departing from the spirit and scope of the application, whether explicit or implicit herein. For example, when reference is made to a particular compound, that compound may be used in various embodiments of the compositions of the application and/or in the methods of the application unless otherwise understood from the context. In other words, within the present application, embodiments have been described and depicted in a manner that enables writing and drawing of clear and concise applications, but it is contemplated and will be appreciated that various combinations or separations of embodiments may be made without departing from the teachings and applications herein. For example, it will be appreciated that all features described and depicted herein are applicable to all aspects of the application described and depicted herein.

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

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

It is to be understood that the expression "at least one" includes each of the recited objects individually and various combinations of two or more of the recited objects after the expression unless otherwise understood from context and use. The expression "and/or" in combination with three or more of the recited objects should be understood to have the same meaning unless otherwise understood from the context.

The use of the terms "include," comprises, "" including, "" has, "" having, "" has, "" containing, "" contains, "or" contains (grammatical equivalents thereof) are generally to be construed as open-ended and non-limiting, e.g., not to exclude additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

When the term "about" is used before a quantitative value, the invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a variation of ±10% from the nominal value unless otherwise indicated or inferred from the context. For example, the term "about 10mg" means a variation of 10mg from 10mg of ±10%, i.e. an amount ranging from 9mg to 11 mg.

Throughout this specification, variables or parameters are disclosed in groups or ranges. It is specifically contemplated that the description includes each and every individual sub-combination of the members of such groups and ranges. For example, integers in the range of 0 to 40 are specifically contemplated to 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 individually, and integers in the range of 1 to 20 are specifically contemplated to disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 individually.

The use of any and all examples, or exemplary language, e.g., "such as" or "comprising," in this document is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

As a general matter, unless otherwise indicated, the indicated percentages of the composition are by weight. Further, if the variable is not defined concomitantly, the previous definition of the variable is in control.

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

By "pharmaceutically acceptable" is meant approved or approvable by a regulatory agency of the federal or a state government or a corresponding agency in a country other than the united states, or listed in the united states pharmacopeia or other generally recognized pharmacopeia for use in animals, and particularly in humans.

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

As known to those skilled in the art, the "salts" 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, p-toluenesulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, 2-naphthalenesulfonic acid, and benzenesulfonic acid. Other acids, such as oxalic acid, although not pharmaceutically acceptable per se, may be used to prepare salts useful as intermediates in obtaining the compounds described herein and pharmaceutically acceptable acid addition salts thereof.

Examples of bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and wherein W is C _1-4 Alkyl NW ₄ ⁺ A compound of (C) and the like.

Examples of salts include, but are not limited to, acetates, adipates, alginates, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorite, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate (flucheptanoate), glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-isethionate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmitate, pectate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and the like. Salt of itExamples thereof include the reaction with a suitable cation such as Na ⁺ 、K ⁺ 、Ca ²⁺ 、NH ₄ ⁺ And NW ₄ ⁺ (wherein W may be C _1-4 Alkyl) and the like.

For therapeutic use, salts of the compounds of the present disclosure are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also be useful, for example, in the preparation or purification of pharmaceutically acceptable compounds.

As used herein, "pharmaceutically acceptable excipient" refers to a substance that facilitates administration of and/or absorption by a subject of an active agent, and may be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, naCl, physiological saline solutions such as phosphate buffered saline solutions, emulsions (e.g., oil/water or water/oil emulsions), ringer's lactate, standard sucrose, standard dextrose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (e.g., ringer's solution), alcohols, oils, gelatin, carbohydrates (e.g., lactose, amylose or starch), fatty acid esters, hydroxymethyl cellulose, polyvinylpyrrolidone, and pigments, and the like. Such formulations may be sterilized and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring and/or aromatic substances and the like, which do not deleteriously react with the compounds of the invention. For examples of excipients see Martin, remington's Pharmaceutical Sciences, 15 th edition, mack publication co., easton, PA (1975).

"subject" contemplated for administration thereto includes, but is not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young, middle-aged, or elderly) and/or non-human animals such as mammals, such as primates (e.g., cynomolgus, rhesus), 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.

As used herein, "solid dosage form" means a dosage of a drug in solid form, such as a tablet, capsule, granule, powder, sachet, reconstitutable powder, dry powder inhaler, and chew.

As used herein, "administration" means 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 such as a micro-osmotic pump to a subject. Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other modes of delivery include, but are not limited to, use of liposomal formulations, intravenous infusion, transdermal patches, and the like.

By "co-administration" is meant administration of a composition described herein immediately before or immediately after one or more additional therapies (e.g., dopamine receptor antagonists, antipsychotics, or for the treatment of a neurodevelopmental disease). The PDE10A inhibitor described above, or a pharmaceutically acceptable salt thereof, may be administered to the subject alone or may be co-administered to the subject. Co-administration is meant to include the simultaneous or sequential administration of compounds, alone or in combination (more than one compound or agent). Thus, the formulation may also be combined with other active substances (e.g. to reduce dopamine overactivity) when desired.

As used herein, the term "concurrently administered" as used herein is not particularly limited and means that the components of the combination therapy are administered substantially simultaneously, e.g., as a mixture or in an immediately subsequent order. As used herein, the term "sequentially administered" is not particularly limited and means that the components of the combination therapy are not administered simultaneously, but rather are administered one after the other, or in groups with a specific time interval therebetween.

As used herein, and unless otherwise indicated, the terms "treatment," "treatment," and "treatment" contemplate actions that occur when a subject suffers from a specified disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition (e.g., "therapeutic treatment"). Whenever a clinically beneficial result occurs, the subject is effectively treated. For example, this may mean complete or significant regression of symptoms of the disorder, a decrease in the frequency, severity and/or duration of symptoms, or a decrease in the progression of the disorder. Thus, an effective treatment may manifest as a reduction in the number, duration, frequency, and/or intensity of repetitions, extensions, hesitation, and disruption of speech flow observed in a subject.

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

A fluency disorder (COFD), also known as stuttering, stuttering or tie-off, is a communication disorder characterized by involuntary repetition and prolongation of sounds, syllables, words or phrases, and involuntary silent pauses or plugs (blocks) in which the stuttered person is unable to make sounds. In certain embodiments, administration of a composition (e.g., a composition described herein) ameliorates COFD symptoms.

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

The term "stuttering" encompasses a wide range of severity, from an almost imperceptible hindrance to the surface (cosmetic) to a severe symptom that effectively impedes verbal communication. Almost 7000 tens of thousands of people worldwide stuttered, of which four fifths are men. It is common for individuals with stuttering for life that their symptoms worsen significantly when they reach over 70 and 80 years of age.

The impact of COFD on an individual's function and emotional state can be severe. This may include fear of having to make a specific vowel or consonant, fear of being found stuttered in social situations, self-isolation, anxiety, stress, shame, low self-esteem, a possible goal of being a decubitus (especially in children), having to use words to replace and rearrange words in sentences to hide stuttering, or a sense of "losing control" during speech. Symptoms of COFD develop between 2 and 7 years of age, with 80 to 90% of cases developing before 6 years of age. While mild stuttering is common in children who learn to speak, when this behavior continues for a period of time, it becomes a fluent disorder and causes pain to the child.

Phosphodiesterase inhibitors

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

Compounds of formula (I)

As set forth in the summary section above, PDE10A inhibitors that may be used in the methods of the invention may be one of the following compounds, or a pharmaceutically acceptable salt thereof: papaverine PF-02545920RO5545965/>、TAK-063AMG 579/>THPP-1

The synthesis of PDE10A inhibitors listed above may follow procedures known in the art. For example, a method of chemically synthesizing compounds of RO5545965 (including example 1 provided herein below) is described in U.S. patent No. 8,349,824, which is incorporated by reference in its entirety.

The compound of formula I as depicted below is a phosphodiesterase 10A (PDE 10A) inhibitor, also known as RO5545965, with 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.

The structure of the compound of formula 1:

the term "compound of formula I" may also be referred to as "compound 1" or "RO554965".

In various embodiments, the pharmaceutically acceptable salt of the compound of formula I may be a salt of the compound of formula (I) with a physiologically compatible mineral acid, such as hydrochloric acid, sulfuric acid, sulfurous acid, or phosphoric acid, or 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.

The compound of formula III, as depicted below, is also known as olanzapine or ZYPREXA under 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 CAS number 132539-06-1.

Structure of the compound of formula III:

the term "compound of formula III" may also be referred to as "compound 3" or "olanzapine".

In various embodiments, the pharmaceutically acceptable salt of the compound of formula III may 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 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.

The present disclosure encompasses methods of treating COFD comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent is a compound of formula I (also known as RO 5545965):

in certain embodiments, the compound is administered once daily in an amount of about 1mg to about 17 mg. In certain embodiments, the compound is administered once daily in an amount of about 2.5mg to about 15 mg. In some embodiments, the compound is administered once daily in an amount of about 5mg to about 15 mg. In certain embodiments, the therapeutic agent is a compound of formula I as a free base (i.e., RO 5545965), or a pharmaceutically acceptable salt thereof, administered once daily in an amount of about 2.0mg, about 2.5mg, about 5.0mg, about 10mg, or about 15 mg.

The present disclosure also encompasses methods of treating COFD comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a crystalline solid of a compound of formula I:

wherein the crystalline solid has a melting point onset of about 210 ℃ to about 214 ℃ (e.g., about 210 ℃, about 211 ℃, about 212 ℃, about 213 ℃, or about 214 ℃) as determined by Differential Scanning Calorimetry (DSC), and the administering comprises administering the crystalline solid once daily in an amount of about 5mg to about 15 mg.

wherein the crystalline solid has a melting point onset of about 210 ℃ to about 214 ℃ (e.g., about 210 ℃, about 211 ℃, about 212 ℃, about 213 ℃, or about 214 ℃) as determined by Differential Scanning Calorimetry (DSC), and the administering comprises administering the crystalline solid once daily in an amount of about 2.5mg to about 15 mg.

Also provided herein are methods of treating a Childhood Onset Fluency Disorder (COFD) in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of: a compound of formula III:

And

a compound of formula I:

or a pharmaceutically acceptable salt thereof.

Also provided herein are compounds of the compounds of formula III:

and

a crystalline solid of formula I:

wherein the crystalline solid has a melting point onset as determined by DSC from about 210 ℃ to about 214 ℃; or a pharmaceutically acceptable salt thereof.

In some embodiments, the crystalline solid of the free base of formula I above has an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 1.

In some embodiments, the crystalline solid of the free base of formula I above has a DSC profile substantially as shown in figure 2.

Pharmaceutical composition

In one aspect, provided herein are methods of treating COFD using a pharmaceutical composition comprising a PDE10A inhibitor (e.g., a compound of formula I or RO 5545965), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for treating COFD in a subject in need thereof.

In general, the PDE10A inhibitors used in the methods of the invention have no effect on insulin resistance.

In various embodiments, the method comprises administering a composition comprising a PDE10A inhibitor, or a pharmaceutically acceptable salt thereof, as the sole active agent.

In various embodiments, the method comprises administering a composition comprising a PDE10A inhibitor, or a pharmaceutically acceptable salt thereof, in combination with another therapeutically active agent.

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

In some embodiments, the other therapeutically active agent is a dopamine receptor D1 (DRD 1) antagonist. An exemplary DRD1 antagonist is ecopipam.

In some embodiments, the other therapeutically active agent is a dopamine receptor D2 (DRD 2) antagonist. Exemplary DRD2 antagonists are olanzapine, risperidone, lurasidone, or Pimozide (Pimozide).

In various embodiments, the PDE10A inhibitor (e.g., a compound of formula I, also referred to as RO 5545965) or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein may be in an amount of about 1mg to about 100mg, about 2mg to about 50mg, about 3mg to about 20mg, about 5mg to about 15mg, about 5mg to about 10mg, or about 2.5mg to about 15mg.

In certain embodiments, the amount of PDE10A inhibitor (e.g., a compound of formula I or RO 5545965) or a pharmaceutically acceptable salt thereof in a pharmaceutical composition described herein can be from about 1.0mg to about 17mg, from about 2.0mg to about 16mg, from about 2.5mg to about 15mg, from about 5.5mg to about 15mg, from about 6mg to about 15mg, from about 6.5mg to about 15mg, from about 7mg to about 15mg, from about 7.5mg to about 15mg, from about 8mg to about 15mg, from about 8.5mg to about 15mg, from about 9mg to about 15mg, from about 9.5mg to about 15mg, from about 10mg to about 15mg, from about 11mg to about 15mg, from about 11.5mg to about 15mg, from about 12mg to about 15mg, from about 12.5mg to about 15mg, from about 13mg to about 15mg, from about 13.5mg to about 15mg, or from about 14mg to about 15mg.

In certain embodiments, the amount of PDE10A inhibitor (e.g., a compound of formula I or RO 5545965) or a pharmaceutically acceptable salt thereof in a pharmaceutical composition described herein can be from about 5mg to about 14.5mg, from about 5mg to about 14mg, from about 5mg to about 13.5mg, from about 5mg to about 13mg, from about 5mg to about 12.5mg, from about 5mg to about 12mg, from about 5mg to about 11.5mg, from about 5mg to about 11mg, from about 5mg to about 10.5mg, from about 5mg to about 10mg, from about 5mg to about 9.5mg, from about 5mg to about 9mg, from about 5mg to about 8.5mg, from about 5mg to about 8mg, from about 5mg to about 7.5mg, from about 5mg to about 7mg, from about 5mg to about 6.5mg, or from about 5mg to about 6mg.

In certain embodiments, the amount of PDE10A inhibitor (e.g., a compound of formula I or RO 5545965) or a pharmaceutically acceptable salt thereof in a pharmaceutical composition described herein can be from about 5mg to about 15mg (e.g., about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 10.5mg, about 11mg, about 11.5mg, about 12mg, about 12.5mg, about 13mg, about 13.5mg, about 14mg, about 14.5mg, or about 15 mg).

In some embodiments, the PDE10A inhibitor, or a pharmaceutically acceptable salt thereof, is administered from about 1mg to about 100mg once per day.

In some embodiments, the PDE10A inhibitor, or a pharmaceutically acceptable salt thereof, is administered from about 5mg to about 15mg once per day.

In some embodiments, the additional therapeutically active agent is administered at about 0.1mg to about 10mg once per day.

In some embodiments, the additional therapeutically active agent is administered at about 0.5mg to about 5mg once per day.

In some embodiments, the PDE10A inhibitor, or a pharmaceutically acceptable salt thereof, is administered from about 5mg to about 15mg once per day; and the dopamine receptor antagonist is administered at about 0.5mg to about 5mg once per day.

In certain embodiments, the PDE10A inhibitor, or a pharmaceutically acceptable salt thereof, is administered from about 5mg to about 15mg once per day; and the compound of formula III is administered at about 2.5mg to about 5.0mg once per day. In certain embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 5mg to about 15mg once per day; and the compound of formula III is administered at about 2.5mg to about 5.0mg once per day.

In embodiments, the compound of formula III or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein may be about 2.5mg to about 5.0mg (e.g., about 2.5mg, about 2.6mg, about 2.7mg, about 2.8mg, about 2.9mg, about 3.0mg, about 3.1mg, about 3.2mg, about 3.3mg, about 3.4mg, about 3.5mg, about 3.6mg, about 3.7mg, about 3.8mg, about 3.9mg, about 4.0mg, about 4.1mg, about 4.2mg, about 4.3mg, about 4.4mg, about 4.5mg, about 4.6mg, about 4.7mg, about 4.8mg, about 4.9mg, about 5.0 mg).

In various embodiments, the amount of the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein may be from about 1.0mg to about 17mg. In various embodiments, the amount of the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein may be from about 2.5mg to about 15mg. In certain embodiments, the amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition described herein may be about 2.5mg. In certain embodiments, the amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition described herein may be about 5.0mg. In certain embodiments, the amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition described herein may be about 10mg. In certain embodiments, the amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition described herein may be about 15mg.

In certain embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 2.5mg to about 15mg once per day.

In certain embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 2.5mg once daily.

In certain embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 5.0mg once daily.

In certain embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 10mg once daily.

In certain embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 15mg once daily.

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

In various embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula I. In some embodiments, the pharmaceutically acceptable salt of the compound of formula I may be a salt of the compound of formula (I) with a physiologically compatible mineral acid, such as hydrochloric acid, sulfuric acid, sulfurous acid, or phosphoric acid, or 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.

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

The pharmaceutical compositions provided herein may also be administered chronically (administered chronically) ("chronically (chronic administration)"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely, e.g., for the remainder of the subject's life. In certain embodiments, chronic administration is expected to provide a constant level of the compound in the blood, for example, over an extended period of time, within a therapeutic window.

The pharmaceutical compositions provided herein may be presented in unit dosage form to facilitate accurate administration. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. In various embodiments, the pharmaceutical dosage forms described herein may be administered as a unit dose. Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules, and the like.

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

In various embodiments, the pharmaceutical compositions provided herein comprise a compound of formula I as the sole active agent or in combination with other active agents.

Although the description of the pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, the skilled artisan will appreciate that such compositions are generally suitable for administration to all kinds of animals. Modifications to pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to a variety of animals are well known and the ordinarily skilled veterinary pharmacologist can design and/or perform such modifications with ordinary 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 edition, lippincott Williams & Wilkins, 2005.

Methods of use and methods of treatment

In one aspect, provided herein is a method for treating COFD in a subject in need thereof, comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent is a compound of formula I:

In various embodiments, administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof comprises administering a composition having an amount of a compound as described herein above.

In various embodiments, the compositions comprise a compound of formula I, or a pharmaceutically acceptable salt thereof, as the sole active agent.

In various embodiments, the compositions comprise a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with another active agent. In certain embodiments, the other active agent is a dopamine receptor antagonist (e.g., a D1 antagonist or a D2 antagonist).

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

In various embodiments, administering comprises administering the compound of formula I, or a pharmaceutically acceptable salt thereof, in a capsule.

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

In various embodiments, the above-described capsules comprise a compound of formula I (or RO 5545965), or a pharmaceutically acceptable salt thereof, in an amount of from about 1mg to about 100mg, from about 2mg to about 50mg, from about 3mg to about 20mg, or from about 5mg to about 15mg. In certain embodiments, the above-described capsules comprise a compound of formula I (or RO 5545965) or a pharmaceutically acceptable salt thereof in an amount of about 5.5mg to about 10mg, about 6mg to about 10mg, about 6.5mg to about 10mg, about 7mg to about 10mg, about 7.5mg to about 10mg, about 8mg to about 10mg, about 8.5mg to about 10mg, about 9mg to about 10mg, about 5mg to about 9.5mg, about 5mg to about 9mg, about 5mg to about 8.5mg, about 5mg to about 8mg, about 5mg to about 7.5mg, about 5mg to about 7mg, about 5mg to about 6.5mg, or about 5mg to about 6mg.

In certain embodiments, the aforementioned capsules comprise a compound of formula I (or RO 5545965), or a pharmaceutically acceptable salt thereof, in an amount of about 5mg to about 15mg (e.g., about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, or about 10 mg).

In various embodiments, the above-described capsules comprise a compound of formula I (or RO 5545965), or a pharmaceutically acceptable salt thereof, in an amount of about 1.0mg to about 17 mg. In various embodiments, the above-described capsules comprise a compound of formula I (or RO 5545965), or a pharmaceutically acceptable salt thereof, in an amount of about 2.5mg to about 15 mg. In certain embodiments, the above-described capsules comprise a compound of formula I (or RO 5545965), or a pharmaceutically acceptable salt thereof, in an amount of about 2.5 mg. In certain embodiments, the above-described capsules comprise a compound of formula I (or RO 5545965), or a pharmaceutically acceptable salt thereof, in an amount of about 5.0 mg. In certain embodiments, the above-described capsules comprise a compound of formula I (or RO 5545965), or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg.

In some embodiments, administering comprises administering the compound of formula I (or RO 5545965), or a pharmaceutically acceptable salt thereof, once daily in an amount of about 5mg to about 15 mg.

In some embodiments, administering comprises administering the compound of formula I (or RO 5545965), or a pharmaceutically acceptable salt thereof, once daily in an amount of about 2.5mg to about 15 mg. In some embodiments, administering comprises administering the compound of formula I (or RO 5545965), or a pharmaceutically acceptable salt thereof, once daily in an amount of about 2.5 mg. In some embodiments, administering comprises administering the compound of formula I (or RO 5545965), or a pharmaceutically acceptable salt thereof, once daily in an amount of about 5.0 mg. In some embodiments, administering comprises administering the compound of formula I (or RO 5545965), or a pharmaceutically acceptable salt thereof, once daily in an amount of about 10 mg. In some embodiments, administering comprises administering the compound of formula I (or RO 5545965), or a pharmaceutically acceptable salt thereof, once daily in an amount of about 15 mg.

In various embodiments, administering comprises administering the compound of formula I, or a pharmaceutically acceptable salt thereof, in an immediate release formulation.

In various embodiments, administering comprises administering the compound of formula I, or a pharmaceutically acceptable salt thereof, in an extended release formulation.

In various embodiments, administration maintains efficacy throughout the day.

In various embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered once, twice, three times, four times, or five times per day. In certain embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered once daily. In certain embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

In various embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered orally.

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

In various embodiments, the compound of formula I is administered as the free base.

In various embodiments, the compounds of formula I are administered in the form of pharmaceutically acceptable salts. In certain embodiments, the pharmaceutically acceptable salt of the compound of formula I may be a salt of the compound of formula (I) with a physiologically compatible mineral acid, such as hydrochloric acid, sulfuric acid, sulfurous acid, or phosphoric acid, or 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. In certain embodiments, the compound of formula I is administered in crystalline form.

and

a compound of formula I:

or a pharmaceutically acceptable salt thereof.

In embodiments, the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 500mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 500mg once per day.

In embodiments, the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 50mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 50mg once per day.

In embodiments, the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 30mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 500 μg to about 20mg once per day.

In embodiments, the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 0.1mg to about 10mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 20mg once per day.

In embodiments, the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 2.5mg to about 5.0mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 5.0mg to about 15mg once per day.

In embodiments, the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 2.5mg to about 5.0mg (e.g., about 2.5mg, about 3.0mg, about 3.5mg, about 4.0mg, about 4.5mg, about 5.0 mg) once daily; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 5.0mg to about 15mg (e.g., about 5.0mg, about 6.0mg, about 7.0mg, about 8.0mg, about 9.0mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15 mg) once daily.

In embodiments, the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 6.0mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 4.0mg to about 16mg once per day. In embodiments, the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 2.5mg, about 2.6mg, about 2.7mg, about 2.8mg, about 2.9mg, about 3.0mg, about 3.1mg, about 3.2mg, about 3.3mg, about 3.4mg, about 3.5mg, about 3.6mg, about 3.7mg, about 3.8mg, about 3.9mg, about 4.0mg, about 4.1mg, about 4.2mg, about 4.3mg, about 4.4mg, about 4.5mg, about 4.6mg, about 4.7mg, about 4.8mg, about 4.9mg, about 5.0 mg; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 5.0mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 10.5mg, about 11mg, about 11.5mg, about 12mg, about 12.5mg, about 13mg, about 13.5mg, about 14mg, about 14.5mg, or about 15 mg.

In embodiments, the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 1mg, about 1.5mg, about 2.0mg, about 2.5mg, about 3.0mg, about 3.5mg, about 4.0mg, about 4.5mg, about 5mg, about 5.5mg, or about 6mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered once daily at about 4.0mg, about 4.5mg, about 5.0mg, about 5.5mg, about 6.0mg, about 6.5mg, about 7.0mg, about 7.5mg, about 8.0mg, about 8.5mg, about 9.0mg, about 9.5mg, about 10mg, about 10.5mg, about 11mg, about 12mg, about 12.5mg, about 13mg, about 13.5mg, about 14mg, about 14.5mg, about 15mg, about 15.5mg, or about 16 mg.

In embodiments, the compound of formula I and the compound of formula III, or a pharmaceutically acceptable salt thereof, are administered simultaneously. In embodiments, the compound of formula I and the compound of formula I or a pharmaceutically acceptable salt thereof are administered sequentially.

In embodiments, the compound of formula III is present in a single dosage form, and the compound of formula I is present in separate dosage forms. In embodiments, the compound of formula III, the compound of formula I, or both the compound of formula III and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered intravenously, intramuscularly, or orally. In embodiments, the compound of formula III and the compound of formula I are contained in a composition, wherein the composition is in the form of an aerosol, inhalable powder, injectable, liquid, solid, capsule or tablet. In embodiments, the composition further comprises an agent selected from mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silicon dioxide, and sodium stearyl fumarate. In embodiments, the composition further comprises an additive selected from the group consisting of gelatin, titanium dioxide, red iron oxide, and yellow iron oxide.

Also provided herein are methods of treating a Childhood Onset Fluency Disorder (COFD) in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of: a compound of the compound of formula III:

and

a crystalline solid of formula I:

In some embodiments, wherein the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 500mg once per day; and the crystalline solid of formula I or a pharmaceutically acceptable salt thereof is administered at about 1mg to about 500mg once per day. In some embodiments, the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 50mg once per day; and the crystalline solid of formula I or a pharmaceutically acceptable salt thereof is administered at about 1mg to about 50mg once per day. In some embodiments, the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 30mg once per day; and the crystalline solid of formula I or a pharmaceutically acceptable salt thereof is administered at about 500 μg to about 20mg once per day. In embodiments, the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 2.5mg to about 5.0mg once per day; and the crystalline solid of formula I or a pharmaceutically acceptable salt thereof is administered at about 5.0mg to about 15mg once per day. In embodiments, the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 1mg, about 1.5mg, about 2.0mg, about 2.5mg, about 3.0mg, about 3.5mg, about 4.0mg, about 4.5mg, about 5mg, about 5.5mg, or about 6mg once per day; and the crystalline solid of formula I, or a pharmaceutically acceptable salt thereof, is administered once daily at about 4.0mg, about 4.5mg, about 5.0mg, about 5.5mg, about 6.0mg, about 6.5mg, about 7.0mg, about 7.5mg, about 8.0mg, about 8.5mg, about 9.0mg, about 9.5mg, about 10mg, about 10.5mg, about 11mg, about 12mg, about 12.5mg, about 13mg, about 13.5mg, about 14mg, about 14.5mg, about 15mg, about 15.5mg, or about 16 mg.

In some embodiments, the compound of formula III and the crystalline solid compound of formula I, or a pharmaceutically acceptable salt thereof, are administered simultaneously. In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is 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 separate dosage forms. 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 pharmaceutically acceptable salt thereof, is administered intravenously, intramuscularly, or orally. In some embodiments, the compound of formula III and the crystalline solid of formula I are contained in a composition, wherein the composition is in the form of an aerosol, inhalable powder, jettable, liquid, solid, capsule, or tablet. In some embodiments, the composition further comprises an agent selected from 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.

Also provided herein are methods of treating a Childhood Onset Fluency Disorder (COFD) in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula III:

and

a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 2.5mg to about 5.0mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 5.0mg to about 15mg once per day.

a crystalline solid of formula I:

or a pharmaceutically acceptable salt thereof, wherein the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 2.5mg to about 5.0mg once per day; and the crystalline solid of formula I or a pharmaceutically acceptable salt thereof is administered at about 5.0mg to about 15mg once per day.

Without further elaboration, it is believed that one skilled in the art can, based on the preceding description, utilize the present invention to its fullest extent. Accordingly, the following specific embodiments should be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

Examples

In order that the disclosure described herein may be more fully understood, the following examples are set forth. The examples described in this disclosure are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be construed as limiting the scope thereof in any way.

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 (a 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- (trimethylbenzenesulfonyl) hydroxylamine (11.22 g,52.1mmol,1 eq.) in dichloromethane (130 ml) was added 4-bromopyridine-2-amine (9.3 g,52.1mmol,1 eq.) in portions (exothermic reaction, requiring some cooling) to give a white suspension. After 1 hour, 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 ℃. MS: M/z=188.2, 190.2 (m+h+).

And (B) step (B): 7-bromo-2-phenyl- [1,2,4]Triazolo [1,5-a ]]Pyridine: a solution of 1, 2-diamino-4-bromopyridinium 2,4, 6-trimethylbenzenesulfonate (15.6 g,40.2 mmol) in pyridine (106 ml) was heated together with benzoyl chloride (9.4 ml,80 mmol) at 100deg.C overnight to give a reddish brown solution and after 2 hours a brown suspension. The reaction mixture was concentrated in vacuo and the residue was triturated in saturated aqueous ammonium chloride (300 ml) for 2.5 hours while neutralising 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 as an off-white solid]Triazolo [1,5-a ]]Pyridine (6.78 g, 61.6%). mp.:189-191 ℃. M is MS:m/z＝276.1，274.2(M+H ⁺ )。

Step C: (2-phenyl- [1,2,4] triazolo [1,5-a ] pyridin-7-yl) -carbamic acid tert-butyl ester: to a nitrogen purged suspension of 7-bromo-2-phenyl- [1,2,4] triazolo [1,5-a ] pyridine (9 g,32.8 mmol) in dioxane (180 ml) was successively added tert-butyl carbamate (4.71 g,39.4 mmol), tris (dibenzylidene-acetone) dipalladium (0) (601 mg,657 μmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (760 mg,1.31 mmol) and cesium carbonate (15 g,46 mmol). The brown mixture was then stirred at 100℃under a nitrogen atmosphere for 22 hours. 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 80ml: and (5) crystallizing. The suspension was stirred in an ice bath for 10 minutes and the solid was collected by filtration, washed with a small amount of cold ethyl acetate and dried to give (2-phenyl- [1,2,4] triazolo [1,5-a ] pyridin-7-yl) -carbamic acid tert-butyl ester (7.09 g) as an off-white solid. The mother liquor was evaporated and the residue (4.79 g) was loaded onto silica (16 g). The product was isolated by chromatography on a 120g silica cartridge (eluent heptane/ethyl acetate 10-50%,45 min) yielding a second 1.748g white solid. mp. 200-201 deg.C. MS: M/z=311.3 (m+h+). Total yield: 86.7%.

Step D: 2-phenyl- [1,2,4 ]]Triazolo [1,5-a ]]Pyridin-7-ylamine: (2-phenyl- [1,2, 4)]Triazolo [1,5-a ]]A suspension of 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. The suspension was diluted with water (about 2 l) and ethyl acetate under cooling, the aqueous layer was washed once with ethyl acetate, made basic with 32% aqueous sodium hydroxide solution and extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and the solvent was removed in vacuo to give 2-phenyl- [1,2,4 as a pale pink solid]Triazolo [1,5-a ]]Pyridin-7-ylamine (5.52 g, 95.9%). mp., 212-213 ℃. MS: M/z=211.2 (m+h) ⁺ )。

Step E: 1-methyl-)5- (2-phenyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-7-ylcarbamoyl) -1H-pyrazole-4-carboxylic acid methyl ester: 2-phenyl- [1,2,4]Triazolo [1,5-a ]]A solution of 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, 10.7ml,18.2 mmol) and diisopropylethylamine (5.1 ml,29.2 mmol) in tetrahydrofuran (54 ml) was stirred at 70℃for 1.25 hours to give a white suspension. The cooled suspension was poured into saturated aqueous sodium bicarbonate (200 ml), stirred at room temperature for 15 min, and the solid was collected by filtration, washed with water and dried to give 1-methyl-5- (2-phenyl- [1,2, 4) as a white solid ]Triazolo [1,5-a ]]Pyridin-7-ylcarbamoyl) -1H-pyrazole-4-carboxylic acid methyl ester (2.596 g, 94.5%). mp. at 243-7deg.C. MS: M/z= 377.2 (m+h) ⁺ )。

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 (29 mg,6.93 mmol) in methanol (100 ml) and water (20 ml) was stirred at 70℃for 1.25 hours to give a colorless solution after 20 minutes. The methanol was removed in vacuo, the residue diluted with water and the cooled aqueous solution was neutralized with 2N aqueous hydrochloric acid (3.46 ml,6.03 mmol). The solid was collected by filtration and dried to give 1-methyl-5- (2-phenyl- [1,2,4] triazolo [1,5-a ] pyridin-7-ylcarbamoyl) -1H-pyrazole-4-carboxylic acid (2.21 g, 97%) as a white solid. mp. >300 ℃. MS: M/z= 361.1 (m+h+).

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. Mu. Mol), morpholine (240. Mu.l, 2.76 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407. Mu.l, 690. Mu. Mol) in tetrahydrofuran (7 ml) was stirred at 70℃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 ℃. MS: M/z=432.4 (m+h ").

Example 2: crystalline forms of a compound of formula I

Preparation of crystalline forms: the amorphous form of the compound of formula I is stirred in water or a 50% water in methanol mixture at 65 ℃ for 3 days to give the crystalline form of the free base of the compound of formula I. The crystalline form is thermodynamically stable at least between 20 ℃ and 60 ℃. XRPD and DSC patterns are substantially as shown in figures 1 and 2. XRPD patterns may be obtained by following schemes known in the art.

Melting point: determination of the maximum melting Point peak (T) of the crystalline form Using DSC _m ) The DSC was performed using Mettler Toledo DSC 821e with Sample Robot TSO 801 RO. 2-5mg of the sample was placed in an AL crucible 40uL with an AL perforated lid and the sample was heated from 25℃to 300℃at a rate of 10℃per minute. Temperatures at the beginning, maximum and end of the crystal melting peak were collected. DSC shows T in crystalline form _m 213.16 ℃.

Solubility: the above crystalline form shows very low solubility (< 0.004 mg/mL) in aqueous solutions with pH > 3. The solubilities in Simulated Gastric Fluid (SGF), fasted simulated intestinal fluid (FaSSIF) and fed simulated intestinal fluid (FeSSIF) were 0.019mg/mL, 0.006mg/mL and 0.022mg/mL, respectively. The solubility is increased by a factor of 50-100 in the presence of a surfactant (e.g., tween-80, sodium lauryl sulfate, dioctyl sulfosuccinate or Pluronic F68) and cyclodextrin; however, it is still quite low. Overall, the crystals showed poor solubility (< 50 mg/mL) not only in aqueous systems but also in most of the organic solvents tested at ambient temperature (22 ℃).

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 performed to investigate the viability of the crystalline form under various stress conditions. Because of the low solubility of the compounds of formula I in the standard solvent ethanol, N-methyl-2-pyrrolidone (NMP) is substituted for ethanol.

A defined amount of the crystalline form of the free base of the compound of formula I (0.2-0.8 mg) is weighed into a 1.8mL HPLC vial and stored either open (75% RH) or closed (ambient) at the indicated temperature and time. After incubation, the compounds were dissolved in 1-1.5mL NMP to a final concentration of 0.2-0.5mg/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 is stable in the solid state (< 0.5% degradation products) at different temperatures, for example at 40-60 ℃ for at least 4 weeks.

TABLE 5 preliminary solid State stability

The crystalline form of the free base of the compound of formula I is stable in solution at 80 ℃ for up to 8 days in the solid state and at RT at pH 3 to pH 7. Degradation is observed at higher or lower pH. In the solid state, the crystalline form is stable upon exposure to light. In solution, it is stable against sunlight and moderately stable to unstable in time dependence in the sun test. It is also stable to oxidation for 1 day, but shows some sensitivity after prolonged exposure. The crystalline form is compatible with almost all excipients; however, the recovery of drug in the CompaS assay strongly depends on the solvent used for extraction.

In suspension vehicle (0.5% HPC/1% Tween 80) for PK, PD and Tox studies, the crystalline form was also stable for up to 5 weeks at RT, with only a small amount of particles growing and no hydrate formation. For parenteral administration, 30% Kleptose formulation (1.5 mg/ml, physiological osmotic pressure, pH 6.2) was developed, with stability at 40 ℃ for at least 4 weeks.

Example 3: safety and efficacy studies of compounds of formula I for treating subjects with COFD

1. Study A

An open label, stage IIa, multicenter, 6 week prospective study is provided below to assess the safety and efficacy of the compound of formula I in adult male patients with COFD at daily doses ranging from 5mg to 15 mg.

Study design

2. Study B

The following provides a study design of a double blind, placebo-controlled, phase IIb, multicentric, six to ten week prospective study to assess the efficacy and safety of the compound of formula I as a PDE10A inhibitor (i.e., compound 1, RO 5545965) in adult male patients with COFD at daily doses ranging from 2.5mg to 15 mg. Endpoint refers to the first visit after the last dose of study medication.

Overall design:after screening to confirm eligibility, at day-7, participants will enter a variable placebo run-in period of up to 5 weeks. Starting from the baseline visit (day 1), participants can be randomized to double-blind, placebo-controlled, parallel-group treatment with a compound of formula I or placebo once daily (od). During the first 3 weeks of treatment following randomization, the participants will receive increasing doses of the compound of formula I or a double blind increasing placebo until their maximum tolerated dose is reached. Thereafter, the participants will remain at that dose until they have completed a total treatment period of 10 weeks.

Population:a total of 67 male participants 18 to 50 years old, who met the DSM-5 standard of fluency disorder (COFD) in childhood morbidity and required medication, and who had a history of stuttering of ≡2 years, had a morbidity consistent with the nature of development by age 8, will be evaluated in the study. It is estimated that 60 participants will be randomly assigned to receive the compound of formula I or placebo.

Target and endpoint:

exclusion criteria:participants were excluded from the study if any of the following criteria were applicable:

medical condition:

1. stuttering is associated with known neurological causes such as stroke and the like.

2. Low IQ as seen by researchers.

3. Patients with uncontrolled epileptic conditions.

4. History of severe traumatic brain injury or stroke.

5. Patients at risk of impending suicide appear to the researcher.

6. Positive for the human immunodeficiency virus test is known.

7. Known substance abuse or dependence diagnosis of DSM-5.

8. Unstable medical diseases or clinically significant abnormalities at the time of screening test/examination.

9. Any unstable medical condition or current illness (e.g., congenital heart disease, arrhythmia, or cancer) at the discretion of the researcher will place them at risk for major adverse events during the trial, be expected to progress during the study, or will interfere with safety and efficacy assessment.

Previous/concomitant therapy:

10. a new stuttering behavior therapy was started within 10 weeks before baseline.

Previous/concurrent clinical study experience:

11. another clinical study with IP administration was enrolled over the past 30 days.

12. Participants with known hypersensitivity reactions to compound 1 or any excipient of the product.

Diagnostic evaluation：

13. Urine drug screening for ***e or non-prescription opioids was positive.

Other exclusions:

14. to planning and/or implementation of the study (applicable to Noema staff and/or staff at the site of the study).

15. If the participant is unlikely to adhere to the study procedure, constraints and requirements, it is judged by the researcher that the participant should not participate in the study.

16. Randomization was previously performed in this study.

Description of the product:

type(s)	Medicament
		Dosage formulation	Capsule
Unit dose strength	2.5mg, 5.0mg and 10mg
		Dosage level	Once daily 2.5 to 15mg
Route of administration	Oral administration

The dose level of the compound of formula I will slowly titrate upward from a starting dose of 2.5mg to a maximum dose of 15mg, depending on the tolerance exhibited by the individual participants.

Example 4: investigation of the effects of the Compounds of formula III (olanzapine) and formula I (RO 5545965) on glucose tolerance (Ogtt)

Three consecutive studies were performed to evaluate the effect of olanzapine (compound of formula III) and compound of formula I (RO 5545965) on glucose tolerance.

The first objective was to verify healthy rats as a predictive model for revealing metabolic side effects induced by olanzapine (compound of formula III). The study was performed on 10 week male SD rats fed with feed. Glucose challenge was performed 1 hour after the last treatment. Glucose loading (2 g/kg BW) was accomplished orally by gavage and the formulation was prepared in saline. Details of the formulation are shown in table 1. Blood glucose and plasma insulin were measured at 0 (pre-challenge), +15, +30, +60, and +120 minutes. Blood was sampled in EDTA-coated tubes and blood samples were stored on ice until centrifugation at 4 ℃. ELISA (Merodia, uppsala, sweden) for insulin and fluorescence for glucose measurement (Accucheck System) were used for the analysis. Data analysis was done using software JMP for Windows (version 5.01,SAS institute Inc, SAS template Drive, cary, NC 27513). Analysis of variance ANOVA (α0.05 and 0.01) was followed by Dunnett's test (comparison to control).

TABLE 1 preparation

Vehicle: 0.3% Tween in water.

Glucose levels during the oral glucose tolerance test are shown in fig. 3, and insulin levels during the oral glucose tolerance test are shown in fig. 4. Studies have shown that acute treatment of SD rats with olanzapine induces a dose-dependent increase in fasting glycemia, glucose intolerance and fasting insulin. Overall, the study revealed that olanzapine induced glucose intolerance.

A second study evaluated the effect of acute treatment with the compound of formula I. The study was performed on 9 week male SD rats fed with feed. Glucose challenge was performed 1 hour after treatment. Glucose loading (2 g/kg BW) was accomplished orally by gavage and the formulation was prepared in saline. Details of the formulation are shown in table 2. Blood glucose and plasma insulin were measured at 0 (pre-challenge), +15, +30, +60, and +120 minutes. Blood was sampled in EDTA-coated tubes and blood samples were stored on ice until centrifugation at 4 ℃. ELISA (Merodia, uppsala, sweden) for insulin and fluorescence for glucose measurement (Accucheck System) were used for the analysis. Data analysis was done using software JMP for Windows (version 5.01,SAS institute Inc, SAS template Drive, cary, NC 27513). Analysis of variance ANOVA (α0.05 and 0.01) was followed by Dunnett's test (comparison to control).

TABLE 2 preparation

Vehicle: 0.3% Tween in water.

Glucose levels during the oral glucose tolerance test are shown in fig. 5. Studies have shown that acute treatment of SD rats with olanzapine induces an increase in fasting blood glucose and glucose intolerance. Details of the formulation are shown in table 3. Studies have also shown that acute treatment with the compounds of formula I does not induce any change in glucose tolerance. A third study assessed the sub-chronic (8 day) effect of the compound of formula I alone or in combination with olanzapine. The study was performed on 10 week male SD rats fed with feed. Glucose challenge was performed 1 hour after treatment. Glucose loading (2 g/kg BW (water)) was accomplished orally by tube feeding. Blood glucose was measured with a glucometer at 0 (before challenge), +15, +30, +60, and +120 minutes. Insulin was measured only at time 0. Blood was sampled in EDTA-coated tubes and blood samples were stored on ice until centrifugation at 4 ℃. ELISA (Merodia, uppsala, sweden) for insulin and fluorescence for glucose measurement (Accucheck System) were used for the analysis. Data analysis was done using software JMP for Windows (version 5.01,SAS institute Inc, SAS template Drive, cary, NC 27513). Analysis of variance ANOVA (α0.05 and 0.01) was followed by Dunnett's test (comparison to control).

TABLE 3 preparation

Vehicle: 0.3% Tween 80 in water.

Body weight and food intake are shown in fig. 6, glucose levels during oral glucose tolerance testing are shown in fig. 7, and insulin levels prior to oral glucose tolerance testing are shown in fig. 8. Studies showed that acute treatment of SD rats with olanzapine induced an increase in fasting glucose and glucose intolerance, and that 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 induces a slight improvement in glucose tolerance, no change in fasting glucose, and a decrease in fasting insulin when administered in combination with olanzapine, relative to olanzapine alone. Studies have shown that compounds of formula I, alone or in combination, do not induce glucose intolerance in healthy rats. In contrast, the study showed a slight improvement in glucose tolerance induced by the compound of formula I alone after 8 days of treatment. Studies have shown the persistence of glucose intolerance induced by olanzapine.

Example 5: composition containing compound 1

The following describes compositions containing 10mg strength capsules of the compound of formula I (i.e., compound 1, ro 5545965). The capsules were characterized as reddish brown, opaque, hard capsule No. 1.

Component (A) ^a	Measuring amount
		Filling quality	Actual weight (mg/capsule)
Compound 1	10.00
		Mannitol	71.60
Microcrystalline cellulose	24.00
		Sodium starch glycolate	6.00
Sucrose monopalmitate	1.20
		Hydroxypropyl methylcellulose	6.00
Colloidal silica	0.60
		Stearyl sodium fumarate	0.60
Weight of the little (filling quality)	120.00

^a Purified water (european pharmacopoeia) was used for wet granulation; it is substantially removed during processing

The following describes compositions containing 5mg strength capsules of the compound of formula I (i.e., compound 1, ro 5545965). The capsules were characterized as reddish brown, opaque, hard capsule No. 1.

Component (A) ^a	Measuring amount
		Filling quality	Actual weight (mg/capsule)
Compound 1	5.00
		Mannitol	76.60
Microcrystalline cellulose	24.00
		Sodium starch glycolate	6.00
Sucrose monopalmitate	1.20
		Hydroxypropyl methylcellulose	6.00
Colloidal silica	0.60
		Stearyl sodium fumarate	0.60
Weight of the little (filling quality)	120.00

Provided below are 2.5mg strength capsules containing a compound of formula I (i.e., compound 1, ro 5545965). The capsules were characterized as reddish brown, opaque, hard capsule No. 1.

Component (A) ^a	Measuring amount
		Filling quality	Actual weight (mg/capsule)
Compound 1	2.50
		Mannitol	79.10
Microcrystalline cellulose	24.00
		Sodium starch glycolate	6.00
Sucrose monopalmitate	1.20
		Hydroxypropyl methylcellulose	6.00
Colloidal silica	0.60
		Stearyl sodium fumarate	0.60
Weight of the little (filling quality)	120.00

Incorporated by reference

The present application relates to various issued patents, published patent applications, journal articles and other publications, all of which are incorporated herein by reference. If a conflict exists between any of the incorporated references and this specification, the specification will control. In addition, any particular embodiment of the disclosure that falls within the prior art may be expressly excluded from any one or more of the claims. Because such embodiments are believed to be known to one of ordinary skill in the art, they may be excluded even if not explicitly stated herein. Any particular embodiment of the disclosure may be excluded from any claim for any reason, whether or not related to the existence of prior art.

Equivalents (Equipped with)

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

Claims

1. A method of treating a Childhood Onset Fluency Disorder (COFD), comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a phosphodiesterase 10A (PDE 10A) inhibitor or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein administering comprises administering the PDE10A inhibitor, or a pharmaceutically acceptable salt thereof, once a day.

3. The method of claim 1 or 2, wherein administering comprises orally administering the PDE10A inhibitor or a pharmaceutically acceptable salt thereof.

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

5. The method of any one of claims 1-4, wherein the PDE10A inhibitor is selected from the group consisting of papaverine, PF-02545920, RO5545965, TAK-063, AMG 579, and THPP-1.

6. The method of any one of claims 1-5, wherein the PDE10A inhibitor has no effect on insulin resistance.

7. The method of any one of claims 1-6, wherein the composition comprises the PDE10A inhibitor, or a pharmaceutically acceptable salt thereof, as the sole active agent.

8. The method of any one of claims 1-6, wherein the composition comprises the PDE10A inhibitor, or a pharmaceutically acceptable salt thereof, in combination with another therapeutically active agent.

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

10. The method of claim 9, wherein the additional therapeutically active agent is a dopamine receptor D1 (DRD 1) antagonist.

11. The method of claim 10, wherein the DRD1 antagonist is ecopipam.

12. The method of claim 9, wherein the additional therapeutically active agent is a dopamine receptor D2 (DRD 2) antagonist.

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

14. The method of any one of claims 1-13, wherein the PDE10A inhibitor, or a pharmaceutically acceptable salt thereof, is administered at between about 1mg and about 100mg once per day.

15. The method of any one of claims 1-14, wherein the PDE10A inhibitor, or a pharmaceutically acceptable salt thereof, is administered at between about 2.5mg and about 15mg once per day.

16. The method of any one of claims 1-15, wherein the PDE10A inhibitor, or a pharmaceutically acceptable salt thereof, is administered at between about 5mg and about 15mg once per day.

17. The method of any one of claims 8-16, wherein the additional therapeutically active agent is administered at about 0.1mg to about 10mg once per day.

18. The method of any one of claims 8-17, wherein the additional therapeutically active agent is administered at about 0.5mg to about 5mg once per day.

19. The method of any one of claims 8-17, wherein the additional therapeutically active agent is administered at about 2.5mg to about 5mg once per day.

20. The method of claim 9, wherein the PDE10A inhibitor or a pharmaceutically acceptable salt thereof is administered at between about 5mg and about 15mg once per day; and the dopamine receptor antagonist is administered at about 0.5mg to about 5mg once daily.

21. A method of treating a Childhood Onset Fluency Disorder (COFD), comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent is a compound of formula I:

22. the method of claim 21, wherein administering comprises administering the compound of formula I in its free base form.

23. The method of claim 21, wherein administering comprises administering the compound of formula I in its pharmaceutically acceptable salt form.

24. The method of any one of claims 21-23, wherein administering comprises orally administering the PDE10A inhibitor, or a pharmaceutically acceptable salt thereof.

25. The method of any one of claims 21-24, wherein the composition comprises the compound of formula I or a pharmaceutically acceptable salt thereof as the sole active agent.

26. The method of any one of claims 21-24, wherein the composition comprises the compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with another therapeutically active agent.

27. The method of any one of claims 21-26, wherein the composition comprises an inactive agent selected from the group consisting of mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silicon dioxide, and sodium stearyl fumarate.

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

29. The method of claim 28, wherein the capsule shell consists of gelatin, titanium dioxide, red iron oxide, and yellow iron oxide.

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

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

32. The method of claim 29, wherein the capsule comprises about 2.5mg, about 5.0mg, or about 10mg of the compound of formula I or a pharmaceutically acceptable salt thereof.

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

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

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

36. A method of treating COFD comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent is a compound of formula I:

wherein administering comprises administering the compound of formula I, or a pharmaceutically acceptable salt thereof, once daily in an amount of about 5mg to about 15 mg.

37. A method of treating COFD comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent is a compound of formula I:

wherein administering comprises administering the compound of formula I, or a pharmaceutically acceptable salt thereof, once daily in an amount of about 2.5mg to about 15 mg.

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

39. A method of treating COFD comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a crystalline solid of a compound of formula I:

wherein the crystalline solid has a melting point onset of about 210 ℃ to about 214 ℃ as determined by DSC, and the administering comprises administering the crystalline solid once a day in an amount of about 2.5mg to about 15 mg.

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

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

42. The method of claim 39, wherein the crystalline solid has an XRPD pattern substantially as shown in figure 1.

43. The method of claim 39, wherein the crystalline solid has a DSC curve substantially as shown in FIG. 2.

44. The method of any one of claims 1-43, wherein the administration results in an improvement of one or more symptoms of COFD selected from the group consisting of sound repetition, syllable repetition, word repetition, and sound prolongation, chinese plug, and struggle behavior.

45. A method of treating a Childhood Onset Fluency Disorder (COFD) in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of:

a compound of formula III:

and

a compound of formula I:

or a pharmaceutically acceptable salt thereof.

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

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

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

49. The method of claim 45, wherein the compound of formula III or pharmaceutically acceptable salt thereof is administered at about 2.5mg to about 5.0mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 5.0mg to about 15mg once per day.

50. The method of any one of claims 45-49, wherein the compound of formula III and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered simultaneously.

51. The method of any one of claims 45-49, wherein the compound of formula III and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered sequentially.

52. The method of claim 51, wherein the compound of formula III is present in a single dosage form and the compound of formula I is present in separate dosage forms.

53. The method of any one of claims 45-52, 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 a pharmaceutically acceptable salt thereof, is administered intravenously, intramuscularly, or orally.

54. The method of any one of claims 45-53, wherein the compound of formula III and the compound of formula I are contained in a composition, wherein the composition is in the form of an aerosol, inhalable powder, injectable, liquid, solid, capsule or tablet.

55. The method 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. The method 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 method of treating a Childhood Onset Fluency Disorder (COFD) in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of:

a compound of the compound of formula III:

and

a crystalline solid of formula I:

wherein the crystalline solid has a melting point onset as determined by DSC from about 210 ℃ to about 214 ℃;

or a pharmaceutically acceptable salt thereof.

58. The method of claim 57, wherein the crystalline solid has an XRPD pattern substantially as shown in figure 1.

59. The method of claim 57, wherein the crystalline solid has a DSC curve substantially as shown in FIG. 2.

60. The method of any one of claims 57-59, wherein the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 500mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 500mg once per day.

61. The method of any one of claims 57-59, wherein the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 50mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 50mg once per day.

62. The method of any one of claims 57-59, wherein the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 30mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 500 μg to about 20mg once per day.

63. The method of any one of claims 57-59, wherein the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 2.5mg to about 5.0mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 5.0mg to about 15mg once per day.

64. The method of any one of claims 57-63, wherein the compound of formula III and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered simultaneously.

65. The method of any one of claims 57-63, wherein the compound of formula III and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered sequentially.

66. The method of claim 65, wherein the compound of formula III is present in a single dosage form and the compound of formula I is present in separate dosage forms.

67. The method of any one of claims 57-66, 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 a pharmaceutically acceptable salt thereof, is administered intravenously, intramuscularly, or orally.

68. The method of claim 57, wherein the crystalline solid has a DSC curve substantially as shown below:

69. the method of any one of claims 57-59, wherein the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 500mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 500mg once per day.

70. The method of any one of claims 57-59, wherein the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 50mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 50mg once per day.

71. The method of any one of claims 57-59, wherein the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 1mg to about 30mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 500 μg to about 20mg once per day.

72. The method of any one of claims 57-59, wherein the compound of formula III, or a pharmaceutically acceptable salt thereof, is administered at about 2.5mg to about 5.0mg once per day; and the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at about 5.0mg to about 15mg once per day.

73. The method of any one of claims 57-63, wherein the compound of formula III and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered simultaneously.

74. The method of any one of claims 57-63, wherein the compound of formula III and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered sequentially.

75. The method of claim 65, wherein the compound of formula III is present in a single dosage form and the compound of formula I is present in separate dosage forms.

76. The method of any one of claims 57-66, 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 a pharmaceutically acceptable salt thereof, is administered intravenously, intramuscularly, or orally.

77. The method of any one of claims 57-67, wherein the compound of formula III and the compound of formula I are contained in a composition, wherein the composition is in the form of an aerosol, inhalable powder, injectable, liquid, solid, capsule, or tablet.

78. The method 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.

79. The method 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.

80. A method of treating a Childhood Onset Fluency Disorder (COFD) in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of:

a compound of formula III:

and

a compound of formula I:

81. A method of treating a Childhood Onset Fluency Disorder (COFD) in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of:

a compound of formula III:

and

a crystalline solid of formula I: