Advantageous benzofuran compositions for mental disorders or mental enhancement

Abstract

The present invention provides pharmaceutically active benzofuran compositions for use in the treatment of psychiatric disorders or for mental enhancement, including for estrus stimulation therapy. The invention also includes benzofuran compounds, compositions, and methods for generally modulating central nervous system activity and treating central nervous system disorders.

Description

[0001] This application is a divisional application of the patent application for invention with the application date of June 8, 2021, application number 202180059254.9, and invention name "Beneficial benzofuran compositions for mental disorders or mental enhancement".

[0002] Cross - reference to related applications

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 036,382 filed on June 8, 2020, U.S. Provisional Application No. 63 / 046,496 filed on June 30, 2020, U.S. Provisional Application No. 63 / 048,616 filed on July 6, 2020, U.S. Provisional Application No. 63 / 055,897 filed on July 23, 2020, U.S. Provisional Application No. 63 / 062,434 filed on August 6, 2020, U.S. Provisional Application No. 63 / 149,223 filed on February 13, 2021, and U.S. Provisional Application No. 63 / 165,731 filed on March 24, 2021. The entire contents of these applications are incorporated herein by reference for all purposes. Technical field

[0004] The present invention pertains to the field of pharmaceutically active benzofuran compositions for treating mental disorders or for mental enhancement, including for entactogenic therapy. The present invention also includes benzofuran compounds, compositions, and methods for generally modulating central nervous system activity and treating central nervous system disorders. Background art

[0005] Mental disorders, including post - traumatic stress disorder (PTSD), are more prevalent in society than most people realize because they can be silent or hidden. The National Institute of Mental Health (NIMH) in the United States reports that 70% of adults experience at least one traumatic event in their lifetime, and 20% of them develop PTSD. The NIMH estimates that approximately 3.6% of U.S. adults have PTSD in any given year. PTSD can severely impair a person's ability to function at work, at home, and socially. While many people associate PTSD with veterans and combat, in fact, it is prevalent in all aspects of society.

[0006] The World Health Organization reports that depression is a serious medical disorder affecting at least 264 million people of all ages globally. When it persists for a long time and is of moderate or severe intensity, depression can become a serious health condition. It is a leading cause of disability and, if untreated, can lead to suicidal thoughts and ideas, which can then progress to suicide and addiction. According to the WHO, suicide is the second leading cause of death among people aged 15 - 29 globally.

[0007] Other mental disorders that may severely affect a person's normal social functioning include anxiety disorders such as generalized anxiety disorder, phobias, panic disorder, separation anxiety disorder, stress-related disorders, adjustment disorders, dissociative disorders, eating disorders (such as bulimia, anorexia, etc.), attention deficit disorder, sleep disorders, disruptive disorders, neurocognitive disorders, obsessive-compulsive disorder, and personality disorders, etc.

[0008] Although medications for a range of mental disorders are available or are in clinical testing, these disorders remain a huge disease burden globally and are not adequately treated. In addition, many medications have a ramp-up period of weeks or longer, during which some patients in need of treatment stop taking the medication due to impatience or the perception that the medication is ineffective.

[0009] Many mental disorders are caused by, affected by, and / or treatable with altered neurotransmitter levels. Neurotransmitters are chemicals that transmit signals from one neuron to another across a synapse. The brain neurotransmitter systems include the serotonin system, the norepinephrine (noradrenaline) system, the dopamine system, and the cholinergic system. Dopamine, serotonin, and norepinephrine (noradrenaline) are classified as phenethylamines, and norepinephrine is also a catecholamine. Drugs that prevent neurotransmitters from binding to their receptors are called receptor antagonists. Drugs that bind to receptors and mimic normal neurotransmitters are receptor agonists. Other drugs interfere with the inactivation of neurotransmitters after their release, thereby prolonging their action. This can be achieved by blocking the reuptake of the transmitter (reuptake inhibitors) or by inhibiting the enzymes that degrade the transmitter. Direct agonists bind directly to their associated receptor sites. Indirect agonists increase the binding of neurotransmitters to target receptors by stimulating the release of neurotransmitters or by blocking the reuptake of neurotransmitters.

[0010] Dopamine receptors are involved in many neural processes such as motivation, pleasure, cognition, memory, learning, and fine motor control. It is the main neurotransmitter involved in the reward pathway. Drugs that increase dopamine may produce a sense of euphoria. Some widely used drugs alter the function of the dopamine transporter (DAT), which is responsible for removing dopamine from the synaptic cleft.

[0011] Norepinephrine, also known as noradrenaline, mobilizes the body for activity and is at high levels during stress or danger. It focuses attention and increases wakefulness and alertness.

[0012] Serotonin (5-hydroxytryptamine or "5-HT") receptors affect various neurological functions such as aggression, anxiety, appetite, cognition, learning, memory, mood, and sleep. 5-HT receptors are targets of both FDA-approved and unapproved drugs, including antidepressants, antipsychotics, and empathogens. There are seven 5-HT receptor families, each with subtypes, forming a highly complex signaling system. For example, when 5-HT 2A is in an agonist state, it typically induces hallucinogenic effects, while 5-HT 2B which is more predominantly present peripherally rather than in the brain, causes toxicity such as valvular heart disease upon chronic agonism. In contrast, 5-HT 1B regulates serotonergic neurons upon agonism and may contribute to the social effects of entactogens.

[0013] Current treatment for a range of mental disorders typically involves the use of selective serotonin reuptake inhibitors (SSRI), such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft). SSRIs block the reuptake (i.e., reabsorption) of serotonin into neurons, thereby increasing the level of serotonin in the brain. However, SSRIs often have difficulty achieving clinically meaningful benefits and can take weeks to produce a therapeutic effect. Additionally, many patients are non-responders and show no benefit at all (Masand et al., Harv. Rev. Psychiatry, 1999, 4:69-84; Rosen et al., J. Clin. Psychopharmacol., 1999, 19:67-85).

[0014] In contrast, bupropion (Wellbutrin), an antidepressant that is a norepinephrine-dopamine reuptake inhibitor, provides more stimulant effects, including weight loss.

[0015] Another class of drugs for treating CNS mental disorders is monoamine releasers. Monoamine releasers induce the release of one or more monoamine neurotransmitters (e.g., dopamine, serotonin, or epinephrine) from neurons in the brain. Monoamine releasers can rapidly modulate brain systems that are affected more slowly by SSRIs. However, their stimulant and euphoric effects often lead to a high propensity for abuse. Thus, although monoamine releasers based on the phenethylamine structure, such as amphetamine (Benzedrine, Dexedrine) and Obetrol, Pervitin were widely used as antidepressants in the mid-20th century, the use of such drugs is now more cautious and is mainly for the treatment of attention deficit hyperactivity disorder (ADHD).

[0016] In searching for alternatives to the defective existing CNS mental disorder therapies, various other classes of chemical structures have been investigated. For example, US Publication No. 2020 / 0000747 A1 discloses rigid 2-aminoindane derivatives used as bulimia regulators. Aminoalkyl dihydrobenzofurans having aryl substituents on the benzofuran ring have been disclosed in US Patent No. 7,396,857 for the treatment of depression and related disorders and in US Patent No. 7,368,477 and US Publication No. 2008 / 0200541 A1 for the treatment of schizophrenia and related disorders. Many secondary amines have also been disclosed in PCT Application WO1994029290 A1 as anti-diabetic and anti-obesity agents for edible animals.

[0017] While the above drugs may be helpful for certain patients or circumstances, there is still a strong need for better alternatives. The widespread use of unapproved drugs for self-medication has prompted the search for a solution that uses additional approved drugs to more fully treat mental disorders or to be able to provide mental enhancement.

[0018] Empathogens (empathy stimulants) have become a more prominent focus for addressing some of these serious health issues. They increase a sense of reality and emotional openness while reducing social anxiety (Baggott et al., Journal of Psychopharmacology 2016, 30.4: 378-87). Empathogens are generally monoamine releasers that appear to act in part by releasing serotonin, which stimulates hypothalamic serotonergic receptors, thereby triggering the release of the hormone oxytocin, while also stimulating serotonergic 5-HT 1B receptors on cells in the nucleus accumbens region of the brain. MDA, MBDB, MDOH, and MDEA are other examples of empathogens, however, these drugs do have diverse and complex effects due to binding to a range of 5-HT receptors.

[0019] Among these, the aminoalkylbenzofurans 1-(1-benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB) and 1-(1-benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB) have been reported to share some effects with empathogens and have undergone preliminary pharmacological analysis (Rickli et al., British Journal of Pharmacology, 2015, 172:3412-3425; Sahai et al., Progress in Neuropsychopharmacology & Biological Psychiatry, 2017, 75(1-9); Fuwa et al., The Journal of Toxicological Sciences, 2016, 41(3), 329-37).

[0020] Before being studied in a laboratory setting, these compounds and a small number of similar compounds, such as 1-(benzofuran-5-yl)-N-methylbutan-2-amine (5-MBPB), were initially sold on the black or grey market for self-medication or their euphoric effects (European Monitoring Centre for Drugs and Drug Addiction – Europol (EMCDDA–Europol) (2015) Annual Report on the Implementation of Council Decision 2005 / 387 / JHA and European Drug Report, Trends and Developments (2020), European Monitoring Centre for Drugs and Drug Addiction). In addition, US Patent No. 7,045,545 discloses certain aminoalkylbenzofurans as agonists of the serotonin 5-HT 2C receptors.

[0021] 5-MAPB and 6-MAPB have been shown to act on many enzymes that regulate neurotransmitter levels. Importantly, racemic 5-MAPB and 6-MAPB inhibit the serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) (i.e., inhibit the reuptake of SERT, DAT, and NET) (Eshleman et al., Psychopharmacology, 2019, 236:939-952; Shimshoni et al., Naunyn-Schmiedeberg’s Archives Pharmacol., 2017, 390(1), 15-24). They have also been shown to affect the agonistic effects of 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors and interact with muscarinic, nicotinic acetylcholine α4β2, adrenergic (α-1, α-2, β-1, β-2), GABA, and dopamine (DA 1 , DA 2S , DA 3 , DA 4 ) receptors (Shimshoni et al., Naunyn-Schmiedeberg’s Archives Pharmacol., 2017, 390(1), 15-24). In addition, they have been shown to be substrates or inhibitors of the enzyme MAO-A and, to a lesser extent, catechol-o-methyltransferase (Shimshoni et al., Naunyn-Schmiedeberg’s Archives Pharmacol., 2017, 390(1), 15-24).

[0022] By interacting with DAT, 5-MAPB increases the extracellular concentration of dopamine in the brain, consistent with its tendency for abuse (Sahai et al., Progress in Neuropsychopharmacology & Biological Psychiatry, 2017, 75(1-9)). Although the mechanism has not been studied, 5-MAPB has also been shown to increase extracellular serotonin, dopamine, and norepinephrine in the striatum of mice (Fuwa et al., The Journal of toxicological sciences, 2016, 41(3), 329-37). Microdialysis studies of racemic 5-MAPB also found that it increased serotonin in the nucleus accumbens of rats and decreased the level of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (Kim et al., Forensic Toxicology, 2019, 37(1), 104-12). The same report determined that racemic 5-MAPB inhibits DAT (IC 50 3.1 μM) and SERT (IC 50 8.5 μM) reuptake.

[0023] The urgent need for more effective treatments for mental disorders, psychostimulation, and other CNS disorders is clear and requires a great deal of new research and attention.

[0024] The object of the present invention is to provide advantageous compositions for the treatment of mental disorders and psychostimulation and their uses and manufacture. Another object is to provide a drug with a faster onset of action for use in a clinical setting, such as counseling, such as PTSD and other disorder counseling, or a home environment, which will open the patient's empathy, compassion, and acceptance. Another object is to provide an effective treatment for a range of CNS disorders. Summary of the Invention

[0025] The present invention provides multiple embodiments of compounds, compositions, and methods for the treatment of mental disorders and more general central nervous disorders, as well as for psychostimulation. The compounds of the present invention provide advantageous pharmacological properties that are well-suited as therapies for mental disorders, particularly as psychotherapies and neurotherapies.

[0026] The embodiments of the present invention are provided to meet the goal of helping people with mental disorders (who desire mental enhancement) or other CNS disorders by providing milder therapeutic agents that act rapidly and reduce properties that degrade the patient experience, counteract the therapy, or have unwanted toxicity. One goal of the present invention is to provide therapeutic compositions that increase empathy, compassion, openness, and acceptance towards oneself and others, which can be taken as part of therapeutic counseling if desired, or occasionally or continuously as prescribed by a healthcare provider when necessary.

[0027] Surprisingly, the compositions and compounds of the present invention exhibit permeability, indicating that the compounds act rapidly in the human body. This represents a significant improvement over SSRIs, which are the current standard of care for many CNS and psychological disorders. Slow onset is one of the most significant drawbacks of SSRI therapy. In contrast, in one embodiment, the compounds of the present invention are used as rapid-acting therapeutics, which represents a significant advancement in clinical applications. It is advantageous to use rapid-acting therapeutic agents in a clinical treatment setting that typically lasts one hour, two hours, or several hours.

[0028] In a first embodiment, it has been found that the empathy-stimulating properties of certain compounds can be improved by administering to a host in need, such as a human, an effective amount of an enantiomerically enriched composition (where the abundance of one enantiomer exceeds that of the other enantiomer), or (for some of the compounds described herein) an essentially pure enantiomer (or diastereomer, if relevant). It has been found that certain enantiomerically enriched forms of empathy stimulants act differently on various 5-HT receptors, dopamine receptors, nicotinic acetylcholine receptors, and norepinephrine receptors than the racemate, producing different effects, and those effects can be selected based on the desired outcome of the patient. Given the complexity of the neurotransmitter system, this cannot be predicted in advance.

[0029] The empathy-stimulating properties of a drug can be evaluated by a variety of publicly available methods, including but not limited to the methods described in Example 28 (evaluation of the empathy-stimulating effect of reduced neuroticism) and Example 29 (evaluation of the authenticity of the empathy-stimulating effect).

[0030] Accordingly, in one aspect of this embodiment, the present invention provides pharmaceutical compositions comprising an enantiomerically enriched or (for some indications) essentially enantiomerically pure R-5-MAPB, S-5-MAPB, R-6-MAPB, or S-6-MAPB, or a pharmaceutically acceptable salt or salt mixture thereof. In certain aspects, pharmaceutical compositions are provided that comprise an enantiomerically enriched mixture of the R- or S-enantiomers of 5-MAPB or 6-MAPB:

[0031]

[0032] In certain embodiments, the isolated enantiomers of the compounds of the invention exhibit improved binding to desired receptors and transporters relevant to the goal of treating mental disorders or mental enhancement.

[0033] It has been found that these entactogen compounds, preferably not racemic mixtures, are S- or R-enantiomer-enriched mixtures. It has surprisingly been found that enantiomer-enriched mixtures with a greater amount of the S-enantiomer of 5-MAPB or 6-MAPB maximize the serotonin receptor-dependent therapeutic effect, and enantiomer-enriched mixtures with a greater amount of the R-enantiomer of 5-MAPB or 6-MAPB maximize the nicotinic receptor-dependent therapeutic effect. Thus, one aspect of the invention is a balanced mixture of S-5-MAPB and R-5-MAPB or a balanced mixture of S-6-MAPB and R-6-MAPB, which achieves a predetermined combination of serotonin-receptor-dependent therapeutic effects and nicotinic-receptor-dependent or dopaminergic therapeutic effects. The effects can be adjusted as needed to obtain an optimal therapeutic effect.

[0034] Thus, in one embodiment, when administered to a host in need thereof (such as a mammal, including a human), an enantiomer-enriched mixture of S-5-MAPB or an enantiomer-enriched mixture of S-6-MAPB maximizes the serotonin receptor-dependent therapeutic effect and minimizes unwanted nicotinic or dopaminergic effects.

[0035] In another embodiment, when administered to a host in need thereof (including a mammal, such as a human), an enantiomer-enriched mixture of R-5-MAPB or an enantiomer-enriched mixture of R-6-MAPB can maximize the nicotinic receptor-dependent or dopaminergic receptor-dependent therapeutic effect while minimizing unwanted effects.

[0036] Surprisingly, an enantiomerically enriched mixture of non-racemic 5-MAPB has relatively large therapeutic effects (such as emotional openness), while having relatively small effects associated with abuse potential (such as a perceptible "good drug effect"). In addition, any such abuse potential is expected to be attenuated to the extent that the substance also increases extracellular serotonin (see, e.g., Wee et al., Journal of Pharmacology and Experimental Therapeutics, 2005, 313(2), 848-854). Accordingly, one aspect of the present invention is a balanced non-racemic mixture of S-5-MAPB and R-5-MAPB or a balanced non-racemic mixture of S-6-MAPB and R-6-MAPB, which achieves a predetermined combination of emotional therapeutic effects and perceptible mood effects. The effects can be adjusted as needed to obtain optimal therapeutic effects.

[0037] Accordingly, in one embodiment, an enantiomerically enriched mixture of S-5-MAPB or an enantiomerically enriched mixture of S-6-MAPB, when administered to a host in need thereof (such as a mammal, including a human), balances emotional openness and perceptible mood effects.

[0038] The present invention also provides methods for modulating CNS activity and / or methods for treating mental disorders (including but not limited to post-traumatic stress disorder and adjustment disorder or any other disorder described herein), said methods comprising administering to a patient such as a human an effective amount of 5-MBPB, 6-MBPB, Bk-5-MAPB or Bk-6-MAPB or a pharmaceutically acceptable salt or salt mixture thereof in enantiomerically enriched form to obtain the desired properties:

[0039]

[0040] In still other embodiments, the present invention provides enantiomerically enriched compounds of formula A, formula B, formula C, formula D, formula E or formula F or pharmaceutically acceptable salts or mixed salts thereof, which are used for any of the uses described herein by administering to a patient such as a human an effective amount of the enantiomerically enriched compound to achieve the desired effect:

[0041]

[0042] wherein

[0043] R is hydrogen or hydroxy;

[0044] R A is —CH 3 、—CH 2 Y、—CHY 2 、—CY 3, —CH 2 CH 3 , —CH 2 CH 2 Y,

[0045] —CH 2 CHY 2 , —CH 2 CY 3 , —CH 2 OH, or —CH 2 CH 2 OH;

[0046] Q is selected from:

[0047] and

[0048] Y is a halogen.

[0049] Non-limiting examples of undesirable effects that can be minimized by careful selection of the enantiomeric balance include hallucinogenic effects, psychoactive effects (such as overstimulation or sedation), physiological effects (such as transient hypertension or appetite suppression), toxic effects (such as effects on the brain or liver), abuse-promoting effects (such as euphoria or dopamine release), and / or other side effects.

[0050] The present invention includes compounds having beneficial selectivity characteristics for neurotransmitter transporters. The balance between weakly activating NET (to reduce the risk of cardiovascular toxicity) and reducing the DAT to SERT ratio relative to the racemate (to increase the therapeutic effect relative to the addiction propensity) is an ideal characteristic of the empathy-provoking therapy demonstrated by the compounds and compositions of the present invention.

[0051] An enantiomerically enriched mixture is a mixture containing a greater amount of one enantiomer than the other. An enantiomerically enriched mixture of the S-enantiomer contains at least 55% of the S-enantiomer, typically at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% of the S-enantiomer. An enantiomerically enriched mixture of the R-enantiomer contains at least 55% of the R-enantiomer, typically at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% of the R-enantiomer. The specific ratio of the S or R enantiomer can be selected by a healthcare professional according to the needs of the patient to balance the desired effects.

[0052] The term enantiomerically enriched mixture as used herein does not include racemic mixtures nor pure or substantially pure enantiomers.

[0053] The present invention also provides new medical uses for the compounds, including but not limited to administering in an effective amount to a host in need (such as a human) for: depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic disorder, adjustment disorder, feeding and eating disorders, bulimia nervosa, body dysmorphic syndrome, addiction, substance abuse or dependence disorders, disruptive behavior disorders impulse control disorders, gaming disorder, gambling disorder, amnesia, attention deficit hyperactivity disorder, personality disorders, attachment disorders, autism or dissociative disorders or any other disorder described herein, including those described in the background art. A particular treatment is directed to adjustment disorder, which is very common in society and has not been fully addressed currently. In a non-limiting aspect, the compounds used in the treatment include, for example, 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, 5-Bk-5-MAPB, 6-Bk-MAPB, Bk-5-MBPB, Bk-6-MBPB, or an enantiomerically enriched composition or substantially pure R- or S-enantiomer of a combination thereof.

[0054] Several benzofuran derivatives of the present invention have been found to be direct 5-HT 1B agonists. Few known substances are 5-HT1B agonists and 5-HT releasing agents, and these substances have significant toxicity. For example, m-chlorophenylpiperazine (mCPP) is an example, but it causes anxiety and headache, thus limiting any clinical application.

[0055] To date, little is known about the general pharmacology of empathogen enantiomers and enantiomeric compositions. They are difficult to separate, and it is not currently easy to predict the therapeutic effects of individual enantiomers or enantiomerically enriched compositions that may be based on the binding of individual complex receptors. In addition, the contribution trends of individual enantiomers usually do not translate to other members of the same class of compounds.

[0056] In the case of amphetamine, it has been observed that enantiomerically enriched mixtures of enantiomers exhibit properties superior to racemic mixtures or either of the individual enantiomers alone (Joyce et al., Psychopharmacology, 2007, 191:669 - 677). The drug Adderall is an example of a mixture of amphetamine enantiomers. The mixture contains equal parts of racemic amphetamine and dextroamphetamine mixed salts (sulfate, aspartate, and saccharate), which results in a ratio of dextroamphetamine to levoamphetamine of approximately 3:1. The differences between these two enantiomers are sufficient to make Adderall have effects different from the racemate or the d-enantiomer. However, to date, no properties have been reported or predicted for the enantiomeric mixtures of the empathogen compounds described herein, nor how such mixtures would be used in therapy.

[0057] Understanding the pharmacology of empathogen enantiomers is complicated because the therapeutic effects of empathogens are not equivalent to the more readily recognizable psychoactive effects. In addition, different enantiomers may differ in potency and activity in different and unpredictable ways. For example, when comparing the enantiomers of 3,4-methylenedioxy-N-ethylamphetamine (MDE) in humans, it was concluded that the therapeutic effects of MDE were due to the S-(+)-enantiomer, while the R-(-)-enantiomer mainly caused unwanted and toxic effects (Spitzer et al., Neuropharmacology, 2001, 41.2: 263-271). Thus, it is not possible to predict which enantiomer will best retain or provide therapeutic activity. Although the enantiomers of 5-MAPB have been at least partially separated (Kadkhodaei et al., Journal of Separation Science, 2018, 41(6): 1274-1286), to the inventors' knowledge, prior to the present invention, there has been no study characterizing the pharmacological effects of the separated enantiomers of benzofuran empathogens.

[0058] As described in non-limiting illustrative Example 9, in one embodiment, the compounds of the present invention are rapid releasers of serotonin. This mechanism of action works in parallel with the inhibition of serotonin reuptake. The combination of reuptake inhibition and increased release significantly increases serotonin levels and enhances therapeutic effects.

[0059] In addition, the selected compounds of the present invention retain the antagonistic effect on the serotonin transporter (SERT), which is considered to be the main mechanism of action of SSRIs. In this way, the present invention provides compounds and methods that act in a manner similar to the current standard of care for many CNS disorders, including mental disorders, but without the critical drawback of delayed onset.

[0060] Finally, the compounds of the present invention exhibit a 5-HT selectivity pattern that is important for therapeutic use. 5-HT 2A receptor agonists can cause feelings of fear and hallucinations, but 5-HT 1B agonism is thought to be related to the prosocial effects of empathogens.

[0061] Surprisingly, it has been found that the enantiomerically enriched compositions of the present invention can be selected to be weak agonists of 5-HT 2A but exhibit activity against 5-HT 1B For example, as described in non-limiting illustrative Example 6, most compounds do not exhibit 5-HT 2Aagonist activity, but does exhibit 5-HT in a non-limiting range of about 5 μM to 0.05 μM or even 3 μM to 0.10 μM 1B agonist activity. Importantly, 5-HT 1B agonist activity occurs through direct action on the receptor and not as an indirect result of serotonin release. This is an unexpected finding as this property has not been previously observed in empathy stimulants. In one embodiment, compared to the 5-HT 2A receptor, the selectivity of the 5-HT 1B receptor allows for a more relaxing and therapeutically productive experience for patients receiving treatment with the compounds of the present invention. In other embodiments, the compounds or compositions of the present invention are provided in an effective amount to treat a host, typically a human, suffering from a CNS disorder, which can be a neurological disorder (a disorder typically treated by a neurologist) or a psychiatric disorder (a disorder typically treated by a psychiatrist). Neurological disorders are generally those that affect the structure, biochemistry, or normal electrical function of the brain, spinal cord, or other nerves. Psychiatric disorders are more commonly considered mental disorders, mainly abnormal thoughts, feelings, or behaviors that cause severe distress or impaired personal functioning.

[0062] Accordingly, the disclosed compounds can be used in an effective amount to improve the neurological or mental function of patients in need thereof. Neurological indications include, but are not limited to, improving neuroplasticity, including treating stroke, traumatic brain injury, dementia, and neurodegenerative diseases. The compounds of the present invention can also be considered small molecules capable of inducing rapid neuroplasticity (Olson, 2018, Journal of experimental neuroscience, 12, 1179069518800508. https: / / doi.org / 10.1177%2F1179069518800508). For example, in certain embodiments, the disclosed compounds and compositions can be used to improve stuttering and other movement disorders or to treat Parkinson's disease or schizophrenia.

[0063] The term "improving mental function" is intended to include mental health and life situations that are not traditionally treated by neurologists but can sometimes be treated by psychiatrists and can also be treated by psychotherapists, life coaches, personal fitness trainers, meditation teachers, counselors, etc. For example, it is expected that the disclosed compounds will allow an individual to effectively consider actual or possible experiences that are typically disturbing or even overwhelming. This includes a person with a life-threatening illness planning their final days and the disposition of their property. This also includes a couple discussing difficulties in their relationship and how to resolve them. This also includes an individual who wishes to plan their career more effectively.

[0064] In other embodiments, the compositions and compounds of the invention can be used in an effective amount to treat a host, typically a human, to modulate an immune or inflammatory response. The compounds disclosed herein alter extracellular serotonin, which is known to alter immune function.

[0065] In other embodiments, the invention provides active compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, or pharmaceutically acceptable salts or mixed salts or compositions thereof for any of the uses described herein. The compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula X are:

[0066]

[0067] Wherein:

[0068] R 1 and R 2 together are -OCH=CH- or -CH=CHO-;

[0069] R 3B and R 4B are independently selected from -H, -X, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 , wherein at least one of R 3B and R 4B is not -H;

[0070] R 3I and R 4I are independently selected from -H, -X, -OH, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , and C 1 -C 4 alkyl; wherein at least one of R 3I and R 4I is not -H;

[0071] R 3J and R 4J are independently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 ;

[0072] R 4E is selected from C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 ;

[0073] R 4H is selected from -X, -CH 2 CH 2 CH 3 CH 2 OH, -CH 2 X, and -CHX 2 ;

[0074] R 5A and R 5G are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 CH 2 CX 3 C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl, provided that when R 5A is C 2 alkyl or H, R 6A is not -H, and when R 5G is -H or C 2 alkyl, R 6G is not -H;

[0075] R 5B is selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 CH 2 CX 3 C 3 -C 4Naphthenyl, and C 1 -C 4 alkyl;

[0076] R 5C is selected from -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 naphthenyl, and C 2 -C 4 alkyl;

[0077] R 5D , R 5E , R 5F and R 5J are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 naphthenyl, and C 1 -C 4 alkyl, when R 5F is -H or C 1 alkyl, R 6F cannot be -H, and when R 5J is C 1 alkyl, R 3J and R 4J at least one of which is not H;

[0078] R 5I is selected from -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl; wherein R 3I , R 4I and R 5I at least one of which is not C 1 alkyl;

[0079] R 6A , R 6B , R 6E , R 6F and R 6G are independently selected from -H and -CH 3 ;

[0080] X is independently selected from -F, -Cl, and -Br; and

[0081] Z is selected from O and CH 2 .

[0082] In certain embodiments, the compounds of Formula I-X are used in enantiomerically enriched form as described herein to achieve the objectives of the present invention. In other embodiments, the compounds are used as racemates or as pure, including substantially pure, enantiomers.

[0083] The present invention also includes methods of treating neurological or psychiatric central nervous system disorders (including psychiatric disorders) or providing cognitive enhancement as further described herein with a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, or a pharmaceutically acceptable salt or mixed salt thereof.

[0084] In a further embodiment, the present invention includes methods of treating neurological or psychiatric central nervous system disorders as further described herein with an enantiomerically enriched compound of Formula XI, Formula XII, or Formula XIII, or a pharmaceutically acceptable salt or mixed salt thereof:

[0085]

[0086] wherein:

[0087] R 1 and R 2 together are -OCH=CH- or -CH=CHO-;

[0088] R 3L and R 4LIndependently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 , where at least one of R 3L and R 4L is not -H;

[0089] R 5K is selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[0090] R 5L and R 5M are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl; and

[0091] R 6K , R 6L and R 6M are independently selected from -H and -CH 3 .

[0092] In certain aspects of these embodiments, one or more selected compounds can be improved or "modulated" by administering to a host in need, such as a human, an enantiomerically enriched composition (where the abundance of one enantiomer exceeds that of the other enantiomer) or a substantially pure enantiomer (or diastereomer, if relevant) or a mixture thereof in a composition form in an effective amount. As described above, the effects of enantiomers on various 5-HT receptors, dopamine receptors, nicotinic acetylcholine receptors, and norepinephrine receptors are different, producing different effects, and those effects can be selected based on the desired outcome of the patient.

[0093] In certain embodiments, any selected compound or mixture of the present invention is administered to a human patient in an effective amount in combination with psychotherapy, cognitive enhancement, or life coaching (pharmacotherapy) or as part of a conventional medical therapy.

[0094] Any compound, including an enantiomerically enriched compound, can be used in the form of a pharmaceutically acceptable salt or a mixture of salts. Non-limiting examples include those in which one or more pharmaceutically acceptable salts are selected from hydrochloride, sulfate, aspartate, saccharate, phosphate, oxalate, acetate, amino acid anions, gluconate, maleate, malate, citrate, mesylate, nitrate, or tartrate, or a mixture thereof.

[0095] Accordingly, the present invention includes at least the following aspects:

[0096] (i) Enantiomerically enriched compounds of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII, or Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F, or pharmaceutically acceptable salts, or salt mixtures, isotope derivatives, or prodrugs, or related diastereomerically enriched forms thereof;

[0097] (ii) Compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, or pharmaceutically acceptable salts or salt mixtures, isotope derivatives, or prodrugs thereof;

[0098] (iii) Enantiomerically enriched compounds of Formula XI, Formula XII, or Formula XIII, or pharmaceutically acceptable salts or salt mixtures, isotope derivatives, or prodrugs thereof;

[0099] (iv) A pharmaceutical composition comprising a compound of (i), (ii) or (iii) or a pharmaceutically acceptable salt or salt mixture, isotopic derivative or prodrug thereof in an effective patient - treating amount, optionally together with a pharmaceutically acceptable carrier or diluent;

[0100] (v) A pharmaceutically acceptable composition of (iv) in solid or liquid, systemic, oral, topical or parenteral dosage forms;

[0101] (vi) A method of treating a patient suffering from any neurological or psychological CNS disorder as described herein, the method comprising administering an effective amount of a compound of (i), (ii) or (iii) to a patient (e.g., a human) in need thereof,

[0102] (vii) A method of treating: PTSD, depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic disorder, adjustment disorder, feeding and eating disorders, bulimia nervosa, body dysmorphic syndrome, addiction, substance abuse or dependence disorders, disruptive behavior and impulse control disorders, gaming disorder, gambling disorder, amnesia, attention - deficit / hyperactivity disorder, personality disorders, attachment disorders, autism or dissociative disorders, the method comprising administering an effective amount of a compound of (i), (ii) or (iii) or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof as described herein to a patient (usually a human) in need thereof;

[0103] (viii) A compound of (i), (ii) or (iii) or a pharmaceutically acceptable salt, salt mixture, isotopic derivative or prodrug thereof for treating any disorder described herein in an effective amount as further described herein;

[0104] (ix) A compound of (i), (ii) or (iii) for the preparation of a medicament for treating any disorder described herein;

[0105] (x) Use of a compound of (i), (ii) or (iii) or a pharmaceutically acceptable salt, salt mixture, isotopic derivative or prodrug thereof in an effective amount as further described herein for treating any disorder described herein;

[0106] A method for preparing a therapeutic product containing an effective amount of a compound, said compound comprising an enantiomerically enriched form of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula A, Formula B, Formula C, Formula D, Formula E or Formula F or a pharmaceutically acceptable salt or mixed salt, isotopic derivative or prodrug thereof, as described herein.

[0107] This application also includes the following embodiments:

[0108] 1. An enantiomerically enriched mixture of the S-enantiomer and R-enantiomer of 5-MAPB:

[0109]

[0110] or a pharmaceutically acceptable salt or mixed salt thereof.

[0111] 2. An enantiomerically enriched mixture of the S-enantiomer and R-enantiomer of 6-MAPB:

[0112]

[0113] or a pharmaceutically acceptable salt or mixed salt thereof.

[0114] 3. An enantiomerically enriched mixture of the S-enantiomer and R-enantiomer of 5-MBPB:

[0115]

[0116] or a pharmaceutically acceptable salt or mixed salt thereof.

[0117] 4. An enantiomerically enriched mixture of the S-enantiomer and R-enantiomer of 6-MBPB:

[0118]

[0119] or a pharmaceutically acceptable salt or mixed salt thereof.

[0120] 5. An enantiomerically enriched mixture of the S-enantiomer and R-enantiomer of 6-Bk-5-MAPB:

[0121]

[0122] or a pharmaceutically acceptable salt or mixed salt thereof.

[0123] 6. An enantiomerically enriched mixture of the S-enantiomer and R-enantiomer of 6-Bk-6-MAPB:

[0124]

[0125] or a pharmaceutically acceptable salt or mixed salt thereof.

[0126] 7. An enantiomerically enriched mixture of the S-enantiomer and R-enantiomer of 6-Bk-5-MBPB:

[0127]

[0128] or a pharmaceutically acceptable salt or mixed salt thereof.

[0129] 8. An enantiomerically enriched mixture of the S-enantiomer and R-enantiomer of 6-Bk-6-MBPB,

[0130]

[0131] or a pharmaceutically acceptable salt or mixed salt thereof.

[0132] 9. The enantiomerically enriched mixture according to any one of embodiments 1-8, wherein the mixture has a higher empathy-inducing effect in humans than the corresponding racemic mixture.

[0133] 10. The enantiomerically enriched mixture according to any one of embodiments 1-8, which has a greater nicotine receptor-dependent therapeutic effect in humans than the corresponding racemic mixture.

[0134] 11. The enantiomerically enriched mixture according to any one of embodiments 1-8, which has a greater serotonin receptor-dependent therapeutic effect in humans than the corresponding racemic mixture.

[0135] 12. The enantiomerically enriched mixture according to any one of embodiments 1-8, which enhances the serotonin receptor-dependent therapeutic effect in humans and reduces the nicotine effect or dopaminergic effect.

[0136] 13. The enantiomerically enriched mixture according to any one of embodiments 1-8, which contains a balance of enantiomers that reduces the hallucinogenic effect compared to the racemate.

[0137] 14. The enantiomerically enriched mixture according to any one of embodiments 1-8, which contains a balance of enantiomers that reduces the unwanted psychoactive effects compared to the racemate.

[0138] 15. An enantiomerically enriched mixture as described in any one of embodiments 1-8, which comprises a balance of enantiomers that reduces the physiological effect compared to the racemate.

[0139] 16. An enantiomerically enriched mixture as described in any one of embodiments 1-8, which comprises a balance of enantiomers that reduces the toxic effect compared to the racemate.

[0140] 17. An enantiomerically enriched mixture as described in any one of embodiments 1-8, which comprises a balance of enantiomers that reduces the likelihood of abuse compared to the racemate.

[0141] 18. An enantiomerically enriched mixture as described in any one of embodiments 1-8, which has at least about 60% of the S-enantiomer.

[0142] 19. An enantiomerically enriched mixture as described in any one of embodiments 1-8, which has at least about 70% of the S-enantiomer.

[0143] 20. An enantiomerically enriched mixture as described in any one of embodiments 1-8, which has at least about 80% of the S-enantiomer.

[0144] 21. An enantiomerically enriched mixture as described in any one of embodiments 1-8, which has at least about 90% of the S-enantiomer.

[0145] 22. An enantiomerically enriched mixture as described in any one of embodiments 1-8, which has at least about 60% of the R-enantiomer.

[0146] 23. An enantiomerically enriched mixture as described in any one of embodiments 1-8, which has at least about 70% of the R-enantiomer.

[0147] 24. An enantiomerically enriched mixture as described in any one of embodiments 1-8, which has at least about 80% of the R-enantiomer.

[0148] 25. An enantiomerically enriched mixture as described in any one of embodiments 1-8, which has at least about 90% of the R-enantiomer.

[0149] 26. An enantiomerically enriched mixture as described in any one of embodiments 1-25, which exhibits a greater therapeutic effect of emotional openness than the corresponding racemic mixture.

[0150] 27. An enantiomerically enriched mixture according to any one of embodiments 1-26, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, aspartate, saccharate, phosphate, oxalate, acetate, amino acid anion, gluconate, maleate, malate, citrate, mesylate, nitrate or tartrate, or a mixture thereof.

[0151] 28. An enantiomerically enriched mixture according to any one of embodiments 1-27, which is both a direct 5-HT 1B agonist and a serotonin releasing agent.

[0152] 29. An enantiomerically enriched mixture according to embodiment 28, which is also a serotonin reuptake inhibitor.

[0153] 30. An enantiomerically enriched mixture according to any one of embodiments 1-29, which has minimal or no 5-HT 2A agonistic effect.

[0154] 31. A compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X:

[0155]

[0156] or a pharmaceutically acceptable salt or mixed salt thereof,

[0157] wherein:

[0158] R 1 and R 2 together are -OCH=CH- or -CH=CHO-;

[0159] R 3B and R 4B are independently selected from -H, -X, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 and -CX 3 wherein at least one of R 3B and R 4B is not -H;

[0160] R 3I and R 4I are independently selected from -H, -X, -OH, -CH 2 OH, -CH 2 X, -CHX 2 -CX 3 and C 1 -C4 alkyl; wherein R 3I and R 4I at least one of which is not -H;

[0161] R 3J and R 4J are independently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 and -CX 3 ;

[0162] R 4E is selected from C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 and -CX 3 ;

[0163] R 4H is selected from -X, -CH 2 CH 2 CH 3 CH, -CH 2 OH, -CH 2 X, and -CHX 2 ;

[0164] R 5A and R 5G are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 -CX 3 -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 -CH 2 CX 3 C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl, when R 5A is C 2 alkyl or H, R 6A is not -H, and when R 5G is -H or C 2 alkyl, R 6G is not -H;

[0165] R5B Selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl;

[0166] R 5C Selected from -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[0167] R 5D , R 5E , R 5F and R 5J independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl, when R 5F is -H or C 1 alkyl, R6F It cannot be -H, and when R 5J is C 1 alkyl, at least one of R 3J and R 4J is not H;

[0168] R 5I is selected from -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl; wherein at least one of R 3I , R 4I and R 5I is not C 1 alkyl;

[0169] R 6A , R 6B , R 6E , R 6F and R 6G are independently selected from -H and -CH 3 ;

[0170] X is independently selected from -F, -Cl and -Br; and

[0171] Z is selected from O and CH 2 .

[0172] 32. The compound according to embodiment 31, wherein the compound has formula I:

[0173]

[0174] or a pharmaceutically acceptable salt or mixed salt thereof.

[0175] 33. The compound according to embodiment 31, wherein the compound has formula II:

[0176]

[0177] or a pharmaceutically acceptable salt or mixed salt thereof.

[0178] 34. The compound according to embodiment 31, wherein the compound has formula III:

[0179]

[0180] or a pharmaceutically acceptable salt or mixed salt thereof.

[0181] 35. The compound according to embodiment 31, wherein the compound has formula IV:

[0182]

[0183] or a pharmaceutically acceptable salt or mixed salt thereof.

[0184] 36. The compound according to embodiment 31, wherein the compound has formula V:

[0185]

[0186] or a pharmaceutically acceptable salt or mixed salt thereof.

[0187] 37. The compound according to embodiment 31, wherein the compound has formula VI:

[0188]

[0189] or a pharmaceutically acceptable salt or mixed salt thereof.

[0190] 38. The compound according to embodiment 31, wherein the compound has formula VII:

[0191]

[0192] or a pharmaceutically acceptable salt or mixed salt thereof.

[0193] 39. The compound according to embodiment 31, wherein the compound has formula VIII:

[0194]

[0195] or a pharmaceutically acceptable salt or mixed salt thereof.

[0196] 40. The compound according to embodiment 31, wherein the compound has formula IX:

[0197]

[0198] or a pharmaceutically acceptable salt or mixed salt thereof.

[0199] 41. The compound according to embodiment 31, wherein the compound has formula X:

[0200]

[0201] or a pharmaceutically acceptable salt or mixed salt thereof.

[0202] 42. The compound according to embodiment 31 or 32, wherein the compound is selected from:

[0203]

[0204] or a pharmaceutically acceptable salt or mixed salt thereof.

[0205] 43. The compound according to embodiment 31 or 33, wherein the compound is selected from:

[0206]

[0207]

[0208] or a pharmaceutically acceptable salt or mixed salt thereof.

[0209] 44. The compound according to embodiment 31 or 37, wherein the compound is selected from:

[0210]

[0211]

[0212]

[0213] or a pharmaceutically acceptable salt or mixed salt thereof.

[0214] 45. The compound according to embodiment 31 or 38, wherein the compound is selected from:

[0215]

[0216] or a pharmaceutically acceptable salt or mixed salt thereof.

[0217] 46. The compound according to embodiment 31 or 40, wherein the compound is selected from:

[0218]

[0219] or a pharmaceutically acceptable salt or mixed salt thereof.

[0220] 47. The compound according to embodiment 42, wherein the compound is selected from:

[0221]

[0222]

[0223] or a pharmaceutically acceptable salt or mixed salt thereof.

[0224] 48. The compound according to embodiment 43, wherein the compound is selected from:

[0225]

[0226]

[0227] or a pharmaceutically acceptable salt or mixed salt thereof.

[0228] 49. The compound according to embodiment 44, wherein the compound is selected from:

[0229]

[0230]

[0231] or a pharmaceutically acceptable salt or mixed salt thereof.

[0232] 50. The compound according to embodiment 45, wherein the compound is selected from:

[0233]

[0234] or a pharmaceutically acceptable salt or mixed salt thereof.

[0235] 51. The compound according to embodiment 46, wherein the compound is selected from:

[0236]

[0237]

[0238] or a pharmaceutically acceptable salt or mixed salt thereof.

[0239] 52. The compound according to embodiment 31 or 37, wherein the compound is selected from:

[0240]

[0241] or a pharmaceutically acceptable salt or mixed salt thereof.

[0242] 53. The compound according to any one of embodiments 31, 37 or 52, wherein the compound has the structure

[0243]

[0244] or a pharmaceutically acceptable salt or mixed salt thereof.

[0245] 54. A compound according to any one of embodiments 31, 37 or 52, wherein the compound has the structure

[0246]

[0247] or a pharmaceutically acceptable salt or mixed salt thereof.

[0248] 55. An enantiomerically enriched mixture of the S - enantiomer and the R - enantiomer of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X:

[0249]

[0250] or a pharmaceutically acceptable salt or mixed salt thereof,

[0251] wherein:

[0252] R 1 and R 2 together are -OCH=CH- or -CH=CHO-;

[0253] R 3B and R 4B are independently selected from -H, -X, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 、and -CX 3 wherein at least one of R 3B and R 4B is not -H;

[0254] R 3I and R 4I are independently selected from -H, -X, -OH, -CH 2 OH, -CH 2 X, -CHX 2 、-CX 3 、and C 1 -C 4 alkyl; wherein at least one of R 3I and R 4I is not -H;

[0255] R 3J and R 4J are independently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 、and -CX3 ;

[0256] R 4E is selected from C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 and -CX 3 ;

[0257] R 4H is selected from -X, -CH 2 CH 2 CH 3 CH 2 OH, -CH 2 X, and -CHX 2 ;

[0258] R 5A and R 5G are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl, provided that when R 5A is C 2 alkyl or H, R 6A is not -H, and when R 5G is -H or C 2 alkyl, R 6G is not -H;

[0259] R 5B is selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3, C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl;

[0260] R 5C is selected from -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[0261] R 5D , R 5E , R 5F and R 5J are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl, provided that when R 5F is -H or C 1 alkyl, R 6F cannot be -H, and when R 5J is C 1 alkyl, at least one of R 3J and R 4J is not H;

[0262] R 5I is selected from -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl; wherein R 3I , R 4I and R 5I in which at least one of them is not C 1 alkyl;

[0263] R 6A , R 6B , R 6E , R 6F and R 6G are independently selected from -H and -CH 3 ;

[0264] X is independently selected from -F, -Cl, and -Br; and

[0265] Z is selected from O and CH 2 .

[0266] 56. The enantiomerically enriched mixture according to embodiment 55, wherein the compound has the formula I:

[0267]

[0268] or a pharmaceutically acceptable salt or mixed salt thereof.

[0269] 57. The enantiomerically enriched mixture according to embodiment 55, wherein the compound has the formula II:

[0270]

[0271] or a pharmaceutically acceptable salt or mixed salt thereof.

[0272] 58. The enantiomerically enriched mixture according to embodiment 55, wherein the compound has the formula III:

[0273]

[0274] or a pharmaceutically acceptable salt or mixed salt thereof.

[0275] 59. The enantiomerically enriched mixture according to embodiment 55, wherein the compound has the formula IV:

[0276]

[0277] or a pharmaceutically acceptable salt or mixed salt thereof.

[0278] 60. The enantiomerically enriched mixture according to embodiment 55, wherein the compound has formula V:

[0279]

[0280] or a pharmaceutically acceptable salt or mixed salt thereof.

[0281] 61. The enantiomerically enriched mixture according to embodiment 55, wherein the compound has formula VI:

[0282]

[0283] or a pharmaceutically acceptable salt or mixed salt thereof.

[0284] 62. The enantiomerically enriched mixture according to embodiment 55, wherein the compound has formula VII:

[0285]

[0286] or a pharmaceutically acceptable salt or mixed salt thereof.

[0287] 63. The enantiomerically enriched mixture according to embodiment 55, wherein the compound has formula VIII:

[0288]

[0289] or a pharmaceutically acceptable salt or mixed salt thereof.

[0290] 64. The enantiomerically enriched mixture according to embodiment 55, wherein the compound has formula IX:

[0291]

[0292] or a pharmaceutically acceptable salt or mixed salt thereof.

[0293] 65. The enantiomerically enriched mixture according to embodiment 55, wherein the compound has formula X:

[0294]

[0295] or a pharmaceutically acceptable salt or mixed salt thereof.

[0296] 66. The enantiomerically enriched mixture according to embodiment 55 or 56, wherein the compound is selected from:

[0297]

[0298]

[0299] or a pharmaceutically acceptable salt or mixed salt thereof.

[0300] 67. The enantiomerically enriched mixture according to embodiment 55 or 57, wherein the compound is selected from:

[0301]

[0302]

[0303] or a pharmaceutically acceptable salt or mixed salt thereof.

[0304] 68. The enantiomerically enriched mixture according to embodiment 55 or 61, wherein the compound is selected from:

[0305]

[0306]

[0307] or a pharmaceutically acceptable salt or mixed salt thereof.

[0308] 69. The enantiomerically enriched mixture according to embodiment 55 or 62, wherein the compound is selected from:

[0309]

[0310]

[0311] or a pharmaceutically acceptable salt or mixed salt thereof.

[0312] 70. The enantiomerically enriched mixture according to embodiment 55 or 64, wherein the compound is selected from:

[0313]

[0314]

[0315] or a pharmaceutically acceptable salt or mixed salt thereof.

[0316] 71. The enantiomerically enriched mixture according to embodiment 55 or 66, wherein the compound is selected from:

[0317]

[0318]

[0319] or a pharmaceutically acceptable salt or mixed salt thereof.

[0320] 72. An enantiomerically enriched mixture as described in embodiment 55 or 67, wherein the compound is selected from:

[0321]

[0322]

[0323] or a pharmaceutically acceptable salt or mixed salt thereof.

[0324] 73. An enantiomerically enriched mixture as described in embodiment 55 or 68, wherein the compound is selected from:

[0325]

[0326]

[0327] or a pharmaceutically acceptable salt or mixed salt thereof.

[0328] 74. An enantiomerically enriched mixture as described in embodiment 55 or 69, wherein the compound is selected from:

[0329]

[0330]

[0331] or a pharmaceutically acceptable salt or mixed salt thereof.

[0332] 75. An enantiomerically enriched mixture as described in embodiment 55 or 70, wherein the compound is selected from:

[0333]

[0334]

[0335] 76. An enantiomerically enriched mixture as described in embodiment 55 or 61, wherein the compound is selected from:

[0336]

[0337] or a pharmaceutically acceptable salt or mixed salt thereof.

[0338] 77. An enantiomerically enriched mixture of the S - enantiomer and the R - enantiomer of a compound of formula XI, formula XII or formula XIII:

[0339]

[0340] or a pharmaceutically acceptable salt or mixed salt thereof,

[0341] wherein:

[0342] R 1 and R 2 together are -OCH=CH- or -CH=CHO-;

[0343] R 3L and R 4L are independently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 , where at least one of R 3L and R 4L is not -H;

[0344] R 5K is selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[0345] R 5L and R 5M are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl;

[0346] R 6K , R 6L and R6M selected from -H and -CH 3 ; and

[0347] X is independently selected from -F, -Cl, and -Br.

[0348] 78. The enantiomerically enriched mixture according to embodiment 77, wherein the compound has the formula XI

[0349]

[0350] or a pharmaceutically acceptable salt or mixed salt thereof.

[0351] 79. The enantiomerically enriched mixture according to embodiment 77, wherein the compound has the formula XII

[0352]

[0353] or a pharmaceutically acceptable salt or mixed salt thereof.

[0354] 80. The enantiomerically enriched mixture according to embodiment 77, wherein the compound has the formula XIII

[0355]

[0356] or a pharmaceutically acceptable salt or mixed salt thereof.

[0357] 81. An enantiomerically enriched mixture of the S-enantiomer and the R-enantiomer of a compound of formula A, formula B, formula C, formula D, formula E, or formula F:

[0358]

[0359] or a pharmaceutically acceptable salt or mixed salt thereof,

[0360] wherein:

[0361] R is hydrogen or hydroxy;

[0362] R A is —CH 3 、—CH 2 Y、—CHY 2 、—CY 3 、—CH 2 CH 3 、—CH 2 CH 2 Y、—CH 2 CHY 2 、—CH 2 CY 3 、—CH 2 OH、or —CH2 CH 2 OH;

[0363] Q is selected from:

[0364] and

[0365] Y is a halogen.

[0366] 82. The enantiomerically enriched mixture according to embodiment 81, wherein the compound has the formula A

[0367]

[0368] or a pharmaceutically acceptable salt or mixed salt thereof.

[0369] 83. The enantiomerically enriched mixture according to embodiment 81, wherein the compound has the formula B

[0370]

[0371] or a pharmaceutically acceptable salt or mixed salt thereof.

[0372] 84. The enantiomerically enriched mixture according to embodiment 81, wherein the compound has the formula C

[0373]

[0374] or a pharmaceutically acceptable salt or mixed salt thereof.

[0375] 85. The enantiomerically enriched mixture according to embodiment 81, wherein the compound has the formula D

[0376]

[0377] or a pharmaceutically acceptable salt or mixed salt thereof.

[0378] 86. The enantiomerically enriched mixture according to embodiment 81, wherein the compound has the formula E

[0379]

[0380] or a pharmaceutically acceptable salt or mixed salt thereof.

[0381] 87. The enantiomerically enriched mixture according to embodiment 81, wherein the compound has the formula F

[0382]

[0383] or a pharmaceutically acceptable salt or mixed salt thereof.

[0384] 88. The enantiomerically enriched mixture according to embodiment 81, wherein the compound is selected from:

[0385]

[0386] or a pharmaceutically acceptable salt or mixed salt thereof.

[0387] 89. The enantiomerically enriched mixture according to embodiment 81 or 88, wherein the compound is selected from:

[0388]

[0389] or a pharmaceutically acceptable salt or mixed salt thereof.

[0390] 90. The enantiomerically enriched mixture according to embodiment 81 or 88, wherein the compound is selected from:

[0391]

[0392] or a pharmaceutically acceptable salt or mixed salt thereof.

[0393] 91. The enantiomerically enriched mixture according to embodiment 81 or 88, wherein the compound is selected from:

[0394]

[0395] or a pharmaceutically acceptable salt or mixed salt thereof.

[0396] 92. The enantiomerically enriched mixture according to embodiment 81 or 88, wherein the compound is:

[0397]

[0398] or a pharmaceutically acceptable salt or mixed salt thereof.

[0399] 93. The enantiomerically enriched mixture according to embodiment 81 or 88, wherein the compound is selected from:

[0400]

[0401] or a pharmaceutically acceptable salt or mixed salt thereof.

[0402] 94. The enantiomerically enriched mixture according to embodiment 81 or 88, wherein the compound is:

[0403]

[0404] or a pharmaceutically acceptable salt or mixed salt thereof.

[0405] 95. A compound as described in any one of embodiments 31-54, wherein the compound has an empathy-stimulating effect in humans.

[0406] 96. A compound as described in any one of embodiments 31-54, wherein the compound has a nicotine receptor-dependent therapeutic effect in humans.

[0407] 97. A compound as described in any one of embodiments 31-54, wherein the compound has a serotonin receptor-dependent therapeutic effect in humans.

[0408] 98. A compound as described in any one of embodiments 31-54, wherein the compound enhances the serotonin receptor-dependent therapeutic effect and reduces the nicotine or dopaminergic effect in humans.

[0409] 99. A compound as described in any one of embodiments 31-54, which is in an enantiomerically enriched form that reduces the hallucinogenic effect compared to the racemate.

[0410] 100. A compound as described in any one of embodiments 31-54, which is in an enantiomerically enriched form that reduces the unwanted psychoactive effect compared to the racemate.

[0411] 101. A compound as described in any one of embodiments 31-54, which is in an enantiomerically enriched form that reduces the physiological effect compared to the racemate.

[0412] 102. A compound as described in any one of embodiments 31-54, which is in an enantiomerically enriched form that reduces the toxic effect compared to the racemate.

[0413] 103. A compound as described in any one of embodiments 31-54, which is in an enantiomerically enriched form that reduces the likelihood of abuse compared to the racemate.

[0414] 104. A compound as described in any one of embodiments 31-54, which is in an enantiomerically enriched form having at least about 60% S-enantiomer.

[0415] 105. A compound as described in any one of embodiments 31-54, which is in an enantiomerically enriched form having at least about 70% S-enantiomer.

[0416] 106. A compound as described in any one of embodiments 31-54, which is in an enantiomerically enriched form having at least about 80% S-enantiomer.

[0417] 107. A compound as described in any one of embodiments 31-54, which is in an enantiomerically enriched form having at least about 90% S-enantiomer.

[0418] 108. A compound according to any one of embodiments 31 - 54, which is in an enantiomerically enriched form having at least about 60% R - enantiomer.

[0419] 109. A compound according to any one of embodiments 31 - 54, which is in an enantiomerically enriched form having at least about 70% R - enantiomer.

[0420] 110. A compound according to any one of embodiments 31 - 54, which is in an enantiomerically enriched form having at least about 80% R - enantiomer.

[0421] 111. A compound according to any one of embodiments 31 - 54, which is in an enantiomerically enriched form having at least about 90% R - enantiomer.

[0422] 112. A compound according to any one of embodiments 31 - 54 or 95 - 111, which exhibits an affect - opening therapeutic effect.

[0423] 113. A compound according to any one of embodiments 31 - 54 or 95 - 112, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, aspartate, saccharate, phosphate, oxalate, acetate, amino acid anion, gluconate, maleate, malate, citrate, mesylate, nitrate or tartrate, or a mixture thereof.

[0424] 114. A compound according to any one of embodiments 31 - 54 or 95 - 113, which is both a direct 5 - HT 1B agonist and a serotonin releaser.

[0425] 115. A compound according to embodiment 114, which is also a serotonin reuptake inhibitor.

[0426] 116. A compound according to any one of embodiments 31 - 54 or 95 - 115, which has minimal or no 5 - HT 2A agonist activity.

[0427] 117. An enantiomerically enriched mixture according to any one of embodiments 55 - 94, wherein the mixture has a higher empathy - eliciting effect in humans than the corresponding racemic mixture.

[0428] 118. An enantiomerically enriched mixture according to any one of embodiments 55 - 94, which has a greater nicotinic receptor - dependent therapeutic effect in humans than the corresponding racemic mixture.

[0429] 119. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which has a greater amount of serotonin receptor - dependent therapeutic effects in the human body than the corresponding racemic mixture.

[0430] 120. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which enhances serotonin receptor - dependent therapeutic effects in humans and reduces nicotinic or dopaminergic effects.

[0431] 121. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which contains an equilibrium of enantiomers that reduces hallucinogenic effects compared to the racemate.

[0432] 122. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which contains an equilibrium of enantiomers that reduces unwanted psychoactive effects compared to the racemate.

[0433] 123. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which contains an equilibrium of enantiomers that reduces physiological effects compared to the racemate.

[0434] 124. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which contains an equilibrium of enantiomers that reduces toxic effects compared to the racemate.

[0435] 125. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which contains an equilibrium of enantiomers that reduces the likelihood of abuse compared to the racemate.

[0436] 126. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which has at least about 60% of the S - enantiomer.

[0437] 127. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which has at least about 70% of the S - enantiomer.

[0438] 128. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which has at least about 80% of the S - enantiomer.

[0439] 129. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which has at least about 90% of the S - enantiomer.

[0440] 130. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which has at least about 60% of the R - enantiomer.

[0441] 131. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, having at least about 70% of the R - enantiomer.

[0442] 132. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, having at least about 80% of the R - enantiomer.

[0443] 133. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, having at least about 90% of the R - enantiomer.

[0444] 134. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94 or 117 - 133, which exhibits a greater amount of the therapeutic effect of emotional openness than the corresponding racemic mixture.

[0445] 135. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94 or 117 - 134, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, aspartate, saccharate, phosphate, oxalate, acetate, amino acid anion, gluconate, maleate, malate, citrate, mesylate, nitrate or tartrate, or a mixture thereof.

[0446] 136. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94 or 117 - 135, which is both a direct 5 - HT 1B agonist and a serotonin releaser.

[0447] 137. The enantiomerically enriched mixture as described in embodiment 136, which is also a serotonin reuptake inhibitor.

[0448] 138. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94 or 117 - 137, which has minimal or no 5 - HT 2A agonistic effect.

[0449] 139. A method of treating a central nervous system disorder, the method comprising administering to a host in need thereof an effective amount of an enantiomerically enriched mixture as described in any one of embodiments 1 - 138.

[0450] 140. A method of treating a central nervous system disorder in a host in need thereof, the method comprising administering an effective amount of a compound of formula XI, formula XII or formula XIII:

[0451]

[0452] or a pharmaceutically acceptable salt or mixed salt thereof,

[0453] wherein:

[0454] R 1 and R 2 together are -OCH=CH- or -CH=CHO-;

[0455] R 3L and R 4L are independently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 , where at least one of R 3L and R 4L is not -H;

[0456] R 5K is selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[0457] R 5L and R 5M are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl;

[0458] R 6K , R 6L and R6M Selected from -H and -CH 3 ; and

[0459] X is independently selected from -F, -Cl, and -Br.

[0460] 141. A method for treating a central nervous system disorder selected from the following in a host in need thereof: depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic disorder, adjustment disorder, feeding and eating disorders, bulimia nervosa, body dysmorphic syndrome, addiction, substance abuse or dependence disorders, disruptive behavior disorders impulse control disorders, gaming disorder, gambling disorder, amnesia, attention deficit hyperactivity disorder, personality disorders, attachment disorders, autism, and dissociative disorders, the method comprising administering an enantiomerically enriched 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, Bk-6-MBPB, or a pharmaceutically acceptable salt or mixed salt thereof.

[0461] 142. The method according to any one of embodiments 139-141, wherein the host is a human.

[0462] 143. The method according to any one of embodiments 139-142, wherein the central nervous system disorder is generalized anxiety.

[0463] 144. The method according to any one of embodiments 139-142, wherein the central nervous system disorder is social anxiety.

[0464] 145. The method according to any one of embodiments 139-142, wherein the central nervous system disorder is depression.

[0465] 146. The method according to any one of embodiments 139-142, wherein the central nervous system disorder is addiction.

[0466] 147. The method according to any one of embodiments 139-142, wherein the central nervous system disorder is an eating disorder.

[0467] 148. The method according to embodiment 147, wherein the eating disorder is bulimia nervosa.

[0468] 149. The method according to embodiment 147, wherein the eating disorder is binge eating.

[0469] 150. The method according to embodiment 147, wherein the eating disorder is anorexia nervosa.

[0470] 151. The method according to any one of embodiments 139 - 142, wherein the central nervous system disorder is an attachment disorder.

[0471] 152. The method according to any one of embodiments 139 - 142, wherein the central nervous system disorder is schizophrenia.

[0472] 153. The method according to any one of embodiments 139 - 152, wherein the compound or enantiomer - enriched mixture is administered in a clinical setting.

[0473] 154. The method according to any one of embodiments 139 - 152, wherein the compound or enantiomer - enriched mixture is administered in a home setting.

[0474] 155. The method according to any one of embodiments 139 - 152, wherein the compound or enantiomer - enriched mixture is administered during a psychotherapy phase.

[0475] 156. The method according to any one of embodiments 139 - 152, wherein the compound or enantiomer - enriched mixture is administered during a counseling phase.

[0476] 157. A pharmaceutical composition comprising a therapeutically effective amount for a patient of a compound according to any one of embodiments 31 - 54 and a pharmaceutically acceptable carrier or excipient.

[0477] 158. A pharmaceutical composition comprising a therapeutically effective amount for a patient of an enantiomer - enriched mixture or compound according to any one of embodiments 1 - 138 and a pharmaceutically acceptable carrier or excipient.

[0478] 159. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered systemically.

[0479] 160. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered orally.

[0480] 161. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered to mucosal tissue.

[0481] 162. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered rectally.

[0482] 163. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered topically.

[0483] 164. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered subcutaneously.

[0484] 165. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered intravenously.

[0485] 166. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered intramuscularly.

[0486] 167. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered by inhalation.

[0487] 168. The pharmaceutical composition according to embodiment 157, wherein the composition is administered as a tablet.

[0488] 169. The pharmaceutical composition according to embodiment 157, wherein the composition is administered as a buccal tablet.

[0489] 170. The pharmaceutical composition according to embodiment 157, wherein the composition is administered as a capsule.

[0490] 171. The pharmaceutical composition according to embodiment 157, wherein the composition is administered as an aqueous emulsion.

[0491] 172. The pharmaceutical composition according to embodiment 157, wherein the composition is administered as an aqueous solution.

[0492] 173. The pharmaceutical composition according to embodiment 157, wherein the composition is administered as a pill.

[0493] 174. The pharmaceutical composition according to embodiment 158, wherein the composition is administered as a lozenge.

[0494] 175. The pharmaceutical composition according to embodiment 158, wherein the composition is administered as a sublingual tablet.

[0495] 176. The pharmaceutical composition according to embodiment 158, wherein the composition is administered as a sublingual lozenge.

[0496] 177. The pharmaceutical composition according to embodiment 163, wherein the composition is administered as a cream.

[0497] 178. The pharmaceutical composition according to embodiment 163, wherein the composition is administered as a topical solution.

[0498] 179. The pharmaceutical composition according to embodiment 160, wherein the composition is administered as an aqueous solution.

[0499] 180. The pharmaceutical composition according to embodiment 160, wherein the composition is administered as a powder.

[0500] 181. The pharmaceutical composition according to embodiment 160, wherein the composition is administered as an aerosol.

[0501] 182. A compound or an enantiomerically enriched mixture thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, according to any one of embodiments 1-138, for treating a central nervous system disorder in a host.

[0502] 183. A compound of formula XI, formula XII or formula XIII or a pharmaceutically acceptable salt or mixed salt thereof or a pharmaceutical composition thereof, for treating a central nervous system disorder in a host:

[0503]

[0504] wherein:

[0505] R 1 and R 2 together are -OCH=CH- or -CH=CHO-;

[0506] R 3L and R 4L are independently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 , wherein at least one of R 3L and R 4L is not -H;

[0507] R 5K is selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[0508] R 5L and R 5M are independently selected from -H, -CH 2OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl;

[0509] R 6K , R 6L and R 6M are independently selected from -H and -CH 3 ; and

[0510] X is independently selected from -F, -Cl, and -Br.

[0511] 184. A compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, for treating a central nervous system disorder selected from the following in a host in need thereof: depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic disorder, adjustment disorder, feeding and eating disorders, bulimia nervosa, body dysmorphic syndrome, addiction, substance abuse or dependence disorders, disruptive behavior disorder impulse control disorder, gaming disorder, gambling disorder, amnesia, attention deficit hyperactivity disorder, personality disorder, attachment disorder, autism, or dissociative disorder, wherein the compound is enantiomerically enriched 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB.

[0512] 185. The compound or enantiomerically enriched mixture according to any one of embodiments 182-184, wherein the host is a human.

[0513] 186. The compound or enantiomerically enriched mixture according to any one of embodiments 182-185, wherein the central nervous system disorder is an anxiety disorder.

[0514] 187. The compound or enantiomerically enriched mixture according to embodiment 186, wherein the anxiety disorder is generalized anxiety.

[0515] 188. The compound or enantiomerically enriched mixture according to embodiment 186, wherein the anxiety disorder is social anxiety.

[0516] 189. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 185, wherein the central nervous system disorder is depression.

[0517] 190. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 185, wherein the central nervous system disorder is post - traumatic stress disorder.

[0518] 191. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 185, wherein the central nervous system disorder is addiction.

[0519] 192. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 185, wherein the central nervous system disorder is an eating disorder.

[0520] 193. A compound or enantiomerically enriched mixture as described in embodiment 192, wherein the eating disorder is bulimia.

[0521] 194. A compound or enantiomerically enriched mixture as described in embodiment 192, wherein the eating disorder is binge eating.

[0522] 195. A compound or enantiomerically enriched mixture as described in embodiment 192, wherein the eating disorder is anorexia.

[0523] 196. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 185, wherein the central nervous system disorder is an attachment disorder.

[0524] 197. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 185, wherein the central nervous system disorder is schizophrenia.

[0525] 198. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 197, wherein the compound or enantiomerically enriched mixture is administered in a clinical setting.

[0526] 199. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 197, wherein the compound or enantiomerically enriched mixture is administered in a home setting.

[0527] 200. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 197, wherein the compound or enantiomerically enriched mixture is administered during a psychotherapy session.

[0528] 201. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 197, wherein the compound or enantiomerically enriched mixture is administered during the consultation phase.

[0529] 202. Use of a compound or its enantiomerically enriched mixture or its pharmaceutically acceptable salt, or its pharmaceutical composition as described in any one of embodiments 55 - 138 for the treatment of central nervous system disorders in a host.

[0530] 203. Use of a compound of formula XI, formula XII or formula XIII or its pharmaceutically acceptable salt or mixed salt or its pharmaceutical composition for the treatment of central nervous system disorders in a host:

[0531]

[0532] Wherein:

[0533] R 1 and R 2 together are -OCH=CH- or -CH=CHO-;

[0534] R 3L and R 4L are independently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 , where at least one of R 3L and R 4L is not -H;

[0535] R 5K is selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[0536] R 5L and R 5M are independently selected from -H, -CH2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl;

[0537] R 6K , R 6L and R 6M are independently selected from -H and -CH 3 ; and

[0538] X is independently selected from -F, -Cl, and -Br.

[0539] 204. Use of a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for treating a central nervous system disorder selected from the following in a host in need thereof: depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic disorder, adjustment disorder, feeding and eating disorders, bulimia nervosa, body dysmorphic syndrome, addiction, substance abuse or dependence disorders, disruptive behavior disorders impulse control disorders, gaming disorder, gambling disorder, amnesia, attention deficit hyperactivity disorder, personality disorder, attachment disorder, autism, or dissociative disorder, wherein the compound is enantiomerically enriched 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB.

[0540] 205. Use of a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as described in any one of embodiments 55 - 138 in the manufacture of a medicament for treating a central nervous system disorder in a host.

[0541] 206. Use of a compound of formula XI, formula XII, or formula XIII or a pharmaceutically acceptable salt or mixed salt thereof or a pharmaceutical composition thereof in the manufacture of a medicament for treating a central nervous system disorder in a host:

[0542]

[0543] wherein:

[0544] R 1 and R 2Combined, it is -OCH=CH- or -CH=CHO-;

[0545] R 3L and R 4L are independently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 、and -CX 3 , where at least one of R 3L and R 4L is not -H;

[0546] R 5K is selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 、-CX 3 、-CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 、-CH 2 CX 3 、C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[0547] R 5L and R 5M are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 、-CX 3 、-CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 、-CH 2 CX 3 、C 3 -C 4 cycloalkyl and C 1 -C 4 alkyl;

[0548] R 6K 、R 6L and R 6M are selected from -H and -CH 3 ; and

[0549] X is independently selected from -F, -Cl, and -Br.

[0550] Use of a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the preparation of a medicament for treating a central nervous system disorder selected from the following in a host in need thereof: depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic disorder, adjustment disorder, feeding and eating disorders, bulimia nervosa, body dysmorphic syndrome, addiction, substance abuse or dependence disorders, disruptive behavior disorder impulse control disorder, gaming disorder, gambling disorder, amnesia, attention deficit hyperactivity disorder, personality disorder, attachment disorder, autism, or dissociative disorder, wherein the compound is enantiomerically enriched 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB.

[0551] Use according to any one of embodiments 202-207, wherein the host is a human.

[0552] Use according to any one of embodiments 202-208, wherein the central nervous system disorder is an anxiety disorder.

[0553] Use according to embodiment 209, wherein the anxiety disorder is generalized anxiety.

[0554] Use according to embodiment 209, wherein the anxiety disorder is social anxiety.

[0555] Use according to any one of embodiments 202-208, wherein the central nervous system disorder is depression.

[0556] Use according to any one of embodiments 202-208, wherein the central nervous system disorder is post-traumatic stress disorder.

[0557] Use according to any one of embodiments 202-208, wherein the central nervous system disorder is addiction.

[0558] Use according to any one of embodiments 202-208, wherein the central nervous system disorder is an eating disorder. BRIEF DESCRIPTION OF THE DRAWINGS

[0559] Figure 1 Structures and names of several compounds mentioned herein are provided.

[0560] Figure 2It is a graph showing the results of the marble burying assay, which is used to measure the reduction in anxiety and neuroticism induced by treatment with S-5-MAPB, RS-5-MAPB, and R-5-MAPB. The x-axis of the graph shows the anxiolytic effect, described as the percentage of remaining unburied marbles compared to placebo. The y-axis gives the compound and dose. Error bars represent the 95% confidence interval. Details of the assay and procedural information are described in Example 5.

[0561] Figure 3 It is a graph showing the results of the marble burying assay, which is used to measure the reduction in anxiety and neuroticism induced by treatment with S-6-MAPB, RS-6-MAPB, and R-6-MAPB. The x-axis of the graph shows the anxiolytic effect, described as the percentage of remaining unburied marbles compared to placebo. The y-axis gives the compound and dose. Error bars represent the 95% confidence interval. Details of the assay and procedural information are described in Example 5.

[0562] Figure 4 It is a graph showing the results of the marble burying assay, which is used to measure the reduction in anxiety and neuroticism induced by treatment with (+)-Bk-5-MAPB, RS-Bk-5-MAPB, and (-)-Bk-R-5-MAPB. The x-axis of the graph shows the anxiolytic effect, described as the percentage of remaining unburied marbles compared to placebo. The y-axis gives the compound and dose. Error bars represent the 95% confidence interval. Details of the assay and procedural information are described in Example 5.

[0563] Figure 5 It is a graph showing the results of the marble burying assay, which is used to measure the reduction in anxiety and neuroticism induced by treatment with (+)-Bk-5-MBPB, RS-Bk-5-MBPB, and (-)-Bk-R-5-MBPB. The x-axis of the graph shows the anxiolytic effect, described as the percentage of remaining unburied marbles compared to placebo. The y-axis gives the compound and dose. Error bars represent the 95% confidence interval. Details of the assay and procedural information are described in Example 5.

[0564] Figure 6 It is a graph showing the results of the marble burying assay, which is used to measure the reduction in anxiety and neuroticism induced by treatment with the individual enantiomers of 5-MAPB compared to the racemic mixture, demonstrating the non-additive effect of the two enantiomers. The x-axis of the graph shows the anxiolytic effect, described as the percentage of remaining unburied marbles compared to placebo. The y-axis gives the compound and dose. Error bars represent the 95% confidence interval. Details of the assay and procedural information are described in Example 5.

[0565] Figure 7Ais a graph showing the results from an in vitro rat synaptosome serotonin uptake inhibition assay. The graph shows the percent reuptake of 3 [3H]-labeled 5-HT as a function of the concentration of RS-5-MBPB, R-5-MBPB, and S-5-MBPB. The data indicate that each test compound rapidly increases extracellular serotonin by inhibiting reuptake. Details of the assay and procedural information are described in Example 9. The x-axis is log[dose] concentration measured in moles, and the y-axis is the 3 [3H]-labeled 5-HT reuptake measured as a percentage.

[0566] Figure 7B is a graph showing the results from an in vitro rat synaptosome serotonin release assay. The graph shows the 3 [3H]-labeled 5-HT release as a function of the concentration of RS-5-MBPB, R-5-MBPB, and S-5-MBPB. These data indicate that each test compound rapidly increases extracellular serotonin by stimulating release. Details of the assay and procedural information are described in Example 9. The x-axis is log[dose] concentration measured in moles, and the y-axis is the 3 [3H]-labeled 5-HT release measured as a percentage.

[0567] Figure 8A is a graph showing the results from an in vitro rat synaptosome serotonin uptake inhibition assay. The graph shows the 3 [3H]-labeled 5-HT percent reuptake as a function of the concentration of RS-6-MBPB, R-6-MBPB, and S-6-MBPB. The data indicate that each test compound rapidly increases extracellular serotonin by inhibiting reuptake. Details of the assay and procedural information are described in Example 9. The x-axis is log[dose] concentration measured in moles, and the y-axis is the 3 [3H]-labeled 5-HT reuptake measured as a percentage.

[0568] Figure 8B is a graph showing the results from an in vitro rat synaptosome serotonin release assay. The graph shows the 3 [3H]-labeled 5-HT release as a function of the concentration of RS-6-MBPB, R-6-MBPB, and S-6-MBPB. These data indicate that each test compound rapidly increases extracellular serotonin by stimulating release. Details of the assay and procedural information are described in Example 9. The x-axis is log[dose] concentration measured in moles, and the y-axis is the 3 [3H]-labeled 5-HT release measured as a percentage.

[0569] Figure 9Ais a graph showing the results from an in vitro rat synaptosome serotonin uptake inhibition assay. The graph shows the 3 percentage of reuptake of [³H]-labeled 5-HT as a function of the concentration of R-5-MAPB and S-5-MAPB. The data indicate that each test compound rapidly increases extracellular serotonin by inhibiting reuptake. Details of the assay and procedural information are described in Example 9. The x-axis is the log[dose] concentration measured in moles, and the y-axis is the 3 [³H]-labeled 5-HT reuptake measured as a percentage.

[0570] Figure 9B is a graph showing the results from an in vitro rat synaptosome serotonin efflux assay. The graph shows the 3 release of [³H]-labeled 5-HT as a function of the concentration of R-5-MAPB and S-5-MAPB. These data indicate that each test compound rapidly increases extracellular serotonin by stimulating release. Details of the assay and procedural information are described in Example 9. The x-axis is the log[dose] concentration measured in moles, and the y-axis is the 3 [³H]-labeled 5-HT release measured as a percentage.

[0571] Figure 10A is a graph showing the results from an in vitro rat synaptosome serotonin uptake inhibition assay. The graph shows the 3 percentage of reuptake of [³H]-labeled 5-HT as a function of the concentration of R-6-MAPB and S-6-MAPB. The data indicate that each test compound rapidly increases extracellular serotonin by inhibiting reuptake. Details of the assay and procedural information are described in Example 9. The x-axis is the log[dose] concentration measured in moles, and the y-axis is the 3 [³H]-labeled 5-HT reuptake measured as a percentage.

[0572] Figure 10B is a graph showing the results from an in vitro rat synaptosome serotonin efflux assay. The graph shows the 3 release of [³H]-labeled 5-HT as a function of the concentration of R-6-MAPB and S-6-MAPB. These data indicate that each test compound rapidly increases extracellular serotonin by stimulating release. Details of the assay and procedural information are described in Example 9. The x-axis is the log[dose] concentration measured in moles, and the y-axis is the 3 [³H]-labeled 5-HT release measured as a percentage.

[0573] Figure 11A is a graph showing the results from an in vitro rat synaptosome serotonin uptake inhibition assay. The graph shows the 3The percent reuptake of [³H]-labeled 5-HT as a function of the concentrations of (-)-Bk-5-MAPB and (+)-Bk-5-MAPB. This data indicates that each test compound rapidly increases extracellular serotonin by inhibiting reuptake. Details of the assay and procedural information are described in Example 9. The x-axis is the log[dose] concentration measured in moles, and the y-axis is the 3 [³H]-labeled 5-HT reuptake.

[0574] Figure 11B is a graph showing the results from an in vitro rat synaptosome serotonin efflux assay. The graph shows the 3 [³H]-labeled 5-HT release as a function of the concentrations of (-)-Bk-5-MAPB and (+)-Bk-5-MAPB. These data indicate that each test compound rapidly increases extracellular serotonin by stimulating release. Details of the assay and procedural information are described in Example 9. The x-axis is the log[dose] concentration measured in moles, and the y-axis is the 3 [³H]-labeled 5-HT release.

[0575] Figure 12A is a graph showing the results from an in vitro rat synaptosome serotonin uptake inhibition assay. The graph shows 3 the percent reuptake of [³H]-labeled 5-HT as a function of the concentrations of (-)-Bk-6-MAPB and (+)-Bk-6-MAPB. This data indicates that each test compound rapidly increases extracellular serotonin by inhibiting reuptake. Details of the assay and procedural information are described in Example 9. The x-axis is the log[dose] concentration measured in moles, and the y-axis is the 3 [³H]-labeled 5-HT reuptake.

[0576] Figure 12B is a graph showing the results from an in vitro rat synaptosome serotonin efflux assay. The graph shows the 3 [³H]-labeled 5-HT release as a function of the concentrations of (-)-Bk-6-MAPB and (+)-Bk-6-MAPB. These data indicate that each test compound rapidly increases extracellular serotonin by stimulating release. Details of the assay and procedural information are described in Example 9. The x-axis is the log[dose] concentration measured in moles, and the y-axis is the 3 [³H]-labeled 5-HT release.

[0577] Figure 13It is the powder XRPD diffraction pattern of Form 1A (5-MAPB hydrochloride or 5-MAPB HCl). The diffraction pattern confirms the crystalline nature of Form 1A. The XRPD diffraction pattern shows the 5-MAPB free base obtained as described in Example 11 and shown in Table 7. The x-axis is 2θ measured in degrees, and the y-axis is intensity measured in arbitrary units.

[0578] Figure 14 It is the powder XRPD diffraction pattern of the 5-MAPB free base recovered after liquid-liquid extraction. The XRPD diffraction pattern shows the 5-MAPB free base obtained as described in Example 11 and shown in Table 7. The diffraction pattern confirms the amorphous nature of the 5-MAPB free base. The x-axis is 2θ measured in degrees, and the y-axis is intensity measured in arbitrary units.

[0579] Figure 15 It is a comparison of XRPD diffraction patterns for salt screening of Form 1A, Form 2A (5-MAPB HBr), and Form 4A (5-MAPB H 3 PO 4 ) in various solvents. The diffraction patterns confirm the crystalline nature of 5-MAPB in various counterions of Form 1A (5-MAPB HCl), Form 1A (5-MAPB HCl in acetone), Form 1A (5-MAPB HCl in MeOH:H 2 O 90:10), Form 2A (5-MAPB HBr in MeOH:H 2 O 90:10), and Form 4A (5-MAPB H 3 PO 4 ). The XRPD diffraction patterns show that salt screening was obtained from most of the test solutions as described in Example 13 and shown in Table 9. The x-axis is 2θ measured in degrees, and the y-axis is intensity measured in arbitrary units.

[0580] Figure 16 It is a comparison of XRPD diffraction patterns of Form 9A (5-MAPB oxalate) and Form 10A (5-MAPB maleate) in various solvents as well as the solvents oxalic acid and maleic acid. The diffraction patterns confirm the crystalline nature of 5-MAPB in various counterions of Form 9A (5-MAPB oxalate in acetone), Form 9A (5-MAPB oxalate in MeOH:H 2 O 90:10), Form 10A (5-MAPB maleate in acetone), and Form 10A (5-MAPB maleate in MeOH:H 2 O 90:10). The XRPD diffraction patterns show that salt screening was obtained from most of the test solutions as described in Example 13 and shown in Table 9. The x-axis is 2θ measured in degrees, and the y-axis is intensity measured in arbitrary units.

[0581] Figure 17 The results are shown in various solvents in mode 1A, mode 2A (5-MAPB HBr) and mode 4B (5-MAPB H 3 PO 4 The diffraction patterns confirmed pattern 1A (5-MAPB HCl), pattern 1A (5-MAPB HCl in DCM), pattern 1A (EtOH: 2 O 90:10 in 5-MAPB HCl), Mode 2A (EtOH:H 2 O 90:10 in 5-MAPB HBr), Mode 4B (5-MAPB HBr in DCM 3 PO 4 ) and Mode 4B (EtOH:H 2 5-MAPB H in O 90:10 3 PO 4 ). The XRPD diffractograms show that salt screening was obtained from most of the solutions tested as described in Example 14 and shown in Table 10. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in arbitrary units.

[0582] Figure 18 The XRPD diffraction patterns of pattern 9A (5-MAPB oxalic acid) and pattern 10A (5-MAPB maleic acid) in various solvents and solvents oxalic acid and maleic acid are compared. The diffraction patterns confirm the XRPD diffraction patterns of pattern 9A (5-MAPB oxalic acid in DCM), pattern 9A (EtOH:H 2 Mode 10A (5-MAPB oxalate in EtOH:H 2 The crystalline properties of 5-MAPB in various counterions of 5-MAPB (maleic acid) in 090:10. The XRPD diffractograms show that salt screening was obtained from most of the tested solutions as described in Example 14 and shown in Table 10. The x-axis is 2θ measured in degrees and the y-axis is intensity measured in arbitrary units.

[0583] Figure 19 In various solvents, mode 4 (5-MAPB H 3 PO 4 The diffraction pattern confirmed the pattern 4A (5-MAPB H in acetone). 3 PO 4 ), Mode 4B (5-MAPB H in DCM 3 PO 4 ) and pattern 4C (5-MAPBH in THF 3PO 4 ) The crystallization properties of 5-MAPB among various counterions. The XRPD diffractogram shows that, as described in Example 15 and shown in Table 11, salt screening was obtained from most of the test solutions. The x-axis is 2θ measured in degrees, and the y-axis is the intensity measured in arbitrary units.

[0584] Figure 20 It is an optical micrograph of Pattern 1A. Pattern 1A seems to have the morphology of irregular aggregates.

[0585] Figure 21 It is an optical micrograph of Pattern 2B (magnification of Pattern 2A). Pattern 2B seems to have the morphology of irregular aggregates.

[0586] Figure 22 It is an optical micrograph of Pattern 10A. Pattern 10A seems to have the morphology of irregular aggregates.

[0587] Figure 23 It is the powder XRPD diffractogram of the Pattern 1A enantiomer (5-MAPB HCl, pure enantiomer). The diffractogram confirms the crystalline nature of the Pattern 1A enantiomer. The XRPD diffractogram shows that the 5-MAPB free base was obtained as described in Example 12. The x-axis is 2θ measured in degrees, and the y-axis is the intensity measured in arbitrary units.

[0588] Figure 24 It is a comparison of the XRPD diffractograms of the Pattern 1A enantiomer (P1AE) in various solvents. The diffractograms confirm the crystalline nature of the Pattern 1A enantiomer (5-MAPB HCl pure enantiomer), Pattern 1AE (5-MAPB HCl pure enantiomer in MeOH:H 2 O 90:10), and Pattern 1AE (5-MAPB HCl pure enantiomer in acetone) among various counterions. The XRPD diffractograms show that, as described in Example 17 and shown in Table 13, salt screening was obtained from most of the test solutions. The x-axis is 2θ measured in degrees, and the y-axis is the intensity measured in arbitrary units.

[0589] Figure 25 It is a comparison of the XRPD diffractograms of Pattern 2A (5-MAPB enantiomer HBr) and Pattern 4A (5-MAPB enantiomer H 3 PO 4 ) in various solvents. The diffractograms confirm the Pattern 2A enantiomer (Pattern 2AE, 5-MAPB enantiomer HBr in acetone), Pattern 2A enantiomer (Pattern 2AE, 5-MAPB enantiomer HBr in MeOH:H 2The crystallization properties of the enantiomer of 5-MAPB in O 90:10 (5-MAPB enantiomer HBr) and the enantiomer of Pattern 4A (Pattern 4AE, 5-MAPB enantiomer H in acetone) 3 PO 4 ) among various counterions of the enantiomer of Pattern 1A (5-MAPB HCl pure enantiomer, P1AE). The XRPD diffractograms show that, as described in Example 17 and shown in Table 13, salt screening was obtained from most of the test solutions. The x-axis is 2θ measured in degrees, and the y-axis is intensity measured in arbitrary units.

[0590] Figure 26 Is a comparison of the XRPD diffractograms of oxalic acid and the enantiomer of Pattern 8A (Pattern 8AE, 5-MAPB enantiomer oxalate) in various solvents. The diffractograms confirm the enantiomer of Pattern 8A (5-MAPB enantiomer oxalate in acetone) and the enantiomer of Pattern 8A (5-MAPB enantiomer oxalate in MeOH:H 2 O 90:10). The crystallization properties of the enantiomer of Pattern 8A (5-MAPB enantiomer oxalate) among various counterions. The XRPD diffractograms show that, as described in Example 17 and shown in Table 13, salt screening was obtained from most of the test solutions. The x-axis is 2θ measured in degrees, and the y-axis is intensity measured in arbitrary units.

[0591] Figure 27 Is a comparison of the XRPD diffractograms of the enantiomer of Pattern 1A (P1AE) in various solvents. The diffractograms confirm the enantiomer of Pattern 1A (5-MAPB HCl pure enantiomer), Pattern 1AE (5-MAPB HCl pure enantiomer in EtOH:H 2 O 90:10), and the enantiomer of Pattern 1AE (5-MAPB HCl pure enantiomer in THF) among various counterions of the enantiomer of Pattern 1A (5-MAPB HCl pure enantiomer, P1AE). The XRPD diffractograms show that, as described in Example 18 and shown in Table 14, salt screening was obtained from most of the test solutions. The x-axis is 2θ measured in degrees, and the y-axis is intensity measured in arbitrary units.

[0592] Figure 28 Is a comparison of the XRPD diffractograms of Pattern 2AE (5-MAPB enantiomer HBr) and Pattern 4AE (5-MAPB enantiomer H 3 PO 4 ). The diffractograms confirm the enantiomer of Pattern 2A (Pattern 2AE, 5-MAPB enantiomer HBr in THF), the enantiomer of Pattern 2A (Pattern 2AE, 5-MAPB enantiomer HBr in EtOH:H 2The crystallization properties of the enantiomer of 5-MAPB in O 90:10 (5-MAPB enantiomer HBr), the enantiomer of Pattern 4A (Pattern 4AE, 5-MAPB enantiomer H 3 PO 4 , in THF) and the enantiomer of Pattern 4A (Pattern 4AE, 5-MAPB enantiomer H 3 PO 4 , in EtOH:H 2 O 90:10). The XRPD diffractograms show that, as described in Example 18 and shown in Table 14, salt screening was obtained from most of the test solutions. The x-axis is 2θ measured in degrees and the y-axis is the intensity measured in arbitrary units.

[0593] Figure 29 is a comparison of the XRPD diffractograms of oxalic acid and the enantiomer of Pattern 8A (Pattern 8AE, 5-MAPB enantiomer oxalate) in various solvents. The diffractograms confirm the crystallization properties of the enantiomer of Pattern 8A (5-MAPB enantiomer oxalate in THF) and the enantiomer of Pattern 8A (5-MAPB enantiomer oxalate in EtOH:H 2 O 90:10). The XRPD diffractograms show that, as described in Example 18 and shown in Table 14, salt screening was obtained from most of the test solutions. The x-axis is 2θ measured in degrees and the y-axis is the intensity measured in arbitrary units.

[0594] Figure 30 is a comparison of the XRPD diffractograms of fumaric acid and the enantiomer of Pattern 10A (Pattern 10AE, 5-MAPB enantiomer fumarate) in EtOH / H 2 O 90:10. The diffractograms confirm the crystallization properties of the enantiomer of Pattern 10A (Pattern 10AE, 5-MAPB enantiomer in fumaric acid) in EtOH / H 2 O 90:10. The XRPD diffractograms show that, as described in Example 18 and shown in Table 14, salt screening was obtained from most of the test solutions. The x-axis is 2θ measured in degrees and the y-axis is the intensity measured in arbitrary units.

[0595] Figure 31Are the XRPD diffractograms of the Pattern 1A enantiomer (Pattern 1AE, 5-MAPB enantiomer HCl), Pattern 1A enantiomer (Pattern 1AE, 5-MAPB enantiomer ACN), Pattern 2A enantiomer (Pattern 2AE, 5-MAPB enantiomer HBr), and Pattern 4A enantiomer (Pattern 4AE, 5-MAPB enantiomer H 3 PO 4 ) for comparison. The diffractograms confirm the crystalline nature of the Pattern 1A enantiomers in the various counterions of Pattern 1AE (5-MAPB enantiomer HCl), Pattern 1AE (5-MAPB enantiomer ACN), Pattern 2AE (5-MAPB enantiomer HBr in ACN), and Pattern 4A (5-MAPB enantiomer H 3 PO 4 ) in various counterions. The XRPD diffractograms show that, as described in Example 15 and shown in Table 15, salt screening was obtained from most of the test solutions. The x-axis is 2θ measured in degrees, and the y-axis is intensity measured in arbitrary units.

[0596] Figure 32 Is an optical micrograph of the Pattern 1A enantiomer (Pattern 1AE). The Pattern 1A enantiomer appears to have an irregular morphology.

[0597] Figure 33 Is an optical micrograph of the Pattern 4A enantiomer (Pattern 4AE). Pattern 4AE appears to have a morphology of irregular aggregates and fine grains.

[0598] Figure 34 Is an optical micrograph of the Pattern 8A enantiomer (Pattern 8AE). Pattern 8AE appears to have a morphology of irregular aggregates.

[0599] Figure 35 Are the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) plots of Pattern 1A (HCl). DSC shows an endotherm (possibly melting) starting at about 194 °C, and TGA shows a weight loss of about 0.09% up to 150 °C and decomposition at higher temperatures (>200 °C). The methods used for DSC / TGA were carried out as described in Table 16 of Example 20. The x-axis is temperature measured in degrees Celsius, and the y-axis is weight measured in percentage and heat flow measured in W / g.

[0600] Figure 36Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of Mode 2A (HBr). DSC shows an endotherm (possibly melting) starting at approximately 135 °C, shows a weight loss of approximately 2.00% up to 150 °C and decomposes at higher temperatures (>240 °C). The method used for DSC / TGA was carried out as described in Table 16 of Example 20. The x-axis is temperature measured in degrees Celsius and the y-axis is weight measured as a percentage and heat flow measured in W / g.

[0601] Figure 37 are differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of Mode 4A (H 3 PO 4 ). DSC shows an endotherm (possibly melting and decomposition) starting at approximately 178 °C, and TGA shows a weight loss of approximately 0.01% up to 150 °C and decomposes at higher temperatures (>180 °C). The method used for DSC / TGA was carried out as described in Table 16 of Example 20. The x-axis is temperature measured in degrees Celsius and the y-axis is weight measured as a percentage and heat flow measured in W / g.

[0602] Figure 38 are differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of Mode 4B (H 3 PO 4 ). DSC shows no significant thermal events and TGA shows a weight loss of approximately 0.42% up to 150 °C. The method used for DSC / TGA was carried out as described in Table 16 of Example 20. The x-axis is temperature measured in degrees Celsius and the y-axis is weight measured as a percentage and heat flow measured in W / g.

[0603] Figure 39 are differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of Mode 4C (H 3 PO 4 ). DSC shows a broad endothermic curve starting at approximately 133 °C and TGA shows a weight loss of approximately 2.82% up to 140 °C. The method used for DSC / TGA was carried out as described in Table 16 of Example 20. The x-axis is temperature measured in degrees Celsius and the y-axis is weight measured as a percentage and heat flow measured in W / g.

[0604] Figure 40 are differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of Mode 9A (oxalic acid). DSC shows an endotherm starting at approximately 122 °C, and TGA shows a weight loss of approximately 1.37% up to 150 °C and decomposes at higher temperatures (>180 °C). The method used for DSC / TGA was carried out as described in Table 16 of Example 20. The x-axis is temperature measured in degrees Celsius and the y-axis is weight measured as a percentage and heat flow measured in W / g.

[0605] Figure 41 These are the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of Form 10A (maleic acid). DSC shows an endotherm starting at approximately 117 °C, and TGA shows a weight loss of approximately 0.45% up to 150 °C and decomposition at higher temperatures (>160 °C). The methods used for DSC / TGA were carried out as described in Table 16 of Example 20. The x-axis is temperature measured in degrees Celsius, and the y-axis is weight measured in percentage and heat flow measured in W / g.

[0606] Figure 42 These are the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of Form 1A enantiomer HCl. DSC shows a sharp endotherm (possibly melting) starting at approximately 199 °C, and TGA shows a weight loss of approximately 0.08% up to 150 °C and decomposition at higher temperatures (>200 °C). The methods used for DSC / TGA were carried out as described in Table 16 of Example 20. The x-axis is temperature measured in degrees Celsius, and the y-axis is weight measured in percentage and heat flow measured in W / g.

[0607] Figure 43 These are the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of Form 2A enantiomer (HBr). DSC shows a sharp endotherm (possibly melting) starting at approximately 161 °C, and TGA shows a weight loss of approximately 1.68% up to 160 °C. The methods used for DSC / TGA were carried out as described in Table 16 of Example 20. The x-axis is temperature measured in degrees Celsius, and the y-axis is weight measured in percentage and heat flow measured in W / g.

[0608] Figure 44 These are the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of Form 4A enantiomer (H 3 PO 4 ). DSC shows no significant thermal events and a noisy baseline at higher temperatures (>150 °C), while TGA shows a weight loss of approximately 0.55% up to 150 °C and decomposition at higher temperatures (>180 °C). The methods used for DSC / TGA were carried out as described in Table 16 of Example 20. The x-axis is temperature measured in degrees Celsius, and the y-axis is weight measured in percentage and heat flow measured in W / g.

[0609] Figure 45 These are the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of Form 8A enantiomer (oxalic acid). DSC shows an endotherm starting at approximately 146 °C, and TGA (blue curve) shows a weight loss of approximately 0.58% up to 150 °C. The methods used for DSC / TGA were carried out as described in Table 16 of Example 20. The x-axis is temperature measured in degrees Celsius, and the y-axis is weight measured in percentage and heat flow measured in W / g.

[0610] Figure 46 These are differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of the (fumaric acid) enantiomer of Form 10A. The DSC shows a broad endotherm with peaks at approximately 106 °C and approximately 124 °C. The TGA shows a weight loss of approximately 0.62% up to 140 °C and decomposition at higher temperatures (>180 °C). The methods used for DSC / TGA were carried out as described in Table 16 of Example 20. The x-axis is temperature measured in degrees Celsius, and the y-axis is weight measured in percentage and heat flow measured in W / g.

[0611] Figure 47 These are powder XRPD diffraction graphs of R-5-MAPB HCl used for liquid-liquid extraction to provide R-5-MAPB as described in Example 25. The x-axis is 2θ measured in degrees, and the y-axis is intensity measured in arbitrary units.

[0612] Figure 48 The names and structures of selected empathy-inducing compounds mentioned herein are provided. Detailed Description

[0613] The present invention provides multiple embodiments of compounds, compositions, and methods for treating mental disorders and more generally central nervous disorders, as well as for cognitive enhancement. The compounds of the present invention provide favorable pharmacological properties that are well-suited as therapies for treating mental disorders, particularly as psychotherapeutic and neurotherapeutic agents.

[0614] Embodiments of the present invention are presented to meet the goal of helping individuals with mental disorders (who desire cognitive enhancement) or other CNS disorders by providing milder therapeutic agents that act rapidly and reduce properties that degrade the patient experience, counteract the therapy, or have unwanted toxicity. One goal of the present invention is to provide therapeutic compositions that increase empathy, compassion, openness, and acceptance towards oneself and others, which can be taken as part of therapeutic counseling if desired, occasionally as prescribed by a healthcare provider when necessary, or even continuously.

[0615] Surprisingly, it has been found that the composition compounds of the present invention exhibit permeability, indicating that the compounds will act rapidly in the human body. This represents a significant improvement over SSRIs, which are the current standard of care for many CNS and psychological disorders. Slow onset is one of the most significant drawbacks of SSRI therapy. In contrast, in one embodiment, the compounds of the present invention are used as rapid-acting therapeutics, which represents a significant advancement in clinical applications. The use of rapid-acting therapeutic agents in a clinical treatment setting, which typically lasts one or two hours, is advantageous.

[0616] 1. In certain embodiments, there are provided the S - enantiomer and R - enantiomer of 5 - MAPB:

[0617]

[0618] or an enantiomer - enriched mixture of its pharmaceutically acceptable salts or mixed salts.

[0619] 2. In certain embodiments, there are provided the S - enantiomer and R - enantiomer of 6 - MAPB:

[0620]

[0621] or an enantiomer - enriched mixture of its pharmaceutically acceptable salts or mixed salts.

[0622] 3. In certain embodiments, there are provided the S - enantiomer and R - enantiomer of 5 - MBPB:

[0623]

[0624] or an enantiomer - enriched mixture of its pharmaceutically acceptable salts or mixed salts.

[0625] 4. In certain embodiments, there are provided the S - enantiomer and R - enantiomer of 6 - MBPB:

[0626]

[0627] or an enantiomer - enriched mixture of its pharmaceutically acceptable salts or mixed salts.

[0628] 5. In certain embodiments, there are provided the S - enantiomer and R - enantiomer of 6 - Bk - 5 - MAPB:

[0629]

[0630] or an enantiomer - enriched mixture of its pharmaceutically acceptable salts or mixed salts.

[0631] 6. In certain embodiments, there are provided the S - enantiomer and R - enantiomer of 6 - Bk - 6 - MAPB:

[0632]

[0633] or an enantiomer - enriched mixture of its pharmaceutically acceptable salts or mixed salts.

[0634] 7. In certain embodiments, there are provided the S - enantiomer and R - enantiomer of 6 - Bk - 5 - MBPB:

[0635]

[0636] An enantiomerically enriched mixture of or a pharmaceutically acceptable salt or mixed salt thereof.

[0637] 8. In certain embodiments, an S-enantiomer and an R-enantiomer of 6-Bk-6-MBPB are provided,

[0638]

[0639] or an enantiomerically enriched mixture of or a pharmaceutically acceptable salt or mixed salt thereof.

[0640] 9. The enantiomerically enriched mixture according to any one of embodiments 1-8, wherein the mixture has more empathy-stimulating effects in humans than the corresponding racemic mixture.

[0641] 10. The enantiomerically enriched mixture according to any one of embodiments 1-8, which has a greater amount of nicotinic receptor-dependent therapeutic effects in humans than the corresponding racemic mixture.

[0642] 11. The enantiomerically enriched mixture according to any one of embodiments 1-8, which has a greater amount of serotonin receptor-dependent therapeutic effects in humans than the corresponding racemic mixture.

[0643] 12. The enantiomerically enriched mixture according to any one of embodiments 1-8, which enhances serotonin receptor-dependent therapeutic effects and reduces nicotinic or dopaminergic effects in humans.

[0644] 13. The enantiomerically enriched mixture according to any one of embodiments 1-8, which contains a balance of enantiomers that reduces hallucinogenic effects compared to the racemate.

[0645] 14. The enantiomerically enriched mixture according to any one of embodiments 1-8, which contains a balance of enantiomers that reduces unwanted psychoactive effects compared to the racemate.

[0646] 15. The enantiomerically enriched mixture according to any one of embodiments 1-8, which contains a balance of enantiomers that reduces physiological effects compared to the racemate.

[0647] 16. The enantiomerically enriched mixture according to any one of embodiments 1-8, which contains a balance of enantiomers that reduces toxic effects compared to the racemate.

[0648] 17. The enantiomerically enriched mixture according to any one of embodiments 1-8, which contains a balance of enantiomers that reduces the likelihood of abuse compared to the racemate.

[0649] 18. An enantiomerically enriched mixture as described in any one of embodiments 1-8, having at least about 60% of the S-enantiomer.

[0650] 19. An enantiomerically enriched mixture as described in any one of embodiments 1-8, having at least about 70% of the S-enantiomer.

[0651] 20. An enantiomerically enriched mixture as described in any one of embodiments 1-8, having at least about 80% of the S-enantiomer.

[0652] 21. An enantiomerically enriched mixture as described in any one of embodiments 1-8, having at least about 90% of the S-enantiomer.

[0653] 22. An enantiomerically enriched mixture as described in any one of embodiments 1-8, having at least about 60% of the R-enantiomer.

[0654] 23. An enantiomerically enriched mixture as described in any one of embodiments 1-8, having at least about 70% of the R-enantiomer.

[0655] 24. An enantiomerically enriched mixture as described in any one of embodiments 1-8, having at least about 80% of the R-enantiomer.

[0656] 25. An enantiomerically enriched mixture as described in any one of embodiments 1-8, having at least about 90% of the R-enantiomer.

[0657] 26. An enantiomerically enriched mixture as described in any one of embodiments 1-25, showing a greater amount of the therapeutic effect of emotional openness than the corresponding racemic mixture.

[0658] 27. An enantiomerically enriched mixture as described in any one of embodiments 1-26, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, aspartate, saccharate, phosphate, oxalate, acetate, amino acid anion, gluconate, maleate, malate, citrate, mesylate, nitrate or tartrate, or a mixture thereof.

[0659] 28. An enantiomerically enriched mixture as described in any one of embodiments 1-27, which is both a direct 5-HT 1B agonist and a serotonin releasing agent.

[0660] 29. The enantiomerically enriched mixture as described in embodiment 28, which is also a serotonin reuptake inhibitor.

[0661] 30. An enantiomerically enriched mixture as described in any one of embodiments 1-29, having minimal or no 5-HT 2A agonistic effect.

[0662] 31. In certain embodiments, there is provided a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X:

[0663]

[0664] or a pharmaceutically acceptable salt or mixed salt or isotopic derivative thereof,

[0665] wherein:

[0666] R 1 and R 2 together are -OCH=CH- or -CH=CHO-;

[0667] R 3B and R 4B are independently selected from -H, -X, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 、and -CX 3 , where at least one of R 3B and R 4B is not -H;

[0668] R 3I and R 4I are independently selected from -H, -X, -OH, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , and C 1 -C 4 alkyl; where at least one of R 3I and R 4I is not -H;

[0669] R 3J and R 4J are independently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 ;

[0670] R 4E is selected from C 1-C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 ;

[0671] R 4H is selected from -X, -CH 2 CH 2 CH 3 , -CH 2 OH, -CH 2 X, and -CHX 2 ;

[0672] R 5A and R 5G are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 , -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl, provided that when R 5A is C 2 alkyl or H, R 6A is not -H, and when R 5G is -H or C 2 alkyl, R 6G is not -H;

[0673] R 5B is selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl;

[0674] R 5C selected from -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[0675] R 5D , R 5E , R 5F and R 5J are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl, provided that when R 5F is -H or C 1 alkyl, R 6F cannot be -H, and when R 5J is C 1 alkyl, at least one of R 3J and R 4J is not H;

[0676] R 5I is selected from -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2CHX 2 、 -CH 2 CX 3 、 C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl; wherein R 3I 、 R 4I and R 5I at least one of which is not C 1 alkyl;

[0677] R 6A 、 R 6B 、 R 6E 、 R 6F and R 6G are independently selected from -H and -CH 3 ;

[0678] X is independently selected from -F, -Cl, and -Br; and

[0679] Z is selected from O and CH 2 .

[0680] 32. The compound according to embodiment 31, wherein the compound has the formula I:

[0681]

[0682] or a pharmaceutically acceptable salt or mixed salt.

[0684] 33. The compound according to embodiment 31, wherein the compound has the formula II:

[0685]

[0686] or a pharmaceutically acceptable salt or mixed salt.

[0688] 34. The compound according to embodiment 31, wherein the compound has the formula III:

[0689]

[0690] or a pharmaceutically acceptable salt or mixed salt.

[0692] 35. The compound according to embodiment 31, wherein the compound has the formula IV:

[0693]

[0694] or a pharmaceutically acceptable salt or mixed salt.

[0696] 36. The compound according to embodiment 31, wherein the compound has the formula V:

[0697]

[0698] or a pharmaceutically acceptable salt or a mixed salt.

[0700] 37. The compound according to embodiment 31, wherein the compound has formula VI:

[0701]

[0702] or a pharmaceutically acceptable salt or a mixed salt.

[0704] 38. The compound according to embodiment 31, wherein the compound has formula VII:

[0705]

[0706] or a pharmaceutically acceptable salt or a mixed salt.

[0708] 39. The compound according to embodiment 31, wherein the compound has formula VIII:

[0709]

[0710] or a pharmaceutically acceptable salt or a mixed salt.

[0712] 40. The compound according to embodiment 31, wherein the compound has formula IX:

[0713]

[0714] or a pharmaceutically acceptable salt or a mixed salt.

[0716] 41. The compound according to embodiment 31, wherein the compound has formula X:

[0717] or a pharmaceutically acceptable salt or a mixed salt.

[0719] 42. The compound according to embodiment 31 or 32, wherein the compound is selected from:

[0720]

[0721]

[0722] or a pharmaceutically acceptable salt or a mixed salt.

[0724] 43. The compound according to embodiment 31 or 33, wherein the compound is selected from:

[0725]

[0726] or a pharmaceutically acceptable salt or mixed salt.

[0727] 44. The compound according to embodiment 31 or 37, wherein the compound is selected from:

[0728]

[0729]

[0730] or a pharmaceutically acceptable salt or mixed salt.

[0731] 45. The compound according to embodiment 31 or 38, wherein the compound is selected from:

[0732]

[0733]

[0734] or a pharmaceutically acceptable salt or mixed salt.

[0735] 46. The compound according to embodiment 31 or 40, wherein the compound is selected from:

[0736]

[0737]

[0738] or a pharmaceutically acceptable salt or mixed salt.

[0739] 47. The compound according to embodiment 42, wherein the compound is selected from:

[0740]

[0741]

[0742] or a pharmaceutically acceptable salt or mixed salt thereof.

[0743] 48. The compound according to embodiment 43, wherein the compound is selected from:

[0744]

[0745] or a pharmaceutically acceptable salt or mixed salt thereof.

[0746] 49. The compound according to embodiment 44, wherein the compound is selected from:

[0747]

[0748]

[0749]

[0750] or a pharmaceutically acceptable salt or mixed salt thereof.

[0751] 50. The compound according to embodiment 45, wherein the compound is selected from:

[0752]

[0753]

[0754] or a pharmaceutically acceptable salt or mixed salt thereof.

[0755] 51. The compound according to embodiment 46, wherein the compound is selected from:

[0756]

[0757]

[0758] or a pharmaceutically acceptable salt or mixed salt thereof.

[0759] 52. The compound according to embodiment 31 or 37, wherein the compound is selected from:

[0760]

[0761] or a pharmaceutically acceptable salt or mixed salt thereof.

[0762] 53. The compound according to any one of embodiments 31, 37 or 52, wherein the compound has the following structure

[0763]

[0764] or a pharmaceutically acceptable salt or mixed salt thereof.

[0765] 54. The compound according to any one of embodiments 31, 37 or 52, wherein the compound has the following structure

[0766]

[0767] or a pharmaceutically acceptable salt or mixed salt thereof.

[0768] 55. In certain embodiments, there is provided an enantiomerically enriched mixture of the S - enantiomer and the R - enantiomer of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X:

[0769]

[0770] or a pharmaceutically acceptable salt or mixed salt thereof,

[0771] wherein:

[0772] R 1 and R 2 together are -OCH=CH- or -CH=CHO-;

[0773] R 3B and R 4B are independently selected from -H, -X, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 , where at least one of R 3B and R 4B is not -H;

[0774] R 3I and R 4I are independently selected from -H, -X, -OH, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , and C 1 -C 4 alkyl; where at least one of R 3I and R 4I is not -H;

[0775] R 3J and R 4J are independently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 ;

[0776] R 4E is selected from C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 ;

[0777] R 4H is selected from -X, -CH 2 CH 2 CH 3, -CH 2 OH, -CH 2 X, and -CHX 2 ;

[0778] R 5A and R 5G are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl, provided that when R 5A is C 2 alkyl or H, R 6A is not -H, and provided that when R 5G is -H or C 2 alkyl, R 6G is not -H;

[0779] R 5B is selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl;

[0780] R 5C is selected from -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH2 CHX 2 、 -CH 2 CX 3 、 C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[0781] R 5D 、 R 5E 、 R 5F and R 5J are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 、 -CX 3 、 -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 、 -CH 2 CX 3 、 C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl, provided that when R 5F is -H or C 1 alkyl, R 6F cannot be -H, and when R 5J is C 1 alkyl, at least one of R 3J and R 4J is not H;

[0782] R 5I is selected from -CH 2 OH, -CH 2 X, -CHX 2 、 -CX 3 、 -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 、 -CH 2 CX 3 、 C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl; wherein at least one of R 3I 、 R 4I and R 5I is not C 1alkyl;

[0783] R 6A , R 6B , R 6E , R 6F and R 6G Independently selected from -H and -CH 3 ;

[0784] X is independently selected from -F, -Cl and -Br; and

[0785] Z is selected from O and CH 2 .

[0786] 56. The enantiomerically enriched mixture of embodiment 55, wherein the compound has formula I:

[0787]

[0788] or a pharmaceutically acceptable salt or mixed salt thereof.

[0789] 57. The enantiomerically enriched mixture of embodiment 55, wherein the compound has formula II:

[0790]

[0791] or a pharmaceutically acceptable salt or mixed salt.

[0792] 58. The enantiomerically enriched mixture of embodiment 55, wherein the compound has formula III:

[0793]

[0794] or a pharmaceutically acceptable salt or mixed salt.

[0795] 59. The enantiomerically enriched mixture of embodiment 55, wherein the compound has formula IV:

[0796]

[0797] or a pharmaceutically acceptable salt or mixed salt thereof.

[0798] 60. The enantiomerically enriched mixture of embodiment 55, wherein the compound has formula V:

[0799]

[0800] or a pharmaceutically acceptable salt or mixed salt.

[0801] 61. The enantiomerically enriched mixture of embodiment 55, wherein the compound has formula VI:

[0802]

[0803] or a pharmaceutically acceptable salt or mixed salt.

[0804] 62. The enantiomerically enriched mixture according to embodiment 55, wherein the compound has formula VII:

[0805]

[0806] or a pharmaceutically acceptable salt or mixed salt.

[0807] 63. The enantiomerically enriched mixture according to embodiment 55, wherein the compound has formula VIII:

[0808]

[0809] or a pharmaceutically acceptable salt or mixed salt.

[0810] 64. The enantiomerically enriched mixture according to embodiment 55, wherein the compound has formula IX:

[0811]

[0812] or a pharmaceutically acceptable salt or mixed salt.

[0813] 65. The enantiomerically enriched mixture according to embodiment 55, wherein the compound has formula X:

[0814]

[0815] or a pharmaceutically acceptable salt or mixed salt.

[0816] 66. The enantiomerically enriched mixture according to embodiment 55 or 56, wherein the compound is selected from:

[0817]

[0818]

[0819] or a pharmaceutically acceptable salt or mixed salt.

[0820] 67. The enantiomerically enriched mixture according to embodiment 55 or 57, wherein the compound is selected from:

[0821]

[0822]

[0823] or a pharmaceutically acceptable salt or mixed salt.

[0824] 68. The enantiomerically enriched mixture according to embodiment 55 or 61, wherein the compound is selected from:

[0825]

[0826]

[0827] or a pharmaceutically acceptable salt or mixed salt.

[0828] 69. The enantiomerically enriched mixture according to embodiment 55 or 62, wherein the compound is selected from:

[0829]

[0830] or a pharmaceutically acceptable salt or mixed salt.

[0831] 70. The enantiomerically enriched mixture according to embodiment 55 or 64, wherein the compound is selected from:

[0832]

[0833] or a pharmaceutically acceptable salt or mixed salt.

[0834] 71. The enantiomerically enriched mixture according to embodiment 55 or 66, wherein the compound is selected from:

[0835]

[0836]

[0837] or a pharmaceutically acceptable salt or mixed salt.

[0838] 72. The enantiomerically enriched mixture according to embodiment 55 or 67, wherein the compound is selected from:

[0839]

[0840]

[0841] or a pharmaceutically acceptable salt or mixed salt thereof.

[0842] 73. The enantiomerically enriched mixture according to embodiment 55 or 68, wherein the compound is selected from:

[0843]

[0844]

[0845]

[0846] or a pharmaceutically acceptable salt or mixed salt thereof.

[0847] 74. The enantiomerically enriched mixture according to embodiment 55 or 69, wherein the compound is selected from:

[0848]

[0849] or a pharmaceutically acceptable salt or mixed salt thereof.

[0850] 75. The enantiomerically enriched mixture according to embodiment 55 or 70, wherein the compound is selected from:

[0851]

[0852] 76. The enantiomerically enriched mixture according to embodiment 55 or 61, wherein the compound is selected from:

[0853]

[0854] or a pharmaceutically acceptable salt or mixed salt thereof.

[0855] 77. An enantiomerically enriched mixture of the S - enantiomer and the R - enantiomer of a compound of formula XI, formula XII or formula XIII:

[0856]

[0857] or a pharmaceutically acceptable salt or mixed salt thereof,

[0858] wherein:

[0859] R 1 and R 2 together are -OCH=CH- or -CH=CHO-;

[0860] R 3L and R 4L are independently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 and -CX 3 wherein at least one of R 3L and R 4L is not -H;

[0861] R 5K is selected from -H, -CH 2 OH, -CH2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[0862] R 5L and R 5M independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl;

[0863] R 6K , R 6L and R 6M independently selected from -H and -CH 3 ; and

[0864] X is independently selected from -F, -Cl, and -Br.

[0865] 78. The enantiomerically enriched mixture according to embodiment 77, wherein the compound has the formula XI

[0866]

[0867] or a pharmaceutically acceptable salt or mixed salt thereof.

[0868] 79. The enantiomerically enriched mixture according to embodiment 77, wherein the compound has the formula XII

[0869]

[0870] or a pharmaceutically acceptable salt or mixed salt thereof.

[0871] 80. The enantiomerically enriched mixture according to embodiment 77, wherein the compound has formula XIII

[0872]

[0873] or a pharmaceutically acceptable salt or mixed salt thereof.

[0874] 81. In certain embodiments, an enantiomerically enriched mixture of the S - enantiomer and the R - enantiomer of a compound of formula A, formula B, formula C, formula D, formula E, or formula F:

[0875]

[0876]

[0877] or a pharmaceutically acceptable salt or mixed salt thereof,

[0878] wherein:

[0879] R is hydrogen or hydroxy;

[0880] R A is —CH 3 、—CH 2 Y、—CHY 2 、—CY 3 、—CH 2 CH 3 、—CH 2 CH 2 Y、—CH 2 CHY 2 、—CH 2 CY 3 、—CH 2 OH、or —CH 2 CH 2 OH;

[0881] Q is selected from:

[0882] and

[0883] Y is halogen.

[0884] 82. The enantiomerically enriched mixture according to embodiment 81, wherein the compound has formula A

[0885]

[0886] or a pharmaceutically acceptable salt or mixed salt thereof.

[0887] 83. The enantiomerically enriched mixture according to embodiment 81, wherein the compound has the formula B

[0888]

[0889] or a pharmaceutically acceptable salt or mixed salt thereof.

[0890] 84. The enantiomerically enriched mixture according to embodiment 81, wherein the compound has the formula C

[0891]

[0892] or a pharmaceutically acceptable salt or mixed salt thereof.

[0893] 85. The enantiomerically enriched mixture according to embodiment 81, wherein the compound has the formula D

[0894]

[0895] or a pharmaceutically acceptable salt or mixed salt thereof.

[0896] 86. The enantiomerically enriched mixture according to embodiment 81, wherein the compound has the formula E

[0897]

[0898] or a pharmaceutically acceptable salt or mixed salt thereof.

[0899] 87. The enantiomerically enriched mixture according to embodiment 81, wherein the compound has the formula F

[0900]

[0901] or a pharmaceutically acceptable salt or mixed salt thereof.

[0902] 88. The enantiomerically enriched mixture according to embodiment 81, wherein the compound is selected from:

[0903]

[0904] or a pharmaceutically acceptable salt or mixed salt thereof.

[0905] 89. The enantiomerically enriched mixture according to embodiment 81 or 88, wherein the compound is selected from:

[0906]

[0907] or a pharmaceutically acceptable salt or mixed salt thereof.

[0908] 90. An enantiomerically enriched mixture as described in embodiment 81 or 88, wherein the compound is selected from:

[0909]

[0910] or a pharmaceutically acceptable salt or mixed salt thereof.

[0911] 91. An enantiomerically enriched mixture as described in embodiment 81 or 88, wherein the compound is selected from:

[0912]

[0913] or a pharmaceutically acceptable salt or mixed salt thereof.

[0914] 92. An enantiomerically enriched mixture as described in embodiment 81 or 88, wherein the compound is:

[0915]

[0916] or a pharmaceutically acceptable salt or mixed salt thereof.

[0917] 93. An enantiomerically enriched mixture as described in embodiment 81 or 88, wherein the compound is selected from:

[0918]

[0919] or a pharmaceutically acceptable salt or mixed salt thereof.

[0920] 94. An enantiomerically enriched mixture as described in embodiment 81 or 88, wherein the compound is:

[0921]

[0922] or a pharmaceutically acceptable salt or mixed salt thereof.

[0923] 95. A compound as described in any one of embodiments 31 - 54, wherein the compound has an empathy - stimulating effect in humans.

[0924] 96. A compound as described in any one of embodiments 31 - 54, wherein the compound has a nicotinic receptor - dependent therapeutic effect in humans.

[0925] 97. A compound as described in any one of embodiments 31 - 54, wherein the compound has a serotonin receptor - dependent therapeutic effect in humans.

[0926] 98. A compound as described in any one of embodiments 31 - 54, wherein the compound enhances the serotonin receptor - dependent therapeutic effect and reduces the nicotinic effect or dopaminergic effect in humans.

[0927] 99. The compound according to any one of embodiments 31-54, which is in an enantiomerically enriched form that reduces the hallucinogenic effect compared to the racemate.

[0928] 100. The compound according to any one of embodiments 31-54, which is in an enantiomerically enriched form that reduces the unwanted psychoactive effect compared to the racemate.

[0929] 101. The compound according to any one of embodiments 31-54, which is in an enantiomerically enriched form that reduces the physiological effect compared to the racemate.

[0930] 102. The compound according to any one of embodiments 31-54, which is in an enantiomerically enriched form that reduces the toxic effect compared to the racemate.

[0931] 103. The compound according to any one of embodiments 31-54, which is in an enantiomerically enriched form that reduces the likelihood of abuse compared to the racemate.

[0932] 104. The compound according to any one of embodiments 31-54, which is in an enantiomerically enriched form having at least about 60% S-enantiomer.

[0933] 105. The compound according to any one of embodiments 31-54, which is in an enantiomerically enriched form having at least about 70% S-enantiomer.

[0934] 106. The compound according to any one of embodiments 31-54, which is in an enantiomerically enriched form having at least about 80% S-enantiomer.

[0935] 107. The compound according to any one of embodiments 31-54, which is in an enantiomerically enriched form having at least about 90% S-enantiomer.

[0936] 108. The compound according to any one of embodiments 31-54, which is in an enantiomerically enriched form having at least about 60% R-enantiomer.

[0937] 109. The compound according to any one of embodiments 31-54, which is in an enantiomerically enriched form having at least about 70% R-enantiomer.

[0938] 110. The compound according to any one of embodiments 31-54, which is in an enantiomerically enriched form having at least about 80% R-enantiomer.

[0939] 111. A compound as described in any one of embodiments 31-54, which is in an enantiomerically enriched form having at least about 90% R-enantiomer.

[0940] 112. A compound as described in any one of embodiments 31-54 or 95-111, which exhibits an affectively open therapeutic effect.

[0941] 113. A compound as described in any one of embodiments 31-54 or 95-112, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, aspartate, saccharate, phosphate, oxalate, acetate, amino acid anion, gluconate, maleate, malate, citrate, mesylate, nitrate or tartrate, or a mixture thereof.

[0942] 114. A compound as described in any one of embodiments 31-54 or 95-113, which is both a direct 5-HT 1B agonist and a serotonin releasing agent.

[0943] 115. A compound as described in embodiment 114, which is also a serotonin reuptake inhibitor.

[0944] 116. A compound as described in any one of embodiments 31-54 or 95-115, which has minimal or no 5-HT 2A agonistic effect.

[0945] 117. An enantiomerically enriched mixture as described in any one of embodiments 55-94, wherein the mixture has more empathy-evoking effect in humans than the corresponding racemic mixture.

[0946] 118. An enantiomerically enriched mixture as described in any one of embodiments 55-94, which has a greater amount of nicotinic receptor-dependent therapeutic effect in humans than the corresponding racemic mixture.

[0947] 119. An enantiomerically enriched mixture as described in any one of embodiments 55-94, which has a greater amount of serotonin receptor-dependent therapeutic effect in humans than the corresponding racemic mixture.

[0948] 120. An enantiomerically enriched mixture as described in any one of embodiments 55-94, which enhances serotonin receptor-dependent therapeutic effect in humans and reduces nicotinic or dopaminergic effects.

[0949] 121. An enantiomerically enriched mixture as described in any one of embodiments 55-94, which contains an equilibrium of enantiomers that reduces hallucinogenic effects compared to the racemate.

[0950] 122. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which comprises an equilibrium of enantiomers that reduces the unwanted psychoactive effects compared to the racemate.

[0951] 123. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which comprises an equilibrium of enantiomers that reduces the physiological effects compared to the racemate.

[0952] 124. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which comprises an equilibrium of enantiomers that reduces the toxic effects compared to the racemate.

[0953] 125. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which comprises an enantiomer equilibrium that reduces the likelihood of abuse compared to the racemate.

[0954] 126. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which has at least about 60% of the S - enantiomer.

[0955] 127. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which has at least about 70% of the S - enantiomer.

[0956] 128. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which has at least about 80% of the S - enantiomer.

[0957] 129. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which has at least about 90% of the S - enantiomer.

[0958] 130. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which has at least about 60% of the R - enantiomer.

[0959] 131. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which has at least about 70% of the R - enantiomer.

[0960] 132. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which has at least about 80% of the R - enantiomer.

[0961] 133. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94, which has at least about 90% of the R - enantiomer.

[0962] 134. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94 or 117 - 133, which exhibits a greater amount of the therapeutic effect of emotional openness than the corresponding racemic mixture.

[0963] 135. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94 or 117 - 134, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, aspartate, saccharate, phosphate, oxalate, acetate, amino acid anion, gluconate, maleate, malate, citrate, mesylate, nitrate or tartrate, or a mixture thereof.

[0964] 136. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94 or 117 - 135, which is both a direct 5 - HT 1B agonist and a serotonin releasing agent.

[0965] 137. The enantiomerically enriched mixture as described in embodiment 136, which is also a serotonin reuptake inhibitor.

[0966] 138. An enantiomerically enriched mixture as described in any one of embodiments 55 - 94 or 117 - 137, which has minimal or no 5 - HT 2A agonistic effect.

[0967] 139. In certain embodiments, there is provided a method for treating a central nervous system disorder, the method comprising administering to a host in need thereof an effective amount of an enantiomerically enriched mixture as described in any one of embodiments 1 - 138.

[0968] 140. In certain embodiments, there is provided a method for treating a central nervous system disorder of a host in need thereof, the method comprising administering an effective amount of a compound of formula XI, formula XII or formula XIII:

[0969]

[0970] or a pharmaceutically acceptable salt or mixed salt thereof,

[0971] wherein:

[0972] R 1 and R 2 together are - OCH = CH - or - CH = CHO -;

[0973] R 3L and R 4L independently selected from - H, - X, - OH, C 1 - C 4 alkyl, - CH 2 OH, - CH2 X, -CHX 2 , and -CX 3 , where at least one of R 3L and R 4L is not -H;

[0974] R 5K is selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[0975] R 5L and R 5M are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl;

[0976] R 6K , R 6L and R 6M are independently selected from -H and -CH 3 ; and

[0977] X is independently selected from -F, -Cl, and -Br.

[0978] 141. In certain embodiments, a method of treating a central nervous system disorder selected from the following in a host in need thereof is provided: depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic disorder, adjustment disorder, feeding and eating disorders, bulimia nervosa, body dysmorphic syndrome, addiction, substance abuse or dependence disorders, disruptive behavior disorders impulse control disorders, gaming disorder, gambling disorder, amnesia, attention deficit hyperactivity disorder, personality disorder, attachment disorder, autism, and dissociative disorder, the method comprising administering an effective amount of enantiomerically enriched 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, Bk-6-MBPB, or a pharmaceutically acceptable salt or mixed salt thereof.

[0979] 142. The method according to any one of embodiments 139-141, wherein the host is a human.

[0980] 143. The method according to any one of embodiments 139-142, wherein the central nervous system disorder is generalized anxiety.

[0981] 144. The method according to any one of embodiments 139-142, wherein the central nervous system disorder is social anxiety.

[0982] 145. The method according to any one of embodiments 139-142, wherein the central nervous system disorder is depression.

[0983] 146. The method according to any one of embodiments 139-142, wherein the central nervous system disorder is addiction.

[0984] 147. The method according to any one of embodiments 139-142, wherein the central nervous system disorder is an eating disorder.

[0985] 148. The method according to embodiment 147, wherein the eating disorder is bulimia nervosa.

[0986] 149. The method according to embodiment 147, wherein the eating disorder is binge eating.

[0987] 150. The method according to embodiment 147, wherein the eating disorder is anorexia nervosa.

[0988] 151. The method according to any one of embodiments 139-142, wherein the central nervous system disorder is an attachment disorder.

[0989] 152. The method according to any one of embodiments 139-142, wherein the central nervous system disorder is schizophrenia.

[0990] 153. The method according to any one of embodiments 139 - 152, wherein the compound or enantiomerically enriched mixture is administered in a clinical setting.

[0991] 154. The method according to any one of embodiments 139 - 152, wherein the compound or enantiomerically enriched mixture is administered in a home environment or other non - clinical setting.

[0992] 155. The method according to any one of embodiments 139 - 152, wherein the compound or enantiomerically enriched mixture is administered during a psychotherapy session.

[0993] 156. The method according to any one of embodiments 139 - 152, wherein the compound or enantiomerically enriched mixture is administered during a counseling session.

[0994] 157. In certain embodiments, there is provided a pharmaceutical composition comprising a therapeutically effective amount for a patient of a compound according to any one of embodiments 31 - 54 and a pharmaceutically acceptable carrier or excipient.

[0995] 158. In certain embodiments, there is provided a pharmaceutical composition comprising a therapeutically effective amount for a patient of an enantiomerically enriched mixture or compound according to any one of embodiments 1 - 138 and a pharmaceutically acceptable carrier or excipient.

[0996] 159. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered systemically.

[0997] 160. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered orally.

[0998] 161. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered to mucosal tissue.

[0999] 162. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered rectally.

[1000] 163. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered topically.

[1001] 164. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered subcutaneously.

[1002] 165. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered intravenously.

[1003] 166. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered intramuscularly.

[1004] 167. The pharmaceutical composition according to embodiment 157 or 158, wherein the composition is administered by inhalation.

[1005] 168. The pharmaceutical composition according to embodiment 157, wherein the composition is administered as a tablet.

[1006] 169. The pharmaceutical composition according to embodiment 157, wherein the composition is administered as a gelcap.

[1007] 170. The pharmaceutical composition according to embodiment 157, wherein the composition is administered as a capsule.

[1008] 171. The pharmaceutical composition according to embodiment 157, wherein the composition is administered as an aqueous emulsion.

[1009] 172. The pharmaceutical composition according to embodiment 157, wherein the composition is administered as an aqueous solution.

[1010] 173. The pharmaceutical composition according to embodiment 157, wherein the composition is administered as a pill.

[1011] 174. The pharmaceutical composition according to embodiment 158, wherein the composition is administered as a lozenge.

[1012] 175. The pharmaceutical composition according to embodiment 158, wherein the composition is administered as a sublingual tablet.

[1013] 176. The pharmaceutical composition according to embodiment 158, wherein the composition is administered as a sublingual strip.

[1014] 177. The pharmaceutical composition according to embodiment 163, wherein the composition is administered as a cream.

[1015] 178. The pharmaceutical composition according to embodiment 163, wherein the composition is administered as a topical solution.

[1016] 179. The pharmaceutical composition according to embodiment 160, wherein the composition is administered as an aqueous solution.

[1017] 180. The pharmaceutical composition according to embodiment 160, wherein the composition is administered as a powder.

[1018] 181. The pharmaceutical composition according to embodiment 160, wherein the composition is administered as an aerosol.

[1019] 182. In certain embodiments, there is provided a compound as described in any one of embodiments 1-138, or an enantiomerically enriched mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating a central nervous system disorder in a host.

[1020] 183. In certain embodiments, there is provided a compound of formula XI, formula XII or formula XIII, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating a central nervous system disorder in a host:

[1021]

[1022] Wherein:

[1023] R 1 and R 2 together are -OCH=CH- or -CH=CHO-;

[1024] R 3L and R 4L are independently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 , wherein at least one of R 3L and R 4L is not -H;

[1025] R 5K is selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[1026] R 5L and R 5M are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX3 、 -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 、 -CH 2 CX 3 、 C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl;

[1027] R 6K 、 R 6L and R 6M are independently selected from -H and -CH 3 ; and

[1028] X is independently selected from -F, -Cl, and -Br.

[1029] 184. In certain embodiments, there is provided a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for treating a central nervous system disorder selected from the following in a host in need thereof: depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic disorder, adjustment disorder, feeding and eating disorders, bulimia nervosa, body dysmorphic syndrome, addiction, substance abuse or dependence disorders, disruptive behavior disorder impulse control disorder, gaming disorder, gambling disorder, amnesia, attention deficit hyperactivity disorder, personality disorder, attachment disorder, autism, and dissociative disorder, wherein the compound is enantiomerically enriched 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB.

[1030] 185. The compound or enantiomerically enriched mixture according to any one of embodiments 182 - 184, wherein the host is a human.

[1031] 186. The compound or enantiomerically enriched mixture according to any one of embodiments 182 - 185, wherein the central nervous system disorder is an anxiety disorder.

[1032] 187. The compound or enantiomerically enriched mixture according to embodiment 186, wherein the anxiety disorder is generalized anxiety.

[1033] 188. The compound or enantiomerically enriched mixture according to embodiment 186, wherein the anxiety disorder is social anxiety.

[1034] 189. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 185, wherein the central nervous system disorder is depression.

[1035] 190. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 185, wherein the central nervous system disorder is post - traumatic stress disorder.

[1036] 191. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 185, wherein the central nervous system disorder is addiction.

[1037] 192. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 185, wherein the central nervous system disorder is an eating disorder.

[1038] 193. A compound or enantiomerically enriched mixture as described in embodiment 192, wherein the eating disorder is bulimia.

[1039] 194. A compound or enantiomerically enriched mixture as described in embodiment 192, wherein the eating disorder is binge - eating.

[1040] 195. A compound or enantiomerically enriched mixture as described in embodiment 192, wherein the eating disorder is anorexia.

[1041] 196. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 185, wherein the central nervous system disorder is an attachment disorder.

[1042] 197. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 185, wherein the central nervous system disorder is schizophrenia.

[1043] 198. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 197, wherein the compound or enantiomerically enriched mixture is administered in a clinical setting.

[1044] 199. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 197, wherein the compound or enantiomerically enriched mixture is administered in a home setting.

[1045] 200. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 197, wherein the compound or enantiomerically enriched mixture is administered during a psychotherapy session.

[1046] 201. A compound or enantiomerically enriched mixture as described in any one of embodiments 182 - 197, wherein the compound or enantiomerically enriched mixture is administered during the consultation phase.

[1047] 202. In certain embodiments, there is provided the use of a compound or an enantiomerically enriched mixture thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as described in any one of embodiments 55 - 138 for the treatment of a central nervous system disorder in a host.

[1048] 203. In certain embodiments, there is provided the use of a compound of formula XI, formula XII or formula XIII or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the treatment of a central nervous system disorder in a host:

[1049]

[1050] Wherein:

[1051] R 1 and R 2 together are -OCH=CH- or -CH=CHO-;

[1052] R 3L and R 4L are independently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 , wherein at least one of R 3L and R 4L is not -H;

[1053] R 5K is selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[1054] R 5L and R5M independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl;

[1055] R 6K , R 6L and R 6M are independently selected from -H and -CH 3 ; and

[1056] X is independently selected from -F, -Cl, and -Br.

[1057] 204. In certain embodiments, there is provided the use of a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for treating a central nervous system disorder selected from the following in a host in need thereof: depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic disorder, adjustment disorder, feeding and eating disorders, bulimia nervosa, body dysmorphic syndrome, addiction, substance abuse or dependence disorders, disruptive behavior disorder impulse control disorder, gaming disorder, gambling disorder, amnesia, attention deficit hyperactivity disorder, personality disorder, attachment disorder, autism, and dissociative disorder, wherein the compound is enantiomerically enriched 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB.

[1058] 205. In certain embodiments, there is provided the use of a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof according to any one of embodiments 55-138 in the manufacture of a medicament for treating a central nervous system disorder in a host.

[1059] 206. In certain embodiments, there is provided the use of a compound of formula XI, formula XII, or formula XIII or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the manufacture of a medicament for treating a central nervous system disorder in a host:

[1060]

[1061] Wherein:

[1062] R 1 and R 2 together are -OCH=CH- or -CH=CHO-;

[1063] R 3L and R 4L are independently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 and -CX 3 wherein at least one of R 3L and R 4L is not -H;

[1064] R 5K is selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 -CX 3 -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 -CH 2 CX 3 C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[1065] R 5L and R 5M are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 -CX 3 -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 -CH 2 CX 3 C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl;

[1066] R 6K 、R 6Land R 6M are independently selected from -H and -CH 3 ; and

[1067] X is independently selected from -F, -Cl, and -Br.

[1068] 207. In certain embodiments, there is provided the use of a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the preparation of a medicament for treating a central nervous system disorder selected from the following in a host in need thereof: depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic disorder, adjustment disorder, feeding and eating disorders, bulimia nervosa, body dysmorphic syndrome, addiction, substance abuse or dependence disorders, disruptive behavior disorders impulse control disorders, gaming disorder, gambling disorder, amnesia, attention deficit hyperactivity disorder, personality disorder, attachment disorder, autism, and dissociative disorder, wherein the compound is enantiomerically enriched 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB.

[1069] 208. The use according to any one of embodiments 202-207, wherein the host is a human.

[1070] 209. The use according to any one of embodiments 202-208, wherein the central nervous system disorder is an anxiety disorder.

[1071] 210. The use according to embodiment 209, wherein the anxiety disorder is generalized anxiety.

[1072] 211. The use according to embodiment 209, wherein the anxiety disorder is social anxiety.

[1073] 212. The use according to any one of embodiments 202-208, wherein the central nervous system disorder is depression.

[1074] 213. The use according to any one of embodiments 202-208, wherein the central nervous system disorder is post-traumatic stress disorder.

[1075] 214. The use according to any one of embodiments 202-208, wherein the central nervous system disorder is addiction.

[1076] 215. The use according to any one of embodiments 202-208, wherein the central nervous system disorder is an eating disorder.

[1077] I. Definitions

[1078] When introducing elements of the present invention or its preferred embodiments, the articles "a", "an", "the" and "said" are intended to mean that there is one or more (one or more) elements. The terms "comprising", "including" and "having" are intended to be inclusive and not exclusive (i.e., there may be other elements in addition to the recited elements). Thus, the terms "comprising", "may comprise" and "including" as used herein refer to the phrase "including but not limited to" and may be used interchangeably with the phrase "including but not limited to".

[1079] When a range of values is provided, it is understood that the upper and lower limits, as well as each intermediate value between the upper and lower limits of the range, are included in the embodiments.

[1080] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention belongs. If a term in this document has multiple definitions, the definition in this section shall prevail unless otherwise stated. Further definitions that may assist the reader in understanding the disclosed embodiments are provided below, and when these terms are used herein, such definitions may be used to interpret the defined terms. However, the examples given in the definitions are generally non-exhaustive and should not be construed as limiting the present invention. It should also be understood that substituents should conform to the bonding rules and steric compatibility limitations associated with the particular molecule to which they are attached.

[1081] As used herein, the term "CNS disorder" refers to a neurological disorder (a disorder typically treated by a neurologist) or a psychiatric disorder (a disorder typically treated by a psychiatrist). Neurological disorders are generally those that affect the structure, biochemistry, or normal electrical function of the brain, spinal cord, or other nerves. Psychiatric disorders are more commonly considered mental disorders, mainly abnormal thoughts, feelings, or behaviors that cause severe distress or impaired personal functioning. Thus, the disclosed compounds can be used in effective amounts to improve the neurological or mental function of patients in need thereof. Neurological indications include, but are not limited to, improving neuroplasticity, including treating stroke, traumatic brain injury, dementia, and neurodegenerative diseases. The compounds of the present invention can be considered small molecules capable of inducing rapid neuroplasticity. For example, in certain embodiments, the disclosed compounds and compositions can be used to improve stuttering and other movement disorders or to treat Parkinson's disease or schizophrenia.

[1082] The term "improvement of mental function" is intended to include mental health and life conditions that are not traditionally treated by neurologists but can sometimes be treated by psychiatrists and can also be treated by psychotherapists, life coaches, personal fitness trainers, meditation teachers, counselors, etc. For example, it is expected that the disclosed compounds will allow an individual to effectively consider actual or possible experiences that are usually disturbing or even overwhelming. This includes a person with a life-threatening illness planning their final days and the disposition of their property. This also includes a couple discussing the difficulties in their relationship and how to resolve them. This also includes an individual who wishes to plan their career more effectively.

[1083] The term "neurotransmission deficiency" is synonymous with CNS disorders that have an adverse effect on normal healthy neurotransmission.

[1084] The present invention also includes compounds, including enantiomerically enriched compounds and their uses, such as 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XII, Formula A, Formula B, Formula C, Formula D, Formula E, and Formula F, having at least one desired atomic isotope substitution in an amount higher than the natural abundance of the isotope, i.e., isotope enrichment. An isotope is an atom having the same atomic number but different mass numbers, i.e., an atom having the same number of protons but different numbers of neutrons.

[1085] Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 36 Cl. In a non-limiting example scenario, isotope-labeled compounds can be used for metabolic studies (with 14 C), reaction kinetics studies (e.g., with 2 H or 3 H), detection or imaging techniques (e.g., positron emission tomography (PET) or single photon emission computed tomography (SPECT), including determination of drug or substrate tissue distribution), or for radiotherapy of patients. In particular, 18Compounds labeled with F may be of particular interest for PET or SPECT studies. The isotopically labeled compounds and prodrugs of the present invention can generally be prepared by substituting non-isotopically labeled reagents with readily available isotopically labeled reagents, by the reaction schemes or examples described below and the procedures disclosed in the preparations.

[1086] As a general example and not by way of limitation, isotopes of hydrogen, such as deuterium ( 2 H) and tritium ( 3 H), can be used anywhere in the structures described to achieve the desired results. Alternatively or additionally, isotopes of carbon, such as 13 C and 14 C, can be used.

[1087] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. In certain embodiments, the isotope is at least 60%, 70%, 80%, 90%, 95% or 99% or more enriched in terms of the isotope at any desired position. In one non-limiting embodiment, deuterium is enriched 90%, 95% or 99% at the desired position.

[1088] In one non-limiting embodiment, substitution of hydrogen atoms by deuterium atoms can be provided in the compounds or compositions described herein. In one non-limiting embodiment, substitution of hydrogen atoms by deuterium atoms occurs within any one of the groups selected from Q, Z, R 1 、R 2 、R 3 、R 4 、R 5 or R 6 . For example, when any group is or contains, by substitution, an alkyl residue such as methyl, ethyl or methoxy, the alkyl residue can be deuterated (in non-limiting embodiments, CDH 2 、CD 2 H、CD 3、 CH 2 CD 3 、CD 2 CD 3 、CHDCH 2 D、CH 2 CD 3 、CHDCHD 2 、OCDH 2 、OCD 2 H、or OCD 3 , etc.). The compounds of the present invention also include isotopically labeled compounds in which one or more atoms have an atomic mass different from that of the atoms conventionally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include 2 H、3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 18 F, and 36 Cl.

[1089] For example, the methyl groups on the nitrogen of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, and Bk-6-MAPB are metabolically removed to produce pharmacologically active metabolites. In some embodiments, 5-MAPB or 6-MAPB is prepared by substituting some or all of the three hydrogens on the N-methyl group with deuterium. In one embodiment, 5-MBPB or 6-MBPB is prepared by substituting some or all of the three hydrogens on the N-methyl group with deuterium. In one embodiment, Bk-5-MAPB or Bk-6-MAPB is prepared by substituting some or all of the three hydrogens on the N-methyl group with deuterium. This results in a higher bond-breaking activation energy and slower formation of methyl metabolites. Similarly, two hydrogens on the furan ring can be substituted with one or two deuteriums to reduce metabolic opening of the furan ring and formation of hydroxylated metabolites.

[1090] Similarly, the methyl groups on the nitrogen of Formula A, Formula B, Formula C, and Formula D of the present invention are metabolically removed to produce pharmacologically active metabolites. In one embodiment, Formula A or Formula B is prepared by substituting some or all of the three hydrogens on the N-methyl group with deuterium. In one embodiment, Formula C or Formula D is prepared by substituting some or all of the three hydrogens on the N-methyl group with deuterium. The primary amines of Formula C and Formula D of the present invention retain the therapeutic effect while presenting a different spectrum of pharmacological effects. Accordingly, where applicable, this disclosure also includes primary amine variants of Formula C and Formula D.

[1091] The ethyl groups on the nitrogen of Formula E and Formula F are also metabolically removed to produce pharmacologically active metabolites. In one embodiment, Formula E or Formula F is prepared by substituting some or all of the three hydrogens on the N-ethyl group with deuterium. The primary amines of Formula E and Formula F of the present invention retain the therapeutic effect while presenting a different spectrum of pharmacological effects. Accordingly, where applicable, this disclosure also includes primary amine variants of Formula E and Formula F.

[1092] When applicable, the methyl or ethyl groups on the nitrogen of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII are also metabolically removed, producing pharmacologically active metabolites. In one embodiment, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII is prepared by substituting some or all of the three hydrogens on the N-ethyl or N-methyl group with deuterium. The primary amines of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, and Formula XIII of the present invention exhibit different pharmacological action profiles while retaining efficacy.

[1093] The term "isotope-labeled" analog refers to an analog such as a "deuterated analog", " 13 C-labeled analog" or a "deuterated / 13 C-labeled analog". The term "deuterated analog" refers to a compound described herein in which the H isotope, i.e., hydrogen / protium ( 1 H), is replaced by the hydrogen isotope, i.e., deuterium ( 2 H). Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium. In certain embodiments, the isotope is at least enriched by 60%, 70%, 80%, 90%, 95%, or 99% or more in terms of the isotope at any desired position. In some embodiments, deuterium is enriched by 90%, 95%, or 99% at the desired position. Unless otherwise stated, the deuteration of the selected position is at least 80%. Deuteration of the nucleoside can occur at any replaceable hydrogen that provides the desired result.

[1094] "Alkyl" refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by removing a hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Typical alkyl groups include methyl; ethyl, such as ethyl, vinyl, ethynyl; propyl, such as propan-1-yl, propan-2-yl, cyclopropyl-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyl, such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutane-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Alkyl is understood to include cyclic alkyl groups, such as cyclopropyl, cyclobutyl and cyclopentyl.

[1095] "Alkyl" includes groups having any degree of saturation or level, i.e., groups having only single carbon-carbon bonds, groups having one or more carbon-carbon double bonds, groups having one or more carbon-carbon triple bonds, and groups having a mixture of carbon-carbon single, double and triple bonds. In cases where a specific degree of saturation is intended, the terms "alkyl", "alkenyl" and "alkynyl" are used. Preferably, alkyl contains 1 to 26 carbon atoms, more preferably 1 to 10 carbon atoms.

[1096] "Halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). For groups containing two or more halogens, such as —CHX 2 or —CX 3 , e.g., "wherein X is halogen", it should be understood that each X is independently selected from halogen.

[1097] "Hydroxy" refers to the group —OH.

[1098] "Oxo" refers to the divalent group ═O.

[1099] "Stereoisomers" include enantiomers, diastereomers, components of racemic mixtures and combinations thereof. Stereoisomers can be prepared or separated as described herein or by using other methods.

[1100] "Isomers" include stereoisomers and geometric isomers, as well as diastereoisomers. Examples of geometric isomers include cis- or trans-isomers across a double bond. Other isomers are contemplated in the compounds of the present disclosure. Isomers can be used in pure form or in admixture with other isomers of the compounds described herein.

[1101] "Agonism" refers to the activation of a receptor or enzyme by a modulator or agonist to produce a biological response.

[1102] "Agonist" refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response. As a non-limiting example, "5HT 1B agonist" can be used to refer to a compound that exhibits an EC 1B not exceeding about 10 μΜ, 25 μΜ or even 50 μM relative to 5HT 50 activity. In some embodiments, "agonist" includes full agonists or partial agonists. "Full agonist" refers to a modulator that binds to and activates a receptor and has the maximum response that an agonist can elicit at the receptor. "Partial agonist" refers to a modulator that binds to and activates a given receptor but has partial efficacy at the receptor relative to a full agonist, i.e., less than the maximum response.

[1103] "Antagonism" refers to the inactivation of a receptor or enzyme by a modulator or antagonist. For example, antagonism of a receptor occurs when a molecule binds to the receptor and does not allow activity to occur.

[1104] "Antagonist" or "neutral antagonist" refers to a modulator that binds to a receptor or enzyme and blocks a biological response. An antagonist has no activity in the absence of an agonist or inverse agonist, but can block the activity of either such that no change in biological response is elicited.

[1105] "DAT to SERT ratio" refers to the tendency of a substance (e.g., a compound or drug) to increase extracellular dopamine relative to increasing extracellular 5-HT concentration. A higher number for this ratio indicates a greater increase in dopamine than in serotonin, while a lower number indicates a greater increase in 5-HT than in dopamine. The exact numbers depend on the assay used. This ratio is calculated herein as (DAT EC50) -1 / (SERT EC50) -1 . Some publications calculate this ratio using the IC50 for inhibition of uptake rather than the EC50 for release, which typically gives very different results for substances that are monoamine releasers. Thus, it is important to review these numbers in light of the assay and measurement used.

[1106] "IC50" refers to the concentration of a substance (e.g., a compound or drug) required to inhibit a biological process by 50%. For example, IC50 refers to the half-maximal (50%) inhibitory concentration (IC) of a substance determined in a suitable assay. Similarly, EC50 refers to the concentration of a substance that elicits a response at the midpoint between baseline activity and maximal response. In some cases, IC50 or EC50 is determined in an in vitro assay system. In some embodiments used herein, IC50 (or EC50) refers to the concentration of a modulator required for 50% inhibition (or activation) of a receptor such as 5HT 1B of a modulator.

[1107] "To modulate" or "modulating" or "modulation" refers to an increase or decrease in the amount, quality, or effect of a particular activity, function, or molecule. By way of illustration and not limitation, agonists, partial agonists, antagonists, and allosteric modulators (e.g., positive allosteric modulators) of G protein-coupled receptors (e.g., 5-HT 1B ) are modulators of the receptor.

[1108] "Neuroplasticity" refers to the ability of the brain to change its structure and / or function throughout the life of a subject. Examples of brain changes include, but are not limited to, the ability to adapt to or respond to internal and / or external stimuli (e.g., due to injury), and the ability to generate new neurites, dendritic spines, and synapses.

[1109] As used in context, "treating" or "treatment" of a disease includes (i) inhibiting the disease, i.e., preventing or reducing the development or progression of the disease or its clinical symptoms; (ii) alleviating the disease, i.e., causing the regression of the disease or its clinical symptoms. For example, inhibiting a disease will include prevention. Thus, those skilled in the art will understand that the amount of treatment necessary to effect treatment for the purposes of the present invention will be, for example, an amount that provides an objective measure of improvement in a patient having clinically diagnosable symptoms. Those of ordinary skill in the art will understand other such measures, benefits, and alternative or clinical endpoints, either alone or in combination.

[1110] II. Compounds of the Invention

[1111] An enantiomerically enriched mixture is a mixture that contains a greater amount of one enantiomer than the other. An enantiomerically enriched mixture of the S-enantiomer contains at least 55% of the S-enantiomer, typically at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or more of the S-enantiomer. An enantiomerically enriched mixture of the R-enantiomer contains at least 55% of the R-enantiomer, typically at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the R-enantiomer. The specific ratio of the S or R enantiomer can be selected by a healthcare professional according to the needs of the patient to balance the desired effects.

[1112] The term enantiomerically enriched mixture as used in this application does not include racemic mixtures and does not include pure isomers or substantially pure isomers. Nevertheless, it should be understood that if any enantiomerically enriched form of a compound described herein achieves the objectives of any of the specifically recited therapeutic methods described herein, it can be used as a substantially pure isomer, including but not limited to 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, 5-Bk-5-MAPB, 6-Bk-MAPB, Bk-5-MBPB or Bk-6-MBPB.

[1113] The chiral carbon commonly referred to in this application is the α-carbon of the amine in the phenethylamine motif. Of course, these compounds can have additional chiral centers, resulting in diastereoisomers. Nevertheless, in this application, the chiral primary carbon referred to in the term "enantiomerically enriched" is the α-carbon of the amine in the provided structure.

[1114] In one aspect of the invention, there is provided a compound comprising an enantiomerically enriched or enantiomerically substantially pure R-5-MAPB, S-5-MAPB, R-6-MAPB or S-6-MAPB, or a pharmaceutically acceptable salt or mixed salt thereof. In one embodiment, there is provided a pharmaceutical composition comprising an enantiomerically enriched mixture of the R- or S-enantiomers of 5-MAPB or 6-MAPB:

[1115]

[1116] In certain embodiments, the isolated enantiomers of the compounds of the invention exhibit improved binding to the desired receptors and transporters relevant to the goal of treating mental disorders or mental enhancement.

[1117] It has been found that enantiomerically enriched mixtures of these empathy-inducing agent compounds that are not racemic mixtures are useful. It has surprisingly been found that enantiomerically enriched mixtures with a greater amount of the S-enantiomer of 5-MAPB or 6-MAPB maximize the serotonin receptor-dependent therapeutic effect, while the enantiomerically enriched R-enantiomer of 5-MAPB or 6-MAPB maximizes the nicotinic receptor-dependent therapeutic effect. Accordingly, one aspect of the invention is a balanced mixture of S-5-MAPB and R-5-MAPB or a balanced mixture of S-6-MAPB and R-6-MAPB that achieves a predetermined combination of serotonin-receptor-dependent therapeutic effects and nicotinic-receptor-dependent or dopaminergic therapeutic effects. The effect can be adjusted as needed to obtain an optimal therapeutic effect.

[1118] Thus, in one embodiment, when administered to a host in need (e.g., a mammal, including a human), an enantiomerically enriched mixture of S-5-MAPB or an enantiomerically enriched mixture of S-6-MAPB maximizes the serotonin receptor-dependent therapeutic effect and minimizes unwanted nicotinic or dopaminergic effects.

[1119] In another embodiment, when administered to a host in need (including a mammal, such as a human), an enantiomerically enriched mixture of R-5-MAPB or an enantiomerically enriched mixture of R-6-MAPB can maximize the nicotinic receptor-dependent or dopaminergic receptor-dependent therapeutic effect while minimizing unwanted effects.

[1120] Non-limiting examples of unwanted effects that can be minimized by careful selection of the enantiomeric balance include hallucinogenic effects, psychoactive effects (such as overstimulation or sedation), physiological effects (such as transient hypertension or appetite suppression), toxic effects (such as effects on the brain or liver), abuse-promoting propensity effects (such as euphoria or dopamine release), and / or other side effects.

[1121] Surprisingly, an enantiomerically enriched mixture of non-racemic 5-MAPB has some relatively large therapeutic effects (such as emotional openness), while having a relatively small effect associated with abuse propensity (such as a perceivable "good drug effect" that can lead to abuse relative to the openness, which results in more peace and tranquility). Thus, one aspect of the present invention is a balanced mixture of S-5-MAPB and R-5-MAPB or a balanced mixture of S-6-MAPB and R-6-MAPB that achieves a predetermined combination of emotional therapeutic effects and perceivable mood effects. The effects can be adjusted as needed to obtain the optimal therapeutic effect.

[1122] Thus, in one embodiment, an enantiomerically enriched mixture of S-5-MAPB or an enantiomerically enriched mixture of S-6-MAPB balances emotional openness and perceivable mood effects when administered to a host in need (e.g., a mammal, including a human).

[1123] In certain embodiments, an S- or R-enantiomerically enriched mixture is preferred. It has surprisingly been found that an enantiomerically enriched mixture with a greater amount of the R-enantiomer of 5-MAPB or 6-MAPB maximizes the nicotinic receptor-dependent therapeutic effect, and an enantiomerically enriched mixture with a greater amount of the S-enantiomer of 5-MAPB or 6-MAPB maximizes the serotonin receptor-dependent therapeutic effect. Accordingly, one aspect of the invention is a balanced mixture of S-5-MAPB and R-5-MAPB or a balanced mixture of S-6-MAPB and R-6-MAPB, which achieves a predetermined combination of serotonin-receptor-dependent therapeutic effects and nicotinic-receptor-dependent therapeutic effects.

[1124] Accordingly, in one embodiment, when administered to a host in need (such as a mammal, including a human), an enantiomerically enriched mixture of S-5-MAPB or an enantiomerically enriched mixture of S-6-MAPB maximizes the serotonin receptor-dependent therapeutic effect and minimizes unwanted nicotinic effects.

[1125] In another embodiment, when administered to a host in need (including a mammal, such as a human), an enantiomerically enriched mixture of R-5-MAPB or an enantiomerically enriched mixture of R-6-MAPB can maximize the nicotinic receptor-dependent therapeutic effect while minimizing unwanted effects.

[1126] The present invention also provides a new medical use of compounds of formula I-X and enantiomerically enriched compositions of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, 5-Bk-5-MAPB, 6-Bk-MAPB, Bk-5-MBPB, Bk-6-MBPB, or compounds of formula A-F, said use being for the treatment of CNS disorders, including but not limited to, depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic disorder, adjustment disorder, feeding and eating disorders, bulimia nervosa, body dysmorphic syndrome, addiction, substance abuse or dependence disorders, disruptive behavior disorder impulse control disorder, gaming disorder, gambling disorder, amnesia, attention deficit hyperactivity disorder, personality disorder, attachment disorder, autism or dissociative disorder or any other disorder described herein, including those described in the background art, by administering an effective amount to a patient (such as a human).

[1127] Several benzofuran derivatives of the invention have been found to be direct 5-HT 1B agonists. Few known substances are 5-HT1B agonists and 5-HT releasers, some of which show significant toxicity. For example, m-chlorophenylpiperazine (mCPP) is an example, but it causes anxiety and headache, thus limiting any clinical application. Accordingly, the 5-HT exhibited by the disclosed compounds1B The unique ratio of stimulation and monoamine release enables different spectra of therapeutic effects, which cannot be achieved by other known empathy stimulants.

[1128] The compounds of the present invention exhibit a 5-HT selectivity pattern that is important for therapeutic use. Various subtypes of 5-HT receptors can elicit different sensory experiences in patients. 5-HT 2A receptor agonism can cause feelings of fear and hallucinations, but 5-HT 1B agonism is thought to be related to the prosocial effects of empathy stimulants. Various subtypes of 5-HT receptors may also pose different toxicity risks to patients. Administration of serotonergic drugs is associated with an increased acute risk of hyponatremia. Stimulation of 5-HT 2 receptors is known to be an important trigger for the release of antidiuretic hormone (Iovino et al., Current pharmaceutical design 18 [Current Drug Design 18], issue 30 (2012): 4714-4724).

[1129] Surprisingly, the enantiomeric compositions of the present invention can be selected as weak agonists of 5-HT 2A but exhibit activity against 5-HT 1B For example, as described in non-limiting illustrative Example 6, most compounds do not exhibit 5-HT 2A agonist activity but exhibit 5-HT 1B agonist activity in the range of about 5 to 0.0005 μM, or 3 to 0.10 μM. Importantly, the 5-HT 1B agonist activity occurs through direct action on the receptor rather than as an indirect result of serotonin release. This is an unexpected finding as this property has not been previously observed in empathy stimulants. In one embodiment, compared to the 5-HT 2A receptor, the selectivity for the 5-HT 1B receptor allows for a more relaxing and therapeutically productive experience for patients receiving treatment with the compounds of the present invention.

[1130] The disclosed compounds exhibit a unique ratio of 5-HT 1B stimulation and 5-HT release that enables different spectra of therapeutic effects and side effects, which cannot be achieved by known empathy stimulants. Adverse effects of 5-HT release may be hyponatremia or loss of appetite. Drugs such as d-fenfluramine, which release 5-HT by interacting with SERT and thereby increase agonism at all serotonin receptors, have been used as anorectics.

[1131] Thus, as described in non-limiting illustrative Example 9, the enantiomeric compositions of the invention have the ability to release 5-HT, with an efficacy (EC50) in the range of about 5 to 0.001 μM or 1.3 to 0.003 μM. Thus, in another embodiment, the selectivity for the 5-HT 1B receptor allows patients treated with the compounds of the invention to have a therapeutically rewarding experience with fewer other side effects of serotonin release, such as decreased appetite or the risk of hyponatremia.

[1132] The invention also includes compounds having beneficial selectivity characteristics for neurotransmitter transporters. The balance between weak activation of NET (to reduce the risk of cardiovascular toxicity) and a relatively low DAT to SERT ratio (to increase the therapeutic effect relative to addictive propensity) is an ideal feature of the empathy-promoting therapies demonstrated by the compounds and compositions of the invention.

[1133] In other embodiments, the invention provides active compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X:

[1134]

[1135]

[1136] wherein:

[1137] R 1 and R 2 together are -OCH=CH- or -CH=CHO-;

[1138] R 3B and R 4B are independently selected from -H, -X, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 and -CX 3 wherein at least one of R 3B and R 4B is not -H;

[1139] R 3I and R 4I are independently selected from -H, -X, -OH, -CH 2 OH, -CH 2 X, -CHX 2 -CX 3 and C 1 -C 4 alkyl; wherein R 3Iand R 4I at least one of them is not -H;

[1140] R 3J and R 4J are independently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 ;

[1141] R 4E is selected from C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 ;

[1142] R 4H is selected from -X, -CH 2 CH 2 CH 3 , -CH 2 OH, -CH 2 X, and -CHX 2 ;

[1143] R 5A and R 5G are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl, when R 5A is C 2 alkyl or H, R 6A is not -H, and when R 5G is -H or C 2 alkyl, R 6G is not -H;

[1144] R 5B is selected from -H, -CH 2OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl;

[1145] R 5C is selected from -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[1146] R 5D , R 5E , R 5F and R 5J are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl, when R 5F is -H or C 1 alkyl, R 6F cannot be -H, and when R 5Jis C 1 When it is an alkyl group, R 3J and R 4J at least one of them is not H;

[1147] R 5I is selected from -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl; wherein R 3I , R 4I and R 5I at least one of them is not C 1 alkyl;

[1148] R 6A , R 6B , R 6E , R 6F and R 6G are independently selected from -H and -CH 3 ;

[1149] X is independently selected from -F, -Cl and -Br; and

[1150] Z is selected from O and CH 2 .

[1151] The compound of formula I-X can be used as a racemic mixture, enantiomerically enriched or diastereomerically enriched or substantially pure or pure isomer to achieve a therapeutic goal.

[1152] In a further embodiment, the present invention includes enantiomerically enriched compounds of formula XI, formula XII and formula XIII or pharmaceutically acceptable salts or mixed salts thereof:

[1153]

[1154]

[1155] Wherein:

[1156] R 1 and R 2Together, they are -OCH=CH- or -CH=CHO-;

[1157] R 3L and R 4L are independently selected from -H, -X, -OH, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 、and -CX 3 , where at least one of R 3L and R 4L is not -H;

[1158] R 5K is selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 、-CX 3 、-CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 、-CH 2 CX 3 、C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl;

[1159] R 5L and R 5M are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 、-CX 3 、-CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 、-CH 2 CX 3 、C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl; and

[1160] R 6K 、R 6L and R 6M are selected from -H and -CH 3 .

[1161] In other embodiments, the present invention provides an enantiomerically enriched compound of Formula A, Formula B, Formula C, Formula D, Formula E or Formula F, or a pharmaceutically acceptable salt or mixed salt thereof, for use in any of the uses described herein by administering to a patient, such as a human, an effective amount of the enantiomerically enriched compound to achieve the desired effect:

[1162]

[1163]

[1164] wherein

[1165] R is hydrogen or hydroxy.

[1166] R A is —CH 3 、—CH 2 Y、—CHY 2 、—CY 3 、—CH 2 CH 3 、—CH 2 CH 2 Y、—CH 2 CHY 2 、—CH 2 CY 3 、—CH 2 OH、or —CH 2 CH 2 OH;

[1167] Q is selected from:

[1168] and

[1169] Y is halogen.

[1170] In certain aspects of these embodiments, an effective amount of a composition of a substantially pure enantiomer (or diastereomer, if relevant) or alternatively an enantiomerically enriched composition (where one enantiomer is in excess over the other) is administered to a host in need, such as a human, and one or more selected compounds of Formulas I - XIII or Formulas A - F can be improved or “modulated”. Thus, as described above, the enantiomeric forms act differently on various 5-HT receptors, dopamine receptors, nicotinic acetylcholine receptors, and norepinephrine receptors, producing different effects, and those effects can be selected based on the desired outcome of the patient.

[1171] In certain embodiments, any selected compound or mixture of the present invention is administered to a patient in an effective amount in combination with psychotherapy, cognitive enhancement, or life coaching (pharmacotherapy) or as part of a conventional medical therapy.

[1172] In one embodiment, the compounds of Formula A and Formula B are halogenated, for example, by replacing one or more hydrogens on the ethyl group attached to the α-carbon with one or more halogens.

[1173] The present invention also provides compounds that can be used in methods for modulating CNS activity and / or in methods for treating CNS disorders (including but not limited to post-traumatic stress disorder and adjustment disorder), said methods comprising administering a compound of Formula C or Formula D or a pharmaceutically acceptable salt thereof:

[1174]

[1175] wherein R A is —CH 3 —, —CH 2 Y, —CHY 2 —, —CY 3 —, —CH 2 CH 3 —, —CH 2 CH 2 —, —CH 2 CHY 2 —, —CH 2 CY 3 —, —CH 2 OH, or —CH 2 CH 2 OH;

[1176] Q is selected from:

[1177] and

[1178] Y is a halogen.

[1179] In one embodiment, the compounds of Formula C and Formula D are halogenated, for example, by replacing one or more hydrogens on the alkyl group attached to the α-carbon with one or more halogens, for example, as defined at position R A (e.g., halo-α-ethyl or α-methyl compounds).

[1180] The present invention also provides compounds that can be used in methods for modulating CNS activity and / or in methods for treating CNS disorders (including but not limited to post-traumatic stress disorder and adjustment disorder), said methods comprising administering a compound of Formula E or Formula F or a pharmaceutically acceptable salt thereof:

[1181]

[1182] wherein R A is —CH 3 —, —CH 2 Y, —CHY 2 —, —CY3 , —CH 2 CH 3 , —CH 2 CH 2 , —CH 2 CHY 2 , —CH 2 CY 3 , —CH 2 , —CH 2 CH 2 OH;

[1183] Q is selected from:

[1184] and

[1185] Y is a halogen.

[1186] In one embodiment, the compounds of Formula E and Formula F are halogenated, for example, by replacing one or more hydrogens on the alkyl group attached to the α-carbon with one or more halogens, for example, as defined at position R A (e.g., halo-α-ethyl or α-methyl compounds).

[1187] The present invention also provides enantiomerically enriched compounds Bk-5-MAPB and Bk-6-MAPB or pharmaceutically acceptable salts or mixed salts thereof:

[1188]

[1189] The compounds can be provided in an enantiomerically enriched composition, for example, a mixture of enantiomers in which one enantiomer is present in excess, particularly 60% or more, 70% or more, 75% or more, 80% or more, 90% or more, 95% or more, or 98% or more (including 100%).

[1190] In certain embodiments, the compounds of the present invention are selected from:

[1191]

[1192] In certain embodiments, the compounds of the present invention are selected from:

[1193] In certain embodiments, the compounds of the present invention are selected from:

[1194]

[1195]

[1196] In certain embodiments, the compounds of the present invention are selected from:

[1197]

[1198]

[1199] In certain embodiments, the compounds of the invention are selected from:

[1200]

[1201]

[1202] In certain embodiments, the compounds of the invention are selected from:

[1203]

[1204]

[1205] In certain embodiments, the compounds of the invention are selected from:

[1206]

[1207]

[1208] In certain embodiments, the compounds of the invention are selected from:

[1209]

[1210] In certain embodiments, the compounds of the invention are selected from:

[1211]

[1212] In certain embodiments, the compounds of the invention are selected from:

[1213]

[1214]

[1215] In certain embodiments, the compounds of the invention are selected from:

[1216]

[1217]

[1218] In certain embodiments, the compounds of the invention are selected from:

[1219]

[1220] In certain embodiments, the compounds of the invention are selected from:

[1221]

[1222] In certain embodiments, the compounds of the present invention are selected from:

[1223]

[1224]

[1225] In certain embodiments, the compounds of the present invention are selected from:

[1226]

[1227]

[1228] In certain embodiments, the compounds of the present invention are selected from:

[1229]

[1230] In certain embodiments, the compounds of the present invention are selected from:

[1231]

[1232]

[1233] In certain embodiments, the compounds of the present invention are selected from:

[1234]

[1235] In certain embodiments, the compounds of the present invention are selected from:

[1236]

[1237]

[1238] In certain embodiments, the compounds of the present invention are selected from:

[1239]

[1240]

[1241] In certain embodiments, the compounds of the present invention are selected from:

[1242]

[1243] In certain embodiments, the compounds of the present invention are selected from:

[1244]

[1245] In certain embodiments, the compounds of the present invention are selected from:

[1246]

[1247]

[1248] In certain embodiments, the compounds of the present invention are selected from:

[1249]

[1250]

[1251] In certain embodiments, the compounds of the present invention are selected from:

[1252]

[1253]

[1254] In certain embodiments, the compounds of the present invention are selected from:

[1255]

[1256]

[1257] In certain embodiments, the compounds of the present invention are selected from:

[1258]

[1259]

[1260] In certain embodiments, the compounds of the present invention are selected from:

[1261]

[1262]

[1263] In certain embodiments, the compounds of the present invention are selected from:

[1264]

[1265] In certain embodiments, the compounds of the present invention are selected from:

[1266]

[1267] In certain embodiments, the compounds of the present invention are selected from:

[1268]

[1269]

[1270] In certain embodiments, the compounds of the present invention are selected from:

[1271]

[1272]

[1273] In certain embodiments, the compounds of the present invention are selected from:

[1274]

[1275]

[1276] In certain embodiments, the compounds of the present invention are selected from:

[1277]

[1278] In certain embodiments, the compounds of the present invention are selected from:

[1279]

[1280] In certain embodiments, the compounds of the present invention are selected from:

[1281]

[1282]

[1283] In certain embodiments, the compounds of the present invention are selected from:

[1284]

[1285]

[1286] In certain embodiments, the compounds of the present invention are selected from:

[1287]

[1288]

[1289] In certain embodiments, the compounds of the present invention are selected from:

[1290]

[1291] In certain embodiments, the compounds of the present invention are selected from:

[1292]

[1293] In certain embodiments, the compounds of the present invention are selected from:

[1294]

[1295] In certain embodiments, the compounds of the present invention are selected from:

[1296]

[1297] In certain embodiments, the compounds of the present invention are selected from:

[1298]

[1299]

[1300] In certain embodiments, the compounds of the present invention are selected from:

[1301]

[1302]

[1303] In certain embodiments, the compounds of the present invention are selected from:

[1304]

[1305] In certain embodiments, the compounds of the present invention are selected from:

[1306]

[1307] In certain embodiments, the compounds of the present invention are selected from:

[1308]

[1309] In certain embodiments, the compounds of the present invention are selected from:

[1310]

[1311]

[1312] In certain embodiments, the compounds of the present invention are selected from:

[1313]

[1314]

[1315] Certain compounds of the present invention may also exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. Accordingly, the chemical structures described herein include all possible tautomeric forms of the depicted compounds. For example, keto-enol tautomerism is the reversible transfer of a hydrogen from an α-carbon adjacent to a carbonyl group, followed by a double bond shift. In solution, compounds spontaneously undergo kinetic conversion from one tautomer to another until equilibrium is reached, typically with a strong preference for the keto tautomer over the enol tautomer, but this depends on factors such as solvent, pH, and temperature. Keto and enol tautomers may have different physicochemical properties; however, since they interconvert in solution, a compound referred to by its keto form (e.g., where Q is ) will be understood to refer to and include its enol form (e.g., where Q is ), unless the context clearly dictates otherwise. These compounds may also exist as ring-chain tautomers, as described below.

[1316] Preparation of Enantiomeric Compounds

[1317] A variety of methods for preparing optically active forms and determining activity are known in the art. Such methods include the standard procedures described herein and other similar assays well known in the art. Examples of methods that can be used to obtain the enantiomers of the compounds according to the present disclosure include, but are not limited to, the following:

[1318] a) Physical separation of crystals, where macroscopic crystals of individual enantiomers are manually separated. This technique can be particularly useful if crystals of the individual enantiomers are present (i.e., the material is a conglomerate) and the crystals are visually distinct;

[1319] b) Simultaneous crystallization (where individual enantiomers crystallize separately from a solution of the racemate), which is only possible when the latter is a solid conglomerate;

[1320] c) Enzymatic resolution, where the racemate is partially or completely separated by the different reaction rates of the enantiomers with an enzyme;

[1321] d) Enzymatic asymmetric synthesis, which is a synthetic technique where at least one synthetic step uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer;

[1322] e) Chemical asymmetric synthesis, where the desired enantiomer is synthesized from achiral precursors under conditions that generate asymmetry (i.e., chirality) in the product, which can be achieved using a chiral catalyst or a chiral auxiliary;

[1323] f) Diastereoisomer separation, in which a racemic compound reacts with an enantiomerically pure reagent (chiral auxiliary), which converts the individual enantiomers into diastereoisomers. The resulting diastereoisomers are then separated by chromatography or crystallization due to their now more distinct structural differences, and the chiral auxiliary is subsequently removed to obtain the desired enantiomer;

[1324] g) First- and second-order asymmetric transformation, whereby the diastereoisomer equilibrium from a racemate is shifted to produce predominantly the diastereoisomers from the desired enantiomer in solution, or in which the preferential crystallization of the diastereoisomers from the desired enantiomer disrupts the equilibrium such that ultimately in principle all of the material is converted to crystalline diastereoisomers from the desired enantiomer. The desired enantiomer is then released from the diastereoisomer;

[1325] h) Kinetic resolution, which involves partial or complete resolution of a racemate (or further resolution of a partially resolved compound) due to the different reaction rates of the enantiomers with a chiral, enantiomerically enriched reagent or catalyst under kinetic conditions;

[1326] i) Enantioselective synthesis from an enantiomerically enriched precursor, whereby the desired enantiomer is obtained from achiral starting materials and the stereochemical integrity is not compromised or only minimally compromised during the synthesis;

[1327] j) Chiral liquid chromatography, in which the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their different interactions with a stationary phase. The stationary phase can be made of a chiral material, or the mobile phase can contain additional chiral material to induce different interactions;

[1328] k) Chiral gas chromatography, in which the racemate is volatilized and the enantiomers are separated according to their different interactions with a column containing a stationary enantiomerically enriched chiral adsorbent phase in the gaseous mobile phase;

[1329] l) Extraction with a chiral solvent, in which enantiomers are separated by preferential dissolution of one enantiomer into a specific chiral solvent; and

[1330] m) Transport across a chiral membrane, in which a racemate is brought into contact with a thin film barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as a concentration or pressure difference causes preferential transport across the membrane barrier. Separation occurs due to the enantiomerically enriched chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through.

[1331] When diastereoisomers are present, the compounds can be used in any diastereoisomeric form or as a mixture of multiple forms, as taught herein, to provide the appropriate therapeutic effect for a patient. Thus, in one embodiment, the compounds of the invention can be administered as a racemic mixture, as the R-enantiomer, as the S-enantiomer, or as an enantiomerically enriched mixture or in diastereoisomeric form.

[1332] The following compounds represent the positions of the major stereocenters when the designated R group is not hydrogen. In certain embodiments, the enantiomers of the invention include:

[1333]

[1334] wherein R 5A is not hydrogen.

[1335] In certain embodiments, the enantiomers of the invention include:

[1336]

[1337] wherein R 5B is not hydrogen.

[1338] In certain embodiments, the enantiomers of the invention include:

[1339]

[1340] wherein R 5C is not hydrogen.

[1341] In certain embodiments, the enantiomers of the invention include:

[1342]

[1343] wherein R 5D is not hydrogen.

[1344] In certain embodiments, the enantiomers of the invention include:

[1345]

[1346] wherein R 5E is not hydrogen.

[1347] In certain embodiments, the enantiomers of the invention include:

[1348]

[1349] wherein R 5F is not hydrogen.

[1350] In certain embodiments, the enantiomers of the present invention include:

[1351]

[1352] wherein R 5G is not hydrogen.

[1353] In certain embodiments, the enantiomers of the present invention include:

[1354]

[1355] wherein R 4H is not hydrogen.

[1356] In certain embodiments, the enantiomers of the present invention include:

[1357]

[1358] In certain embodiments, the enantiomers of the present invention include:

[1359]

[1360] wherein R 5J is not hydrogen.

[1361] In certain embodiments, the enantiomers of the present invention include:

[1362]

[1363] wherein R 5K is not hydrogen.

[1364] In certain embodiments, the enantiomers of the present invention include:

[1365]

[1366] wherein R 5L is not hydrogen.

[1367] In certain embodiments, the enantiomers of the present invention include:

[1368]

[1369] wherein R 5M is not hydrogen.

[1370] Enantiomerically enriched pharmaceutical composition

[1371] The chiral compounds of the present invention can be prepared from racemic or enantiomerically enriched free amines by chiral chromatography. Pharmaceutically acceptable salts of the chiral compounds can be prepared by fractional crystallization of salts of racemic or enantiomerically enriched free amines and chiral acids. Alternatively, the free amine can be reacted with a chiral auxiliary, the enantiomers separated by chromatography, and then the chiral auxiliary removed to regenerate the free amine. In addition, the separation of enantiomers can be carried out at any convenient point in the synthesis of the compounds of the present invention. The compounds of the present invention can also be prepared using chiral synthesis.

[1372] An enantiomerically enriched mixture is a mixture containing a greater amount of one enantiomer than the other. An enantiomerically enriched mixture of the S-enantiomer contains at least 55% of the S-enantiomer, more usually at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% of the S-enantiomer. An enantiomerically enriched mixture of the R-enantiomer contains at least 55% of the R-enantiomer, more usually at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% of the R-enantiomer.

[1373] In one embodiment, an enantiomerically enriched mixture having a greater amount of the R-enantiomer maximizes the nicotinic receptor-dependent therapeutic effect. In one embodiment, an enantiomerically enriched mixture having a greater amount of the S-enantiomer maximizes the serotonin receptor-dependent therapeutic effect. Thus, in one embodiment, an enantiomerically enriched mixture of S-5-MAPB or an enantiomerically enriched mixture of S-6-MAPB, when administered to a host in need (e.g., a mammal, including a human), maximizes the serotonin receptor-dependent therapeutic effect and minimizes the unwanted nicotinic effects. In another embodiment, an enantiomerically enriched mixture of R-5-MAPB or an enantiomerically enriched mixture of R-6-MAPB, when administered to a host in need (including a mammal, such as a human), can maximize the nicotinic receptor-dependent therapeutic effect while minimizing the unwanted effects.

[1374] Non-limiting examples of unwanted effects that can be minimized include psychoactive effects (e.g., overstimulation or sedation), physiological effects (e.g., transient hypertension or appetite suppression), toxic effects (e.g., effects on the brain or liver), pro-abuse propensity effects (such as euphoria or dopamine release), and other side effects.

[1375] One aspect of the present invention is a balanced mixture of S-5-MAPB and R-5-MAPB (non-racemic) or a balanced mixture of S-6-MAPB and R-6-MAPB (non-racemic) that achieves a predetermined combination of serotonin-receptor-dependent therapeutic effects and nicotinic-receptor-dependent therapeutic effects.

[1376] In certain embodiments, pharmaceutical compositions are provided that are enantiomerically enriched formulations of 5-MAPB or 6-MAPB. In one embodiment, the pharmaceutical composition is enriched in S-5-MAPB. In one embodiment, the pharmaceutical composition is enriched in R-5-MAPB. In one embodiment, the pharmaceutical composition is enriched in S-6-MAPB. In one embodiment, the pharmaceutical composition is enriched in R-6-MAPB.

[1377] Example 1 below provides non-limiting examples for preparing certain enantiomerically enriched formulations of 5-MAPB (i.e., containing S-5-MAPB and R-5-MAPB). Enantiomerically enriched formulations of 6-MAPB (i.e., S-6-MAPB, R-6-MAPB) can be produced similarly using racemic 6-MAPB HCl.

[1378] The pharmaceutical compositions of the present invention, including specific embodiments of enantiomerically enriched pharmaceutical compositions, include:

[1379] a) S-5-MAPB;

[1380] b) R-5-MAPB;

[1381] c) S-6-MAPB;

[1382] d) R-6-MAPB;

[1383] e) Embodiments (a)-(d), wherein the compound is a free base;

[1384] f) Embodiments (a)-(d), wherein the compound is a salt;

[1385] g) Embodiment (f), wherein the compound is a hydrochloride salt;

[1386] h) A mixture of S-5-MAPB and R-5-MAPB, with more S-enantiomers than R-enantiomers;

[1387] i) A mixture of S-5-MAPB and R-5-MAPB, with fewer S-enantiomers than R-enantiomers;

[1388] j) A mixture of S-6-MAPB and R-6-MAPB, with more S-enantiomers than R-enantiomers;

[1389] k) A mixture of S-6-MAPB and R-6-MAPB, with fewer S-enantiomers than R-enantiomers;

[1390] l) A mixture of S-5-MAPB and R-5-MAPB, about 65% of the mixture is the S-enantiomer and about 35% of the mixture is the R-enantiomer;

[1391] m) A mixture of S-5-MAPB and R-5-MAPB, more than 65% of the mixture is the S-enantiomer and less than 35% of the mixture is the R-enantiomer;

[1392] n) A mixture of S-5-MAPB and R-5-MAPB, more than 90% of the mixture is the S-enantiomer and less than 10% of the mixture is the R-enantiomer;

[1393] o) A mixture of S-5-MAPB and R-5-MAPB, about 35% of the mixture is the S-enantiomer and about 65% of the mixture is the R-enantiomer;

[1394] p) A mixture of S-5-MAPB and R-5-MAPB, less than 35% of the mixture is the S-enantiomer and more than 65% of the mixture is the R-enantiomer;

[1395] q) A mixture of S-5-MAPB and R-5-MAPB, less than 10% of the mixture is the S-enantiomer and more than 90% of the mixture is the R-enantiomer;

[1396] r) A mixture of S-6-MAPB and R-6-MAPB, about 65% of the mixture is the S-enantiomer and about 35% of the mixture is the R-enantiomer;

[1397] s) A mixture of S-6-MAPB and R-6-MAPB, more than 65% of the mixture is the S-enantiomer and less than 35% of the mixture is the R-enantiomer;

[1398] t) A mixture of S-6-MAPB and R-6-MAPB, more than 90% of the mixture is the S-enantiomer and less than 10% of the mixture is the R-enantiomer;

[1399] u) A mixture of S-6-MAPB and R-6-MAPB, 35% or less of the mixture is the S-enantiomer and 65% or more of the mixture is the R-enantiomer;

[1400] v) A mixture of S-6-MAPB and R-6-MAPB, about 35% of the mixture is the S-enantiomer and about 65% of the mixture is the R-enantiomer; and

[1401] w) A mixture of S-6-MAPB and R-6-MAPB, less than 10% of the mixture is the S-enantiomer and more than 90% of the mixture is the R-enantiomer.

[1402] x) S-5-MBPB;

[1403] y) R-5-MBPB;

[1404] z) S-6-MBPB;

[1405] aa) R-6-MBPB;

[1406] bb) Embodiments (x)-(aa), wherein the compound is a free base;

[1407] cc) Embodiments (x)-(aa), wherein the compound is a salt;

[1408] dd) Embodiment (cc), wherein the compound is a hydrochloride salt;

[1409] ee) A mixture of S-5-MBPB and R-5-MBPB, with more S-enantiomer than R-enantiomer;

[1410] ff) A mixture of S-5-MBPB and R-5-MBPB, with less S-enantiomer than R-enantiomer;

[1411] gg) A mixture of S-6-MBPB and R-6-MBPB, with more S-enantiomer than R-enantiomer;

[1412] hh) A mixture of S-6-MBPB and R-6-MBPB, with less S-enantiomer than R-enantiomer;

[1413] ii) A mixture of S-5-MBPB and R-5-MBPB, wherein about 65% of the mixture is the S-enantiomer and about 35% of the mixture is the R-enantiomer;

[1414] jj) A mixture of S-5-MBPB and R-5-MBPB, with more than about 65% of the mixture being the S-enantiomer and less than about 35% of the mixture being the R-enantiomer;

[1415] kk) A mixture of S-5-MBPB and R-5-MBPB, with more than about 90% of the mixture being the S-enantiomer and less than about 10% of the mixture being the R-enantiomer;

[1416] ll) A mixture of S-5-MBPB and R-5-MBPB, wherein about 35% of the mixture is the S-enantiomer and about 65% of the mixture is the R-enantiomer;

[1417] A mixture of S-5-MBPB and R-5-MBPB, less than about 35% of the mixture is the S-enantiomer, and more than about 65% of the mixture is the R-enantiomer;

[1418] nn) A mixture of S-5-MBPB and R-5-MBPB, less than about 10% of the mixture is the S-enantiomer, and more than about 90% of the mixture is the R-enantiomer;

[1419] oo) A mixture of S-6-MBPB and R-6-MBPB, about 65% of the mixture is the S-enantiomer, and about 35% of the mixture is the R-enantiomer;

[1420] pp) A mixture of S-6-MBPB and R-6-MBPB, more than about 65% of the mixture is the S-enantiomer, and less than about 35% of the mixture is the R-enantiomer;

[1421] qq) A mixture of S-6-MBPB and R-6-MBPB, more than about 90% of the mixture is the S-enantiomer, and less than about 10% of the mixture is the R-enantiomer;

[1422] rr) A mixture of S-6-MBPB and R-6-MBPB, about 35% or less of the mixture is the S-enantiomer, and about 65% or more of the mixture is the R-enantiomer;

[1423] ss) A mixture of S-6-MBPB and R-6-MBPB, about 35% of the mixture is the S-enantiomer, and about 65% of the mixture is the R-enantiomer; and

[1424] tt) A mixture of S-6-MBPB and R-6-MBPB, less than about 10% of the mixture is the S-enantiomer, and more than about 90% of the mixture is the R-enantiomer.

[1425] uu) S-Bk-5-MAPB;

[1426] vv) R-Bk-5-MAPB;

[1427] ww) S-Bk-6-MAPB;

[1428] xx) R-Bk-6-MAPB;

[1429] yy) Embodiments (uu)-(xx), wherein the compound is a free base;

[1430] zz) Embodiments (uu)-(xx), wherein the compound is a salt;

[1431] aaa) Embodiment (zz), wherein the compound is a hydrochloride;

[1432] bbb) A mixture of S-Bk-5-MAPB and R-Bk-5-MAPB, with more S-enantiomers than R-enantiomers;

[1433] ccc) A mixture of S-Bk-5-MAPB and R-Bk-5-MAPB, with fewer S-enantiomers than R-enantiomers;

[1434] ddd) A mixture of S-Bk-6-MAPB and R-Bk-6-MAPB, with more S-enantiomers than R-enantiomers;

[1435] eee) A mixture of S-Bk-6-MAPB and R-Bk-6-MAPB, with fewer S-enantiomers than R-enantiomers;

[1436] fff) A mixture of S-Bk-5-MAPB and R-Bk-5-MAPB, approximately 65% of the mixture is S-enantiomers and approximately 35% of the mixture is R-enantiomers;

[1437] ggg) A mixture of S-Bk-5-MAPB and R-Bk-5-MAPB, more than approximately 65% of the mixture is S-enantiomers and less than approximately 35% of the mixture is R-enantiomers;

[1438] hhh) A mixture of S-Bk-5-MAPB and R-Bk-5-MAPB, more than approximately 90% of the mixture is S-enantiomers and less than approximately 10% of the mixture is R-enantiomers;

[1439] iii) A mixture of S-Bk-5-MAPB and R-Bk-5-MAPB, approximately 35% of the mixture is S-enantiomers and approximately 65% of the mixture is R-enantiomers;

[1440] jjj) A mixture of S-Bk-5-MAPB and R-Bk-5-MAPB, less than approximately 35% of the mixture is S-enantiomers and more than approximately 65% of the mixture is R-enantiomers;

[1441] kkk) A mixture of S-Bk-5-MAPB and R-Bk-5-MAPB, less than approximately 10% of the mixture is S-enantiomers and more than approximately 90% of the mixture is R-enantiomers;

[1442] lll) A mixture of S-Bk-6-MAPB and R-Bk-6-MAPB, approximately 65% of the mixture is S-enantiomers and approximately 35% of the mixture is R-enantiomers;

[1443] mmm) A mixture of S-Bk-6-MAPB and R-Bk-6-MAPB, where more than about 65% of the mixture is the S-enantiomer and less than about 35% of the mixture is the R-enantiomer;

[1444] nnn) A mixture of S-Bk-6-MAPB and R-Bk-6-MAPB, where more than about 90% of the mixture is the S-enantiomer and less than about 10% of the mixture is the R-enantiomer;

[1445] ooo) A mixture of S-Bk-6-MAPB and R-Bk-6-MAPB, where about 35% or less of the mixture is the S-enantiomer and about 65% or more of the mixture is the R-enantiomer;

[1446] ppp) A mixture of S-Bk-6-MAPB and R-Bk-6-MAPB, where about 35% of the mixture is the S-enantiomer and about 65% of the mixture is the R-enantiomer; and

[1447] qqq) A mixture of S-Bk-6-MAPB and R-Bk-6-MAPB, where less than about 10% of the mixture is the S-enantiomer and more than about 90% of the mixture is the R-enantiomer.

[1448] rrr) S-Bk-5-MBPB;

[1449] sss) R-Bk-5-MBPB;

[1450] ttt) S-Bk-6-MBPB;

[1451] uuu) R-Bk-6-MBPB;

[1452] vvv) Embodiments (rrr)-(uuu), where the compound is the free base;

[1453] www) Embodiments (rrr)-(uuu), where the compound is a salt;

[1454] xxx) Embodiment (www), where the compound is the hydrochloride salt;

[1455] yyy) A mixture of S-Bk-5-MBPB and R-Bk-5-MBPB, where the S-enantiomer is more than the R-enantiomer;

[1456] zzz) A mixture of S-Bk-5-MBPB and R-Bk-5-MBPB, where the S-enantiomer is less than the R-enantiomer;

[1457] aaaa) A mixture of S-Bk-6-MBPB and R-Bk-6-MBPB, with more S-enantiomers than R-enantiomers;

[1458] bbbb) A mixture of S-Bk-6-MBPB and R-Bk-6-MBPB, with fewer S-enantiomers than R-enantiomers;

[1459] cccc) S-Bk-5-MBPB and R-Bk-5-MBPB, approximately 65% of the mixture is the S-enantiomer and approximately 35% of the mixture is the R-enantiomer;

[1460] dddd) S-Bk-5-MBPB and R-Bk-5-MBPB, more than approximately 65% of the mixture is the S-enantiomer and less than approximately 35% of the mixture is the R-enantiomer;

[1461] eeee) S-Bk-5-MBPB and R-Bk-5-MBPB, more than approximately 90% of the mixture is the S-enantiomer and less than approximately 10% of the mixture is the R-enantiomer;

[1462] ffff) S-Bk-5-MBPB and R-Bk-5-MBPB, approximately 35% of the mixture is the S-enantiomer and approximately 65% of the mixture is the R-enantiomer;

[1463] gggg) A mixture of S-Bk-5-MBPB and R-Bk-5-MBPB, less than approximately 35% of the mixture is the S-enantiomer and more than approximately 65% of the mixture is the R-enantiomer;

[1464] hhhh) A mixture of S-Bk-5-MBPB and R-Bk-5-MBPB, less than approximately 10% of the mixture is the S-enantiomer and more than approximately 90% of the mixture is the R-enantiomer;

[1465] iiii) S-Bk-6-MBPB and R-Bk-6-MBPB, approximately 65% of the mixture is the S-enantiomer and approximately 35% of the mixture is the R-enantiomer;

[1466] jjjj) S-Bk-6-MBPB and R-Bk-6-MBPB, more than approximately 65% of the mixture is the S-enantiomer and less than approximately 35% of the mixture is the R-enantiomer;

[1467] kkkk) S-Bk-6-MBPB and R-Bk-6-MBPB, more than approximately 90% of the mixture is the S-enantiomer and less than approximately 10% of the mixture is the R-enantiomer;

[1468] llll) A mixture of S-Bk-6-MBPB and R-Bk-6-MBPB, wherein about 35% or less of the mixture is the S-enantiomer and about 65% or more of the mixture is the R-enantiomer;

[1469] mmmm) A mixture of S-Bk-6-MBPB and R-Bk-6-MBPB, wherein about 35% of the mixture is the S-enantiomer and about 65% of the mixture is the R-enantiomer; and

[1470] nnnn) A mixture of S-Bk-6-MBPB and R-Bk-6-MBPB, wherein less than about 10% of the mixture is the S-enantiomer and more than about 90% of the mixture is the R-enantiomer.

[1471] It should be understood that the above-described embodiments and categories of embodiments can be combined to form additional preferred embodiments.

[1472] III. Methods for Treating CNS Disorders, Including Mental Disorders, and Cognitive Enhancement

[1473] The present invention provides methods and uses for treating CNS disorders (including but not limited to the mental disorders described herein, including post-traumatic stress disorder and adjustment disorder), including administering a benzofuran compound or composition described herein or a pharmaceutically acceptable salt or salt mixture thereof. Surprisingly, these compounds exhibit many pharmacological properties that favor their use as therapeutic agents and represent an improvement over existing therapeutic agents.

[1474] The present invention also provides, for example, methods for treating disorders including but not limited to depression, dysthymia, anxiety and fear disorders (including generalized anxiety, social anxiety, panic disorder, post-traumatic stress and adjustment disorder), feeding and eating disorders (including binge eating disorder, bulimia nervosa, and anorexia nervosa), other binge eating disorders, body dysmorphic syndrome, alcoholism, tobacco abuse, drug abuse or dependence disorders, disruptive behavior disorders, impulse control disorders, gaming disorder, gambling disorder, amnesia, attention deficit hyperactivity disorder, personality disorders (including antisocial, avoidant, borderline, histrionic, narcissistic, obsessive-compulsive, paranoid, schizoid and schizotypal personality disorders), attachment disorders, autism, and dissociative disorders.

[1475] In addition to treating various diseases and disorders, the methods for modulating the activity of the serotonergic system employed are particularly useful for improving CNS function in non-disease states, such as reducing neuroticism and psychological defenses, increasing openness to experience, increasing creativity, and assisting in decision-making.

[1476] In other embodiments, a compound or composition of the invention is provided in an effective amount to treat a host, typically a human, having a CNS disorder, which can be a neurological disorder (a disorder typically treated by a neurologist) or a psychiatric disorder (a disorder typically treated by a psychiatrist). Neurological disorders are generally those that affect the structure, biochemistry, or cause electrical abnormalities in the brain, spinal cord, or other nerves. Psychiatric disorders are more commonly considered mental disorders, mainly abnormal thoughts, feelings, or behaviors that cause severe distress or impaired personal functioning.

[1477] Accordingly, the disclosed compounds can be used in an effective amount to improve the neurological or psychiatric function of a patient in need thereof. Neurological indications include, but are not limited to, improving neuroplasticity, including treating stroke, traumatic brain injury, dementia, and neurodegenerative diseases. The compounds of the invention can also be considered small molecules capable of inducing rapid neuroplasticity (Olson, 2018, Journal of experimental neuroscience, 12, 1179069518800508. https: / / doi.org / 10.1177%2F1179069518800508). For example, in certain embodiments, the disclosed compounds and compositions can be used to improve stuttering and other movement disorders or to treat Parkinson's disease or schizophrenia.

[1478] The term "improving psychiatric function" is intended to include mental health and life conditions that are not traditionally treated by neurologists but are sometimes treated by psychiatrists and can also be treated by psychotherapists, life coaches, personal fitness trainers, meditation teachers, counselors, etc. For example, it is expected that the disclosed compounds will allow an individual to effectively consider actual or possible experiences that are usually disturbing or even overwhelming. This includes a person with a life-threatening illness planning their final days and the disposition of their property. This also includes a couple discussing the difficulties in their relationship and how to resolve them. This also includes an individual who wishes to plan their career more effectively.

[1479] In other embodiments, the compositions and compounds of the invention can be used in an effective amount to treat a host, typically a human, to modulate an immune or inflammatory response. The compounds disclosed herein alter extracellular serotonin, which is known to alter immune function.

[1480] The following non-limiting examples are relevant to any of the disorders, indications, methods of use, or dosing regimens described herein.

[1481] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII, or a pharmaceutically acceptable salt or mixed salt, isotopically labeled derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 99%.

[1482] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII, or a pharmaceutically acceptable salt or mixed salt, isotopically labeled derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 95%.

[1483] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII, or a pharmaceutically acceptable salt or mixed salt, isotopically labeled derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 90%.

[1484] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII, or a pharmaceutically acceptable salt or mixed salt, isotopically labeled derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 85%.

[1485] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII, or a pharmaceutically acceptable salt or mixed salt, isotopically labeled derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 80%.

[1486] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII, or a pharmaceutically acceptable salt, mixed salt, isotopically labeled derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 75%.

[1487] In certain embodiments, a host, such as a human, is treated with an enantiomer-enriched mixture of enantiomers of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 70%.

[1488] In certain embodiments, a host, such as a human, is treated with an enantiomer-enriched mixture of enantiomers of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 65%.

[1489] In certain embodiments, a host, such as a human, is treated with an enantiomer-enriched mixture of enantiomers of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 60%.

[1490] In certain embodiments, a host, such as a human, is treated with an enantiomer-enriched mixture of enantiomers of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 55%.

[1491] In certain embodiments, a host, such as a human, is treated with an enantiomer-enriched mixture of enantiomers of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII, or a pharmaceutically acceptable salt or mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 95%.

[1492] In certain embodiments, a host, such as a human, is treated with an enantiomer-enriched mixture of enantiomers of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII, or a pharmaceutically acceptable salt or mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 95%.

[1493] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII or formula XIII, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 90%.

[1494] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII or formula XIII, or a pharmaceutically acceptable salt or mixed salt, isotopic derivative or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 85%.

[1495] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII or formula XIII, or a pharmaceutically acceptable salt or mixed salt, isotopic derivative or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 80%.

[1496] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII or formula XIII, or a pharmaceutically acceptable salt or mixed salt, isotopic derivative or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 75%.

[1497] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII or formula XIII, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 70%.

[1498] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII or formula XIII, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 65%.

[1499] In certain embodiments, a host, such as a human, is treated with an enantiomer-enriched mixture of enantiomers of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, or formula XIII, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 60%.

[1500] In certain embodiments, a host, such as a human, is treated with an enantiomer-enriched mixture of enantiomers of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, or formula XIII, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 55%.

[1501] In certain embodiments, a host, such as a human, is treated with an enantiomer-enriched mixture of enantiomers of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, or formula XIII, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 55% or 60%.

[1502] In certain embodiments, a host, such as a human, is treated with an enantiomer-enriched mixture of enantiomers of a compound of formula A, formula B, formula C, formula D, formula E, or formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 95%.

[1503] In certain embodiments, a host, such as a human, is treated with an enantiomer-enriched mixture of enantiomers of a compound of formula A, formula B, formula C, formula D, formula E, or formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 90%.

[1504] In certain embodiments, a host, such as a human, is treated with an enantiomer-enriched mixture of enantiomers of a compound of formula A, formula B, formula C, formula D, formula E, or formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 85%.

[1505] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of formula A, formula B, formula C, formula D, formula E, or formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 80%.

[1506] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of formula A, formula B, formula C, formula D, formula E, or formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 75%.

[1507] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of formula A, formula B, formula C, formula D, formula E, or formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 70%.

[1508] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of formula A, formula B, formula C, formula D, formula E, or formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 65%.

[1509] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of formula A, formula B, formula C, formula D, formula E, or formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 60%.

[1510] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of formula A, formula B, formula C, formula D, formula E, or formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 55%.

[1511] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of formula A, formula B, formula C, formula D, formula E, or formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 55% or 60%.

[1512] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 99%.

[1513] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 95%.

[1514] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 90%.

[1515] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 85%.

[1516] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 80%.

[1517] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 75%.

[1518] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 70%.

[1519] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 65%.

[1520] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 60%.

[1521] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 55%.

[1522] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a compound of Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 55% or 60%.

[1523] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 99%.

[1524] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 95%.

[1525] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a therapeutically effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 90%.

[1526] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a therapeutically effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 85%.

[1527] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a therapeutically effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 80%.

[1528] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a therapeutically effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 75%.

[1529] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a therapeutically effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 70%.

[1530] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a therapeutically effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 65%.

[1531] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a therapeutically effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 60%.

[1532] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a therapeutically effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 55%.

[1533] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a therapeutically effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the R enantiomer is greater than about 55% or 60%.

[1534] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of a therapeutically effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 99%.

[1535] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of an effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 95%.

[1536] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of an effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 90%.

[1537] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of an effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 85%.

[1538] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of an effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 80%.

[1539] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of an effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 75%.

[1540] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of an effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 70%.

[1541] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of an effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 65%.

[1542] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of an effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 60%.

[1543] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of an effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 55%.

[1544] In certain embodiments, a host, such as a human, is treated with an enantiomerically enriched mixture of enantiomers of an effective amount of 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB, or a pharmaceutically acceptable salt, mixed salt, isotopic derivative, or prodrug thereof, wherein the percentage of the S enantiomer is greater than about 55% or 60%.

[1545] The present invention also provides a method of modulating the CNS of a mammal (including a human) in need thereof by administering a pharmaceutically effective amount of a compound of the present invention, said compound comprising S-5-MAPB, R-5-MAPB, S-6-MAPB, and / or R-6-MAPB, or a pharmaceutically acceptable salt or mixed salt thereof.

[1546] In some embodiments, methods are provided for modulating the CNS of a mammal (including a human) in need thereof by administering a pharmaceutically effective amount of 5-MBPB and / or 6-MBPB or a pharmaceutically acceptable salt thereof. In one embodiment, a method is provided for modulating the CNS of a mammal (including a human) in need thereof by administering a pharmaceutically effective amount of Formula A and / or Formula B or a pharmaceutically acceptable salt thereof. In one embodiment, a method is provided for modulating the CNS of a mammal (including a human) in need thereof by administering a pharmaceutically effective amount of Formula C and / or Formula D or a pharmaceutically acceptable salt thereof. In one embodiment, a method is provided for modulating the CNS in a mammal (including a human) in need thereof by administering a pharmaceutically effective amount of Formula E and / or Formula F or a pharmaceutically acceptable salt thereof. In one embodiment, a method is provided for modulating the CNS of a mammal (including a human) in need thereof by administering a pharmaceutically effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII or a pharmaceutically acceptable salt thereof. In one embodiment, a method is provided for modulating the CNS of a mammal (including a human) in need thereof by administering a pharmaceutically effective amount of a compound of Formula XI, Formula XII, and / or Formula XIII or a pharmaceutically acceptable salt thereof.

[1547] In one embodiment, a method is provided for treating a disease or disorder associated with insufficient neurotransmission function in the CNS, which comprises administering 5-MBPB and 6-MBPB or a pharmaceutically acceptable salt thereof to a host in need thereof.

[1548] In one embodiment, a method is provided for treating a disease or disorder associated with insufficient neurotransmission function in the CNS, which comprises administering 5-MBPB and 6-MBPB or a pharmaceutically acceptable salt thereof to a host in need thereof.

[1549] In one embodiment, a method is provided for treating a disease or disorder associated with insufficient neurotransmission function in the CNS, which comprises administering Bk-5-MAPB and Bk-6-MAPB or a pharmaceutically acceptable salt thereof to a host in need thereof.

[1550] In one embodiment, a method is provided for treating a disease or disorder associated with insufficient neurotransmission function in the CNS, which comprises administering Bk-5-MBPB and Bk-6-MBPB or a pharmaceutically acceptable salt thereof to a host in need thereof.

[1551] In one embodiment, a method is provided for treating a disease or disorder associated with insufficient neurotransmission function in the CNS, which comprises administering Formula A and Formula B or a pharmaceutically acceptable salt thereof to a host in need thereof.

[1552] In one embodiment, there is provided a method of treating a disease or disorder associated with insufficient neurotransmission function in the CNS, which comprises administering a compound of formula C and a compound of formula D or a pharmaceutically acceptable salt thereof to a host in need thereof.

[1553] In one embodiment, there is provided a method of treating a disease or disorder associated with insufficient neurotransmission function in the CNS, which comprises administering a compound of formula E and a compound of formula F or a pharmaceutically acceptable salt thereof to a host in need thereof.

[1554] In one embodiment, there is provided a method of treating a disease or disorder associated with insufficient neurotransmission function in the CNS, which comprises administering a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII or formula XIII or a pharmaceutically acceptable salt thereof to a host in need thereof.

[1555] In one embodiment, there is provided a method of treating a disease or disorder associated with insufficient neurotransmission function in the CNS, which comprises administering a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII or formula XIII or a pharmaceutically acceptable salt thereof to a host in need thereof.

[1556] The present invention also provides for S-5-MAPB, R-5-MAPB, S-6-MAPB and / or R-6-MAPB or a pharmaceutically acceptable salt or composition thereof for treating maladaptive responses to perceived psychological threats. In one embodiment, S-5-MAPB, R-5-MAPB, S-6-MAPB and / or R-6-MAPB or a pharmaceutically acceptable salt or composition thereof is administered in the context of psychotherapy. In one embodiment, S-5-MAPB, R-5-MAPB, S-6-MAPB and / or R-6-MAPB or a pharmaceutically acceptable salt or composition thereof is administered as a monotherapy.

[1557] The present invention also provides for administering an effective amount of 5-MBPB and / or 6-MBPB or a pharmaceutically acceptable salt or composition thereof to a host (typically a human) to treat maladaptive responses to perceived psychological threats. In one embodiment, 5-MBPB and / or 6-MBPB or a pharmaceutically acceptable salt or composition thereof is administered in the context of psychotherapy. In one embodiment, 5-MBPB and / or 6-MBPB or a pharmaceutically acceptable salt or composition thereof is administered as a monotherapy.

[1558] The present invention also provides an effective amount of Formula A or Formula B or a pharmaceutically acceptable salt or composition for treating maladaptive responses to perceived psychological threats. In one embodiment, Formula A or Formula B or a pharmaceutically acceptable salt or composition is administered in the context of psychotherapy. In one embodiment, Formula A or Formula B or a pharmaceutically acceptable salt or composition is administered as a monotherapy.

[1559] The present invention also provides the use of Formula C or Formula D or a pharmaceutically acceptable salt or composition for treating maladaptive responses to perceived psychological threats. In one embodiment, Formula C or Formula D or a pharmaceutically acceptable salt or composition is administered in the context of psychotherapy. In one embodiment, Formula C or Formula D or a pharmaceutically acceptable salt or composition is administered as a monotherapy.

[1560] The present invention also provides the use of Formula E and / or Formula F or a pharmaceutically acceptable salt or composition for treating maladaptive responses to perceived psychological threats. In one embodiment, Formula E and / or Formula F or a pharmaceutically acceptable salt or composition is administered in the context of psychotherapy. In one embodiment, Formula E and / or Formula F or a pharmaceutically acceptable salt or composition is administered as a monotherapy.

[1561] The present invention also provides the use of Bk-5-MAPB and / or Bk-6-MAPB or a pharmaceutically acceptable salt or composition for treating maladaptive responses to perceived psychological threats. In one embodiment, Bk-5-MAPB and / or Bk-6-MAPB or a pharmaceutically acceptable salt or composition is administered in the context of psychotherapy. In one embodiment, Bk-5-MAPB and / or Bk-6-MAPB or a pharmaceutically acceptable salt or composition is administered as a monotherapy.

[1562] The present invention also provides the use of Bk-5-MBPB and / or Bk-6-MBPB or a pharmaceutically acceptable salt or composition for treating maladaptive responses to perceived psychological threats. In one embodiment, Bk-5-MBPB and / or Bk-6-MBPB or a pharmaceutically acceptable salt or composition is administered in the context of psychotherapy. In one embodiment, Bk-5-MBPB and / or Bk-6-MBPB or a pharmaceutically acceptable salt or composition is administered as a monotherapy.

[1563] Non-limiting examples of pharmaceutical uses

[1564] Psychotherapy, cognitive enhancement, or life coaching using the compounds or pharmaceutically acceptable salts described herein as an adjunct (hereinafter referred to as "pharmacotherapy") is typically conducted over long intervals, with one, two, or rarely three or more administrations of an empathy inducer per session. These sessions can be as frequent as once a week, but more commonly are about once a month or even less. In most cases, a patient will need to undergo a small number of pharmacotherapy sessions (about one to three) to experience significant clinical progress, e.g., as indicated by a reduction in signs and symptoms of mental distress, an improvement in functioning in a particular area of life, the achievement of a satisfactory solution to a problem, or an increase in feelings of closeness and understanding of other people. In some embodiments, the psychotherapy, cognitive enhancement, or life coaching is conducted with an effective amount of enantiomerically enriched S-5-MAPB, R-5-MAPB, S-6-MAPB, and / or R-6-MAPB or a pharmaceutically acceptable salt thereof. In some embodiments, the psychotherapy, cognitive enhancement, or life coaching is conducted with an effective amount of enantiomerically enriched Bk-5-MAPB and / or Bk-6-MAPB or a pharmaceutically acceptable salt thereof. Alternatively, the psychotherapy, cognitive enhancement, or life coaching is conducted with an effective amount of enantiomerically enriched Bk-5-MBPB and / or Bk-6-MBPB or a pharmaceutically acceptable salt thereof. In one embodiment, the psychotherapy, cognitive enhancement, or life coaching is conducted with an effective amount of enantiomerically enriched Formula A and / or Formula B or a pharmaceutically acceptable salt thereof. In one embodiment, the psychotherapy, cognitive enhancement, or life coaching is conducted with an effective amount of enantiomerically enriched Formula C and / or Formula D or a pharmaceutically acceptable salt thereof. In one embodiment, the psychotherapy, cognitive enhancement, or life coaching is conducted with an effective amount of enantiomerically enriched Formula E and / or Formula F or a pharmaceutically acceptable salt thereof.

[1565] In one embodiment, the psychotherapy, cognitive enhancement, or life coaching is conducted with an effective amount of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, and / or Formula XIII or a pharmaceutically acceptable salt thereof.

[1566] In one embodiment, the psychotherapy, cognitive enhancement, or life coaching is conducted with an effective amount of Formula XI, Formula XII, and / or Formula XIII or a pharmaceutically acceptable salt thereof.

[1567] The following section provides detailed examples of pharmacotherapy. While common procedures are described, these are illustrative, non-limiting examples. It is anticipated that prescribing physicians and treatment teams may wish to specify procedures different from those described herein based on their clinical judgment of the patient's needs.

[1568] The example treatment method can also be modified with very minor changes to treat multiple patients simultaneously, including couples or families. Thus, "patient" should be understood to refer to one or more individuals.

[1569] Use of the compounds or compositions of the invention in combination with conventional psychotherapy or counseling

[1570] In one embodiment, the use of the compounds or compositions of the invention for medical treatment is integrated into ongoing psychotherapy or counseling (hereinafter simply referred to as "psychotherapy") of the patient. If a patient in need of medical treatment is not in ongoing psychotherapy, a prescribing physician and a treating psychotherapist, physician, coach, clergy, or other similar professional or a person acting under the supervision of such a professional (hereinafter referred to as "therapist") may initiate psychotherapy and add medical treatment after agreeing that medical treatment is necessary and after sufficient meetings have been held between the patient and the therapist to establish an effective therapeutic alliance.

[1571] If the patient has no experience with medical treatment, the therapist or other members of the treatment team will typically engage in a conversation to address the patient's questions and concerns about the medication and to familiarize the patient with the process of the adjunctive medical treatment phase. The therapist describes the various experiences that can be expected during the medical treatment. Optionally, portions of this conversation are in written, recorded, or interactive digital explanations, such as those that might be used in the informed consent process of a clinical trial. The therapist may also commit to supporting the participant's healthcare and wellness process. In turn, the patient may be asked to make their own commitments (such as not harming themselves or others and abstaining from prohibited drugs or medications during appropriate periods before and after the medical treatment).

[1572] The compounds and compositions of the invention (or alternatively, for convenience, referred to herein as "medication") are administered shortly before or during a predetermined psychotherapy phase, optionally choosing the time such that the therapeutic effect begins at the start of the psychotherapy. Shortly before or after administration, the therapist typically reminds them of their mutual commitments and expected events during the treatment phase.

[1573] The psychotherapy phase is carried out by the therapist, optionally the therapist can be remote and communicate with the patient using communication means suitable for telehealth or telemedicine, such as telephone, video, or other remote two-way communication methods. Optionally, video or other monitoring of the patient's responses or behavior is used to record or measure the phase. The therapist uses their clinical judgment and available data to adjust the phase according to the patient's needs. Many therapists consider their responsibility to be to facilitate rather than direct the patient's experience. This may sometimes involve silent empathic listening, while other times may include more active support to help the patient gain a new perspective on their life.

[1574] The therapeutic effects of the drug are expected to enable the patient to make faster therapeutic progress than normal. These effects include reducing nervousness and increasing a sense of reality. Patients are typically able to think calmly about actual or possible experiences that would normally be frustrating or even overwhelming. In addition to mental health, this can facilitate decision-making and creativity.

[1575] Optionally, the prescribing physician may permit a second or even third administration of the drug or another psychotherapeutic agent to prolong the therapeutic effects. Optionally, a modified-release drug formulation is used to make this unnecessary.

[1576] Since the duration of the scheduled psychotherapy phase may be shorter than the therapeutic effects of the drug, the therapist may recommend that the patient engage in activities that support further psychotherapeutic progress after the psychotherapy phase ends. Alternatively, the therapist may continue to work with the patient until the therapeutic effects of the drug become clinically minimal.

[1577] During subsequent non-drug psychotherapy phases, the therapist and patient typically discuss the patient's experiences during the drug therapy phase. The therapist typically helps the patient recall the therapeutic effects and helps them integrate these experiences into daily life.

[1578] Based on the judgment of the treating physician and the treatment team regarding the patient's needs, the drug therapy phase may be repeated as needed.

[1579] Use of the compounds or compositions of the invention outside of conventional psychotherapy

[1580] In one embodiment, the compounds or compositions of the invention are administered outside of conventional psychotherapy. This exemplary method is a broader and more flexible approach to drug therapy that is not centered around therapist supervision. These drug therapy phases can be conducted in many different quiet and safe environments, including the patient's home. The environment typically chosen is one that provides a quiet setting with minimal distractions and allows the patient to feel psychologically safe and emotionally relaxed. The environment can be the patient's home or a clinic, a convalescent center, or a hotel room.

[1581] In an alternative embodiment, the patient takes the drug regularly to maintain a therapeutic concentration of the active compound in the blood. In another alternative embodiment, the drug is taken as needed for a prescribed psychotherapy phase.

[1582] Optionally, a checklist can be followed to prepare the immediate environment to minimize distractions and maximize the therapeutic or decision-making benefits. The checklist may include the following items: muting the phone and other communication devices, cleaning and tidying the environment, preparing snacks, preparing a playlist of appropriate music, and arranging transportation at the end of the phase in advance if the patient is not receiving the drug therapy at home.

[1583] Before the pharmacological treatment phase, treatment goals or other life-related goals (e.g., decision-making, increased creativity, or simply enjoying life) may be preliminarily determined, which will be the focus of the pharmacological treatment phase. These goals are optionally determined in advance with the support of a therapist.

[1584] Optionally, the therapist may assist the patient in selecting stimuli, such as photos, videos, augmented or virtual reality scenarios, or small objects such as personal items, which will help focus the patient's attention on the goals of the pharmacological treatment phase or the patient's broader life journey. As illustrative but non-limiting examples, these stimuli may include photos of the patient when they were young, which can increase self-compassion, or may include stimuli related to traumatic events or phobias the patient has experienced, which can help the patient re-evaluate and change their response to such stimuli. Optionally, the patient selects these stimuli without assistance (e.g., without the involvement of a therapist) or does not use any stimuli. Optionally, the stimuli are selected in real-time by the therapist or an algorithm based on phase events, with the aim of maximizing the benefit to the patient.

[1585] If the patient has no experience with pharmacological treatment, the therapist conducts a conversation to address the patient's questions and concerns about the medication and familiarize the patient with the process of the pharmacological treatment adjunct phase. The therapist describes the various experiences that can be expected during the pharmacological treatment adjunct phase. Optionally, parts of this conversation are in written, recorded, or interactive digital form, as might be used in the informed consent process for a clinical trial. The therapist may also commit to supporting the participant's healthcare and wellness process. In turn, the patient may be asked to make their own commitments (e.g., not to harm themselves or others and to abstain from prohibited drugs or medications during appropriate periods before and after pharmacological treatment).

[1586] The selected phase goals and any commitments or other agreements regarding behavior between the patient and the treatment team are reviewed immediately before administration. Depending on the pharmaceutical formulation and route of administration, the therapeutic effects of the medication typically begin within an hour. Typical therapeutic effects include reducing neuroticism and increasing a sense of reality. The patient is usually able to calmly think about actual or possible experiences that would typically be frustrating or even overwhelming. In addition to mental health, this can also facilitate decision-making and creativity.

[1587] Optionally, a sleep mask and headphones with music or soothing noise can be used to reduce environmental distractions. Optionally, a virtual reality or immersive reality system can be used to provide stimuli that support the treatment process. Optionally, these stimuli are preselected; optionally, they are selected in real time by an individual or an algorithm based on events in the phase, with the aim of maximizing the benefit to the patient. Optionally, a therapist or another person familiar to the patient is nearby or available by phone, video, or other communication methods in case the patient wishes to talk; however, the patient can choose to undergo the treatment phase without the help of a therapist. Optionally, the patient can write or create artworks related to the goals of the selected treatment phase. Optionally, the patient can practice stretching exercises or other beneficial physical movements, such as yoga ("physical activity").

[1588] Optionally, in other embodiments, the patient can practice physical activities that include more strenuous physical movements, such as dancing or other aerobic exercises. The physical activity can also use fitness equipment such as a treadmill or a bicycle.

[1589] In some additional embodiments, music, video, auditory messages, or other perceptual stimuli can be presented to the patient. Optionally, these stimuli can be adjusted according to the patient's movements or other measurable aspects. This adjustment can be done by a therapist with or without the help of a computer, or by the computer alone in response to the patient aspects, including through algorithms or artificial intelligence, and "computer" broadly refers to any electronic tool suitable for such purposes, whether worn or attached to the patient (e.g., watches, fitness trackers, "wearable devices" and other personal devices; biosensors or medical sensors; medical devices), whether directly coupled or wired to the patient or wirelessly connected (including desktops, laptops, and notebooks; tablets, smartphones, and other mobile devices; etc.), whether in the treatment room or remotely (e.g., cloud-based systems).

[1590] For example, the measurable aspects of the patient from these tools (e.g., facial expressions, eye movements, respiratory rate, pulse rate, skin color changes, patient voice quality or content, patient responses to questions) can be individually transformed into scores on a standardized scale by subtracting the typical value and then multiplying by a constant, and these scores can be further multiplied by a constant and added together to create a total score, which can optionally be transformed by multiplying by a link function such as a logit function to create a total score. This score can be used to select or adjust the stimuli, such as selecting music with a higher or lower beat per minute or faster or slower notes, selecting images, audio, or video with different emotional or autobiographical meanings, or selecting activities in which the patient participates (e.g., specific actions, diary prompts, or meditation mantras).

[1591] It should be readily understood that patients can engage in a number of therapeutically beneficial activities, where such engagement occurs after or in conjunction with the administration of a compound or composition of the present invention, including writing about a preselected topic, participating in yoga or other physical activities, meditation, creating art, viewing photographs or videos or objects that evoke emotions, using virtual reality or augmented reality systems, talking to people, and thinking about preselected questions or topics. It should be understood that such engagement can occur with or without the involvement or guidance of a therapist.

[1592] Optionally, the prescribing physician may permit a second or even third administration of the drug or another psychotherapeutic agent to prolong the therapeutic effect. Optionally, a modified-release pharmaceutical formulation is used to obviate this need.

[1593] Typically within eight hours, the patient generally remains in the immediate environment until the acute therapeutic effect of the drug has clinically minimized. After this point, the phase is considered complete.

[1594] The treatment plan generally includes a follow-up phase with the therapist. The follow-up phase occurs after the end of the drug treatment phase, typically the next day, but sometimes several days later. During this phase, the patient discusses their experiences during the drug treatment phase with the therapist, and the therapist can help them recall the therapeutic effects and help them integrate these experiences into their daily lives.

[1595] The drug treatment phase can be repeated as needed, depending on the judgment of the treating physician and treatment team regarding the patient's needs.

[1596] IV. Pharmaceutical Compositions and Salts

[1597] The compounds and compositions described herein can be administered as pure chemicals in effective amounts, but more typically are administered as pharmaceutical compositions in effective amounts to a host (usually a human) in need of such treatment to treat any of the disorders described herein. The compounds or compositions disclosed herein can be administered orally, topically, systemically, parenterally, by inhalation, insufflation or spraying, mucosally (e.g., oral, sublingual), sublingually, transdermally, rectally, intravenously, intra-aortically, intracranially, subcutaneously, intraperitoneally, intramuscularly, by inhalation, intranasally, subcutaneously, via nasal or by other means in dosage unit formulations containing conventional pharmaceutically acceptable carriers. Such compositions are prepared in a manner well known in the pharmaceutical art and contain at least one active compound. (See, e.g., Remington, 2005, Remington: The science and practice of pharmacy, 21st ed., Lippincott Williams & Wilkins.)

[1598] The pharmaceutical composition can be formulated into any pharmaceutically useful form, such as an aerosol, cream, gel, pill, injection or infusion solution, capsule, tablet, syrup, transdermal patch, subcutaneous patch, dry powder, inhalation preparation, suppository, buccal or sublingual preparation, parenteral preparation, eye drops or medical device. Some dosage forms, such as tablets and capsules, are subdivided into appropriately sized unit doses, each containing a suitable amount of the active ingredient, such as an effective amount to achieve the desired purpose.

[1599] Accordingly, a "pharmaceutically acceptable composition" means at least one compound of the present invention (which may be a mixture of enantiomers or diastereomers, as fully described herein) and a pharmaceutically acceptable vehicle, excipient, diluent or other carrier, in an amount effective to treat a host, typically a human, who may be a patient.

[1600] In certain non-limiting embodiments, the pharmaceutical composition is a dosage form containing from about 0.1 mg to about 1500 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 1500 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples are dosage forms having at least 0.1, 1, 5, 10, 20, 25, 40, 50, 100, 125, 150, 200, 250, 300, 400, 500, 600, 700, or 750 mg of the active compound or its salt or mixed salts.

[1601] The pharmaceutical compositions described herein can be formulated into any suitable dosage form, including tablets, capsules, caplets, aqueous oral dispersions, aqueous oral suspensions, solid dosage forms, including oral solid dosage forms, aerosols, controlled release preparations, fast dissolving preparations, effervescent preparations, self-emulsifying dispersions, solid solutions, liposomal dispersions, lyophilized preparations, pills, powders, sustained release preparations, immediate release preparations, modulated release preparations, extended release preparations, pulsatile release preparations, multiparticulate preparations and mixed immediate release and controlled release preparations. Generally, the composition should be administered in an effective amount such that a certain amount of the active agent of the present invention reaches a plasma level commensurate with an effective concentration in vivo for a sustained effective period of time to elicit the desired therapeutic effect without a tendency for abuse.

[1602] In preparing the compositions used in the present invention, the active ingredient is usually admixed with excipients, diluted with excipients, or enclosed within a carrier in the form of capsules, sachets, papers or other containers. When the excipient serves as a diluent, it can be a solid, semi-solid or liquid material serving as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets (including orally disintegrating, swallowable, sublingual, buccal, and chewable tablets), pills, powders, troches, lozenges, oral films, flakes, granules, flat capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid or liquid media), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, dry powders for inhalation, liquid preparations for vaporization and inhalation, topical preparations, transdermal patches, sterile injectable solutions, and sterile packaged powders. The compositions can be formulated for immediate release, controlled release, sustained release (extended release) or modified release formulations.

[1603] The compositions of the present invention can be administered by a variety of routes, which may vary among different patients depending on the preferences of the different patients, co-morbidities, side effect profiles and other factors (IV, PO, transdermal, etc.). In one embodiment, the pharmaceutical composition includes other substances known to those skilled in the art having active drugs, such as fillers, carriers, gels, skin patches, lozenges or other modifications in the formulation to facilitate absorption through various routes (e.g., but not limited to the gastrointestinal tract, transdermal, etc.) and / or to prolong the action of the drug, and / or to achieve higher or more stable serum levels or to enhance the therapeutic action of the active drug in the combination.

[1604] In preparing the formulation, it may be necessary to grind the active compound to provide a suitable particle size before combining it with the other ingredients. If the active compound is substantially insoluble, it is usually ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size is usually adjusted by grinding to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.

[1605] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations can additionally include, but are not limited to, lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweetening agents; and flavoring agents. The compositions of the present invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient using procedures known in the art.

[1606] The composition is preferably formulated into unit dosage forms, each dosage containing at least about 0.05 to about 350 mg or less, more preferably at least about 5.0 to about 180 mg or less of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of the active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.

[1607] The active compounds are effective over a wide dosage range. For example, the dosage as needed usually falls within the range of at least about 0.01 mg / kg to about 4 mg / kg or less. In adult therapy, a single dose in the range of at least about 0.2 mg / kg to about 3 mg / kg or less is particularly preferred.

[1608] It should be understood that the amount of the compound actually administered will be determined by the physician in accordance with relevant circumstances, including the disorder to be treated, the route of administration selected, the one or more compounds actually administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms. Thus, the above dosage ranges are not intended to limit the scope of the invention in any way.

[1609] In some cases, dosage levels below the lower limit of the above range may be entirely sufficient, while in other cases, larger doses may be used without causing any harmful side effects, provided that, for example, such larger doses can be first divided into several smaller administered doses.

[1610] Generally, the pharmaceutical compositions of the present invention can be administered and given in accordance with good medical practice, taking into account the method and timing of administration, previous and concomitant medications and medical supplements, the clinical condition of the individual patient and the severity of the underlying disease, the age, sex, weight of the patient, and other such factors relevant to the medical practitioner, as well as the knowledge of the one or more specific compounds used. Thus, the starting dosage level and the maintenance dosage level can vary for individual patients at different times, and for different pharmaceutical compositions, but should be determinable with ordinary skill.

[1611] In one embodiment, a powder comprising the active agent of the present invention described herein can be formulated to include one or more pharmaceutical excipients and flavoring agents. Such a powder can be prepared, for example, by mixing the active agent of the present invention with optional pharmaceutical excipients to form a bulk blend composition. Further embodiments also include suspending agents and / or wetting agents....

Claims

1. An enantiomerically enriched mixture of the S-enantiomer and the R-enantiomer of an enantiomer pair of formula A, formula B, formula C, formula D, formula E or formula F below, or a pharmaceutically acceptable salt or mixed salt thereof, wherein the separated enantiomerically enriched mixture has 65% to 85% of the S-enantiomer: Wherein: R is hydrogen or hydroxy; R A is -CH 3 、-CH 2 Y, -CHY 2 、-CY 3 、-CH 2 CH 3 、-CH 2 CH 2 Y, -CH 2 CHY 2 、-CH 2 CY 3 、—CH 2 OH, or —CH 2 CH 2 OH; Q is selected from: and Y is F or C1.

2. The separated enantiomerically enriched mixture according to claim 1, wherein the enantiomer pair is selected from those in the following a) to h): a) b) c) d) e) f) g) or h) Or a pharmaceutically acceptable salt or mixed salt thereof.

3. An enantiomerically enriched mixture of the S-enantiomer and the R-enantiomer of an enantiomer pair of formula A, formula B, formula C, formula D, formula E or formula F below, or a pharmaceutically acceptable salt or mixed salt thereof, wherein the separated enantiomerically enriched mixture has 65% to 85% of the R-enantiomer: Wherein: R is hydrogen or hydroxy; RA is —CH 3 、—CH 2 Y、—CHY 2 、—CY 3 、—CH 2 CH 3 、—CH 2 CH 2 Y、—CH 2 CHY 2 、—CH 2 CY 3 、—CH 2 OH、 or —CH 2 CH 2 OH; Q is selected from: and Y is F or Cl.

4. The separated enantiomerically enriched mixture according to claim 3, wherein the enantiomer pair is selected from those in the following a) to h): a) b) c) d) e) f) g) or h) Or a pharmaceutically acceptable salt or mixed salt thereof.

5. A compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X: Or a pharmaceutically acceptable salt or mixed salt thereof, Wherein: R 1 and R 2 together are -OCH=CH- or -CH=CHO-; R 3B and R 4B are independently selected from -H, -X, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 , wherein at least one of R 3B and R 4B is not -H; R 3I and R 4I are independently selected from -H, -X, -OH, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , and C 1 -C 4 alkyl; wherein at least one of R 3I and R 4I is not -H; R 3J and R 4J are independently selected from -H, -X, -OH, C 1 -C 4 -alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 ; R 4E selected from C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 and -CX 3 ; R 4H Selected from -X, -CH 2 CH 2 CH 3 , -CH 2 OH, -CH 2 X, and -CHX 2 ; R5 A and R5 G are independently selected from -H, -CH 2 OH, -CH2X, -CHX2, -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH2CHX 2 , -CH2CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl, provided that when R5 A is C 2 alkyl or H, R6 A is not -H, and provided that when R5 G is -H or C 2 alkyl, R6 G is not -H; R 5B selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH2CHX2, -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl; R5 C selected from -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH2CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl; R 5D , R 5E , R 5F and R 5J Independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 、-CX 3 、-CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 、-CH 2 CX 3 , C 3 -C 4 Cycloalkyl, and C 1 -C 4 Alkyl, when R 5F Yes - H or C 1 When alkyl, R 6F Cannot be -H, and when R 5J It is C 1 When alkyl, R 3J and R 4J At least one of them is not H; R5I is selected from -CH 2 OH, -CH2X, -CHX2, -CX 3 , -CH2CH 2 OH, -CH2CH2X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl; wherein at least one of R 3I , R 4I and R5I is not C 1 alkyl; R 6A 、R 6B 、R 6E 、R 6F and R 6G are independently selected from -H and -CH 3 ; X is independently selected from -F, -Cl and -Br; and Z is selected from O and CH 2 .

6. An enantiomerically enriched mixture of the S-enantiomer and the R-enantiomer of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X: Or a pharmaceutically acceptable salt or mixed salt thereof, Wherein: R 1 and R 2 together are -OCH=CH- or -CH=CHO-; R 3B and R 4B are independently selected from -H, -X, C 1 -C 4 -alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 , wherein at least one of R 3B and R 4B is not -H; R 3I and R 4I are independently selected from -H, -X, -OH, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , and C 1 -C 4 -alkyl; wherein at least one of R 3I and R 4I is not -H; R 3J and R 4J are independently selected from -H, -X, -OH, C 1 -C 4 -alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 ; R 4E Selected from C 1 -C 4 alkyl, -CH 2 OH, -CH 2 X, -CHX 2 and -CX 3 ; R 4H Selected from -X, -CH 2 CH 2 CH 3 , -CH 2 OH, -CH 2 X, and -CHX 2 ; R5 A and R5 G are independently selected from -H, -CH 2 OH, -CH2X, -CHX2, -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH2CHX 2 , -CH2CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl, provided that when R5 A is C 2 alkyl or H, R6 A is not -H, and provided that when R5 G is -H or C 2 alkyl, R6 G is not -H; R 5B selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH2CHX2, -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl; R 5C Selected from -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH2CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl; R 5D , R 5E , R 5F and R 5J Independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 、-CX 3 、-CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 、-CH 2 CX 3 , C 3 -C 4 Cycloalkyl, and C 1 -C 4 Alkyl, when R 5F Yes - H or C 1 When alkyl, R 6F Cannot be -H, and when R 5J It is C 1 When alkyl, R 3J and R 4J At least one of them is not H; R5I is selected from -CH 2 OH, -CH2X, -CHX 2 , -CX 3 , -CH2CH 2 OH, -CH2CH2X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl; wherein at least one of R 3I , R 4I and R5I is not C 1 alkyl; R 6A , R 6B , R 6E , R 6F and R 6G Independently selected from -H and -CH 3 ; X is independently selected from -F, -C1 and -Br; and Z is selected from O and CH 2 .

7. An enantiomerically enriched mixture of the S-enantiomer and the R-enantiomer of a compound of formula XI, formula XII or formula XIII: Or a pharmaceutically acceptable salt or mixed salt thereof, Wherein: R 1 and R 2 together are -OCH=CH- or -CH=CHO-; R 3L and R 4L are independently selected from -H, -X, -OH, C 1 -C 4 -alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 , wherein at least one of R 3L and R 4L is not -H; R 5K Selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH2CHX2, -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl; R 5L and R 5M are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH2CHX 2 , -CH2CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl; R 6K , R 6L and R 6M Selected from -H and -CH 3 ;and X is independently selected from -F, -Cl and -Br.

8. Use of the compound according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the treatment of central nervous system disorders.

9. Use of a compound of formula XI, formula XII or formula XIII or a pharmaceutically acceptable salt or mixed salt thereof or a pharmaceutical composition thereof, in the preparation of a medicament for the treatment of central nervous system disorders: Wherein: R 1 and R 2 together are -OCH=CH- or -CH=CHO-; R 3L and R 4L are independently selected from -H, -X, -OH, C 1 -C 4 -alkyl, -CH 2 OH, -CH 2 X, -CHX 2 , and -CX 3 , wherein at least one of R 3L and R 4L is not -H; R 5K Selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH2X, -CH2CHX2, -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl; R 5L and R 5M are independently selected from -H, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 0H, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl; R 6K , R 6L and R 6M Selected from -H and -CH 3 ;and X is independently selected from -F, -Cl and -Br.

10. Use of a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the preparation of a medicament for treating a central nervous system disorder selected from the group consisting of: depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic disorder, adjustment disorder, feeding and eating disorders, bulimia nervosa, body dysmorphic syndrome, addiction, substance abuse or dependence disorders, disruptive behavior disorders impulse control disorders, gaming disorder, gambling disorder, amnesia, Alzheimer's disease, attention deficit hyperactivity disorder, personality disorder, attachment disorder, autism or dissociative disorder, wherein the compound is an isolated enantiomerically enriched 5-MAPB, 6-MAPB, 5-MBPB, 6-MBPB, Bk-5-MAPB, Bk-6-MAPB, Bk-5-MBPB, or Bk-6-MBPB.

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