Use of phosphodiesterase 10 inhibitor gemlapodect for weight loss

Abstract

Provided herein are methods of reducing body weight in a subject in need thereof by administering to the subject compositions comprising a PDE10 inhibitor. Also disclosed are crystalline solid forms of the compound of Formula I and uses thereof : (I)

Description

USE OF A PHOSPHODIESTERASE 10 INHIBITOR FOR WEIGHT LOSSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of, and priority to, U.S.S.N. 63 / 698,875, filed onSeptember 25, 2024, the contents of which are incorporated herein by reference in their entirety.BACKGROUND

[0002] Excessive weight gain and obesity in individuals are characterized by an increased amount of body fat relative to their height and age. Increased body weight and obesity are associated with health complications and comorbidities, such as cardiovascular diseases and metabolic disorders, as well as increased risk for developing joint problems, sleep and breathing issues, and some cancer types. An estimated 30% of adults and 16% of children between the ages of 2 to 19 in the United States were reported to be overweight in 2017-2018.

[0003] Current methods for treating excessive weight gain include lifestyle management, pharmacotherapy, and surgery. The success of available pharmacological interventions vary greatly across individuals, and long-term management has not been found effective.

[0004] Therefore, there is an unmet need to develop new methods of reducing body weight in individuals.SUMMARY

[0005] In one aspect, provided is a method of reducing body weight in a subject in need thereof, the method comprising administering to the subject an agent (or compound) of Formula I:or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, the method reduces body mass index (BMI) and / or body fat of the subject.

[0007] In some embodiments, the agent, or a pharmaceutically acceptable salt thereof, is administered once daily.

[0008] In some embodiments, the agent, or a pharmaceutically acceptable salt thereof, is administered orally.

[0009] In some embodiments, the agent is administered at a dose of about 2.5 mg to about 15 mg.

[0010] In some embodiments, the agent is administered at a dose of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

[0011] In some embodiments, the agent is administered at an initial dose of about 2.5 mg.

[0012] In some embodiments, the dose is increased by about 2.5 mg weekly up to a dose of about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

[0013] In some embodiments, the body weight reduction is mild.

[0014] In some embodiments, the body weight reduction is moderate.

[0015] In some embodiments, the subject’s body weight is reduced by about 0.1% to about 20%.

[0016] In some embodiments, the subject’s body weight is reduced by about 7% to about 20%.

[0017] In some embodiments, the subject’s body weight is reduced by about 1 kg to about 10 kg.

[0018] In some embodiments, the reduction in body weight occurs by about 29 days, by about 57 days, by about 71 days, or by about 85 days from administration

[0019] In some embodiments, the subject is overweight.

[0020] In some embodiments, the subject does not have diabetes or diabetes-related obesity.

[0021] In some embodiments, the subject has a BMI of about 25 kg / m2to about 29.9 kg / m2.

[0022] In another aspect, provided is a method of preventing weight gain in a subject in need thereof, the method comprising administering to the subject an agent (or compound) of FormulaI:or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the method prevents an increase in body mass index (BMI) and / or body fat of the subject.

[0024] In some embodiments, the agent, or a pharmaceutically acceptable salt thereof, is administered once daily.

[0025] In some embodiments, the agent, or a pharmaceutically acceptable salt thereof, is administered orally.

[0026] In some embodiments, the agent is administered at a dose of about 2.5 mg to about 15 mg.

[0027] In some embodiments, the agent is administered at a dose of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

[0028] In some embodiments, the agent is administered at an initial dose of about 2.5 mg.

[0029] In some embodiments, the dose is increased by about 2.5 mg weekly up to a dose of about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

[0030] In some embodiments, the present disclosure provides an agent (or compound) ofFormula I:or a pharmaceutically acceptable salt thereof, for use in reducing body weight in a subject in need thereof.

[0031] In some embodiments, the present disclosure provides use of an agent (or compound) ofFormula I:or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for reducing body weight in a subject in need thereof.

[0032] In some embodiments, the use reduces body mass index (BMI) and / or body fat of the subject.

[0033] In some embodiments, the agent, or a pharmaceutically acceptable salt thereof, is administered once daily.

[0034] In some embodiments, the agent, or a pharmaceutically acceptable salt thereof, is administered orally.

[0035] In some embodiments, the agent is administered at a dose of about 2.5 mg to about 15 mg.

[0036] In some embodiments, the agent is administered at a dose of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

[0037] In some embodiments, the agent is administered at an initial dose of about 2.5 mg.

[0038] In some embodiments, the dose is increased by about 2.5 mg weekly up to a dose of about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

[0039] In some embodiments, the body weight reduction is mild.

[0040] In some embodiments, the body weight reduction is moderate.

[0041] In some embodiments, the subject’s body weight is reduced by about 0.1% to about 20%.

[0042] In some embodiments, the subject’s body weight is reduced by about 7% to about 20%.

[0043] In some embodiments, the subject’s body weight is reduced by about 1 kg to about 10 kg.

[0044] In some embodiments, the reduction in body weight occurs by about 29 days, by about 57 days, by about 71 days, or by about 85 days from administration

[0045] In some embodiments, the subject is overweight.

[0046] In some embodiments, the subject does not have diabetes or diabetes-related obesity.

[0047] In some embodiments, the subject has a BMI of about 25 kg / m2to about 29.9 kg / m2.

[0048] In another aspect, provided is an agent (or compound) of Formula I:or a pharmaceutically acceptable salt thereof, for use in preventing weight gain in a subject in need thereof.

[0049] In another aspect, the present disclosure provides use of an agent (or compound) ofFormula I:or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing weight gain in a subject in need thereof.

[0050] In some embodiments, the use prevents an increase in body mass index (BMI) and / or body fat of the subject.

[0051] In some embodiments, the agent, or a pharmaceutically acceptable salt thereof, is administered once daily.

[0052] In some embodiments, the agent, or a pharmaceutically acceptable salt thereof, is administered orally.

[0053] In some embodiments, the agent is administered at a dose of about 2.5 mg to about 15 mg.

[0054] In some embodiments, the agent is administered at a dose of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

[0055] In some embodiments, the agent is administered at an initial dose of about 2.5 mg.

[0056] In some embodiments, the dose is increased by about 2.5 mg weekly up to a dose of about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.BRIEF DESCRIPTION OF THE DRAWINGS

[0057] FIG. 1 depicts an exemplary XRPD pattern of a crystalline solid of the free base of the compound of Formula I.

[0058] FIG. 2 depicts an exemplary DSC curve of a crystalline solid of the free base of the compound of Formula I.DETAILED DESCRIPTION

[0059] As generally described herein, the present disclosure provides methods of reducing body weight in a subject in need thereof. The present disclosure also describes a crystalline form of the free base of the compound of Formula I, and uses thereof.Definitions

[0060] To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

[0061] 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. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0062] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0063] In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element orcomponent can be selected from the group consisting of two or more of the recited elements or components.

[0064] Further, it should be understood that elements and / or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present invention and / or in methods of the present invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.

[0065] 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. By way of example, “an element” means one element or more than one element.

[0066] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0067] It should be understood that the expression “at least one of’ includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and / or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.

[0068] The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0069] Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As usedherein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred from the context.

[0070] At various places in the present specification, variable or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0071] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention.

[0072] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

[0073] As used herein, “pharmaceutical composition” or “pharmaceutical formulation” refers to the combination of an active agent or compound with an excipient or a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0074] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0075] As used herein, “pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present invention (e.g., the compound of Formula I), which salt is compatible with pharmaceutical administration.

[0076] As is known to those of skill in the art, “salts” of compounds may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic,lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acid. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0077] 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 compounds of formula NW4+, wherein W is CM alkyl, and the like.

[0078] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na+, K+, Ca2+, NH4+, and NW4+(where W can be a Ci-4 alkyl group), and the like.

[0079] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0080] As used herein, “pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and / or absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, such as a phosphate buffered saline solution, emulsions (e.g., such as an oil / water or water / oil emulsions), lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fattyacid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the invention. For examples of excipients, see Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0081] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a nonhuman animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, 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. In certain embodiments, the subject is a male. In certain embodiments, the subject is a female.

[0082] As used herein, “solid dosage form” means a pharmaceutical dose(s) in solid form, e.g., tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewables.

[0083] As used herein, “administering” 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 the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.

[0084] By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., other weight modulating therapies, e.g., weight loss therapies). The compound of Formula I, or a pharmaceutically acceptable salt thereof, can be administered alone or can be co-administered toa subject. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

[0085] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (e.g., “therapeutic treatment”).

[0086] The phrase "therapeutically effective amount" as used herein means an amount of a composition (e.g., a composition described herein), or a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is effective for producing some desired therapeutic effect in a subject.

[0087] As used herein, and unless otherwise specified, the terms “overweight,” “being overweight,” “obesity,” and “being obese” refer to the state of having an excess of fat in proportion to lean body mass. In accordance with guidance from the Centers for Disease Control and Prevention (CDC), an adult is considered overweight if their body mass index (BMI) is between 25 and 29.9 kg / m2. Furthermore, an adult is considered obese if their BMI is 30 kg / m2or greater. An adult having a BMI of 30 or greater and less than 35 kg / m2is considered to have class I obesity. An adult having a BMI of 35 kg / mg2or greater and less than 40 kg / m2is considered to have class II obesity. An adult having a BMI of 40 kg / mg2or greater is considered to have class III obesity. A child is considered overweight if their BMI is above the 85th percentile and less than the 95th percentile compared to other children of the same age and gender. Furthermore, a child is considered obese if their BMI is at the 95th percentile or greater compared to other children of the same age and gender. A subject may be overweight or obese without having co-morbidities, such as diabetes. For instance, a subject may be a metabolically healthy obese subject or have metabolically healthy obesity (MHO). Furthermore, a subject may be obese but not have diabetes-related obesity. Even further, a subject may be metabolically abnormal and obese or have metabolically abnormal obesity (MAO), wherein the metabolic abnormality is not diabetes or diabetes-related.

[0088] As used herein, and unless otherwise specified, the phrases “reduction in body weight,” “weight reduction,” “reducing body weight,” “promoting weight loss,” or “effecting weight loss” refer to a decrease in the body weight of an subject. A reduction in body weight may be indicated by, for instance, a decrease in BMI, a decrease in body weight, and / or a decrease in body fat. The terms “preventing weight gain,” and “inhibiting further weight gain,” relate to the prevention of weight gain, i.e., maintaining a set body weight. Reduction in body weight and / or prevention of weight gain can be measured over the course of a set time period (e.g., about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, or longer).

[0089] As used herein, and unless otherwise specified, the terms “mild,” “moderate,” and “severe” are used for defining the changes in the body weight of a subject relative to a baseline, where the baseline is the weight of the subject at the start of the administration of a compound as disclosed herein (e.g., Formula I). For instance, the term “mild” weight loss refers to a loss of up to about 5% body weight relative to baseline. “Moderate” weight loss refers to a loss of between about 5% and about 10% body weight relative to baseline. “Severe” weight loss refers to a loss of more than about 10% body weight relative to baseline.Compound

[0090] The compound (or agent) of Formula I, as depicted below, is a phosphodiesterase 10 (PDE10) inhibitor, also known as l-methyl-4-(morpholine-4-carbonyl)-N-(2- phenyl[l,2,4]triazolo[l,5-a]pyridin-7-yl)-lH-pyrazole-5-carboxamide. The compound of Formula I may also be referenced as “Compound 1” or “RO554965.”

[0091] A method of chemically synthesizing the compound of Formula I (including Example 1 provided herein, infra) is described in U.S. Patent No. 8,349,824, which is incorporated by reference in its entirety.

[0092] In various embodiments, the pharmaceutically acceptable salt of the compound of Formula I can be a salt of the compound of Formula I with physiologically compatible mineral acids, such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid; or with organic acids, such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.

[0093] This invention also covers a solid form of a compound of Formula I:(I), wherein the solid form is a crystalline solid of the free base of the compound of Formula I, and the crystalline solid has a melting point by differential scanning calorimetry (DSC) of about 210- 214 °C (e.g., about 210 °C, about 211 °C, about 212 °C, about 213 °C, or about 214 °C).

[0094] In some embodiments, the above described solid form is a crystalline solid of the free base of Formula I, having an X-ray powder diffraction (XRPD) pattern as substantially shown in FIG. 1.

[0095] In some embodiments, the above described solid form is a crystalline solid of the free base of Formula I, having a DSC figure as substantially shown in FIG. 2.Pharmaceutical Compositions

[0096] In one aspect, provided herein is a pharmaceutical composition comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for the reduction of body weight in a subject in need thereof. It should be understoodthat the compound of Formula I as described herein includes the crystalline solid of the free base of the compound of Formula I as described herein.

[0097] In various embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be from about 1 mg to about 15 mg, about 1.5 mg to about 15 mg, about 2 mg to about 15 mg, about 2.5 mg to about 15 mg, about 3 mg to about 15 mg, about 3.5 mg to about 15 mg, about 4 mg to about 15 mg, about 4.5 mg to about 15 mg, about 5 mg to about 15 mg, about 6 mg to about 15 mg, about 7 mg to about 15 mg, about 8 mg to about 15 mg, about 9 mg to about 15 mg, about 10 mg to about 15 mg, about 11 mg to about 15 mg, about 12 mg to about 15 mg, about 13 mg to about 15 mg, about 14 mg to about 15 mg, about 1 mg to about 14 mg, about 1 mg to about 13 mg, about 1 mg to about 12 mg, about 1 mg to about 11 mg, about 1 mg to about 10 mg, about 1 mg to about 9 mg, about 1 mg to about 8 mg, about 1 mg to about 7 mg, about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 1 mg to about 4.5 mg, about 1 mg to about 4 mg, about 1 mg to about 3.5 mg, about 1 mg to about 3 mg, about 1 mg to about 2.5 mg, about 1 mg to about 2 mg, about 1 mg to about 1.5 mg, about 1.5 mg to about 9 mg, about 1.5 mg to about 8 mg, about 1.5 mg to about 7 mg, about 1.5 mg to about 6 mg, about 1.5 mg to about 5 mg, about 1.5 mg to about 4.5 mg, about 1.5 mg to about 4 mg, about 1.5 mg to about 3.5 mg, about 1.5 mg to about 3 mg, about 1.5 mg to about 2.5 mg, about 1.5 mg to about 2 mg, about 2 mg to about 9 mg, about 2 mg to about 8 mg, about 2 mg to about 7 mg, about 2 mg to about 6 mg, about 2 mg to about 5 mg, about 2 mg to about 4.5 mg, about 2 mg to about 4 mg, about 2 mg to about 3.5 mg, about 2 mg to about 3 mg, about 2 mg to about 2.5 mg, about 2.5 mg to about 9 mg, about 2.5 mg to about 8 mg, about 2.5 mg to about 7 mg, about 2.5 mg to about 6 mg, about 2.5 mg to about 5 mg, about 2.5 mg to about 4.5 mg, about 2.5 mg to about 4 mg, about 2.5 mg to about 3.5 mg, about 2.5 mg to about 3 mg, about 3 mg to about 9 mg, about 3 mg to about 8 mg, about 3 mg to about 7 mg, about 3 mg to about 6 mg, about 3 mg to about 5 mg, about 3 mg to about 4.5 mg, about 3 mg to about 4 mg, about 3 mg to about 3.5 mg, about 3.5 mg to about 9 mg, about 3.5 mg to about 8 mg, about 3.5 mg to about 7 mg, about 3.5 mg to about 6 mg, about 3.5 mg to about 5 mg, about 3.5 mg to about 4.5 mg, about 3.5 mg to about 4 mg, about 4 mg to about 9 mg, about 4 mg to about 8 mg, about 4 mg to about 7 mg, about 4 mg to about 6 mg, about 4 mg to about 5 mg, about 4 mg to about 4.5 mg, about 4.5 mg to about 9mg, about 4.5 mg to about 8 mg, about 4.5 mg to about 7 mg, about 4.5 mg to about 6 mg, about4.5 mg to about 5 mg, about 5 mg to about 9 mg, about 5 mg to about 8 mg, about 5 mg to about 7 mg, about 5 mg to about 6 mg, about 6 mg to about 9 mg, about 6 mg to about 8 mg, about 6 mg to about 7 mg, about 7 mg to about 9 mg, about 7 mg to about 8 mg, or about 8 mg to about 9 mg. In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be from about2.5 mg to about 5 mg. In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be from about 5 mg to about 10 mg. In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be from about 10 mg to about 15 mg.

[0098] In various embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, or about 15 mg. In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be about 2.5 mg. In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be about 5 mg. In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be about 10 mg.

[0099] In another aspect, provided herein is a pharmaceutical composition comprising from about 2.5 mg to about 5 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, for the reduction of body weight in a subject in need thereof. In another aspect, provided herein is a pharmaceutical composition comprising from about 5 mg to about 10 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, for thereduction of body weight in a subject in need thereof. In another aspect, provided herein is a pharmaceutical composition comprising from about 10 mg to about 15 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, for the reduction of body weight in a subject in need thereof. In another aspect, provided herein is a pharmaceutical composition comprising from about 5 mg to about 15 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, for the reduction of body weight in a subject in need thereof.

[0100] In another aspect, provided herein is a pharmaceutical composition comprising from about 2.5 mg to about 15 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, for the reduction of body weight in a subject in need thereof.

[0101] In various embodiments, for effective reduction of body weight in a subject in need thereof, the compound of Formula I, or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition can be administered in a daily dosage from about 1 mg to about 20 mg, about 2 mg to about 19 mg, about 3 mg to about 18 mg, about 4 mg to about 17 mg, about 5 mg to about 16 mg, about 5 mg to about 15 mg, about 6 mg to about 14 mg, about 7 mg to about 13 mg, about 8 mg to about 12 mg, about 9 mg to about 11 mg, or about 9 mg to about 10 mg. In certain embodiments, the amount of the daily dosing can be from about 2.5 mg to about 5 mg. In certain embodiments, the amount of the daily dosing can be from about 5 mg to about 10 mg. In certain embodiments, the amount of the daily dosing can be from about 10 mg to about 15 mg. In certain embodiments, the amount of the daily dosing can be from about 5 mg to about 15 mg.

[0102] In various embodiments, for effective reduction of body weight in a subject in need thereof, the compound of Formula I, or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition can be administered in a daily dosage of about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about18.5 mg, about 19 mg, about 19.5 mg, about 20 mg, about 20.5 mg. In certain embodiments, the amount of the daily dosing can be about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about4.5 mg, or about 5 mg. In certain embodiments, the amount of the daily dosing can be about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

[0103] In various embodiments, the agent is administered at an initial dose of about 2.5 mg. In certain embodiments, the dose is increased by about 2.5 mg weekly up to a dose of about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg. In certain embodiments, the dose is increased by about 2.5 mg weekly up to a dose of about 5 mg. In certain embodiments, the dose is increased by about 2.5 mg weekly up to a dose of about 7.5 mg. In certain embodiments, the dose is increased by about 2.5 mg weekly up to a dose of about 10 mg. In certain embodiments, the dose is increased by about 2.5 mg up to a dose of about 12.5 mg. In certain embodiments, the dose is increased by about 2.5 mg up to a dose of about 15 mg. In certain embodiments, the dose is not increased.

[0104] In various embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the free base form of the compound of Formula I.

[0105] In various embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a pharmaceutically acceptable salt of the compound of Formula I. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula I can be a salt of the compound of Formula I with physiologically compatible mineral acids, such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid; or with organic acids, such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.

[0106] The pharmaceutical compositions provided herein can 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.

[0107] The pharmaceutical compositions provided herein may also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be continued indefinitely, for example, for the rest of the subject’s life. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.

[0108] The pharmaceutical compositions provided herein may be presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” 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 can be administered as a unit dose. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.

[0109] In various embodiments, the pharmaceutical compositions provided herein are administered to the 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.

[0110] In various embodiments, the pharmaceutical compositions provided herein comprise the compound of Formula I as the sole active agent, or in combination with other active agents.

[0111] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, forexample, in Remington: The Science and Practice of Pharmacy 21stecL, Lippincott Williams & Wilkins, 2005.Methods of Use and Treatment

[0112] In one aspect, provided herein are methods of reducing body weight in a subject in need thereof. In certain embodiments, the subject is overweight. In certain embodiments, the subject is obese. In certain embodiments, the subject has class I obesity. In certain embodiments, the subject has class II obesity. In certain embodiments, the subject has class III obesity. In certain embodiments, the subject does not have diabetes-related obesity. In certain embodiments, the subject has metabolically healthy obesity (MHO). In certain embodiments, the subject has metabolically abnormal obesity (MAO), wherein the metabolic abnormality is not diabetes or diabetes-related.

[0113] In various embodiments, provided herein are methods for reducing body weight in a subject in need thereof, comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent is a compound of Formula I:(I)-

[0114] In various embodiments, the reduction in body weight is of about 0.1% to about 20%. In certain embodiments, the reduction in body weight is of about 0.5% to about 20%. In certain embodiments, the reduction in body weight is of about 1% to about 20%. In certain embodiments, the reduction in body weight is of about 1.5% to about 20%. In certain embodiments, the reduction in body weight is of about 2% to about 20%. In certain embodiments, the reduction in body weight is of about 2.5% to about 20%. In certain embodiments, the reduction in body weight is of about 3% to about 20%. In certain embodiments, the reduction in body weight is of about 3.5% to about 20%. In certainembodiments, the reduction in body weight is of about 4% to about 20%. In certain embodiments, the reduction in body weight is of about 4.5% to about 20%. In certain embodiments, the reduction in body weight is of about 5% to about 20%. In certain embodiments, the reduction in body weight is of about 5.5% to about 20%. In certain embodiments, the reduction in body weight is of about 6% to about 20%. In certain embodiments, the reduction in body weight is of about 6.5% to about 20%. In certain embodiments, the reduction in body weight is of about 7% to about 20%. In certain embodiments, the reduction in body weight is of about 7.5% to about 20%. In certain embodiments, the reduction in body weight is of about 8% to about 20%. In certain embodiments, the reduction in body weight is of about 8.5% to about 20%. In certain embodiments, the reduction in body weight is of about 9% to about 20%. In certain embodiments, the reduction in body weight is of about 10% to about 20%. In certain embodiments, the reduction in body weight is of about 11% to about 20%. In certain embodiments, the reduction in body weight is of about 12% to about 20%. In certain embodiments, the reduction in body weight is of about 13% to about 20%. In certain embodiments, the reduction in body weight is of about 14% to about 20%. In certain embodiments, the reduction in body weight is of about 15% to about 20%. In certain embodiments, the reduction in body weight is of about 16% to about 20%. In certain embodiments, the reduction in body weight is of about 17% to about 20%. In certain embodiments, the reduction in body weight is of about 18% to about 20%. In certain embodiments, the reduction in body weight is of about 19% to about 20%. In certain embodiments, the reduction in body weight is of about 0.5% to about 19%. In certain embodiments, the reduction in body weight is of about 0.5% to about 18%. In certain embodiments, the reduction in body weight is of about 0.5% to about 17%. In certain embodiments, the reduction in body weight is of about 0.5% to about 16%. In certain embodiments, the reduction in body weight is of about 0.5% to about 15%. In certain embodiments, the reduction in body weight is of about 0.5% to about 14%. In certain embodiments, the reduction in body weight is of about 0.5% to about 13%. In certain embodiments, the reduction in body weight is of about 0.5% to about 12%. In certain embodiments, the reduction in body weight is of about 0.5% to about 10%. In certainembodiments, the reduction in body weight is of about 0.5% to about 9.5%. In certain embodiments, the reduction in body weight is of about 0.5% to about 9%. In certain embodiments, the reduction in body weight is of about 0.5% to about 8.5%. In certain embodiments, the reduction in body weight is of about 0.5% to about 8%. In certain embodiments, the reduction in body weight is of about 0.5% to about 7.5%. In certain embodiments, the reduction in body weight is of about 0.5% to about 7%. In certain embodiments, the reduction in body weight is of about 0.5% to about 6.5%. In certain embodiments, the reduction in body weight is of about 0.5% to about 6%. In certain embodiments, the reduction in body weight is of about 0.5% to about 5.5%. In certain embodiments, the reduction in body weight is of about 0.5% to about 5%. In certain embodiments, the reduction in body weight is of about 0.5% to about 4.5%. In certain embodiments, the reduction in body weight is of about 0.5% to about 4%. In certain embodiments, the reduction in body weight is of about 0.5% to about 3.5%. In certain embodiments, the reduction in body weight is of about 0.5% to about 3%. In certain embodiments, the reduction in body weight is of about 0.5% to about 2.5%. In certain embodiments, the reduction in body weight is of about 0.5% to about 2%. In certain embodiments, the reduction in body weight is of about 0.5% to about 1.5%. In certain embodiments, the reduction in body weight is of about 0.5% to about 1%.

[0115] In various embodiments, the reduction in body weight is of about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.

[0116] In various embodiments, the reduction in body weight is of about 1 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 1.2 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 1.4 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 1.6 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 1.8 kg to about 10 kg. In various embodiments, the reduction in body weight is of about 2 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 2.2 kg to about 10 kg. In certainembodiments, the reduction in body weight is of about 2.4 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 2.6 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 2.8 kg to about 10 kg. In various embodiments, the reduction in body weight is of about 3 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 3.2 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 3.4 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 3.6 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 3.8 kg to about 10 kg. In various embodiments, the reduction in body weight is of about 4 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 4.2 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 4.4 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 4.6 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 4.8 kg to about 10 kg. In various embodiments, the reduction in body weight is of about 5 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 5.2 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 5.4 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 5.6 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 5.8 kg to about 10 kg. In various embodiments, the reduction in body weight is of about 6 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 6.2 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 6.4 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 6.6 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 6.8 kg to about 10 kg. In various embodiments, the reduction in body weight is of about 7 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 7.2 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 7.4 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 7.6 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 7.8 kg to about 10 kg. In various embodiments, the reduction in body weight is of about 8 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 8.2 kg to about 10 kg. In certainembodiments, the reduction in body weight is of about 8.4 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 8.6 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 8.8 kg to about 10 kg. In various embodiments, the reduction in body weight is of about 9 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 9.2 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 9.4 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 9.6 kg to about 10 kg. In certain embodiments, the reduction in body weight is of about 9.8 kg to about 10 kg. In various embodiments, the reduction in body weight is of about 1 kg to about 9.8 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 9.6 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 9.4 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 9.2 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 9 kg. In various embodiments, the reduction in body weight is of about 1 kg to about 8.8 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 8.6 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 8.4 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 8.2 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 8 kg. In various embodiments, the reduction in body weight is of about 1 kg to about 7.8 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 7.6 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 7.4 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 7.2 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 7 kg. In various embodiments, the reduction in body weight is of about 1 kg to about 6.8 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 6.6 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 6.4 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 6.2 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 6 kg. In various embodiments, the reduction in body weight is of about 1 kg to about 5.8 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 5.6 kg. In certainembodiments, the reduction in body weight is of about 1 kg to about 5.4 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 5.2 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 5 kg. In various embodiments, the reduction in body weight is of about 1 kg to about 4.8 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 4.6 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 4.4 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 4.2 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 3 kg. In various embodiments, the reduction in body weight is of about 1 kg to about 3.8 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 3.6 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 3.4 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 3.2 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 3 kg. In various embodiments, the reduction in body weight is of about 1 kg to about 2.8 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 2.6 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 2.4 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 2.2 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 2 kg. In various embodiments, the reduction in body weight is of about 1 kg to about 1.8 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 1.6 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 1.4 kg. In certain embodiments, the reduction in body weight is of about 1 kg to about 1.2 kg.

[0117] In various embodiments, the reduction in body weight is of about 1 kg, about 1.2 kg, about 1.4 kg, about 1.6 kg, about 1.8 kg, about 2 kg, about 2.2 kg, about 2.4 kg, about 2.6 kg, about 2.8 kg, about 3 kg, about 3.2 kg, about 3.4 kg, about 3.6 kg, about 3.8 kg, about 4 kg, about 4.2 kg, about 4.4 kg, about 4.6 kg, about 4.8 kg, about 5 kg, about 5.2 kg, about 5.4 kg, about 5.6 kg, about 5.8 kg, about 6 kg, about 6.2 kg, about 6.4 kg, about 6.6 kg, about 6.8 kg, about 7 kg, about 7.2 kg, about 7.4 kg, about 7.6 kg, about 7.8 kg, about 8 kg, about 8.2 kg, about 8.4 kg, about 8.6 kg, about 8.8 kg, about 9 kg, about 9.2 kg, about 9.4 kg, about 9.6 kg, about 9.8 kg, or about 10 kg.

[0118] In various embodiments, the reduction in body weight occurs by about 20 days to about 90 days, In certain embodiments, the reduction in body weight occurs by about 30 days to about 90 days, In certain embodiments, the reduction in body weight occurs by about 40 days to about 90 days, In certain embodiments, the reduction in body weight occurs by about 50 days to about 90 days, In certain embodiments, the reduction in body weight occurs by about 60 days to about 90 days, In certain embodiments, the reduction in body weight occurs by about 70 days to about 90 days, In certain embodiments, the reduction in body weight occurs by about 80 days to about 90 days, In certain embodiments, the reduction in body weight occurs by about 20 days to about 80 days, In certain embodiments, the reduction in body weight occurs by about 20 days to about 70 days, In certain embodiments, the reduction in body weight occurs by about 20 days to about 60 days, In certain embodiments, the reduction in body weight occurs by about 20 days to about 50 days, In certain embodiments, the reduction in body weight occurs by about 20 days to about 40 days, In certain embodiments, the reduction in body weight occurs by about 20 days to about 30 days. In certain embodiments, the reduction in body weight occurs by about 20 days, by about 30 days, by about 40 days, by about 50 days, by about 60 days, by about 70 days, by about 80 days, or by about 90 days. In certain embodiments, the reduction in body weight occurs by about 29 days, by about 43 days, by about 57 days, by about 64 days, by about 71 days, or by about 85 days.

[0119] In various embodiments, the subject to receive a provided composition has a BMI of about 25 kg / m2to about 29.9 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 25.5 kg / m2to about 29.9 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 26 kg / m2to about 29.9 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 26.5 kg / m2to about 29.9 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 27 kg / m2to about 29.9 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 27.5 kg / m2to about 29.9 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 28 kg / m2to about 29.9 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 28.5 kg / m2to about 29.9 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 29 kg / m2to about 29.9 kg / m2. Incertain embodiments, the subject to receive a provided composition has a BMI of about 29.5 kg / m2to about 29.9 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 25 kg / m2to about 29.5 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 25 kg / m2to about 29 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 25 kg / m2to about 28.5 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 25 kg / m2to about 28 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 25 kg / m2to about 27.5 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 25 kg / m2to about 27 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 25 kg / m2to about 26.5 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 25 kg / m2to about 26 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 25 kg / m2to about 25.5 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 25 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 25.5 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 26 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 26.5 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 27 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 27.5 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 28 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 28.5 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 29 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 29.5 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 29.5 kg / m2. In certain embodiments, the subject to receive a provided composition is overweight and has a BMI about 25 kg / m2to about 29.9 kg / m2.

[0120] In various embodiments, the subject to receive a provided composition has a BMI of about 30 kg / m2or greater than 30 kg / m2. In certain embodiments, the subject to receive a provided composition has a BMI of about 30 kg / m2. In certain embodiments, the subject toreceive a provided composition has a BMI greater than 30 kg / m2. In certain embodiments, the subject to receive a provided composition is obese and has a BMI of about 30 kg / m2or greater than 30 kg / m2.

[0121] In various embodiments, administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, comprises administering a composition having an amount of the compound as described herein, supra.

[0122] In various embodiments, the composition comprises the compound of Formula I, or a pharmaceutically acceptable salt thereof, as the sole active agent.

[0123] In various embodiments, the composition comprises inactive agents selected from the group consisting of mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silicon dioxide, and sodium stearyl fumarate.

[0124] In various embodiments, administering comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, in a capsule.

[0125] In various embodiments, the capsule shell consists of gelatine, titanium dioxide, red iron oxide, and yellow iron oxide.

[0126] In various embodiments, the capsule described above comprises about 1 mg to about 10 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0127] In various embodiments, the capsule comprises about 2.5 mg to about 5 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0128] In various embodiments, administering comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 2.5 mg to about 5 mg once daily.

[0129] In various embodiments, administering comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 5 mg to about 15 mg once daily.

[0130] In various embodiments, administering comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 1 mg to about 20 mg once daily.

[0131] In various embodiments, administering comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg once daily.

[0132] In various embodiments, administering comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, or about 20 mg once daily. In various embodiments, administering comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 2.5 mg once daily. In various embodiments, administering comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 5 mg once daily. In various embodiments, administering comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an immediate release formulation.

[0133] In various embodiments, administering comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an extended release formulation.

[0134] In various embodiments, administering maintains efficacy throughout the day.

[0135] In various embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered once, twice, three, four, or five times daily. In certain embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered once daily.

[0136] In various embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered orally.

[0137] In various embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered as a unit dose.

[0138] In various embodiments, the compound of Formula I is administered in free base form.

[0139] In various embodiments, the compound of Formula I is administered in the form of a pharmaceutically acceptable salt. In certain embodiments, the pharmaceutically acceptable salt of the compound of Formula I can be a salt of the compound of Formula I with physiologically compatible mineral acids, such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid; or with organic acids, such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. In certain embodiments, the compound of Formula I is administered in a crystalline form.

[0140] In various embodiments, provided herein are methods of reducing body weight in a subject in need thereof, comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a phosphodiesterase 10 (PDE10) inhibitor or a pharmaceutically acceptable salt thereof, wherein the PDE10 inhibitor is a compound of Formula I:(I)-

[0141] In various embodiments, the compound of Formula I is administered as a monotherapy.

[0142] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following specific examples are therefore to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.EXAMPLES

[0143] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered toillustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.Example 1: Synthesis of l-methyl-4-(morpholine-4-carbonyl)-N-(2- phenyl[l,2,4]triazolo[l,5-a]pyridin-7-yl)-lH-pyrazole-5-carboxamide (Compound of Formula I) [See US Patent No. 8,349,824]. l-methyl-5-(2-phenyl-fl,2,4]triazolofl,5-a]pyridin-7-ylcarbamoyl}-lH-pyrazole-4-carboxylic acid methyl ester

[0144] Step A - l,2-diamino-4-bromo-pyridinium2,4,6-trimethyl-benzenesulfonate: to a cooled suspension of O-(mesitylsulfonyl)hydroxylamine (11.22 g, 52.1 mmol, 1 eq) in dichloromethane (130 ml) was portionwise added 4-bromopyridin-2-amine (9.3 g, 52.1 mmol, 1 eq.) (exothermic reaction, some cooling is needed) giving 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 affording 1 ,2-diamino-4-bromo-pyridinium 2,4,6- trimethyl-benzenesulfonate (16.74 g, 82.7%) as white crystals, mp.: 176-180° C. MS: m / z = 188.2, 190.2 (M+H+).

[0145] Step B - 7-bromo-2-phenyl-[l,2,4]triazolo[l,5-a]pyridine: 1 ,2-Diamino-4- bromopyridinium 2,4,6-trimethylbenzenesulfonate (15.6 g, 40.2 mmole) in pyridine (106 ml) was heated overnight at 100 °C, with benzoyl chloride (9.4 ml, 80 mmole) giving a redbrown solution and after 2 hrs a brown suspension. The reaction mixture was concentrated in vacuo and the residue was triturated for 2.5 hr in saturated aqueous ammonium chloride solution (300 ml), while neutralizing to pH 6-7 with saturated aqueous sodium bicarbonate solution. The solid was collected by filtration, washed with water (40 ml) and dried affording 7-bromo-2-phenyl- [1, 2, 4]triazolo[l,5-a]pyridine (6.78 g, 61.6%) as an off-white solid, mp.: 189-191° C. MS: m / z = 276.1, 274.2 (M+H+).

[0146] Step C - (2-phenyl-[l,2,4]triazolor[l,5-a]pyridin-7-yl)-carbamic acid tert-butyl ester: to an nitrogen purged suspension of 7-bromo-2-phenyl-[l,2,4]triazolo[l,5-a]pyridine (9 g, 32.8 mmol) in dioxane (180 ml) was added successively tert-butyl carbamate (4.71 g, 39.4 mmol), tris(dibenzylidene-acetone)dipalladium(0) (601 mg, 657 pmol), 4,5-bis(diphenylphos- phino)-9,9-dimethylxanthene (760 mg, 1.31 mmol) and cesium carbonate (15 g, 46 mmol). Thebrown mixture was then stirred for 22 hours at 100 °C, under nitrogen atmosphere. The solvent was removed in vacuo and the brown residue partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed with water (3x120 ml) and with brine and dried with magnesium sulfate. The solution was concentrated in vacuo to ca 80 ml: crystallization. The suspension was stirred for 10 min in an ice bath and the solid was collected by filtration, washed with little cold ethyl acetate and dried affording (2-phenyl-[l,2,4]triazolo[l,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) loaded on silica (16 g). The product was isolated by chromatography on a 120 g silica cartridge (eluent heptane / ethyl acetate 10-50%, 45 min) yielding a second crop of 1.748 g of a white solid, mp.: 200-201° C. dec. MS: m / z = 311.3 (M+H+). Total yield: 86.7%.

[0147] Step D - 2-phenyl-[l,2,4]triazolo[l,5-a]pyridin-7-ylamine: a suspension of (2- phenyl-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-carbamic acid tert-butyl ester (8.5 g, 27.4 mmol) in hydrochloric acid (6 N in diethyl ether, 175 ml) was stirred overnight at room temperature. The suspension was diluted under cooling with water (ca 2 1) and ethyl acetate, the aqueous layer was washed once with ethyl acetate, made alkaline with 32% aqueous sodium hydroxide and extracted twice with ethyl acetate. The combined organic layers were dried with magnesium sulfate and the solvent was removed in vacuo affording 2-phenyl-[l,2,4]triazolo[l,5-a]pyridin-7- ylamine (5.52 g, 95.9%) as a light pink solid, mp.: 212-213° C. MS: m / z = 211.2 (M+H+).

[0148] Step E - l-methyl-5-(2-phenyl-[l,2,4]triazolo[l,5-a]pyridin-7-ylcarbamoyl)-lH- pyrazole-4-carboxylic acid methyl ester: a solution of 2-phenyl-[l,2,4]triazolo[l,5-a]pyridin-7- ylamine (1.534 g, 7.3 mmol), 4-(methoxycarbonyl)-l -methyl- lH-pyrazole-5 -carboxylic acid (1.61 g, 8.76 mmol), propylphosphonic anhydride (50% in ethyl acetate, 10.7 ml, 18.2 mmol) and diisopropylethylamine (5.1 ml, 29.2 mmol) in tetrahydrofurane (54 ml) was stirred at 70 °C, for 1.25 hr giving a white suspension. The cooled suspension was poured in saturated aqueous sodium bicarbonate solution (200 ml), stirred at room temperature for 15 min and the solid was collected by filtration, washed with water and dried affording l-methyl-5-(2-phenyl- [l,2,4]triazolo[l,5-a]pyridin-7-ylcarbamoyl)-lH-pyrazole-4-carboxylic acid methyl ester (2.596 g, 94.5%) as a white solid, mp.: 243-7° C. MS: m / z = 377.2 (M+H+).l-Methyl-5-(2-phenyl-[ 1 ,2,41triazolo[ 1 ,5-a lpyridin-7-ylcarbamoyl}-lH-pyrazole-4-carboxylic acid

[0149] A white suspension of l-methyl-5-(2-phenyl-[l,2,4]triazolo[l,5-a]pyridin-7- ylcarbamoyl)-lH-pyrazole-4-carboxylic acid methyl ester (2.37 g, 6.3 mmol) and lithium hydroxide monohydrate (291 mg, 6.93 mmol) in methanol (100 ml) and water (20 ml) was stirred for 1.25 hr at 70 °C, giving after 20 min a colorless solution. The methanol was removed in vacuo, the residue was 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 affording l-methyl-5-(2-phenyl-[l,2,4]triazolo[l,5-a]pyridin-7-ylcarbamoyl)-lH- pyrazole-4-carboxylic acid (2.21 g, 97%) as a white solid, mp.: >300° C. MS: m / z = 361.1 (M+H+).

[0150] A mixture of l-methyl-5-(2-phenyl-[l,2,4]-triazolo[l,5-a]pyridin-7-ylcarbamoyl)- lH-pyrazole-4-carboxylic acid (100 mg, 276 pmol), morpholine (240 pl, 2.76 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 pl, 690 pmol) in tetrahydrofurane (7 ml) was stirred for 3 hours at 70 °C. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogencarbonate solution and brine. The organic layer was separated, dried with magnesium sulfate and the solvent evaporated. The residue (76 mg white foam) was triturated with diethylether and ethyl acetate affording l-methyl-4-(morpholine-4- carbonyl)-N-(2-phenyl-[l,2,4]triazolo[1.5-a]pyridin-7-yl)-lH-pyrazole-5-carboxamide (53 mg, 44.5%) as a white solid, mp.: 203-207 °C. MS: m / z = 432.4 (M+H+).Example 2: A Crystalline Form of Compound of Formula I

[0151] Preparation of Crystalline Form: Amorphous form of the compound of Formula I was stirred in water or a mixture of 50% water in methanol at 65 °C for 3 days to afford a crystalline form of the free base of the compound of Formula I. The crystalline form is thermodynamically stable at least between 20 °C and 60 °C. The XRPD and DSC graphs wereas substantially shown in FIGS. 1 and 2. The XRPD pattern can be obtained by following protocols known in the field.

[0152] Melting Point: The maximal melting point peak (Tm) of the crystalline form was determined using DSC, which was performed using a Mettler Toledo DSC 821e with Sample Robot TSO 801RO. A sample of 2-5 mg was placed in AL-crucibles 40 pL with AL-piercing lids and the sample was heated at a rate of 10 °C / min from 25 °C to 300 °C. Temperatures at crystalline melting peak start, peak onset, peak max, and peak end were collected. DSC shows the Tmof the crystalline form was 213.16 °C.

[0153] Solubility: The above crystalline form showed a very low solubility in aqueous solutions at pH > 3 (<0.004 mg / mL). Solubility in simulated gastric fluid (SGF), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF) was 0.019 mg / ml, 0.006 mg / mL, and 0.022 mg / mL, respectively. Solubility increased 50-100-fold in the presence of surfactants (e.g., Tween-80, sodium dodecyl sulfate, dioctyl sulfosuccinate, or Pluronic F68) and cyclodextrins; however it was still rather low. Overall, the crystalline exhibited a poor solubility at ambient temperature (22 °C) not only in aqueous systems, but also in most of the tested organic solvents (<50 mg / mL).

[0154] Stability: Preliminary forced degradation study of the crystalline form of the free base of the compound of Formula I in acidic, basic, oxidative, and photolytic stress conditions was conducted to investigate the viability of the crystalline form in various stress conditions. Since the solubility of the compound of Formula I was low in the standard solvent ethanol, ethanol was replaced by N-methyl-2-pyrrolidone (NMP).

[0155] A defined amount of the crystalline form of the free base of the compound of Formula I (0.2-0.8 mg) was weighed into a 1.8 mL HPLC vial and stored open (75% RH) or closed (ambient) at the temperature and the time indicated. After incubation, compound was dissolved in 1-1.5 mL NMP to a final concentration of 0.2-0.5 mg / mL and submitted to UPLC analysis (254 nm). The results are as substantially shown in Table 1 below. The data show that the crystalline form was stable at various temperatures in solid state (<0.5% degradation products), e.g., stable for at least 4 weeks at 40-60°C.Table 1. Preliminary Solid State Stability

[0156] The crystalline form of the free base of the compound of Formula I was stable for up to 8 days in solid state at 80°C and in solution at pH 3 to pH 7 at RT. At higher or lower pH, degradation was observed. The crystalline form was stable after exposure to light in solid state. In solution, it was stable towards daylight and, time dependent, moderately stable to unstable in the Suntest. It was also stable towards oxidation for 1 day, but showed some sensitivity upon prolonged exposure. The crystalline form was compatible with almost all excipients; however drug recovery in the CompaS assay strongly depended on the solvent used for extraction.

[0157] In the suspension vehicle used for PK, PD, and Tox studies (0.5% HPC / 1%Tween 80), The crystalline form was also stable for up to 5 weeks at RT, with only minor particle growth and no hydrate formation. For parenteral administration, a 30% Kleptose formulation (1.5 mg / ml, physiologic osmolality, pH 6.2), with a stability of at least 4 weeks at 40°C was developed.Example 3: Composition Containing Compound 1

[0158] Described in Table 2 is a composition of a 10 mg strength capsule containing the Compound of Formula I (i.e., Compound 1, RO5545965). The capsule is characterized as a reddish brown, opaque, size 1 hard capsule.Table 2. Composition of 10 mg strength capsule containing Compound 1aPurified water (Ph. Eur.) is used for wet granulation; it is essentially removed during processing.

[0159] Described in Table 3 is a composition of a 5 mg strength capsule containing theCompound of Formula I (i.e., Compound 1, RO5545965). The capsule is characterized as a reddish brown, opaque, size 1 hard capsule.Table 3. Composition of 5 mg strength capsule containing Compound 1bPurified water (Ph. Eur.) is used for wet granulation; it is essentially removed during processing.

[0160] Described in Table 4 is a composition of a 2.5 mg strength capsule containing the Compound of Formula I (i.e., Compound 1, RO5545965). The capsule is characterized as a reddish brown, opaque, size 1 hard capsule.Table 4. Composition of 2.5 mg strength capsule containing Compound 1cPurified water (Ph. Eur.) is used for wet granulation; it is essentially removed during processing.Example 4: A Study of the Effects of Compound of Formula I on Body Weight and BMI

[0161] Following randomization to Compound 1 or placebo, patients received doubleblind weekly escalating doses of Compound 1 (2.5, 5.0, 10, and 15 mg) in a 2.5 mg, 5.0 mg, 10 mg, or 15 mg capsule, or placebo over 4 weeks, until the maximum tolerated dose (MTD) or the 15 mg dose was reached, and were maintained at the latest dose received / tolerated for up to 10 weeks or up to Study Day 71 (depending on the randomization timepoint), whichever came first. Patients in this example were part of study assessing the efficacy of Compound 1 in treating adults with childhood onset fluency disorder.

[0162] Recorded in Table 5 are the weight and BMI measurements of the patients administered with either Compound 1 or placebo, at baseline (Day 1) versus Day 71. The results show that patients administered with Compound 1 exhibited a decrease in body weight and BMI at Day 71 relative to baseline compared to those administered with the placebo.Table 5. Body weight and BMI measurements observed in subjects administered with Compound 1 versus placebo at baseline and Day 71

[0163] This example demonstrates that administration of Compound 1 results in an average weight loss of 1.75 kg (-3.86 lbs) and an average BMI reduction of 0.53 kg / m2after 71 days.Example 5: A Study of the Effects of Compound of Formula I on Body Weight

[0164] Eligible patients were assigned a starting dose of 5.0 mg once daily, or 2.5 mg once daily. The first dose of study treatment was taken in the clinic and the patient remained under observation for 2 hours. Subsequent doses were taken at home, preferably in the eveningwith food. Treatment was to continue for a maximum of 12 weeks or until unacceptable intolerance or patient withdrawal of consent. Dose escalation was allowed at the investigator’s discretion in increments of 2.5 mg every week up to a maximum of 15 mg once daily. During the study, if intolerance occurred at any given dose, the daily dose of Compound 1 could be reduced by 2.5 mg. Patients in this example were part of study assessing the efficacy of Compound 1 in treating adults with Tourette Syndrome.

[0165] Recorded in Table 6 are the weight measurements of patients treated with Compound 1, at baseline (Day 1), Day 29, Day 57, and Day 85. The results show that patients administered with Compound 1 show a reduction in body weight at Days 29, 57, and 85 relative to baseline.Table 6. Body weight measurements observed in subjects administered with Compound 1 at baseline, Day 29, Day 57, and Day 85

[0166] Recorded in Table 7 are the weight measurements (in kg) and weight loss (in kg and %) of patients at Day 85 / end of treatment (EoT) with the modal dose (in mg) of Compound 1 administered. 9 out of 15 (60%) of the patients showed weight reduction at Day 85 / EoT. Of the 9 patients who showed some level of weight reduction, 3 (20%) showed a weight reduction of less than or equal to 7%, and 6 (40%) of them showed a weight reduction greater than 7% and less than or equal to 20%. No patients reported a weight reduction of greater than 20%. The results show that patients administered with Compound 1 show a reduction in body weight at Day 85 / EoT in a dose-dependent manner.Table 7. Weight and weight loss observed in patients at Day 85 / EoT administered with doses of Compound 1

[0167] This example demonstrates that administration of Compound 1 results in an average weight loss of 6.04 kg (-13.32 lbs). This example also demonstrates that weight loss is observed in a dose-dependent manner with administration of Compound 1.Example 6: A Pre-Clinical Study of the Effects of Compound of Formula I on Body Weight on Rats

[0168] Three (4-week, 13-week, and 26-week) studies were conducted to evaluate effects of Compound 1 on body weight on rats. For each study, rats were administered 10 mg / kg / day, 100 mg / kg / day, or 1,000 mg / kg / day of Compound 1, or control / vehicle.

[0169] Recorded in Table 8 are percentages for maximum weight loss observed in rats administered with Compound 1 for 4 weeks, 13 weeks, and 26 weeks.Table 8. Maximum weight loss observed in 4-, 13-, and 26-week studies in rats administered with Compound 1

[0170] Recorded in Table 9 are percentages for weight loss observed in female and male rats administered with 10 mg / kg / day, 100 mg / kg / day, or 1,000 mg / kg / day of Compound 1 for 4 weeks relative to control groups. A dose-dependent reduction in body weight gain was observed in both male and female rats. The reductions in weight gain observed were accompanied by reduced food consumption during administration of Compound 1. During recovery (following termination of dosing of Compound 1), an increase in absolute and percent body weight gain was observed in the recovery animals.Table 9. Percent weight change observed in rats administered with 10, 100, and 1,000 mg / kg / day of Compound 1 for 4 weeks

[0171] Recorded in Table 10 are percentages for weight loss observed in female and male rats administered with 10 mg / kg / day, 100 mg / kg / day, or 1,000 mg / kg / day of Compound 1 for 13 weeks relative to control groups. There were significant dose-related reductions in bodyweight gains in males and females at all dose levels. During the recovery period (when dosing was stopped), there were compensatory increases in weight gains in all treatment groups. The observed reduction in body weight gain was associated with modest reduction in food consumption over the entire treatment period, but the differences were not proportional to the dose administered.Table 10. Percent weight change observed in rats administered with 10, 100, and 1,000 mg / kg / day of Compound 1 for 13 weeks

[0172] Recorded in Table 11 are percentages for weight loss observed in female and male rats administered with 10 mg / kg / day, 100 mg / kg / day, or 1,000 mg / kg / day of Compound 1 for 26 weeks relative to control groups. Reduced body weight was observed during the time of the study in rats treated with Compound 1. However, the reduction in weight gain was not dose- related. A higher body weight gain was observed in treated animals during the recovery period for both male and female rats, indicative of ongoing recovery. A decrease in food consumption was observed in all treated animals throughout the dosing period, but the differences were not proportional to the amount of Compound 1 administered.Table 11. Percent weight change observed in rats administered with 10, 100, and 1,000 mg / kg / day of Compound 1 for 26 weeks

[0173] These results indicate that administration of Compound 1 leads to weight reduction, which is recovered when Compound 1 administration is stopped.Example 7: A Pre-Clinical Study of the Effects of Compound of Formula I on Body Weight on Monkeys

[0174] Two (4-week and 13 -week) studies were conducted to evaluate effects of Compound 1 on body weight on cynomolgus monkeys. For each study, monkeys were administered 3 mg / kg / day, 30 mg / kg / day, 100 mg / kg / day, or 300 mg / kg / day of Compound 1, or control / vehicle.

[0175] Recorded in Table 12 are percentages for maximum weight loss observed in monkeys administered with Compound 1 for 4 weeks and 13 weeks.Table 12. Maximum weight loss observed in 4- and 13-week studies in monkeys

[0176] Recorded in Table 13 are percentages for weight loss observed in female and male monkeys administered with control or 3 mg / kg / day, 30 mg / kg / day, 100 mg / kg / day, or 300 mg / kg / day of Compound 1 for 4 weeks. All animals gained or maintained weight during the recovery period. Food consumption was reduced in some animals in the medium and high dose groups.Table 13. Percent weight change observed in monkeys administered with 3, 30, 100, or 300 mg / kg / day of Compound 1 for 4 weeks

[0177] Recorded in Table 14 are percentages for weight loss observed in female and male monkeys administered with control or 3 mg / kg / day, 15 mg / kg / day, or 100 mg / kg / day of Compound 1 for 13 weeks. Slight body weight loss and reduction in body weight gain were observed in monkeys administered with 3, 15 and 100 mg / kg / day of Compound 1. By the end ofthe recovery period, body weight gains were comparable between control, 3 mg / kg / day, and 15 mg / kg / day male and female animals. However, the overall body weight gain was slightly reduced for recovery male and female animals dosed at 100 mg / kg / day. Reduced food consumption was noted sporadically in individual animals.

[0178] These results indicate that administration of Compound 1 leads to weight reduction, which is recovered when Compound 1 administration is stopped.Table 14. Percent weight change observed in monkeys administered with 3, 15, or 100 mg / kg / day of Compound 1 for 13 weeksINCORPORATION BY REFERENCE

[0179] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims.Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.EQUIVALENTS

[0180] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to beconsidered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of reducing body weight in a subject in need thereof, the method comprising administering to the subject an agent of Formula I:or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the method reduces body mass index (BMI) and / or body fat of the subject.

3. The method of claim 1 or 2, wherein the agent, or a pharmaceutically acceptable salt thereof, is administered once daily.

4. The method of any one of claims 1-3, wherein the agent, or a pharmaceutically acceptable salt thereof, is administered orally.

5. The method of any one of claims 1-4, wherein the agent is administered at a dose of about 2.5 mg to about 15 mg.

6. The method of any one of claims 1 -4, wherein the agent is administered at a dose of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

7. The method of any one of claims 1-4, wherein the agent is administered at an initial dose of about 2.5 mg.

8. The method of claim 7, wherein the dose is increased by about 2.5 mg weekly up to a dose of about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

9. The method of any one of claims 1-8, wherein the body weight reduction is mild.

10. The method of any one of claims 1-8, wherein the body weight reduction is moderate.

11. The method of any one of claims 1-10, wherein the subject’s body weight is reduced by about 0.1% to about 20%.

12. The method of any one of claims 1-10, wherein the subject’s body weight is reduced by about 7% to about 20%.

13. The method of any one of claims 1-10, wherein the subject’s body weight is reduced by about 1 kg to about 10 kg.

14. The method of any one of claims 1-13, wherein the reduction in body weight occurs by about 29 days, by about 57 days, by about 71 days, or by about 85 days from administration.

15. The method of any one of claims 1-14, wherein the subject is overweight.

16. The method of claim 15, wherein the subject does not have diabetes or diabetes-related obesity.

17. The method of any one of claims 1-16, wherein the subject has a BMI of about 25 kg / m2to about 29.9 kg / m2.

18. A method of preventing weight gain in a subject in need thereof, the method comprising administering to the subject an agent of Formula I:or a pharmaceutically acceptable salt thereof.

19. The method of claim 18, wherein the method prevents an increase in body mass index (BMI) and / or body fat of the subject.

20. The method of claim 18 or 19, wherein the agent, or a pharmaceutically acceptable salt thereof, is administered once daily.

21. The method of any one of claims 18-20, wherein the agent, or a pharmaceutically acceptable salt thereof, is administered orally.

22. The method of any one of claims 18-21, wherein the agent is administered at a dose of about 2.5 mg to about 15 mg.

23. The method of any one of claims 18-22, wherein the agent is administered at a dose of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

24. The method of any one of claims 18-23, wherein the agent is administered at an initial dose of about 2.5 mg.

25. The method of claim 24, wherein the dose is increased by about 2.5 mg weekly up to a dose of about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

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