WO2025038420A1 - Kappa opioid receptor antagonist and methods and products related thereto - Google Patents

Abstract

The invention relates to kappa-opioid receptor (KOR) antagonists and methods of their use and preparation, as well as to products containing the same. The KOR antaonist has the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof: (I) Pharmaceutical compositions comprising the same are also provided, as well as methods related to their use and preparation.

Description

KAPPA OPIOID RECEPTOR ANTAGONIST

AND METHODS AND PRODUCTS RELATED THERETO

FIELD OF THE INVENTION

The invention relates to kappa-opioid receptor (KOR) antagonists and methods of their use and preparation, as well as to products containing the same.

BACKGROUND

KOR antagonists are recognized for their utility in treating major depression and disorders related to substance abuse or addiction, particularly in the context of rapidly acting treatments which avoid the drawbacks associated with the prototypical KOR antagonists discussed above. Other studies have shown that KOR antagonists may be particularly useful for the treatment of stress-mediated symptoms, as well as for treating social anxiety disorder and phobias. Prophylactic therapy has also been suggested to prevent adverse conditions arising from stress, and in this regard KOR antagonism has been proposed as a preventative treatment of PTSD in individuals at risk of the same. Other therapeutic applications of KOR antagonism include the treatment of impairment in reward-related function as it frequently occurs in patients with mood and anxiety spectrum disorders, and which may also occur with other types of conditions such as schizophrenia or a schizoaffective disorder.

A promising class of KOR antagonists is provided in WO2018/170492 to Roberts et al. which discloses compounds of the following structure (I):

Within the above genus, Compound No. 142 (also known as navacaprant, BTRX- 335140 or NMRA-335140) has been advanced for clinical development as a selective KOR antagonist in the context of treating neurob ehavi oral disorders such as major depressive disorder (MDD):

Cpd. No. 142

While significant advances have been made in this field, including the advancement of Compound No. 142 for clinical development, there remains a need for new and/or improved KOR antagonists, as well as for methods related to their use and manufacture, and for pharmaceutical products containing the same.

SUMMARY OF THE INVENTION

The present invention is directed to active metabolites of Compound No. 142 discovered during the course of clinical development (referred to as Metabolite M2, Compound M2 or Cpd. M2) and having the following structure:

Compound M2 contains a chiral carbon (i.e., the carbon bearing the hydroxyl group) and may exist in two enantiomeric forms, referred to herein as Compound M2a and Compound M2b (or Cpd. M2a and Cpd. M2b) as depicted below:

or

It should be understood that resolution of the two entantiomers of Compound M2 has yet to be confirmed. Thus, reference herein to Compound M2a means that the compound is one of the two entaniomers shown above, while reference herein to Compound M2b means that the compound is one of the two entaniomers shown above, with the caveat that Compounds M2a and M2b are not the same enantiomer (z.e., they are a pair of enantiomers).

In one embodiment, a method is provided for antagonizing the KOR, the method comprising contacting the receptor with an effective amount of a compound having the structure of Cpd. M2, or a pharmaceutically acceptable isomer (e.g., Cpd. M2a or Cpd. M2b), racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same.

In another embodiment, a method is provided for treatment of a malcondition in a subject for which antagonism of the KOR is medically indicated. Such method comprises administering to the subject an effective amount of a compound having the structure of Compound M2, or a pharmaceutically acceptable isomer (e.g., Cpd. M2a or Cpd. M2b), racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for duration sufficient to provide a beneficial effect to the subject.

In a further embodiment, a pharmaceutical composition is provided comprising a compound having the structure of Compound M2, or a pharmaceutically acceptable isomer isomer (e.g., Cpd. M2a or Cpd. M2b), racemate, hydrate, solvate, isotope or salt thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient. Such a composition may take the form of, for example, a capsule, tablet, or pill as address in more detail herein below.

In still further embodiments, a compound is provided having the structure of Compound M2, or a pharmaceutically acceptable isomer isomer (e.g., Cpd. M2a or Cpd. M2b), racemate, hydrate, solvate, isotope or salt thereof, as well as a method of synthesis of the same. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates concentrations (Mean ± Standard Deviation) of Compound M2a in plasma of rats and mice on day 7 of oral administration of Compound 142 daily for seven days.

Figure 2 illustrates concentrations (Mean ± Standard Deviation) of Compound M2b in plasma of rats and mice on day 7 of oral administration of Compound 142 daily for seven days.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned above, the invention relates to active metabolites of Compound No. 142 as disclosed in WO2018/170492 to Roberts et al. discovered during the course of clinical development; namely, Compound M2. The invention also provides for a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof.

As used herein, “isomer” is used to encompass all chiral, diastereomeric or racemic forms of a structure, unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of certain embodiments of the invention. The isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called “enantiomers.” Single enantiomers of a pure compound are optically active (z.e., they are capable of rotating the plane of plane polarized light and designated R or 5).

“Isolated optical isomer” means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula. For example, the isolated isomer may be at least about 80%, at least 80% or at least 85% pure. In other embodiments, the isolated isomer is at least 90% pure or at least 98% pure, or at least 99% pure by weight.

“Substantially enantiomerically or diasteromerically” pure means a level of enantiomeric or diasteromeric enrichment of one enantiomer with respect to the other enantiomer or diasteromer of at least about 80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%. The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. A racemate is labeled “(±)” because it is not optically active (z.e., will not rotate plane-polarized light in either direction since its constituent enantiomers cancel each other out).

As mentioned above, Compound M2 contains a chiral carbon (z.e., the carbon bearing the hydroxyl group) and may exist in two enantiomeric forms, referred to herein as Compound M2a and Compound M2b (or Cpd. M2a and Cpd. M2b) as depicted below:

Cpd. M2a (or Cpd. M2b) Cpd. M2b (or Cpd. M2a)

The above compounds are labed in the alternative (e.g., Cpd. M2a or Cpd. M2b) because resultion of the two enantiomers has yet to be confirmed.

Accordingly, each of Cpd. M2a and Cpd. M2b are isomers of Cpd. M2, as that term is used and defined herein, and when present in an equal mixture constitutes a racemic mixture. Conversely, when one isomer is enriched over the other isomer it may constitute an isolated optical isomer or a substantially enantiomerically pure compound, depending upon its level of islolation or purification as defined above.

A "hydrate" is a compound that exists in combination with water molecules. The combination can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a "hydrate" refers to a solid form; that is, a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used herein.

A "solvate" is similar to a hydrate except that a solvent other that water is present. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric. As the term is used herein a "solvate" refers to a solid form; that is, a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used herein.

“Isotope” refers to atoms with the same number of protons but a different number of neutrons, and an isotope of a compound of Formula (I) includes any such compound wherein one or more atoms are replaced by an isotope of that atom. For example, carbon 12, the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons. Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). While fluorine has a number of isotopes, fluorine 19 is longest-lived. Thus, an isotope of a compound having the structure of Formula (I) includes, but not limited to, compounds of Formula (I) wherein one or more carbon 12 atoms are replaced by carbon 13 and/or 14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and/or tritium, and/or wherein one or more fluorine atoms are replaced by fluorine 19.

"Salt" generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, in combination with a counter ion. For example, salts formed between acids in their anionic form and cations are referred to as “acid addition salts”. Conversely, salts formed between bases in the cationic form and anions are referred to as “base addition salts.”

Co-crystal forms of compounds having the structure of Formula (I) are also included within the scope of this invention; namely, solids that are crystalline single phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts.

The term "pharmaceutically acceptable" refers an agent that has been approved for human consumption and is generally non-toxic. For example, the term "pharmaceutically acceptable salt" refers to nontoxic inorganic or organic acid and/or base addition salts (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int J. Pharm., 33, 201-217, 1986) (incorporated by reference herein).

Pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, 7V,7V-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (/'/-methylglucamine) and procaine.

Pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, panthothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, -toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, P-hydroxybutyric, salicylic, galactaric and galacturonic acid.

Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of the disclosed compounds, for example in their purification by recrystallization.

In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of the invention together with at least one pharmaceutically acceptable carrier, diluent or excipient. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxy ethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

The formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds. Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances preserving agents, sweetening agents or flavoring agents. The compositions can also be sterilized if desired.

The route of administration can be any route which effectively transports the active compound of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.

For parenteral administration, the carrier will typically comprise sterile water, although other ingredients that aid solubility or serve as preservatives can also be included. Furthermore, injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents and the like can be employed.

For topical administration, the compounds of the present invention can be formulated using bland, moisturizing bases such as ointments or creams.

If a solid carrier is used for oral administration, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

Injectable dosage forms generally include aqueous suspensions or oil suspensions which can be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms can be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer’s solution, or an isotonic aqueous saline solution. Alternatively, sterile oils can be employed as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the formulation can also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations can optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. A unit dosage form for injection can be in ampoules or in multi-dose containers.

The formulations of the invention can be designed to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. Thus, the formulations can also be formulated for controlled release or for slow release.

Compositions contemplated by the present invention can include, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended- release form to provide a prolonged storage and/or delivery effect. Therefore, the formulations can be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections. Such implants can employ known inert materials such as silicones and biodegradable polymers, e.g., polylactide-polyglycolide. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).

For nasal administration, the preparation can contain a compound of the invention, dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol application. The carrier can contain additives such as solubilizing agents, e.g., propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

Dosage forms can be administered once a day, or more than once a day, such as twice or thrice daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician. Dosing regimens include, for example, dose titration to the extent necessary or useful for the indication to be treated, thus allowing the patient’s body to adapt to the treatment and/or to minimize or avoid unwanted side effects associated with the treatment. Other dosage forms include delayed or controlled-release forms. Suitable dosage regimens and/or forms include those set out, for example, in the latest edition of the Physicians' Desk Reference, incorporated herein by reference.

When used to prevent the onset disease or condition, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for developing a particular disease or condition generally include those that have a family history of the same, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.

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.

In another embodiment, there are provided methods of making a composition of a compound described herein including formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the methods can further include the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the methods further include the step of lyophilizing the composition to form a lyophilized preparation.

In another embodiment, a method is provided for antagonizing the KOR, the method comprising contacting the receptor with an effective amount of Compound M2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same.

As used herein, "KOR" and "0PRK1" refer to the kappa-opioid receptor (KOR) that is encoded by the 0PRK1 gene ("KOR" and "0PRK1" are used interchangeably herein). Similarly, "DOR" and "OPRD" refer to the delta-opioid receptor (DOR) that is encoded by the OPRD gene ("DOR" and "OPRD" are used interchangeably herein), and "MOR" and "0PRM1" refer to the mu-opioid receptor (MOR) that is encoded by the 0PRM1 gene ("MOR" and "0PRM1" are used interchangeably herein).

The term “antagonism” is used herein to encompass molecules that interact in some way with a receptor and thereby function as an antagonist, either by binding to the receptor at the binding site of its natural ligand or at locations other than the binding site. The “kappa opioid receptor” or “KOR” is a member of the opioid receptor family which binds the opioid peptide dynorphin as the primary endogenous ligand. The phrase to “KOR antagonism” used herein to encompass molecules that interact in some way with KOR and thereby function as an antagonist, either by binding to KOR at the site of dynorphin, or at a location other than the binding site (i.e., allosteric binding).

In an embodiment, a method is provided for treatment of a neuropsychiatric or behavioral condition, whether organic, stress-induced or iatrogenic, that is characterized by elevations in serum prolactin and respond to KOR antagonist administration with a reduction in serum prolactin. Such method comprises administering to the subject an effective amount of a compound having the structure of Formula (I) through (XVII), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for duration sufficient to provide a beneficial effect to the subject.

In a further embodiment, a method is provided for treatment of a malcondition in a subject for which antagonism of the KOR is medically indicated. Such method comprises administering to the subject an effective amount of a compound having the structure of Formula (I) through (XVII), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for duration sufficient to provide a beneficial effect to the subject.

As used herein, a “subject” means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, e.g., apes and monkeys; cattle; horses; sheep; and goats. Non-mammals include, for example, fish and birds.

“Treating” or "treatment" within the meaning herein refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder in certain conditions.

The expression “effective amount”, when used to describe use of a compound of the invention in providing therapy to a subject suffering from a disorder or malcondition mediated by KOR refers to the amount of a compound of the invention that is effective to bind to as an antagonist the KOR in the individual's tissues, wherein the KOR is implicated in the disorder, wherein such binding occurs to an extent sufficient to produce a beneficial therapeutic effect on the subject.

The term "malcondition” is used to describe any disease, disorder, or condition, and are used interchangeably, and in the context of this application refers to a disease, disorder, or condition wherein KOR plays a role in the biochemical mechanisms involved in the malcondition, or symptoms thereof, such that a therapeutically beneficial effect can be achieved by acting on such KOR.

In certain embodiments, the present invention provides a method for antagonizing a KOR with a compound of the invention. The method involves contacting the receptor with a suitable concentration of the compound to antagonize the receptor. The contacting can take place in vitro, for example in carrying out an assay to determine the KOR inhibition activity of an inventive compound undergoing experimentation related to a submission for regulatory approval.

In certain embodiments, the method for antagonizing a KOR can also be carried out in vivo, that is, within the living body of a mammal, such as a human patient or a test animal (referred to as a “subject” herein). The inventive compound can be supplied to the living organism via one of the routes as described above, e.g., orally, or can be provided locally within the body tissues. In the presence of the inventive compound, inhibition of the receptor takes place, and the effect thereof can be studied. Methods of treatments provided by the invention include administration of a compound of the invention, alone or in combination with another pharmacologically active agent or second medicament to a subject or patient having a malcondition for which antagonizing the KOR is medically indicated, such as: an addictive disorder, including disorders related to substance abuse or addiction; CNS-related disorders; anxiety disorders; depressive disorders; mood disorders; schizophrenia or schizoaffective disorders; stress-related disorders; obesity and eating disorder; migraine; postnatal depression; neurodegenerative diseases and disorders, including disorders of mood and behavior associated with neurodegenerative diseases; postnatal depression; anesthesia and/or sedation; epilepsy; status epilepticus; and seizure.

In an embodiment, a method is provided for treatment of an addictive disorder, including a disorders related to substance abuse or addiction, and compulsive behavior, comprising administering to a subject in need thereof an effective amount of Compound M2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.

Disorders related to substance abuse or addiction as described herein can include gambling, drug addiction, drug abuse, alcohol dependence, alcohol abuse, substance-induced depression and mood disorders induced by substances such as alcohol, nicotine, amphetamine, methamphetamine, cocaine, opiate addiction, heroin addiction, benzodiazepines and the like.

In an embodiment, a method is provided for treatment of CNS-related disorder, comprising administering to a subject in need thereof an effective amount of Compound M2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.

CNS-related disorders include substance abuse related disorders and/or withdrawal syndromes, mood disorders, anxiety disorders, schizophrenia spectrum disorders, pain, personality disorders, autism spectrum disorders, eating disorder; sleep disorder; disorders of memory and/or cognition, head shock and traumatic brain injury; vascular diseases and cognitive disorders.

Exemplary CNS conditions include substance abuse disorders and/or withdrawal syndromes (including addiction to opiates, cocaine, and/or alcohol); mood disorders (including depression, bipolar depression, dysthymic disorder, bipolar disorder); anxiety disorders and including compulsive disorders such as obsessive-compulsive disorder (OCD), social phobia, generalized anxiety disorder (GAD), social anxiety disorder; stress, post-traumatic stress disorder (PTSD); schizophrenia spectrum disorders (including schizophrenia, schizoaffective disorder); pain (including migraine, neuropathic pain, injury related pain syndromes, acute pain, chronic pain); personality disorders (including anti-social personality disorder, obsessive compulsive personality disorder); autism spectrum disorders (ASD) (including autism, monogenetic causes of autism such as synaptophathy's, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome); eating disorders; sleep disorders (including insomnia); disorders of memory and/or cognition (including attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (including Alzheimer's type dementia, Lewis body type dementia, vascular type dementia), head shock and traumatic brain injury (TBI); vascular diseases (including stroke, ischemia, vascular malformations) and cognitive disorders (including Alzheimer's disease and other forms of dementia).

In an embodiment, a method is provided for treatment of an anxiety disorder, comprising administering to a subject in need thereof an effective amount of Compound M2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.

Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders, including generalized anxiety disorder, panic disorder, stress-related disorders, obsessive compulsive disorder, phobia, social anxiety disorder, separation anxiety disorder and post-traumatic stress disorder (PTSD). In one embodiment, the anxiety disorder is a social anxiety disorder. In one embodiment, the anxiety disorder is phobia. In one embodiment, the anxiety disorder is a stress-related disorder. In one embodiment, the anxiety related disorder is PTSD.

Generalized anxiety disorder is a common chronic disorder characterized by long- lasting anxiety that is not focused on any one object or situation. A person suffering from generalized anxiety experience non-specific persistent fear and worry and become overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.

In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent. In addition to recurrent unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attack’s potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes in heartbeat are noticed by a panic sufferer, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived physiological change is interpreted as a possible life-threatening illness (i.e. extreme hypochondriasis).

Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific acts or rituals). The OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist. Often the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm. And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness. In a minority of cases, sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions.

The single largest category of anxiety disorders is that of phobia, which includes all cases in which fear and anxiety is triggered by a specific stimulus or situation. Sufferers typically anticipate terrifying consequences from encountering the object of their fear, which can be anything from social phobia, specific phobia, agoraphobia, phobia of an animal to a location to a bodily fluid.

Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression.

In an embodiment, a method is provided for treatment of a depressive disorder, depression, or depressive illness, comprising administering to a subject in need thereof an effective amount of Compound M2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for duration sufficient to provide a beneficial effect to the subject. Examples of such disorders include major depression, bipolar depression, drug-resistant depression, dysthymia and bipolar disorder.In an embodiment, a method is provided for treatment of a mood disorder, or a affective disorder comprising administering to a subject in need thereof an effective amount of Compound M2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for duration sufficient to provide a beneficial effect to the subject.

Examples of a mood disorder or an affective disorder include major depressive disorder (MDD); bipolar depression, bipolar disorder; anhedonia; dysthymia; psychotic major depression (PMD), or psychotic depression; postpartum depression; seasonal affective disorder (SAD); and catatonic depression is a rare and severe form of major depression involving disturbances of motor behavior and other symptoms.

The terms “anhedonia” and “anhedonic symptom” are used interchangeably and is defined as the inability to experience pleasure from activities usually found enjoyable, e.g. exercise, hobbies, music, sexual activities or social interactions. The terms “anhedonia” and “anhedonic symptom” are closely related to criterion of “depressive disorder with melancholic features” which is defined in DSM-5 as melancholic depression characterized by a loss of pleasure in most or all activities, a failure of reactivity to pleasurable stimuli, a quality of depressed mood more pronounced than that of grief or loss, a worsening of symptoms in the morning hours, early morning waking, psychomotor retardation, excessive weight loss, or excessive guilt. The term “treatment of depressive disorder with melancholic features” comprises treatment of both the depressive disorder and melancholic features associated herewith. In one embodiment, the mood disorder is anhedonia. In one embodiment, the mood disorder is major depression. In one embodiment, the mood disorder is seasonal affective disorder (SAD).

In other embodiments, a method is provided for treatment of a schizophrenia or a schizoaffective disorder, comprising administering to a subject in need thereof an effective amount of Compound M2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for duration sufficient to provide a beneficial effect to the subject.

In other embodiments, a method is provided for treatment of obesity or an eating disorder, comprising administering to a subject in need thereof an effective amount of Compound M2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for duration sufficient to provide a beneficial effect to the subject. Obesity and eating disorders as described here can include bulimia, anorexia nervosa, and the like.

In other embodiments, a method is provided for treatment of migraine, comprising administering to a subject in need thereof an effective amount of Compound M2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for duration sufficient to provide a beneficial effect to the subject. In another embodiment, prophylactic therapy is provided to prevent migraine. In this regard KOR antagonism is proposed as a preventative treatment of migraine in individuals at risk of the same.

In an embodiment, a method is provided for treatment of postnatal depression, comprising administering to a subject in need thereof an effective amount of Compound M2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.

Immediately after birth, progesterone levels decrease dramatically leading to the onset of postnatal depression (PND). The symptoms of PND range from mild depression to psychosis requiring hospitalization. PND is also associated with severe anxiety and irritability. PND-associated depression is not amenable to treatment by classic antidepressants, and women experiencing PND show an increased incidence of premenstrual syndrome (PMS).

In other embodiments, a method is provided for treatment of a neurodegenerative disease or disorder, including disorders of mood and behavior associated with neurodegenerative diseases; anesthesia and/or sedation; epilepsy; seizure; diabetes, diabetic complications, diabetic retinopathy; sexual/reproductive disorders; hypertension; cerebral hemorrhage; congestive heart failure; atherosclerosis; rheumatoid arthritis; hyperlipidemia, hypertriglycemia, hyperglycemia, hyperlipoproteinemia; compulsive behavior disorders (such as paw licking in dog) and spinal damage, comprising administering to a subject in need thereof an effective amount of Compound M2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for duration sufficient to provide a beneficial effect to the subject.

In an embodiment, a method is provided for treatment of disorders of mood and behavior associated with a neurodegenerative disease or disorder, comprising administering to a subject in need thereof an effective amount of Compound M2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.

The term "neurodegenerative disease" includes diseases and disorders that are associated with the progressive loss of structure or function of neurons, or death of neurons. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease (including the associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and convulsion (including for the treatment and prevention and prevention of seizures that are caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign forgetfulness; brain edema; cerebellar ataxia including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusive injuries (e.g., spinal cord injury and head injury); dementias including multi-infarct dementia and senile dementia; disturbances of consciousness; Down syndrome; drug- induced or medication-induced Parkinsonism (such as neuroleptic-induced acute akathisia, acute dystonia, Parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or medication- induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette's syndrome; head trauma; hearing impairment and loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders including akinesias and akinetic (rigid) syndromes (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism, and progressively supranuclear palsy); muscular spasms and disorders associated with muscular spasticity or weakness including chorea (such as benign hereditary chorea, drug- induced chorea, hemiballism, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea), dyskinesia (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal cyloclonus), tremor (such as rest tremor, postural tremor, and intention tremor) and dystonia (including axial dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, and spasmodic dysphonia and torticollis); neuronal damage including ocular damage, retinopathy or macular degeneration of the eye; neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson's disease; seizure; status epilecticus; stroke; tinnitus; tubular sclerosis, and viral infection induced neurodegeneration (e.g., caused by acquired immunodeficiency syndrome (AIDS) and encephalopathies). Neurodegenerative diseases also include, but are not limited to, neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methods of treating or preventing a neurodegenerative disease also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorder.

In an embodiment, a method is provided for anesthesia and/or sedation, comprising administering to a subject in need thereof an effective amount of Compound M2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.

Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, decreased stress response, or all of these simultaneously. These effects can be obtained from a single drug which alone provides the correct combination of effects, or occasionally with a combination of drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achieve very specific combinations of results. Anesthesia allows patients to undergo surgery and other procedures without the distress and pain they would otherwise experience. Sedation is the reduction of irritability or agitation by administration of a pharmacological agent, generally to facilitate a medical procedure or diagnostic procedure. Sedation and analgesia include a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.

Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state during which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular functions are typically unaffected.

Moderate sedation/analgesia (conscious sedation) is a drug-induced depression of consciousness during which the patient responds purposefully to verbal command, either alone or accompanied by light tactile stimulation. No interventions are usually necessary to maintain a patent airway. Spontaneous ventilation is typically adequate. Cardiovascular function is usually maintained.

Deep sedation/analgesia is a drug-induced depression of consciousness during which the patient cannot be easily aroused, but responds purposefully (not a reflex withdrawal from a painful stimulus) following repeated or painful stimulation. Independent ventilatory function may be impaired and the patient may require assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained. General anesthesia is a drug-induced loss of consciousness during which the patient is not arousable, even to painful stimuli. The ability to maintain independent ventilatory function is often impaired and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to depressed spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired. Sedation in the intensive care unit (ICU) allows the depression of patients' awareness of the environment and reduction of their response to external stimulation. It can play a role in the care of the critically ill patient, and encompasses a wide spectrum of symptom control that will vary between patients, and among individuals throughout the course of their illnesses. Heavy sedation in critical care has been used to facilitate endrotracheal tube tolerance and ventilator synchronization, often with neuromuscular blocking agents.

Duration of sedation (e.g., long-term sedation, continuous sedation) is induced and maintained in the ICU for a prolonged period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 week, 3 weeks, 1 month, 2 months). Long-term sedation agents may have long duration of action. Sedation agents in the ICU may have short elimination half-life. Procedural sedation and analgesia, also referred to as conscious sedation, is a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows a subject to tolerate unpleasant procedures while maintaining cardiorespiratory function.

In an embodiment, a method is provided for treatment of epilepsy, comprising administering to a subject in need thereof an effective amount of Compound M2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.

Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy can include, but are not limited to generalized epilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.

In an embodiment, a method is provided for treatment of status epilepticus, comprising administering to a subject in need thereof an effective amount of Compound M2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject. Status epilepticus (SE) can include, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures, and can include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus. Early status epilepticus is treated with a first line therapy. Established status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered. Refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line and a second line therapy, and a general anesthetic is generally administered. Super refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, a second line therapy, and a general anesthetic for 24 hours or more.

Non-convulsive status epilepticus can include, e.g., focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., late onset absence non-convulsive status epilepticus, atypical absence non- convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

In an embodiment, a method is provided for treatment of seizure, comprising administering to a subject in need thereof an effective amount of Compound M2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.

A seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." Convulsions are when a person's body shakes rapidly and uncontrollably. During convulsions, the person's muscles contract and relax repeatedly. Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called local or focal). Classifying the type of seizure helps doctors diagnose whether or not a patient has epilepsy. Generalized seizures are produced by electrical impulses from throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain generating the seizures is sometimes called the focus.

There are six types of generalized seizures. The most common and dramatic, and therefore the most well-known, is the generalized convulsion, also called the grand-mal seizure. In this type of seizure, the patient loses consciousness and usually collapses. The loss of consciousness is followed by generalized body stiffening (called the "tonic" phase of the seizure) for 30 to 60 seconds, then by violent jerking (the "clonic" phase) for 30 to 60 seconds, after which the patient goes into a deep sleep (the "postictal" or after-seizure phase). During grand-mal seizures, injuries and accidents may occur, such as tongue biting and urinary incontinence.

Absence seizures cause a short loss of consciousness (just a few seconds) with few or no symptoms. The patient, most often a child, typically interrupts an activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of "losing time." Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe the jerks as brief electrical shocks. When violent, these seizures may result in dropping or involuntarily throwing objects. Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time. Tonic seizures are characterized by stiffening of the muscles. Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.

Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonus seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. EXAMPLES

The invention is further illustrated by the following examples. The examples below are non-limiting and are merely representative of various aspects of the invention. Solid and dotted wedges within the structures herein disclosed illustrate relative stereochemistry, with absolute stereochemistry depicted only when specifically stated or delineated.

EXAMPLE 1

Preparation of Compound M2

Preparation of l-(2-amino-3-fluoro-5-vinylphenyl)ethan-l-one (2)

1 ,4-Dioxane/H₂O

(1) Reflux ⁽²⁾

A mixture of l-(2-amino-5-bromo-3-fluoro-phenyl)ethanone (1); 2.5 g, 10.76 mmol), potassium vinyltrifluoroborate (3.6 g, 26.94 mmol) and cesium carbonate (10.52 g, 32.28 mmol) in dioxane / water (1 : 1, 64 mL) was purged with nitrogen for 5 min followed by the addition of Pd(dppf)C12 (866 mg, 1.184 mmol). The reaction mixture was heated at reflux for 4 h. Full conversion was detected by LCMS. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with water (2x) and brine, dried over anhydrous MgSCh and filtered. The filtrate was evaporated, and the residue was subjected to flash column purification on CombiFlash (220 g SG cartridge, gradient EtOAc/hexane 0->100% over 100 min). The desired fractions were combined and evaporated to afford l-(2-amino-3-fluoro-5-vinylphenyl)ethan-l-one (2) (1.76 g, 91% yield) as a yellowish oil which crystallized on standing.

Preparation of 8-fluoro-4-methyl-3- 3-methyl-L2,4-oxadiazol-5-yl)-6-vinylquinolin-2 -one

To a solution of l-(2-amino-3-fluoro-5-vinylphenyl)ethan-l-one (2); 1.66 g, 9.27 mmol), (3-methyl-[l,2,4]oxadiazol-5-yl)-acetic acid potassium salt (2.5g, 13.91 mmol) and DIPEA (4.84 mL, 27.84 mmol) in CH3CN (25 mL) was added POCI3 (1.724 mL, 18.54 mmol) over the period of 1 h at 50 °C with stirring under nitrogen. The reaction mixture was stirred at 50 °C for 90 min. Full conversion was detected by LCMS. The reaction mixture was diluted with water (18 mL) and maintained at 50 °C for 2 h followed by stirring at ambient temperature overnight. The temperature of the reaction mixture was allowed to cool to ambient temperature and stirring was continued overnight. The precipitate which was formed was filtered, washed with a mixture of CH3CN / water (1 : 1, 3x) and dried in air to afford 8-fluoro-4-methyl-3-(3-methyl- l,2,4-oxadiazol-5-yl)-6-vinylquinolin-2(U7)-one (3) (1.842 g, 70% yield) as a light beige solid.

Preparation of l-(8-fluoro-4-methyl-3-(3-methyl-L2,4-oxadiazol-5-yl)-6-vinylquinolin-2-yl)-N- (tetrahvdro-2H-pyran-4-yl)piperidin-4-amine (4)

To a solution of 8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)-6- vinylquinolin-2(U7)-one (3) (14.469 g, 50.72 mmol) and DIPEA (11.47 mL, 65.93 mmol) in ACN (90 mL) was added TfzO (11.08 mL, 65.93 mmol) at 50 °C over a period of 1 h. The reaction mixture (solution A) was stirred at 50 °C for 1 h and then cooled to ambient temperature. According to LCMS the reaction was complete. To a solution of N-(tetrahydro-27/-pyran-4- yl)piperidin-4-amine dihydrochloride (13.05 g, 65.93 mmol) in ACN (190 mL) was added K2CO3 (17.53 g, 126.8 mmol) at ambient temperature and the reaction mixture was warmed to 60 °C. The reaction mixture was stirred at 60 °C for 1 h (solution B). Solution A was diluted up to 250 mL after precipitation occurred and then added to solution B at 60 °C over a period of 1 h. Stirring was continued at 60 °C overnight. According to LCMS analysis, the reaction was complete. The mixture was diluted with water (150 mL) and stirred for 1 h at ambient temperature. The volatile portion was distilled off, and the residue was dissolved in EtOAc and washed water (3x) and brine, dried over MgSO4 and filtered. The filtrate was evaporated, and the residue subjected to flash purification on CombiFlash to afford l-(8-fhioro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)-6- vinyl-quinolin-2-yl)-A-(tetrahydro-2J/-pyran-4-yl)piperidin-4-amine (4) (19.81 g, 86%) as a yellowish glass-like material.

Preparation of l-(8-fluoro-4-methyl-3-(3-methyl-1.2,4-oxadiazol-5-yl)-2-(4-((tetrahydro-2H-pyran-4- yl)amino)-piperidin-l-yl)quinolin-6-yl)ethan-l-one (5)

l-(8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)-6-vinylquinolin-2-yl)-7V- (tetra-hydro-2J/-pyran-4-yl)piperidin-4-amine (4) (2 g, 4.425 mmol) andPd(OAc)2 (298 mg, 1.328 mmol) were placed into 100 mL round bottom flask under rubber septum and flashed with oxygen (oxygen balloon). DMSO (40 mL), water (4 mL) and trifluoroacetic acid (1.02 mL, 13.27 mmol) were sequentially added to the system via syringe under an oxygen atmosphere. The reaction mixture was stirred at 70 °C for 4 h. According to LCMS conversion was -90%. The reaction was quenched with bicarbonate and extracted with EtOAc (2x). The organic layer was washed with water (2x) and brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated, and the residue was dissolved in CH2CI2 and subjected to column chromatography (SiO2). The desired fractions were collected and evaporated to afford 1 -(8-fluoro-4-methyl-3 -(3 -methyl- 1,2,4- oxadiazol-5-yl)-2-(4-((tetra-hydro-2J/-pyran-4-yl)amino)piperidin-l-yl)-quinolin-6-yl)ethan-l- one (5) (900 mg, 43% yield) as a yellow solid.

Preparation of l-18-Fluoro-4-methyl-3-(3-methyl-rL2,41oxadiazol-5-yl)-2-14-(tetrahvdro-pyran- 4-yl-amino)-piperidin-l-yl1-quinolin-6-yn -ethanol (Cpd. M2)

To a solution of l-{8-fluoro-4-methyl-3-(3-methyl-[l,2,4]oxadiazol-5-yl)-2-[4- (tetrahydro-pyran 4-ylamino)-piperidin-l-yl]-quinolin-6-yl}-ethan-l-one (5) (1.71 g, 3.65 mmol) in a mixture of CH3OH (30 mL) and CH2CI2 (6 mL), was added sodium borohydride (553 mg, 14.62 mmol) portion-wise at 0 °C, and stirring was continued for 10 min. Full conversion was detected by LCMS. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous MgSCh and filtered. The filtrate was evaporated, and the residue was dissolved in CH2CI2 and subjected to flash purification on CombiFlash. The desired fractions were combined and evaporated to afford the crude product. The material was re-purified by HPLC. The pH of the fraction containing product was adjusted to 8 with 5% aqueous bicarbonate solution. The volatile portion of the fraction was evaporated. The precipitate was filtered, washed with water and dried in air to afford l-{8-Fluoro-4-methyl-3-(3- methyl-[l,2,4]oxadiazol-5-yl)-2-[4-(tetrahydro-pyran-4-yl-amino)-piperidin-l-yl]-quinolin-6- yl}-ethanol (Cpd. M2) as a yellowish solid. Cpd. M2 was obtained in this manner as a racemic mixture of Compounds M2a and M2b. EXAMPLE 2

Preparation of Compounds M2a and M2b

co nam e a en ne

Single Enantiomer of Unknown Absolute Configuration, but Opposite Enantiomer to M2a

Preparation of M2a

A solution of l-{8-fluoro-4-methyl-3-(3-methyl-[l,2,4]oxadiazol-5-yl)-2-[4- (tetrahydro-pyran 4-ylamino)-piperidin-l-yl]-quinolin-6-yl}-ethan-l-one (5) (300 mg, 0.642 mmol) and glucose (173 mg, 0.963 mmol) in DMSO (0.6 mL) and phosphate buffered saline (6 mL) was adjusted to pH 7.0. Glucose dehydrogenase (GDH, 60 mg), nicotinamide adenine dinucleotide phosphate (NADP, 30 mg) and enzyme phosphokinase PK076 (300 mg) were added, and the reaction mixture stirred at 25 °C for 5 h. The mixture was then diluted with water and extracted with EtOAc three times. The combined EtOAc fractions were washed twice with saturated brine, then dried over Na2SO4 and concentrated at 45 °C under reduced pressure until no further distillate was observed. The residue was purified by column chromatography (SiCh), eluting with ethyl acetate, then 15: 1 CH2CI2/CH3OH. Fractions containing product were combined and the solvent removed under vacuum to provide l-{8-fluoro-4-methyl-3-(3-m ethyl - [ 1 ,2,4]oxadiazol-5-yl)-2-[4-(tetrahydro-pyran-4-yl-amino)-piperidin- 1 -yl]-quinolin-6-yl } -ethanol (Cpd. M2a) as a yellow solid.

Preparation of M2b

A solution of l-{8-fluoro-4-methyl-3-(3-methyl-[l,2,4]oxadiazol-5-yl)-2-[4- (tetrahydro-pyran 4-ylamino)-piperidin-l-yl]-quinolin-6-yl}-ethan-l-one (5) (400 mg, 0.856 mmol) and S-CBS (IM in THF, 4 mL) in THF (4 mL) was cooled to 0 °C. To this was charged BHs-THF (IM in THF, 4 mL) and the reaction mixture was stirred for 1 h. The reaction was then quenched with CH3OH (20 mL), heated to 65 °C, and stirred for 0.5 h. Volatiles were removed under vacuum, and the residue purified by column chromatography (SiCh), eluting with 50: 1 CH2CI2/CH3OH. Fractions containing product were combined and the solvent removed under vacuum to provide l-{8-fluoro-4-methyl-3-(3-methyl-[l,2,4]oxadiazol-5-yl)-2-[4-(tetrahydro- pyran-4-yl-amino)-piperidin-l-yl]-quinolin-6-yl}-ethanol (Cpd. M2b) as a yellow solid.

EXAMPLE 3

Plasma, Brain and CSF Concentrations of Compound M2 Following IV Bolus Administration

This study evaluated the concentrations of Compound M2 (racemic mixture) in plasma, brain, and CSF following IV bolus administration of Compound M2 to male Sprague Dawley rats.

Compound M2 was prepared as a solution in phosphate buffer saline at a concentration of 0.5 mg/mL for IV bolus administration of 1 mg/kg. After formulation preparation, two aliquots of prepared dosing solution were analyzed in LC-MS/MS to confirm dose concentration. The dosing solution was serial diluted 5000 fold using acetonitrile:water (7:3 v:v). The diluted samples were then quantified using a standard curve prepared with same solvent. Three male Sprague Dawley rats were administered with Compound M2 at 1 mg/kg by IV bolus. Animals were not fasted overnight prior to dose administration. A summary of the study design is presented in Table 1. Table 1

Study Design

Blood, CSF, and brain samples were collected at 1 hour after dosing. Blood samples were centrifuged at 4°C, 3000g for 5 min within half an hour of collection and the plasma fraction was stored frozen at -80°C prior to bioanalysis. CSF samples were obtained following blood collection and brain tissues were collected and weighted. The brain tissues were homogenized at 1 :4 (v:v) ratio with pre-chilled water. CSF and brain samples were stored frozen at -80° C prior to bioanalysis.

The plasma, brain homogenate, and CSF samples were protein-precipitated with acetonitrile with labetalol and tolbutamide as internal standards. The protein-precipitated samples were centrifuged at 3900 RPM for 10 minutes at 4°C, then supernatants were mixed with water 1 : 1. The prepared samples were injected onto a Water ACQUITY UPLC BEH 1.7 pm C18 130A column (30 mm x 2.1 mm) at a flow rate of 0.7 mL/min. Mobile phase A consisted of 0.1 % formic acid in water and mobile phase B consisted of 0.1% formic acid in acetonitrile. A linear gradient was used, and total run time was 1.6 minutes. The mass spectrometer was operated in positive ion multiple reaction monitoring mode (MRM). The transitions of the precursor ions to the selected product ions were m/z 470.2 to m/z 315.2 for Compound M2, m/z 329.2 to m/z 162.1 for labetalol, and m/z 271.1 tO m/z 155.3 for tolbutamide. The assay quantitation range for plasma, brain, and CSF samples was 1.00 to 3000 ng/mL.

The concentration of the prepared dose formulation was within 20% of nominal values. Following an IV bolus administration of Compound M2 to male Sprague Dawley rats, the concentration of Compound M2 was measured in the plasma, brain, and CSF 1 hour after dose administration. Total concentrations of Compound M2 in the brain and CSF were 25% and 8% of the concentration in plasma, indicating that Compound M2 penetrates the blood-brain barrier to a moderate degree.

Summary concentrations and tissue ratios of Compound M2 following IV bolus administration of 1 mg/kg Compound M2 to male Sprague Dawley rats are in Table 2. Individual plasma and tissue concentrations and ratios are in Table 3 and Table 4. Table 2

Mean ± SD Compound M2 Plasma, Brain, and CSF Concentrations and Ratios

Table 3

Individual Compound M2 Plasma, Brain, and CSF Concentrations

Table 4

Individual Compound M2 Brain:Plasma, CSF:Plasma, and CSF:Brain Ratios

EXAMPLE 4

Pharmacokinetics of Compound M2 Following Repeated Oral Administration of Compound 142

The study evaluated the pharmacokinetics of metabolites M2a, M2b following 7 days of repeated oral (PO) administration of 30 mg/kg/day Compound 142 to male and female Sprague Dawley rats and male and female CD-I mice. A summary of the study design is presented in Table 5.

Table 5

Study Design

Compound 142 dose formulations were prepared as a suspension in 0.5% methylcellulose (MC) in reverse osmosis (RO) water at a concentration of 3 mg/mL for administration of 30 mg/kg/day. For all studies, Compound 142 HC1 salt was used, and the purity was 99.3%. A correction factor of 1.09 was used for formulation preparation. Doses and concentrations of Compound 142 are expressed in terms of the free base.

In one study, 4 male and 4 female Sprague Dawley rats were administered Compound 142 by oral gavage at a dose of 30 mg/kg/day for 7 days. Blood samples were collected on Day 7 via a jugular vein cannula at 2, 4, and 8 hours after dosing. Terminal blood samples (24 hours post dose) were collected through cardiac puncture after euthanasia by CO2 inhalation. Blood was collected into sample tubes containing K2EDTA. Samples were centrifuged and the plasma fraction was stored frozen at -80 °C prior to bioanalysis.

In another study, 16 male and 16 female CD-I mice were administered Compound 142 by oral gavage at a dose of 30 mg/kg/day for 7 days. Following the final dose on Day 7, terminal blood samples were collected at 2, 4, 8, and 24 hours post dose through cardiac puncture after euthanasia by CO2 from 4 mice/sex/timepoint. Blood was collected into sample tubes containing K2EDTA. Samples were centrifuged and the plasma fraction was stored frozen at -80 °C prior to bioanalysis.

Concentrations of Compound 142 metabolites M2a and M2b in rat and mouse plasma were determined using LC-MS/MS. Non-compartmental pharmacokinetic parameters of were calculated with Microsoft Excel. Individual plasma concentration profiles over time were used for rats and composite profiles were used for mice. Predose samples were not collected but time zero (predose) levels were imputed with the concentration in plasma at 24 hours.

The following parameters were calculated:

T_max Time of maximal plasma concentration

C max Maximum concentration in p ¹ lasma

AUCO-24 Area under the plasma concentration-time curve from time 0 to 24 hours

Plasma concentration data and pharmacokinetic parameters were reported to 3 significant figures. All data calculations were performed prior to rounding. Summary statistics were calculated using Microsoft Excel 2013, and graphs were prepared with GraphPad Prism Version 9.

Summary pharmacokinetic parameters of metabolites M2a and M2b following 7 days of repeat oral daily administration of 30 mg/kg Compound 142 HC1 salt to male and female Sprague Dawley rats are shown in Table 6. Table 6

Summary of Pharmacokinetic Parameters of Compounds M2a and M2b

Plasma concentration versus time profiles of Compounds M2a and M2b on Day 7 of administration of 30 mg/kg/day BTRX-335140 are shown in Figure 1 and Figure 2, respectively.

This study showed that following oral administration of 30 mg/kg/day of Compound 142 to male and female rats and mice, all animals were exposed to measurable levels of Compounds M2a and M2b.

EXAMPLE 5

Pharmacokinetics of Compound M2 Following Repeated Oral Administration of Compound 142

This study was conducted to assess the pharmacokinetics of Compound 142 and its metabolite, Compound M2, in plasma, brain, and CSF of male Sprague Dawley rats following single PO administration of Compound 142 (HC1 salt form).

Compound 142 was formulated in 0.5% CMC (400 - 800 cps) in reverse osmosis water as 10 mg/mL suspension for PO administration dose volume of 10 mL/kg. Due to the salt form, a correction factor of 1.08 was used for formulation preparation. Twelve male Sprague Dawley rats were fed with maintenance food for laboratory rats and had been fasted from 18:00 pm before the dosing day overnight and fed at 4 hr post-dose. Drinking water was available daily ad libitum to all animals. Compound 142 (HC1 salt form) was administered to the rats by oral administration at 100 mg/kg, expressed in term of free base. Blood, brain, and CSF samples were collected at 1, 2, 4, and 8 hours post dose. Blood samples were collected via cephalic vein into EDTA-K2 tubes, samples were centrifuged at 4°C, 6000 rpm for 5 minutes within half an hour of collection and the plasma fraction was stored in -80°C freezer prior to the bioanalysis. Blank brain homogenate and brain homogenates from dosed animals were prepared by homogenizing tissue with water at 1 :4 ratio (w/v). CSF and brain samples were stored frozen in -80°C freezer prior to the bioanalysis.

The 50-pL aliquot of plasma and brain samples were transferred to tube with 200 pL as internal standard (ISTD, 100 ng/mL Tolbutamide in MeOH/ Acetonitrile (1 : 1, v/v)). The samples were mixed for 1 minute and centrifuged at 4000 rpm at 4°C for 15 minutes. The plasma and brain supernatants were diluted with MeOH/FFO (v:v=l:l,with 0.1% formic acid) 5x and 3x, respectively. The diluted samples were transferred to LC-MS/MS for injection.

The 30-pL aliquot of CSF samples was transferred to tubes with 200 pL ISTD (ISTD, 100 ng/mL Tolbutamide in MeOH/ Acetonitrile (1 : 1, v/v)). The sample was mixed for 1 minute and centrifuged at 4000 rpm at 4°C for 15 minutes. The supernatants was diluted 3x with MeOH/H₂O (v:v=l : l,with 0.1% formic acid). The diluted samples were transferred to LC-MS/MS for injection. The dose verification sample was prepared by diluting one hundred thousand-fold from the original dosing formulation in MeOH. The injection sample was prepared by adding 5- pL of diluted sample into 100 pL of IS (100 ng/mL Tolbutamide in MeOH/acetonitrile (1 : 1, v/v)) and 100 pL of 50% MeOH with 0.1% formic acid.

The concentrations of Compund 142 and Metabolite M2 in rat plasma, brain, and CSF, and Compound 142 dose solution were determined using LC-MS/MS. The HPLC was performed using a LC-30AD pump (Shimadzu, Japan) coupled to a mass spectrometer (Triple Quad 5500+, Applied Biosy stems/MDS SCIEX Instruments, Foster City, CA). The prepared samples (1 or 2 pL) were injected onto a Kinetex 2.6 pm C18 100A column (50 mm x 2.10 mm) at room temperature with a flow rate of 0.6 mL/min. The mobile phase A consisted of 0.1% formic acid in water and mobile phase B consisted of 0.1% formic acid in acetonitrile. The mass spectrometer was operated in positive ion multiple reaction monitoring mode (MRM). The further analyzer settings were as follows: curtain gas 20 psi, collision gas 9 psi, ionspray voltage 5500 V, temperature 500 °C, ion source GAS1 55 psi and ion source GAS2 55 psi.

The standards and QC samples of plasma were prepared in blank male Sprague Dawley rat plasma. The standard curve ranges were 1-2000 ng/mL with a LLOQ of 1 ng/mL. Three levels of QC samples were used at 2, 200, and 1600 ng/mL for standard curve ranges 1-2000 ng/mL. The standards and QC samples of CSF were prepared in blank artificial CSF. The standard curve ranges were 0.5-500 ng/mL with a LLOQ of 0.5 ng/mL. Three levels of QC samples were used at 1, 200, and 400 ng/mL for standard curve ranges 0.5-500 ng/mL.

The standards and QC samples of brain were prepared in blank male Sprague Dawley rat brain homogenate. The standard curve ranges were 1-2000 ng/mL with a LLOQ of 1 ng/mL. Three levels of QC samples were used at 2, 200, 1600 ng/mL for standard curve ranges 1- 2000 ng/mL.

For each analytical batch prepared in plasma, brain, and CSF, more than three fourths of calculated standard curve values did not deviate by more than 20% of the nominal concentrations using a 1/x² weighted linear regression based on the ratio of analyte to internal standard peak areas, and more than two-third of the QC values were within 20% of the nominal concentrations. Data were analyzed using the standard software Analyst 1.7.1.

The pharmacokinetic parameters of Compound 142 and Compound M2 were determined by non-compartmental analysis using Phoenix WinNonlin Version 8.2.0 (Certara). The area under the curve from the time of dosing to the last measurable concentration, AUCi_ast, was calculated by the linear trapezoidal rule. The area under the concentration-time curve extrapolated to infinity, AUC_mf, was calculated using a regression of the natural logarithm of the concentration values versus sampling times of the terminal slope (Lambda Z, k). This value is also used to calculate half-life (ti/₂) as follows: ti/2 ⁼ 0.693/k

Mean residence time (MRT) was calculated as follows:

MRTinf = AUMCinf / AUCinf

The analyzed Compound 142 dose solution was within the 20% of nominal dose concentration. Following PO administration at 100 mg/kg to male Sprague Dawley rats, body weight change and clinical signs of rats were monitored for pharmacokinetic study. No abnormalities were detected. Following PO administration, Compound 142 and Compound M2 were measurable in plasma, brain, and CSF samples for all timepoints. A summary of the mean pharmacokinetic parameters for Compound 142 are shown in Table 7. A summary of the mean pharmacokinetic parameters for metabolite M2 are shown in Table 8. Table 7

Mean (n= 12) Pharmacokinetic Parameters of Compound 142 in Plasma, Brain, and C SF

Table 8

Mean (n=12) Pharmacokinetic Parameters of Compound M2 in Plasma, Brain, and CSF

Brain to plasma concentration ratio of Compound 142 is shown in Table 9. CSF to plasma concentration ratio is shown in Table 10. Brain to Plasma concentration ratio of Compound M2 is shown in Table 11. CSF to Plasma concentration ratio of Compound M2 is shown in Table 12. Individual brain data of Compound 142 and Compound M2 after is shown in Table 13. Table 9

Brain/Plasma of Compound 142 after PO Dose of 100 mg/kg in Male SD Rats

Table 10

CSF/Plasma of Compound 142 after PO Dose of 100 mg/kg in Male SD Rats

Table 11

Brain/Plasma of Compound M2 after PO Dose of 100 mg/kg in Male SD Rats

Table 12

CSF/Plasma of Compound M2 after PO Dose of 100 mg/kg in Male SD Rats

Table 13

Individual Brain Data of Compound 142 and Compound M2 Following Oral Administration to Male SD Rats at 100 mg/kg

EXAMPLE 6

Contribution of Compound M2 to Pharmacology of Compund 142 in a Phase I Study of Absorption, Metabolism, and Excretion of l¹⁴C1-Compound 142 Following a Single Oral Dose in Healthy Make Subjects

In humans given an oral dose of Compound 142, Compound M2 was found as a major metabolite in plasma and accounted for 13% of total drug-related plasma exposure. A minor metabolite (Compound M2b) was also found and accounted for 3.6% of total drug related material. In plasma of humans given a single 80-mg oral dose of Compound 142, the AUC of M2a and M2b was approximately 43% and 12% that of the parent Compound 142, respectively. As noted above, M2a and M2b are enantiomers (collectively M2) and the AUC of M2 therefore is approximately 55% that of parent Compound 142, calculated as the sum of M2a (43%) and M2b (12%).

While Compound M2 was present at a lower plasma concentration than Compound 142, it is pharmacologically active as a kappa opioid receptor antagonist and may therefore contribute to the pharmacodynamics of Compound 142 in humans. This example summarizes the potency and CNS penetration of M2a and M2b individually, and collectively as M2, relative to that of Compund 142, to assess the potential for M2 to contribute to the pharmacodynamics of Compound 142 in humans.

These results of this study are summarized in Table 14.

Table 14

Potential Contribution of Metabolite M2 Based on the Potencies of M2a and M2b, their Plasma Protein binding, their CNS penetration, and the Levels of Compound 142, M2a, and M2b in Human Plasma

Key results of this study include the following: (1) Compund M2a was approximately 1.53-fold more potent than Compound 142, and M2b was approximately 32% as potent as Compound 142 for kappa opioid receptor binding affinity; (2) Compound M2 had a free fraction in human plasma that was approximately 3.5-fold higher than parent Compound 142; (3) the unbound brain/plasma ratio (Kpuu) of Compound M2 was approximately 27% that of parent Compound 142; and (4) based on the potencies of Compounds M2a and M2b, their plasma protein binding, their CNS penetration, and the levels of Compound 142, Compounds M2a, and M2b in human plasma, Compund M2 (sum of M2a and M2b) contributes to potential CNS activity at a level 65% that of the parent Compound 142.

The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, including U.S. Provisional Patent Application No. 63/519,136, filed on August 11, 2023, are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications, and publications to provide yet further embodiments. These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

CLAIMS We claim:

1. A pharmaceutical composition comprising Compound M2 having the following structure, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, and a pharmaceutically acceptable carrier, diluent or exipient:

2. The pharmaceutical composition of claim 1 wherein Compound M2 is a racemic mixture of compounds having the following structures, or a pharmaceutically acceptable hydrate, solvate, isotope or salt thereof:

3. The pharmaceutical composition of claim 1 wherein Compound M2 is a substantially enantiomerically pure form a compound having the following structure, or a pharmaceutically acceptable hydrate or solvate, isotope or salt thereof:

4. The pharmaceutical composition of claim 1 wherein Compound M2 is a substantially enantiomerically pure form of a compound having the following structure, or a pharmaceutically acceptable hydrate or solvate, isotope or salt thereof:

5. The pharmaceutical composition of any one of claims 1-4 further comprising Compound 142 having the following structure, or a pharmaceutically acceptable hydrate or solvate, isotope or salt thereof:

6. A method for antagonizing the KOR, comprising contacting the KOR with an effective amount of a pharmaceutical composition of any one of claims 1-5.

7. A method for antagonizing the KOR of a subj ect in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition of any one of claims 1-5.

8. The method of claim 7, wherein KOR antagonism occurs in the CNS of the subject.

9. The method of claim 7, wherein KOR antagonism occurs in the brain of the subject.

10. A method for reducing serum prolactin levels, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of any one of claims

1-5, at a frequency and for duration sufficient to provide a beneficial effect to the subject.

11. A method for treating a neuropsychiatric or behavioral condition, whether organic, stress-induced or iatrogenic, that is characterized by elevations in serum prolactin, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of any one of claims 1-5, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.

12. A method for treating a of disorders related to substance abuse or addiction, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of any one of claims 1-5, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.

13. A method treating a CNS-related disorder, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of any one of claims 1-5, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.

14. A method for treating an anxiety disorder, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of any one of claims 1-5, at a frequency and for duration sufficient to provide a beneficial effect to the subject.

15. The method of claim 14, wherein the anxiety disorder is a social anxiety disorder.

16. The method of claim 14 wherein the anxiety disorder is phobia.

17. The method of claim 14 wherein the anxiety disorder is a stress-related disorder.

18. The method of claim 14 wherein the anxiety disorder is PTSD.

19. The method of claim 14 wherein the anxiety disorder is GAD.

20. A method for treating a depressive disorder, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of any one of claims 1-5, at a frequency and for duration sufficient to provide a beneficial effect to the subject.

21. The method of claim 20 wherein the depressive disorder is major depression.

22. The method of claim 20 wherein the depressive disorder is MDD.

23. A method for treating a mood disorder, comprising administering to a subject in need thereof a pharmaceutical composition of any one of claims 1-5, at a frequency and for duration sufficient to provide a beneficial effect to the subject.

24. The method of claim 23 wherein the mood disorder is anhedonia.

25. The method of claim 23 wherein the mood disorder is major depression.

26. The method of claim 23 wherein the mood disorder is MDD.

27. A method for treating a schizophrenia or a schizoaffective disorder, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of any one of claims 1-5, at a frequency and for duration sufficient to provide a beneficial effect to the subject.

28. A method for treating obesity or an eating disorder, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of any one of claims 1-5, at a frequency and for duration sufficient to provide a beneficial effect to the subject.

29. A method for treating migraine, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of any one of claims 1-5, at a frequency and for duration sufficient to provide a beneficial effect to the subject.

30. The method of claim 29, wherein the method for treating migraine is for migraine prophylaxis.

31. A method for treating postnatal depression, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of any one of claims 1-5, at a frequency and for duration sufficient to provide a beneficial effect to the subject.