Azetidinyl tryptamine and methods for treating mental disorders

Abstract

The present disclosure includes azetidinyltryptamines and methods of treating psychiatric disorders with such compounds. Pharmaceutical compositions containing the azetidinyltryptamines are also provided.

Description

[Technical Field]

[0001] Technical field Novel azetidinyltryptamines and methods for treating mental disorders with such compounds. Pharmaceutical compositions comprising azetidinyltryptamines are also provided. [Background technology]

[0002] background Tryptamine is a diverse class of alkaloids that contains a structural scaffold for the natural alkaloid tryptamine. [ka]

[0003] There are many tryptamine compounds, including naturally occurring compounds as well as synthetic and semi-synthetic chemical derivatives with similar structures. Tryptamines are known to have diverse psychoactive and physiological effects. Some tryptamines are serotonin 2A (5-HT2A) receptor agonists and / or modulators of other serotonin receptors and are known to be psychoactive and / or vasoconstrictive. In some cases, such compounds induce persistent hallucinations. Other tryptamines are modulators of monoamine transporters. The most well-known tryptamines are psychedelic compounds, including compounds derived from hallucinogenic fungi (psilocybin and psilocine), DMT, LSD, 5-MeO-DMT, bufotenine, and ibogaine. These compounds are known to have significant effects on thought, perception, and behavior. However, due to their high potential for abuse, lack of acceptable medical use, and lack of established safety, these compounds are now classified as Schedule I drugs under the Controlled Substances Act. Furthermore, tryptamines are metabolized in some cases by several pathways, including monoamine oxidase, which limits the oral bioavailability of some compounds. [Overview of the Initiative]

Problems to be Solved by the Invention

[0004] Therefore, there is still a need for a safe and effective tryptamine compound that can be reliably used in the treatment of mental disorders.

Means for Solving the Problems

[0005] Overview The present disclosure relates to a compound having the general formula I:

Chemical Formula

[0006] This disclosure further provides pharmaceutical compositions comprising one or more of the compounds of this disclosure.

[0007] This disclosure further provides a method for treating a mental illness or disorder in a patient in need thereof, the method comprising the step of administering to the subject a composition comprising an effective amount of the compound of this disclosure. Brief explanation of the drawing [Brief explanation of the drawing]

[0008] [Figure 1] This figure shows immobility time in Fasting-to-Study (FST). One-way ANOVA revealed a significant main effect of treatment on total immobility time in FST (F(5,54)=19.35, P<0.0001). Dunnett's multiple comparison test was used to examine whether a group was significantly different from the vehicle. All treatments were significantly different from the vehicle. ****P<.0001 vs. vehicle. [Figure 2] This figure shows swimming time in Fast-Track Day (FST). One-way ANOVA revealed a significant main effect of the treatment on total swimming time in FST (F(5,54)=9.606, P<0.0001). Dunnett's multiple comparison test was used to examine whether one group was significantly different from the vehicle group. **P<.01, ****P<.0001 vs. vehicle. [Modes for carrying out the invention]

[0009] Detailed explanation Numerous specific details are provided in the detailed description below to give a thorough understanding of this disclosure. However, it will be understood by those skilled in the art that this disclosure can be put into practice without these specific details. Where otherwise, well-known methods, procedures, and components are not described in detail so as not to make this disclosure difficult to understand.

[0010] This specification describes novel azetidinyltryptamines and methods for treating mental disorders with such compounds. Pharmaceutical compositions comprising azetidinyltryptamines are also provided. The compounds provided have superior efficacy as serotonin 1A (5-HT1A) receptor agonists compared to their acyclic counterparts, such as tryptamines supported with N,N-dimethyl substituents. Furthermore, the compounds have better metabolic stability than such N,N-dimethyl counterparts.

[0011] This disclosure relates to compounds having general formula I: [ka] [In the formula, R 1 ~R 6 Each of these is independently selected from the group consisting of -H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 heteroalkyl, C2-C5 heteroalkenyl, C2-C5 heteroalkynyl, and C1-C5 halo-alkyl. R 7 ~R 10 and R 12 -H, -F, -Cl, -Br, -I, -CF3, -SF5, C1~C 10 Alkyl, C2~C 10 Alkenyl, C2~C 10 Alkinyl, C1~C 10 Heteroalkyl, C2~C 10 Heteroalkenyl, C2~C 10 Heteroalkynyl, C1~C10 Halo-alkyl, -CN, -O-(C1~C 10 Alkyl), -O-(C1~C 10 Heteroalkyl), -S-(C1~C 10 Alkyl), -S-(C1~C 10 Heteroalkyl), -S(O)-(C1~C 10 Alkyl), -SO2-(C1~C 10 Alkyl), OH, -CO2H, -C(O)-NH2, -C(O)-NH-(C1~C 10 Alkyl), -CO2-(C1~C 10 Alkyl), -OC(O)-(C1~C 10 Alkyl), -OP(O)(OH)(OH), NH2, -NH-(C1~C 10 Alkyl), -N(C1~C 10 Alkyl)(C1~C 10 They are independently selected from the group consisting of alkyl, -NO2, and -OCF3, R 11 [Selected from the group consisting of -H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 heteroalkyl, C2-C5 heteroalkenyl, C2-C5 heteroalkynyl, and C1-C5 halo-alkyl] Alternatively, a pharmaceutically acceptable salt or ester thereof is provided.

[0012] In the embodiment, R 1 ~R 6 These are independently selected from the group consisting of -H, -Me, -Et, -n-Pr, -i-Pr, cyclopropyl, -CH=CH2 (vinyl), -C≡CH (ethynyl), and -CH2CHCH2 (allyl). R 7 ~R 10 and R 12These are independently selected from the group consisting of -H, -F, -Cl, -Br, -I, -CF3, -SF5, -Me, -Et, -n-Pr, -i-Pr, cyclopropyl, -CH=CH2 (vinyl), -C≡CH (ethynyl), -CH2CHCH2 (allyl), -CN, -OMe, -OEt, -SMe, -SEt, -OH, -OAc, -CO2H, -C(O)-NH2, -CO2Me, -OC(O)-(C1~C5 alkyl), -OP(O)(OH)(OH), -NH2, -NO2, and -OCF3. R 11 This is selected from the group consisting of -H, -Me, -Et, -n-Pr, -i-Pr, cyclopropyl, and -CH2CHCH2 (allyl). or a pharmaceutically acceptable salt or ester thereof.

[0013] In the embodiment, R 1 ~R 6 These are independently selected from the group consisting of -H, -Me, and -Et, R 7 ~R 10 and R 12 Each of these is independently selected from the group consisting of -H, -F, -Cl, -Br, -I, -CF3, -SF5, -Me, -Et, -CN, -OMe, -SMe, -OH, -OAc, -C(O)-NH2, -OP(O)(OH)(OH), -NH2, -NO2, and -OCF3. R 11 is selected from the group consisting of -H, -Me, and -Et. or a pharmaceutically acceptable salt or ester thereof.

[0014] In the embodiment, R 1 ~R 6 These are independently selected from the group consisting of -H, -Me, and -Et, R 7 ~R 10 and R 12Each of these is independently selected from the group consisting of -H, -F, -Cl, -Br, -I, -CF3, -Me, -CN, -OMe, -OH, -OAc, -C(O)-NH2, -OP(O)(OH)(OH), and -NH2. R 11 is -H, or a pharmaceutically acceptable salt or ester thereof.

[0015] In some embodiments, the compound is of formula (Ia): [ka] It is represented by or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, R 7 -H, -OH, -O-(C1~C 10 Alkyl), -OC(O)-(C1~C 10 Selected from the group consisting of alkyl and -OP(O)(OH)(OH). In some embodiments, R 7 R is selected from the group consisting of -H, -OH, -OAc, and -OP(O)(OH)(OH). In some embodiments, R 8 -H, -OH, -O-(C1~C 10 Alkyl) and -OC(O)-(C1~C 10 Selected from the group consisting of alkyls. In some embodiments, R 8 The group is selected from -H, -OH, -OMe, and -OAc.

[0017] In embodiments, the compounds of the present disclosure are [ka] [ka] Selected from, or a pharmaceutically acceptable salt or ester thereof.

[0018] In embodiments, the compounds of the present disclosure are [ka] Selected from, or a pharmaceutically acceptable salt or ester thereof.

[0019] In embodiments, the compounds of the present disclosure are [ka] [ka] [ka] It is selected from or a pharmaceutically acceptable salt thereof.

[0020] In embodiments, the compounds of the present disclosure are [ka] Selected from, or a pharmaceutically acceptable salt or ester thereof.

[0021] In embodiments, the compounds of the present disclosure have the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0022] In embodiments, the compounds of the present disclosure have the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0023] In embodiments, the compounds of the present disclosure have the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0024] In embodiments, the compounds of the present disclosure have the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0025] In embodiments, the compounds of the present disclosure have the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0026] This disclosure further provides pharmaceutical compositions comprising one or more of the compounds of this disclosure.

[0027] This disclosure further provides a method for treating a mental illness or disorder in a patient in need thereof, the method comprising the step of administering to the subject a composition comprising an effective amount of the compound of this disclosure.

[0028] In the embodiment, the mental disorder or condition is selected from the group consisting of major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, severe mood dysregulation, substance / medication-induced depressive disorder, and depressive disorder resulting from another medical condition.

[0029] In the embodiment, the mental disorder or disorder is selected from the group consisting of bipolar disorder type I, bipolar disorder type II, cyclothymic disorder, substance / medication-induced bipolar and related disorders, and bipolar and related disorders resulting from another medical condition.

[0030] In this embodiment, the mental illness or disorder is a substance-related disorder or a substance use disorder.

[0031] In the embodiment, the mental disorder or condition is selected from the group consisting of separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder, panic disorder, panic attach, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, and anxiety disorders resulting from another medical condition.

[0032] In the embodiment, the mental disorder or illness is selected from the group consisting of obsessive-compulsive disorder and related disorders, trauma and stressor-related disorders, eating and feeding disorders, borderline personality disorder, attention deficit / hyperactivity disorder, and autism spectrum disorder.

[0033] In this embodiment, the mental disorder is a neurocognitive disorder.

[0034] In this embodiment, the mental illness or disorder is a treatment-resistant illness or disorder.

[0035] In embodiments, the method may address sadness or apathy or fatigue, depressed mood, loss of sensation, feelings of anxiety and distress, fear, feeling tense, feeling restless, decreased interest in all or nearly all activities, difficulty initiating activities, significant increase or decrease in appetite leading to weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness or low self-esteem, strong negative beliefs or pessimistic thoughts about oneself, others or the world, helplessness, lack of concentration or distractibility, recurring thoughts of death or suicide, guilt, memory complaints, affirmation It provides improvement in at least one symptom selected from the group consisting of difficulty experiencing emotional states, feeling alienated or distant from others, hyperarousal, risk-taking behavior, avoidance of thoughts about stressful or traumatic events, pain and discomfort, rumination and obsessive thinking, compulsive behavior, talking to strangers or people you don't know well, seeking attention, disturbing intrusive thoughts, inability to get through a week without using the drug, guilt about using the drug, problems with friends or family due to drug use, and withdrawal symptoms from drug use.

[0036] This disclosure further provides a method for enhancing creativity or cognition in a subject, the method comprising administering to the subject a composition comprising an effective amount of a compound of this disclosure.

[0037] In embodiments, methods and compositions may be used to treat mental disorders including depressive disorders, such as major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, severe mood dysregulation, substance / medication-induced depressive disorder, and depressive disorders resulting from other medical conditions.

[0038] Methods for treating patients suffering from treatment-resistant depression, such as depressive disorders that do not respond and / or have not responded to at least one or at least two adequate processes of other antidepressant compounds or therapeutic agents, are also provided herein. As used herein, “depressive disorder” encompasses treatment-resistant depression.

[0039] In embodiments, methods and compositions may be used to treat mental disorders, including bipolar and related disorders, such as bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medicine-induced bipolar and related disorders, and bipolar and related disorders resulting from another medical condition.

[0040] In embodiments, methods and compositions may be used to treat mental disorders, including substance-related disorders, for example, to prevent cravings for substance use, reduce cravings for substance use, and / or to facilitate the discontinuation or withdrawal of substance use. Substance use disorders involve the abuse of psychoactive compounds, such as alcohol, caffeine, cannabis, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. As used herein, “substances” refers to psychoactive compounds that can be addictive, such as alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. For example, methods and compositions may be used to facilitate smoking cessation or the discontinuation of opioid use.

[0041] In embodiments, methods and compositions may be used to treat mental disorders including anxiety disorders, such as separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, and anxiety disorders resulting from other medical conditions.

[0042] In embodiments, methods and compositions may be used to treat mental disorders including obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair-pulling disorder), dermatophatosis (skin-picking disorder), substance / medication-induced obsessive-compulsive disorder and related disorders, and obsessive-compulsive disorder resulting from another medical condition.

[0043] In embodiments, the methods and compositions may be used to treat mental disorders, including trauma and stressor-related disorders, such as reactive attachment disorder, disinhibited social interaction disorder, post-traumatic stress disorder, acute stress disorder, and adjustment disorder.

[0044] In embodiments, methods and compositions may be used to treat mental disorders including eating behaviors and eating disorders, such as anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, and avoidance / restriction food eating disorder.

[0045] In embodiments, methods and compositions may be used to treat mental disorders including neurocognitive disorders, such as delirium, major neurocognitive disorders, mild neurocognitive disorders, major or mild neurocognitive disorders due to Alzheimer's disease, major or mild frontotemporal neurocognitive disorders, major or mild neurocognitive disorders with Lewy bodies, major or mild vascular neurocognitive disorders, major or mild neurocognitive disorders due to traumatic brain injury, substance / pharmaceutical-induced major or mild neurocognitive disorders, major or mild neurocognitive disorders due to HIV infection, major or mild neurocognitive disorders due to prion diseases, major or mild neurocognitive disorders due to Parkinson's disease, major or mild neurocognitive disorders due to Huntington's disease, major or mild neurocognitive disorders resulting from other medical conditions, and major or mild neurocognitive disorders due to multiple etiologies.

[0046] In embodiments, methods and compositions may be used to treat mental disorders, including neurodevelopmental disorders, such as autism spectrum disorder, attention deficit / hyperactivity disorder, stereotypic movement disorder, tic disorder, Tourette syndrome, persistent (chronic) motor or vocal tic disorder, and provisional tic disorder.

[0047] In embodiments, the methods and compositions may be used to treat mental disorders, including personality disorders, such as borderline personality disorder.

[0048] In embodiments, methods and compositions may be used to treat mental disorders including sexual dysfunction, such as delayed ejaculation, erectile dysfunction, female orgasm disorder, female sexual interest / arousal disorder, genital-pelvic pain / insertion disorder, male hypoactive sexual desire disorder, premature ejaculation, and substance / pharmaceutical-induced sexual dysfunction.

[0049] In embodiments, the methods and compositions may be used to treat mental disorders, including gender dysphoria, for example, gender dysphoria.

[0050] In other embodiments, methods and compositions for treating migraines or cluster headaches are provided by administering the compounds of the present disclosure to patients in need thereof.

[0051] In embodiments, the term “effective dose” or “therapeutic dose” means an amount of compound, material, composition, pharmaceutical or other material that is effective in achieving certain pharmacological and / or physiological effects, including but not limited to reducing the frequency or severity of sadness or apathy, depressed mood, anxiety or sad feelings, decreased interest in all or nearly all activities, a marked increase or decrease in appetite leading to weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness, helplessness, lack of concentration, and recurrent thoughts of death or suicide, or in providing a desired pharmacological and / or physiological effect, such as reducing, inhibiting or reversing one or more underlying pathophysiological mechanisms underlying neurological dysfunction, modulating dopamine levels or signaling, modulating serotonin levels or signaling, modulating norepinephrine levels or signaling, modulating glutamate or GABA levels or signaling, modulating synaptic connections or neurogenesis in a particular brain region, or a combination thereof. The precise dosage will vary depending on various factors, such as subject-dependent variables (e.g., age, immune system health, clinical symptoms, etc.), the disease or disorder being treated, and the route of administration and pharmacokinetics of the active ingredient being administered.

[0052] In embodiments, the method includes treating a mental disorder, such as a depressive disorder, by administering to a patient in need a pharmaceutical composition containing about 0.01 mg to about 400 mg of the compound of the present disclosure. In embodiments, doses are, for example, about 0.01 to 400 mg, 0.01 to 300 mg, 0.01 to 250 mg, 0.01 to 200 mg, 0.01 to 150 mg, 0.01 to 100 mg, 0.01 to 75 mg, 0.01 to 50 mg, 0.01 to 25 mg, 0.01 to 20 mg, 0.01 to 15 mg, 0.01 to 10 mg, 0.01 to 5 mg, 0.01 to 1 mg, 0.01 to 0.5 mg, 0.01 to 0.1 mg, 0.1 to 400 mg, 0.1 to 300mg, 0.1 to 250mg, 0.1 to 200mg, 0.1 to 150mg, 0.1 to 100mg, 0.1 to 75mg, 0.1 to 50mg, 0.1 to 25mg, 0.1 to 20mg, 0.1 to 15mg, 0.1 to 10mg, 0.1 to 5mg, 0.1 to 1mg, 10 to 400mg, 10 to 300mg, 10 to 250mg, 10 to 200mg, 10 to 150mg, 10 to 100mg, 10 to 50mg, 10 to 25mg, 10 to 15mg The amounts may be within the range of 20 to 400 mg, 20 to 300 mg, 20 to 250 mg, 20 to 200 mg, 20 to 150 mg, 20 to 100 mg, 20 to 50 mg, 50 to 400 mg, 50 to 300 mg, 50 to 250 mg, 50 to 200 mg, 50 to 150 mg, 50 to 100 mg, 100 to 400 mg, 100 to 300 mg, 100 to 250 mg, and 100 to 200 mg, for example, approximately 0.01 mg, 0.025 mg, 0.05 mg, 0.1 Examples of dosages include mg, 0.15 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, and 400 mg.

[0053] In specific embodiments, the dosage may include, for example, amounts of the compound or pharmaceutically acceptable salt thereof in the range of approximately 1 mg to 50 mg, 1 mg to 40 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 10 mg, 0.1 mg to 10 mg, 0.1 to 5 mg, or 0.1 to 1 mg, such as 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 0.5mg, 1.0mg, 1.75mg, 2mg, 2.5mg, 2.75mg, 3mg, 3.5mg, 3.75mg, 4mg, 4.5mg, 4.75mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 10mg, 11mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 27.5mg, 30mg, 35mg, 40mg, 45mg, and 50mg are specific examples of dosages.

[0054] Typically, the dosage of the compounds of this disclosure or pharmaceutically acceptable salts thereof is administered to patients who require it once, twice, three or four times daily, every other day, every three days, twice a week, once a week, twice a month, or once a month. In embodiments, the dosage is, for example, about 0.1 to 400 mg / day, 0.1 to 300 mg / day, 0.1 to 250 mg / day, 0.1 to 200 mg / day, 0.1 to 100 mg / day, 0.1 to 50 mg / day, or 0.1 to 25 mg / day, for example, 300 mg / day, 250 mg / day, 200 mg / day, 150 mg / day, 100 mg / day, 75 mg / day, 50 mg / day, 25 mg / day, 20 mg / day, 10 mg / day, 5 mg / day, 2.5 mg / day, 1 mg / day, 0.5 mg / day, 0.25 mg / day, or 0.1 mg / day. In embodiments, the above-mentioned dosage range examples may be delivered over intervals longer than one day, for example, 0.1 to 400 mg / week.

[0055] In embodiments, pharmaceutical compositions for parenteral or inhalation administration, such as by spray or mist, of the compounds of the present disclosure or pharmaceutically acceptable salts thereof have concentrations ranging from about 0.005 mg / mL to about 500 mg / mL. In embodiments, the composition contains the compound of the Disclosure or a pharmaceutically acceptable salt thereof at concentrations, for example, about 5 mg / mL to about 500 mg / mL, about 5 mg / mL to about 100 mg / mL, about 5 mg / mL to about 50 mg / mL, about 1 mg / mL to about 100 mg / mL, about 1 mg / mL to about 50 mg / mL, about 0.1 mg / mL to about 25 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 5 mg / mL, about 0.05 mg / mL to about 1 mg / mL, about 0.005 mg / mL to about 1 mg / mL, about 0.005 mg / mL to about 0.25 mg / mL, or about 0.005 mg / mL to about 0.1 mg / mL.

[0056] In embodiments, the composition contains the compound of the Disclosure or a pharmaceutically acceptable salt thereof at concentrations, for example, about 0.05 mg / mL to about 500 mg / mL, about 0.05 mg / mL to about 100 mg / mL, about 0.05 mg / mL to about 50 mg / mL, about 0.05 mg / mL to about 25 mg / mL, about 0.05 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 5 mg / mL, about 0.005 mg / mL to about 1 mg / mL, about 0.005 mg / mL to about 0.25 mg / mL, about 0.005 mg / mL to about 0.05 mg / mL, or about 0.005 mg / mL to about 0.025 mg / mL. In the embodiment, the pharmaceutical composition is formulated in a total volume of, for example, about 0.1 mL, 0.25 mL, 0.5 mL, 1 mL, 2 mL, 5 mL, 10 mL, 20 mL, 25 mL, 50 mL, 100 mL, 200 mL, 250 mL, or 500 mL.

[0057] Typically, the dosage may be administered to the subject once, twice, three or four times daily, every other day, every three days, twice a week, once a week, twice a month, once a month, three times a year, twice a year, or once a year. In embodiments, the compound of the Disclosure or a pharmaceutically acceptable salt thereof is administered to the subject once in the morning or once in the evening. In embodiments, the compound of the Disclosure or a pharmaceutically acceptable salt thereof is administered to the subject once in the morning and once in the evening. In embodiments, the compound of the Disclosure or a pharmaceutically acceptable salt thereof is administered to the subject three times a day (e.g., at breakfast, lunch, and dinner) in doses of, for example, 0.5 mg / dose (e.g., 1.5 mg / day).

[0058] In the embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to subjects in a single or multiple dose at a dose of 0.5 mg / day. In the embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to subjects in a single or multiple dose at a dose of 1 mg / day. In the embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to subjects in a single or multiple dose at a dose of 2.5 mg / day. In the embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to subjects in a single or multiple dose at a dose of 5 mg / day. In the embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to subjects in a single or multiple dose at a dose of 10 mg / day. In the embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to subjects in a single or multiple dose at a dose of 15 mg / day. In the embodiments, the compound of the Disclosure or a pharmaceutically acceptable salt thereof is administered to the subject in a single or multiple dose at a dose of 20 mg / day. In the embodiments, the compound of the Disclosure or a pharmaceutically acceptable salt thereof is administered to the subject in a single or multiple dose at a dose of 25 mg / day. In the embodiments, the compound of the Disclosure or a pharmaceutically acceptable salt thereof is administered to the subject in a single or multiple dose at a dose of 30 mg / day. In the embodiments, the compound of the Disclosure or a pharmaceutically acceptable salt thereof is administered to the subject in a single or multiple dose at a dose of 40 mg / day. In the embodiments, the compound of the Disclosure or a pharmaceutically acceptable salt thereof is administered to the subject in a single or multiple dose at a dose of 50 mg / day.

[0059] In embodiments, the dosage of the compound of the Disclosure or a pharmaceutically acceptable salt thereof is 0.0005 to 5 mg / kg, 0.001 to 1 mg / kg, 0.01 to 1 mg / kg, or 0.1 to 5 mg / kg once, twice, three or four times a day. For example, in embodiments, the dosage is 0.0005 mg / kg, 0.001 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.025 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.15 mg / kg, 0.2 mg / kg, 0.25 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 1 mg / kg, 2.5 mg / kg, or 5 mg / kg once, twice, three or four times a day. In the embodiments, subjects are administered a total daily dose of 0.01 mg to 500 mg of the compound or a pharmaceutically acceptable salt thereof once, twice, three or four times daily. In the embodiment, the total amount administered to the subject within 24 hours is, for example, 0.01 mg, 0.025 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 60 mg, 75 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, and 500 mg. In the embodiment, the subject can start with a low dose and the dosage is gradually increased. In the embodiment, the subject can start with a high dose and the dosage is decreased.

[0060] In embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are administered to a patient under the supervision of a healthcare provider.

[0061] In embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are administered to patients in a clinic specializing in the administration of psychoactive treatments under the supervision of a healthcare provider.

[0062] In embodiments, the compounds of the present disclosure are administered to patients under the supervision of a healthcare provider in high doses intended to induce a psychedelic experience in the subject, such as 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg.

[0063] In this embodiment, high-dose administration to a patient under the supervision of a healthcare provider occurs periodically, for example, every three days, twice a week, once a week, twice a month, once a month, four times a year, three times a year, twice a year, or once a year, in order to maintain the therapeutic effect in the patient.

[0064] In embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are administered by the patient themselves, at home or otherwise, away from the supervision of a healthcare provider.

[0065] In embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are administered by the patient themselves at home or otherwise away from the supervision of a healthcare provider in low doses intended to be sub-perceptual or induce a threshold psychoactive effect, such as 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, or 4 mg.

[0066] In this embodiment, the patient administers a low dose periodically to maintain the therapeutic effect in the patient, for example, daily, every other day, every three days, twice a week, once a week, twice a month, or once a month.

[0067] In embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof may be administered at specified intervals, for example, by inhalation or orally. For example, during treatment, a patient may be administered the compounds of the Disclosure at intervals of, for example, 1 year, 6 months, 4 months, 90 days, 60 days, 30 days, 14 days, 7 days, 3 days, 24 hours, 12 hours, 8 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 hour, 0.75 hours, 0.5 hours, or 0.25 hours.

[0068] Suitable dosage forms for the compounds of this disclosure or pharmaceutically acceptable salts thereof include, but are not limited to, oral forms such as tablets, hard or soft gelatin capsules, powders, granules and oral solutions, syrups or suspensions, lozenges, and sublingual, oral, tracheal, intraocular or intranasal forms, forms adapted for inhalation, topical forms, transdermal forms, or parenteral forms such as forms adapted for intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intramuscular or subcutaneous administration. In embodiments, for such parenteral administration, the pharmaceutical composition may be in the form of a sterile aqueous solution that may contain other substances, such as a salt or glucose sufficient to make the solution isotonic with blood. The aqueous solution should be buffered, if necessary, preferably (preferably to a pH of 3 to 9). Preparation of suitable parenteral formulations under sterile conditions is readily carried out by standard pharmaceutical techniques well known to those skilled in the art.

[0069] Pharmaceutical compositions as described herein may have immediate-release, delayed-release, sustained-release, or regulated-release profiles. In embodiments, pharmaceutical compositions with different drug-release profiles may be combined to create two-phase or three-phase release profiles. For example, a pharmaceutical composition may have both immediate-release and sustained-release profiles. In embodiments, a pharmaceutical composition may have both sustained-release and delayed-release profiles. Such compositions may be provided as pulse formulations, multilayer tablets, or capsules containing tablets, beads, granules, etc. The compositions may be prepared using a pharmaceutically acceptable “carrier” composed of materials considered safe and effective. The “carrier” includes all components other than the active ingredient(s) present in the pharmaceutical formulation. The term “carrier” includes, but is not limited to, diluents, binders, lubricants, flow enhancers, disintegrants, fillers, and coating compositions.

[0070] As used herein, the term “pharmaceutically acceptable” means “generally considered safe,” for example, physiologically tolerable, and does not typically produce any allergic or similar adverse reactions when administered to humans. In embodiments, the term means molecular entities and compositions that have been subjected to premarket review and approval by the FDA or a similar list, the United States Pharmacopeia or another generally accepted pharmacopoeia for use in animals and especially in humans, and that have been approved by a federal or state regulatory agency as a GRAS (Generally Recognized As Safe) under Sections 204(s) and 409 of the Federal Food, Drug, and Cosmetic Act.

[0071] As used herein, the term “pharmaceutically acceptable salt” includes acid addition salts and salts of free bases, where the compound is modified by the preparation of its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues, e.g., mineral or organic salts of amines, and acidic residues, e.g., alkali or organic salts of carboxylic acids. pharmaceutically acceptable salts also include, for example, conventional non-toxic salts or quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, maleic acid, toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, and oxalic acid. Pharmaceutically acceptable salts of the compounds of this disclosure can be synthesized by conventional chemical methods from parent compounds containing basic or acidic moieties.

[0072] The terms “about” or “approximately,” as used herein, mean a range of acceptable error for a particular value as determined by those skilled in the art, which is determined, in part, by how the value is measured or determined, i.e., by the limitations of the measuring system. For example, “about” may mean a standard deviation of 3 or more than 3 per practice in the art. Alternatively, “about” may mean a range of up to 20%, up to 10%, up to 5%, and / or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term may mean within one order of magnitude of a value, for example, within 5 times, or within 2 times. “About” and “approximately” are used interchangeably herein.

[0073] In the context of this disclosure, the term “5-HT2A receptor agonist” is intended to mean any compound or substance that activates the 5-HT2A receptor. The agonist may be a partial or full agonist.

[0074] In the context of this disclosure, the term “5-HT1A receptor agonist” is intended to mean any compound or substance that activates the 5-HT1A receptor. The agonist may be a partial or full agonist.

[0075] The pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, oral, and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration, or administration via implants. The compositions may be prepared by any method well known in the field of compounding.

[0076] Such methods include the step of associating the compounds used in this disclosure or combinations thereof with any auxiliary agent. Auxiliaries, also referred to as adjuncts, include those commonly used in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavorings, antioxidants, and wetting agents. Such auxiliary agents are preferably selected with respect to the intended dosage form and route, as well as to be consistent with conventional pharmaceutical practice.

[0077] Pharmaceutical compositions suitable for oral administration may be presented in discontinuous dosage units, such as pills, tablets, sugar-coated tablets, or capsules, or as powders or granules, or as liquids or suspensions. The active ingredient may be presented as a bolus or paste. The composition may be further processed into suppositories or enemas for rectal administration.

[0078] Tablets may contain the active ingredient compound and suitable binders, lubricants, disintegrants, colorants, flavorings, flow inducers, and melting agents. Gelatin capsules may contain the active ingredient compound and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Compressed tablets can be prepared using similar diluents. Compressed tablets may be sugar-coated or film-coated to mask any unpleasant tastes and protect the tablets from the air, or enterically coated for selective disintegration in the gastrointestinal tract. For example, for oral administration in dosage units of tablets or capsules, the active drug component may be combined with an orally, non-toxic, pharmaceutically acceptable inert carrier, such as lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, and wax. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. Disintegrants are not limited to starch, methylcellulose, agar, bentonite, and xanthan gum.

[0079] For oral administration in liquid dosage forms, the oral drug component is combined with any oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, or water. Examples of suitable liquid dosage forms include liquids or suspensions, emulsions, syrups, or elixirs in water, pharmaceutically acceptable fats and oils, alcohols, or other organic solvents containing esters; suspensions reconstituted from non-foaming granules; and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and melting agents. Liquid dosage forms for oral administration may contain colorants and flavorings to increase patient acceptance.

[0080] Suitable compositions for parenteral administration include aqueous and non-aqueous sterile solutions. Generally, water, suitable oils, physiological saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, a suitable stabilizer, and, if necessary, a buffer. Antioxidants, such as sodium bisulfite, sodium sulfite, or ascorbic acid, are suitable stabilizers, either alone or in combination. Citric acid and its salts, as well as sodium EDTA, are also used. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Compositions can be presented in unit-dose or multi-dose containers, such as sealed vials and ampoules, and can be stored in a freeze-dried state requiring only the addition of a sterile liquid carrier, such as water, before use. For transdermal administration, gels, patches, or sprays may be considered. For example, compositions or formulations suitable for intrapulmonary administration by nasal inhalation include fine dust or mist, which can be generated using a quantitatively pressurized aerosol, nebulizer, or injector. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system selected.

[0081] The compounds used in the methods of this disclosure may be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. The liposomes may be formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. The compounds may be administered as components of tissue-targeted emulsions.

[0082] The compounds used in the methods of this disclosure may be coupled with soluble polymers as targetable drug carriers or prodrugs. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl aspartamidophenol, or polyethylene oxide-polylysine, which are substituted with palmitoyl residues. Furthermore, the compounds may be coupled with a class of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0083] The pharmaceutical compositions described herein may have immediate-release, delayed-release, sustained-release, or regulated-release profiles. In some embodiments, pharmaceutical compositions having different drug-release profiles may be combined to create a two-phase or three-phase release profile. For example, a pharmaceutical composition may have both immediate-release and sustained-release profiles. In some embodiments, a pharmaceutical composition may have both sustained-release and delayed-release profiles. Such compositions may be provided as pulsed formulations, multilayer tablets, or capsules containing tablets, beads, granules, etc.

[0084] The pharmaceutical compositions described herein can be made to have abuse-deterrent properties by, for example, by producing tablets that are difficult to crush or dissolve in water using techniques known in the art.

[0085] This disclosure further includes the pharmaceutical composition as described above, combined with packaging material including instructions for use of the composition as described above.

[0086] The precise dosage and regimen of the composition will inevitably depend on the type and magnitude of the therapeutic or nutritional effect to be achieved, and may vary depending on factors such as the specific compound, formula, route of administration, or the age and condition of the individual subject to whom the composition is administered.

[0087] The compounds used in the methods of this disclosure may be administered in various forms, including those detailed herein. Treatment with the compounds may be a component of combination therapy or adjunct therapy, i.e., a subject or patient in need of the drug is treated or given one or more of the compounds of the present invention in combination with another drug for the disease. This combination therapy may be sequential therapy, in which the patient is first treated with one drug, and then the other or two drugs are given simultaneously. Depending on the dosage form used, these may be administered independently via the same route or via two or more different routes of administration.

[0088] In embodiments, deuterium-enhanced azetidinyltryptamines and their uses are intended, within the scope of the methods and compositions described herein. Deuterium can be incorporated synthetically in place of hydrogen (protium) at any position according to synthetic procedures known in the art. For example, deuterium can be incorporated via proton-deuterium equilibrium exchange at various positions having exchangeable protons, such as amine NH. Thus, deuterium can be incorporated selectively or non-selectively by methods known in the art. Exemplary deuterium-enhanced azetidinyltryptamines are: [ka] or comprising a pharmaceutically acceptable salt thereof [wherein D represents a deuterium-enhanced H site].

[0089] In the embodiment, each D represents a deuterium-enhanced H site, and the level of deuterium at each deuterium-enhanced H site of the compound ranges from 0.02% to 100%.

[0090] In this embodiment, each D represents a deuterium-enhanced H site, and the level of deuterium at each deuterium-enhanced H site of the compound is 50%~100%, 70%~100%, 90%~100%, 95%~100%, 96%~100%, 97%~100%, 98%~100%, or 99%~100%.

[0091] Tryptamine may be a racemic and / or optically active isomer thereof. In this regard, some compounds may have an asymmetric carbon atom and therefore may exist either as a racemic mixture or as individual optical isomers (enantiomers). Compounds described herein that contain a chiral center include all possible stereoisomers of the compound, including a racemic mixture of two enantiomers, a scalemic mixture of two enantiomers, or a mixture containing each enantiomer individually and substantially no other enantiomers. Thus, for example, what is intended herein is a composition containing an S enantiomer of a compound substantially free of the R enantiomer, or an R enantiomer substantially free of the S enantiomer. Where a named compound contains more than one chiral center, the scope of this disclosure also includes compositions containing mixtures of variable proportions between diastereomers, and compositions containing one or more diastereomers substantially free of one or more of the other diastereomers. "Substantially contained" means that the composition contains 25%, 15%, 10%, 8%, 5%, less than 3%, or less than 1% of the secondary enantiomers or diastereomers.

[0092] Methods for synthesizing, isolating, preparing, and administering various stereoisomers are known in the art. Separation of diastereomers or cis and trans isomers can be achieved by prior art, for example, by fractional crystallization, chromatography, or high-performance liquid chromatography (HPLC) of stereoisomerized mixtures of the active substance or a suitable salt or derivative thereof. Individual enantiomers of the compounds of the disclosed compounds can also be prepared from the corresponding optically pure intermediates or by separation, for example, by HPLC of the corresponding racemate using a suitable chiral support, or by fractional crystallization of diastereomer salts formed by the reaction of the corresponding racemate with a suitable optically active acid or base as appropriate.

[0093] This disclosure further provides pharmaceutical compositions comprising the compounds of this disclosure and a pharmaceutically acceptable carrier.

[0094] In the context of this disclosure, the term “alkyl” should be understood to mean a linear, branched, or, where possible, cyclic hydrocarbon chain containing the indicated number of carbon atoms, where all bonds connecting the atoms are sigma bonds.

[0095] In the context of this disclosure, the term “alkenyl” should be understood to mean a linear, branched, or, where possible, cyclic hydrocarbon chain containing the indicated number of carbon atoms, wherein at least one bond between any two carbon atoms in the chain is a double (pi) bond.

[0096] In the context of this disclosure, the term “alkynyl” should be understood to mean a linear, branched, or, where possible, cyclic hydrocarbon chain containing the indicated number of carbon atoms, wherein at least one bond connecting two carbon atoms in the chain is a triple bond.

[0097] In the context of this disclosure, the term “halo-alkyl” should be understood to mean a linear, branched, or, where possible, cyclic hydrocarbon chain containing the indicated number of carbon atoms, where all bonds connecting the atoms are sigma bonds, and where at least one of the hydrogen atoms in the chain is replaced by a halogen atom selected from F, Cl, Br, and I.

[0098] In the context of this disclosure, the term “heteroalkyl” should be understood to mean a linear, branched, or, where possible, cyclic hydrocarbon chain containing the indicated number of carbon atoms, where the chain is interrupted or terminated by at least one heteroatom (selected from O, N, and S), and where all bonds connecting the atoms are sigma bonds.

[0099] In the context of this disclosure, the term “heteroalkenyl” should be understood to mean a linear, branched, or, where possible, cyclic hydrocarbon chain containing the indicated number of carbon atoms, wherein the chain is interrupted or terminated by at least one heteroatom (selected from O, N, and S), and at least one bond between any two carbon atoms in the chain is a double (pi) bond.

[0100] In the context of this disclosure, the term “heteroalkynyl” should be understood to mean a linear, branched, or, where possible, cyclic hydrocarbon chain containing the indicated number of carbon atoms, wherein the chain is interrupted or terminated by at least one heteroatom (selected from O, N, and S), and at least one bond connecting two carbon atoms in the chain is a triple bond.

[0101] The disclosure of this subject matter is also intended to include all isotopes of atoms present in the compounds disclosed herein. Isotopes include those atoms that have the same atomic number but different mass numbers. As a general example, and not limited to, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include, 13 C and 14 Includes C.

[0102] Throughout this application, any annotation of carbon in a structure, if used without further annotation, refers to all isotopes of carbon, for example. 12 C, 13 C or 14 Please note that this is intended to represent C. Furthermore, 13 C or 14 Any compound containing C may specifically have one of the structures of the compounds disclosed herein.

[0103] Throughout this application, any annotation of hydrogen in the structure, if used without further annotation, refers to all isotopes of hydrogen, for example. 1 H, 2 H or 3 It should also be noted that this is intended to represent H. Furthermore, 2 H or 3 Any compound containing H may specifically have one of the structures of the compounds disclosed herein.

[0104] Isotope-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, using appropriate isotope-labeling reagents instead of the unlabeled reagents that were previously used.

[0105] Each embodiment disclosed herein is intended to be applicable to each of the other disclosed embodiments. Therefore, all combinations of the various elements described herein are within the scope of this disclosure.

[0106] General synthesis of compounds The compounds of this disclosure can be prepared by techniques that are well known in organic synthesis and are familiar to practitioners of the ordinary skill in the art. For example, the compounds can be prepared by synthetic transformations shown in schemes 1 to 4 and in the following specific examples. However, these may not be the only means of synthesizing or obtaining the desired compounds.

[0107] Scheme 1. General approach for the synthesis of azetidinyltryptamines by alkylation.

Chem.

[0108] Scheme 2. General approach for the synthesis of azetidinyltryptamines by acylation followed by reduction of the resulting glyoxalylamide.

Chem.

[0109] Scheme 3. Examples of late-stage transformation of azetidinyltryptamines to obtain additional analogs.

Chem.

[0110] Scheme 4. Preparation example of 3-(2-bromoethyl)indole intermediate.

Chem.

[0111] Example 1. Preparation of Compound 1

Chem.

[0112] Step 1: Preparation of 1-(azetidine-1-yl)-2-(1H-indole-3-yl)ethane-1-one. To a mixture of azetidine hydrochloride (5.61 g, 59.94 mmol, 1.5 equivalents) and triethylamine (12.13 g, 119.87 mmol, 16.68 mL, 3 equivalents) in DCM (70 mL), 2-(1H-indole-3-yl)acetic acid (7 g, 39.96 mmol, 1 equivalent) was added all at once under N2 at 0°C. To the solution, HATU (22.79 g, 59.94 mmol, 1.5 equivalents) was added all at once under N2 at 0°C, and the mixture was heated to 20°C and stirred for 2 hours. After completion, the reaction mixture was quenched at 20°C by adding aqueous NH4Cl solution (50 mL), and then extracted with DCM (50 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column = Phenomenex C18 (250 × 100 mm, 10 μm); mobile phase = water (NH4HCO3)-ACN, B% = 15%~50%, run time 20 minutes) to obtain 1-(azetidine-1-yl)-2-(1H-indole-3-yl)ethane-1-one as a white solid (3 g, 14.00 mmol, 35% yield). 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (br s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.15 (s, 1H), 7.03 (t, J= 7.6 Hz, 1H), 6.97 - 6.90 (m, 1H), 4.11 (t, J= 7.6 Hz, 2H), 3.79 (t, J= 7.6 Hz, 2H), 3.42 (s, 2H), 2.11 (quintet, J= 7.6 Hz, 2H).

[0113] Step 2: Preparation of 3-(2-(azetidine-1-yl)ethyl)-1H-indol fumarate (1). A solution of 1-(azetidine-1-yl)-2-(1H-indole-3-yl)ethane-1-one (1 g, 4.67 mmol, 1 equivalent) in THF (50 ml) was cooled to 0°C. Then, LAH (265.68 mg, 7.00 mmol, 1.5 equivalents) was added, and the mixture was heated to 20°C and stirred for 2 hours. After completion, the mixture was cooled to 0°C, the reaction was quenched with Na2SO4·10H2O until foaming stopped, the mixture was filtered and concentrated. The residue was purified by preparative HPLC (column = Waters Crossbridge C18 (150 × 50 mm, 10 μm); mobile phase = water (NH4HCO3)-ACN, B% = 1%~40%; run time 10 minutes) to obtain a solution of 3-(2-(azetidine-1-yl)ethyl)-1H-indole in a mixture of water (800 mL) and MeCN (50 mL). To this solution, a solution of fumaric acid (231.82 mg, 2.00 mmol) in MeCN (2 mL) was added all at once under N2 at 20°C. The solution was then lyophilized to produce 3-(2-(azetidine-1-yl)ethyl)-1H-indole fumarate (1) as a brown solid (550 mg, 1.90 mmol, 41% yield, 1:fumarate = 1:0.77). 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (br s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.34 (d, J= 8,0 Hz, 1H), 7.15 (d, J= 2.4 Hz, 1H), 7.07 (dt, J= 1.2, 7.6 Hz, 1H ), 6.98 (dt, J= 1.2, 7.6 Hz, 1H), 6.48 (s, 1.54H = fumarate, 0.77 mol equivalent), 3.46 (t, J = 7.6 Hz, 4H), 2.93 - 2.86 (m, 2H), 2.78 - 2.71 (m, 2H), 2.15 - 2.04 (m, 2H); 13 C NMR (101 MHz, DMSO-d6) δ 168.56, 136.68, 135.77, 127.48, 123.32, 121.41, 118.72, 111.88, 111.54, 58.16, 54.27, 22.38, 17.21; LCMS (RT = 1.334 min, MS calculated value: 200.13, [M+H] + = 201.1); qNMR = 89%.

[0114] Methods for the failed workup and purification of Compound 1: Multiple alternative methods for working up the LAH reduction and purifying the resulting Product 1 led to partial or complete decomposition and no pure product was obtained. These failed workup / purification methods are summarized below.

[0115] Method 1: Workup: After completion, H2O and 30% aqueous NaOH were added to the mixture, the mixture was filtered, and concentrated.

[0116] Purification: The residue was purified by preparative HPLC (column = Waters CrossBridge BEH C18 (100×25 mm, 5 μm); mobile phase = water (NH4HCO3)-ACN, B% = 2% - 40%; run time of 10 min). After lyophilization of the eluate, 1 1H NMR indicated that the product was impure.

[0117] Method 2: Workup: After completion, the mixture was cooled to 0 °C, the reaction was quenched with Na2SO4·10H2O, the mixture was filtered, and concentrated.

[0118] Purification: The residue was purified by preparative HPLC (HCl) (column = Phenomenex Luna C18 (80×40 mm, 3 μm); mobile phase = water (HCl)-ACN, B% = 1% - 25%; run time of 7 min). After lyophilization of the eluate, LCMS and 1 1H NMR indicated that the product was impure.

[0119] Method 3: Workup: The same as Method 2.

[0120] Purification: The residue was purified by preparative HPLC (column = Phenomenex Luna C18 (250 × 70 mm, 15 μm); mobile phase = water (FA)-ACN, B% = 1%~30%; run time 20 minutes). After lyophilization of the eluate, LC-MS and 1 1H NMR showed that the product was impure.

[0121] Method 4: Workup: Same as Method 2.

[0122] Purification: The residue was purified by preparative HPLC (column = Phenomenex C18 (250 × 50 mm, 10 μm); mobile phase = water (NH3H2O ​​+ NH4HCO3)-ACN, B% = 3%~33%; run time 20 minutes). After lyophilization of the eluate, the residue was tritulated with MTBE and the supernatant was removed, but the remaining solid was subjected to LCMS and 1 1H NMR showed that the product was impure.

[0123] Method 5: Workup: Same as Method 2.

[0124] Purification: The residue was purified by preparative TLC (DCM / MeOH = 5:1) and column chromatography (DCM / MeOH = 100 / 1 to 1:1), but LC-MS showed that the product remained impure.

[0125] Method 6: Workup: Same as Method 2.

[0126] Purification: The residue was purified by preparative HPLC (column = Phenomenex C18 (250 × 50 mm, 10 μm); mobile phase = water (0.05% ammonium hydroxide)-ACN, B% = 5%~40%; run time 20 minutes). After lyophilization of the eluate, the product was impure. Then, fumaric acid (approximately 0.5 equivalents) in a mixture of H2O and ACN was added, the mixture was lyophilized again, the residue was triturated with ether, and the supernatant was removed. However, LCMS and 1 1H NMR showed that the product remained impure.

[0127] Example 2. Preparation of Compound 2 [ka]

[0128] Step 1: Preparation of 3-(2-chloro-2-oxoacetyl)-1H-indole-4-yl acetate. To a solution of 1H-indole-4-yl acetate (25 g, 142.71 mmol, 1 equivalent) in THF (250 mL) at 0°C, (COCl)2 (27.17 g, 214.06 mmol, 18.74 mL, 1.5 equivalents) was added. The mixture was then heated to 20°C and stirred for 12 hours. Upon completion, the reaction mixture was concentrated to yield 3-(2-chloro-2-oxoacetyl)-1H-indole-4-yl acetate as a yellow solid (37.91 g, 142.71 mmol, 100% yield).

[0129] Step 2: 3-(2-(azetidine-1-yl)-2-oxoacetyl)-1H-indole-4-yl acetate. To a solution of azetidine hydrochloride (19.22 g, 205.48 mmol, 1.5 equivalents) in DCM (100 mL), DIPEA (70.82 g, 547.94 mmol, 95.44 mL, 4 equivalents) was added, and the mixture was stirred at 20°C for 30 minutes. At this point, the mixture was cooled to 0°C, and 3-(2-chloro-2-oxo-acetyl)-1H-indole-4-yl acetate (36.39 g, 136.99 mmol, 1 equivalent) in THF (100 mL) was added, and the mixture was heated to 20°C and stirred for 3 hours. After completion, aqueous NH4Cl (100 mL) was added, and the mixture was stirred for 5 minutes. The aqueous phase was extracted using DCM (50 mL x 3), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1 to 0 / 1) to yield 3-(2-(azetidine-1-yl)-2-oxoacetyl)-1H-indole-4-yl acetate as a yellow solid (26 g, 90.82 mmol, 66% yield).1 H NMR (400 MHz, DMSO-d6) δ 12.47 (br s, 1H), 8.42 (s, 1H), 7.48 - 7.39 (m, 1H), 7.28 (t, J= 7.9 Hz, 1H), 6.90 (d, J= 7.3 Hz,1H), 4.16 (t, J= 7.7 Hz, 2H), 4.04 (t, J = 7.8 Hz, 2H), 2.34 (s, 3H), 2.27 (quintet, J= 7.8 Hz, 2H).

[0130] Step 3: Preparation of 3-(2-(azetidine-1-yl)ethyl)-1H-indole-4-ol (2). To a solution of 3-(2-(azetidine-1-yl)-2-oxoacetyl)-1H-indole-4-yl acetate (4 g, 13.97 mmol, 1 equivalent) in THF (150 mL), LAH (5.30 g, 139.72 mmol, 10 equivalents) was added at 0°C. The mixture was then heated at 70°C for 7 hours. After completion, the mixture was cooled to 0°C, quenched with H2O (5.3 mL), filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, DCM / MeOH = 10 / 1 to 0 / 1) to obtain 3-(2-(azetidine-1-yl)ethyl)-1H-indole-4-ol(2) as a pale yellow solid (1.1 g, 5.09 mmol, 36% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (br s, 1H), 10.57 (br s, 1H), 6.89 (d, J= 2.4 Hz, 1H), 6.84 - 6.70 (m, 2H), 6.28 (dd, J= 0.8, 7.2 Hz, 1H), 3.19 (t, J= 7.2 Hz, 4H), 2.77 - 2.61 (m, 4H), 2.06 - 1.93 (m, 2H); 13 LCMS (R T= 2.021 min, MS calculated: 216.13, [M+H] + 217.1); qNMR = 93%.

[0131] Note: Product 2 is unstable and should be stored frozen, protected from light, and kept under an inert gas. When properly stored, its stability was confirmed by qNMR for at least one month.

[0132] Preparation of 3-(2-(azetidine-1-yl)ethyl)-1H-indole-4-ol fumarate (2 fumarate). To a solution of 3-(2-(azetidine-1-yl)ethyl)-1H-indole-4-ol (2, 100 mg, 462.37 μmol, 1 equivalent) in MeCN (5 mL), H2O (20 mL) and a solution of fumaric acid (37.57 mg, 323.66 μmol, 0.7 equivalents) in MeCN (2 mL) were added all at once under N2 at 20°C. The mixture was freeze-dried to obtain 3-(2-(azetidine-1H-yl)ethyl)-1H-indole-4-ol fumarate (2 fumarate) as a yellow solid (125 mg, 2:fumarate = 1:0.65). 1 H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 6.94 (d, J= 2.0 Hz, 1H), 6.86 - 6.72 (m, 2H), 6.51 (s, 1H), 6.33 (dd, J= 0.8, 7.2 Hz, 1H), 3.69 (t, J= 7.6 Hz, 4H), 3.10 (br d, J = 7.6 Hz, 2H), 2.88 (s, 2H), 2.19 (br t, J= 7.6 Hz, 2H); qNMR = 86%.

[0133] Failed workup and purification methods for compound 2: Several alternative methods for workup-ing LAH reduction and purifying the resulting product 2 resulted in partial or complete degradation, failing to yield a pure product. These failed workup / purification methods are summarized below.

[0134] Method 1: Workup: Once completed, H2O and a 30% NaOH aqueous solution were added to the mixture, and the resulting slurry was filtered and concentrated.

[0135] Purification: The residue was purified by preparative HPLC (column = Welch Extimate C18 (250 × 70 mm, 10 μm); mobile phase = water (NH4HCO3)-ACN, B% = 5%~35%; run time 20 minutes). After lyophilization of the eluate, LC-MS and 1 While the 1H NMR appeared to indicate that the obtained product was pure, the qNMR pointed to only 62% of the assay, suggesting the presence of polymeric or insoluble impurities that were invisible by both LC-MS and NMR.

[0136] Method 2: Workup: Once complete, H2O and a 30% NaOH aqueous solution were added to the mixture, the resulting slurry was filtered, fumaric acid (approximately 0.5-1 equivalent) was added to the filtrate, and the filtrate was concentrated.

[0137] Purification: The residue was then purified by preparative HPLC (column = Waters Crossbridge Preparative OBD C18 (150 × 40 mm × 10 μm); mobile phase = water-ACN, B% = 0%~30%; run time 20 minutes), but the product decomposed during this purification trial.

[0138] Method 3: Workup: Same as Method 1.

[0139] Purification: The residue was purified by preparative HPLC (column = Welch Extimate C18 (250 × 70 mm, 10 μm); mobile phase = water (NH4HCO3)-ACN, B% = 5%~35%, 20 min) to obtain the product in solution of H2O and CH3CN. To this solution, a solution of fumaric acid (approximately 0.5~1 equivalent) in H2O was added, and the mixture was freeze-dried to obtain the product, which was then subjected to LC-MS and 1 If the sample appeared pure by 1H NMR, but the results were insufficient using Method 1, qNMR was not performed to confirm its purity.

[0140] Example 3. Preparation of Compound 3 [ka]

[0141] Step 1: Preparation of 2-(5-methoxy-1H-indole-3-yl)-2-oxoacetyl chloride. To a solution of 5-methoxy-1H-indole (5 g, 33.97 mmol, 1 equivalent) in 50 mL of THF at 0°C, (COCl)2 (6.47 g, 50.96 mmol, 4.46 mL, 1.5 equivalents) was added dropwise. The mixture was then heated to 20°C and stirred for 12 hours. TLC (PE:EA = 3:1, Rf product = 0.1) indicated that the reaction was successful. The mixture was concentrated to yield crude 2-(5-methoxy-1H-indole-3-yl)-2-oxoacetyl chloride as a brown solid (8 g), which was used directly in the next step without further purification.

[0142] Step 2: Preparation of 1-(azetidine-1-yl)-2-(5-methoxy-1H-indole-3-yl)ethane-1,2-dione. To a solution of azetidine hydrochloride (4.72 g, 50.50 mmol, 1.5 equivalents) in DCM (50 ml), DIPEA (17.40 g, 134.66 mmol, 23.46 mL, 4 equivalents) was added, and the mixture was stirred at 20°C for 0.5 hours. At this point, the solution was cooled to 0°C, and 2-(5-methoxy-1H-indole-3-yl)-2-oxoacetyl chloride (8 g, 33.66 mmol, 1 equivalent) in THF (100 mL) was added, and the mixture was heated to 20°C and stirred for 12 hours. TLC (PE:EA = 0:1, Rf product = 0.26) indicated that the reaction was complete. The reaction mixture was quenched at 20°C by adding saturated NH4Cl aqueous solution (10 mL), and then extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified at 20°C by recrystallization from PE (50 mL) and DCM (20 mL) to obtain 1-(azetidine-1-yl)-2-(5-methoxy-1H-indole-3-yl)ethane-1,2-dione as a white solid (4.2 g, 16.26 mmol, 48% yield over two steps). 1 H NMR (400 MHz, DMSO-d6) δ 12.13 (br s, 1H), 8.42 (br s, 1H), 7.68 (br s, 1H), 7.42 (br d, J= 8.7 Hz, 1H), 6.88 (br d, J= 7.8 Hz, 1H), LCMS (R T = 1.226 min, MS calculated: 258.10, [M+H] + 259.1);

[0143] Step 3: Preparation of 3-(2-(azetidine-1-yl)ethyl)-5-methoxy-1H-indole fumarate (3). To a solution of 1-(azetidine-1-yl)-2-(5-methoxy-1H-indole-3-yl)ethane-1,2-dione (1 g, 3.87 mmol, 1 equivalent) in THF (50 mL), LAH (440.86 mg, 11.62 mmol, 3 equivalents) was added at 0°C. The mixture was then heated at 70°C for 8 hours. After completion, the mixture was cooled to 0°C, Na2SO4·10H2O was added until foaming stopped, the mixture was filtered, and concentrated. The residue was subjected to preparative HPLC (column = Waters Crossbridge Preparative OBD). The solution was purified using C18 (150 × 40 mm, 10 μm; mobile phase = water (NH4HCO3)-ACN, B% = 5%~35%; run time 8 minutes) to obtain a solution of 3-(2-(azetidine-1-yl)ethyl)-5-methoxy-1H-indole in a mixture of H2O (400 mL) and MeCN (100 mL). To this solution, a solution of fumaric acid (approximately 1 equivalent) in MeCN (2 mL) was added and incubated under N2 at 20°C in one batch. The mixture was added. The mixture was stirred at 20°C for 20 minutes, then freeze-dried to obtain 3-(2-(azetidine-1-yl)ethyl)-5-methoxy-1H-indole fumarate (3) as a yellow solid (300 mg, 0.91 mmol, 24% yield, 3:fumarate = 1:0.86), which was confirmed by LC-MS (ET47030-21-P1A1, Rt = 1.543 min, M + H = 231.1). 1 H NMR (400 MHz, DMSO-d6) δ 10.71 (br s, 1H), 7.22 (d, J = 8.70 Hz, 1H), 7.10 (d, J = 2.03 Hz, 1H), 7.02 (d, J = 2.27 Hz, 1H), 6.71 (dd, J 8.70, 2.38 Hz, 1H), 6.48 (s, 1.71H = fumarate, 0.86 mol equivalent), 3.76 (s, 3H), 3.53 (t, J = 7.45 Hz, 4H), 2.89 - 2.99 (m, 2H), 2.69 - 2.77 (m, 2H), 2.12 (quintet, J = 7.51 Hz, 2H); LCMS (R T = 1.543 min, MS calculated: 230.14, [M+H] + = 231.1).

[0144] Failed workup and purification methods for compound 3: Several alternative methods for workup-ing LAH reduction and purifying the resulting product 3 resulted in partial or complete degradation, failing to yield a pure product. These failed workup / purification methods are summarized below.

[0145] Method 1: Workup: Once completed, H2O and a 30% NaOH aqueous solution were added to the mixture, and the resulting slurry was filtered and concentrated.

[0146] Purification: The residue was purified by preparative HPLC (column = Waters Crossbridge Preparative OBD C18 (150 × 40 mm, 10 μm); mobile phase = water (NH4HCO3)-ACN, B% = 1%~25%; run time 8 minutes). After lyophilization of the eluate, 1 1H NMR showed that the product was impure.

[0147] Method 2: Workup: Same as Method 1.

[0148] Purification: The residue was purified by preparative HPLC (column = Phenomenex C18 (75 × 30 mm, 3 μm); mobile phase = water (NH3·H2O + NH4HCO3)-ACN, B% = 1%~30%; run time 8 minutes). After lyophilization of the eluate, 1 1H NMR showed that the product was impure.

[0149] Example 4. Preparation of Compound 4 [ka]

[0150] Step 1: Preparation of 3-(2-(azetidine-1-yl)ethyl)-1H-indole-4-yl acetate (4). A mixture of 3-(2-(azetidine-1-yl)ethyl)-1H-indole-4-ol (2, 50 mg, 231.18 μmol, 1 equivalent) and pyridine (23.77 mg, 300.54 μmol, 24.26 μL, 1.3 equivalents) in DCM (1 mL) was cooled to 0°C. Then, acetic anhydride (25.96 mg, 254.30 μmol, 23.82 μL, 1.1 equivalents) was added dropwise at 0°C, and the resulting mixture was stirred at 25°C for 1 hour. At this point, the solvent was removed, and the residue was purified by preparative HPLC (column = Waters Crossbridge BEH C18 (100 × 30 mm, 10 μm); mobile phase = water (NH4HCO3)-ACN, B% = 5%~40%; run time 10 minutes) to obtain 3-(2-(azetidine-1-yl)ethyl)-1H-indole-4-yl acetate (4) as a white solid (20 mg, 33% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (br s, 1 H), 7.22 (d, J = 8.0 Hz, 1 H), 7.11 (d, J= 1.6 Hz, 1 H), 7 02 (t, J = 8.0 Hz, 1 H), 6.64 (d, J = 7.6 Hz, 1 H), 3.09 (t, J = 6.8 Hz, 4 H), 2.57-2.54 (m, 4 H), 2.32 (s, 3 H), 1.96 - 1.90 (m, 2 H); LCMS (R T = 0.983 min, MS calculated value: 258.14, [M+H] + = 259.1).

[0151] Note: Product 4 is susceptible to hydrolysis, and hydrolysis was observed during analysis by LC-MS and HPLC using an aqueous mobile phase.

[0152] Example 5. Metabolic stability in human liver microsomes The disclosed compounds were tested for stability in human liver microsomes (HLMs), and the results are summarized in Table 1. Azetidinyl compounds 1, 2, and 3 exhibited superior metabolic stability compared to their dimethyl counterparts, N,N-dimethyltryptamine (DMT), psilosine, and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), respectively. Therefore, azetidinyl compounds are expected to have superior oral bioavailability compared to their dimethyl counterparts.

[0153] Test compounds. Compounds 1, 2, and 3 were prepared as described above. All other compounds were commercially available.

[0154] HLM stability. Pooled HLM (Corning 452117) from adult male and female donors was used. Microsome incubation was performed in multi-well plates. The liver microsome incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (1 mM), and NADPH (1 mM), with 0.50 mg of liver microsomal protein per mL. A control incubation was performed by replacing the NADPH-cofactor system with PBS. The test compound (1 μM, final solvent concentration 1.0%) was incubated with microsomes at 37°C with continuous shaking. Six time points were analyzed over 60 minutes, and 60 μL aliquots of the reaction mixture were taken at each time point. The reaction aliquot was stopped by adding 180 μL of cold (4°C) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS). The mixture was then shaken for 10 minutes, followed by protein precipitation by centrifugation at 4,000 rpm for 20 minutes at 4°C. The supernatant sample (80 μL) was diluted with water (240 μL), and the remaining parent compound was analyzed using a suitable liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0155] Data analysis. Exclusion constant (k e1 ), half-life (t 1 / 2) and inherent clearance (CL int The value was determined using linear regression analysis and plotted using natural logarithm (AUC) versus time.

[0156] [Table 1]

[0157] Example 6. Stability in the presence of monoamine oxidase. The stability of the disclosed compounds in human liver mitochondrial preparations in the presence of monoamine oxidases A and B (MAO-A and MAO-B) was tested, and the results are summarized in Table 2. Azetidinyl compounds 1 and 3 exhibited superior stability compared to their dimethyl counterparts, N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), respectively. Therefore, azetidinyl compounds are expected to undergo reduced cerebral metabolism compared to their dimethyl counterparts. Azetidinyl compound 2 exhibited similar stability to its already stable dimethyl counterpart, psilocine, in this preparation.

[0158] Test compounds. Compounds 1, 2, and 3 were prepared as described above. All other compounds were commercially available.

[0159] Liver mitochondrial incubation. Human liver mitochondria (Xenotech H0610.M) were used. Mitochondrial incubation was performed in a multi-well plate. The liver mitochondrial incubation medium consisted of PBS (100 mM, pH 7.4) with 0.30 mg of liver mitochondrial protein per mL. The test compound (1 μM, final solvent concentration 1.0%) was incubated with liver mitochondrial protein at 37°C with continuous shaking (total reaction volume 100 μL per well). Six time points were analyzed over 60 minutes. At each time point, the reaction was stopped by adding 300 μL of cold (4°C) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS), followed by shaking for 10 minutes, and then protein precipitation by centrifugation at 4,000 rpm for 20 minutes at 4°C. The supernatant sample (100 μL) was diluted with 5% trichloroacetic acid in water (300 μL), and the remaining parent compound was analyzed using a suitable liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0160] Data analysis. Exclusion constant (k e1 ), half-life (t 1 / 2 ) and inherent clearance (CL int The value was determined using linear regression analysis and plotted using natural logarithm (AUC) versus time.

[0161] [Table 2]

[0162] Example 7. Stability in mouse brain homogenate The disclosed compounds were tested for stability in mouse brain homogenate (Table 3). Azetidinyl compounds 1, 2, and 3 all exhibited good stability under experimental conditions and were far more stable than N,N-dimethyltryptamine (DMT).

[0163] Test compounds. Compounds 1, 2, and 3 were prepared as described above. All other compounds were commercially available.

[0164] Brain homogenate stability. Frozen mouse brain homogenate (pooled from male CD-1 mice, BioreclamationIVT, MSE00BRAINMZA) was thawed in a 37°C water bath immediately before use. Positive controls and test compounds (final concentrations in incubation medium = 1 μM for the test compound and 2 μM for the control, all with 2% DMSO added) were incubated in pairs at 37°C in mouse brain homogenate at 100 μL total reaction volume at each time point (0, 10, 30, 60, and 120 minutes). At the end of each incubation period, the reaction mixture was immediately quenched with 400 μL of acetonitrile containing internal standards (200 ng / mL tolbutamine and 200 ng / mL labetalol) and thoroughly mixed. The plate was then sealed and shaken for 20 minutes, followed by centrifugation at 4,000 rpm at 4°C for 20 minutes. Aliquots of each supernatant (50 μL) were diluted in 100 μL of water, and the mixtures were then shaken again for 10 minutes. The resulting mixtures were analyzed for the remaining parent compounds using a suitable LC-MS / MS method.

[0165] [Table 3]

[0166] Example 8. Stability of rat brain homogenate The disclosed compounds were tested for stability in rat brain homogenate (Table 4). Azetidinyl compounds 1, 2, and 3 all exhibited good stability under experimental conditions and were more stable than their dimethyl counterparts, N,N-dimethyltryptamine (DMT), psilosine, and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), respectively.

[0167] Test compounds. Compounds 1, 2, and 3 were prepared as described above. All other compounds were commercially available.

[0168] Brain homogenate stability. Frozen rat brain homogenate (pooled from male Sprague-Dolly rats, BioreclamationIVT, RAT00BRAINMZA) was thawed in a 37°C water bath immediately before use. Positive controls and test compounds (final concentrations in incubation medium = 1 μM for the test compound and 2 μM for the control, all with 2% DMSO added) were incubated in pairs at 37°C in rat brain homogenate at 100 μL total reaction volume at each time point (0, 10, 30, 60, and 120 minutes). At the end of each incubation period, the reaction mixture was immediately quenched with 400 μL of acetonitrile containing internal standards (200 ng / mL tolbutamine and 200 ng / mL labetalol) and thoroughly mixed. The plate was then sealed and shaken for 20 minutes, followed by centrifugation at 4,000 rpm at 4°C for 20 minutes. Aliquots of each supernatant (50 μL) were diluted in 100 μL of water, and the mixtures were then shaken again for 10 minutes. The resulting mixtures were analyzed for the remaining parent compounds using a suitable LC-MS / MS method.

[0169] [Table 4]

[0170] Example 9. Functional activity of serotonin receptors The disclosed compound is Ca 2+Agonist activity in several serotonin receptor subtypes (5-HT2A, 2-HT2B, 5-HT2C, and 5-HT1A) was tested using a flux function assay, and the results are summarized in Table 5. All compounds exhibited potent agonist activity in 5-HT2A, suggesting potential hallucinogenic activity and possible therapeutic effects. However, azetidinyl compounds generally showed far superior potency in 5-HT1A compared to closely related compounds. For example, compound 1 was more than 50 times potent in this receptor than its dimethyl and methylethyl counterparts, N,N-dimethyltryptamine (DMT) and N-methyl-N-ethyltryptamine (MET; N-ethyl-2-(1H-indole-3-yl)-N-methylethane-1-amine), respectively. Similarly, compound 2 was more than five times potent in 5-HT1A than its dimethyl and methyl ethyl counterparts, psilocine, and 4-hydroxy-N-methyl-N-ethyltryptamine (4-HO-MET; 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-4-ol), respectively. Finally, compound 3 was more than ten times potent in 5-HT1A than its dimethyl counterpart, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). These increases in 5-HT1A potency for azetidinyl compounds 1, 2, and 3, coupled with similar or slightly reduced potency in 5-HT2A, meant that there was a relative reduction in 5-HT2A selectivity for these compounds compared to 5-HT1A compared to their dimethyl and methyl ethyl counterparts. Since 5-HT1A agonists are known to have anxiolytic and antidepressant effects, increased activity at this target is expected to enhance the therapeutic activity of azetidinil compounds used to treat mood disorders.

[0171] Test compounds. Compounds 1, 2, and 3 were prepared as described above. All other compounds were commercially available.

[0172] Functional assays of 5-HT2A, 5-HT2B, and 5-HT1A receptors. Agonist activity of 5-HT2A, 5-HT2B, and 5-HT1A receptors is measured using FLIPR Ca 2+ Flux assays were performed at WuXi AppTec (Hong Kong) Limited according to their standard protocol. Briefly, stably transfected cells expressing the target receptor (HEK293 for 5-HT2A and 5-HT2B; CHO cells for 5-HT1A) were grown, cultured in 384-well plates, and incubated overnight at 37°C and 5% CO2. A fresh solution of 250 mM probenecid in 1 mL of FLIPR assay buffer was prepared. This was combined with a fluorescent dye (Fluo-4 Direct®) to a final assay concentration of 2.5 mM. The compound was diluted 1:3.16 ten times, and 750 nL was added to the 384-well compound plate using ECHO with 30 μL of assay buffer. The fluorescent dye was then added to the assay plate with assay buffer to a final volume of 40 μL. The cell plates were incubated at 37°C and 5% CO2 for 50 minutes, and then placed in FLIPR tetras along with the compound plates. Next, 10 μL of reference material and compound were transferred from the compound plate to the cell plate, and the fluorescence signals were read.

[0173] Functional assay in 5-HT2C. Agonist activity in 5-HT2C was evaluated using FLIPR Ca 2+Flux assays were performed at Eurofins DiscoverX (Fremont, CA) according to their standard protocol. Briefly, stably transfected cells expressing the human 5-HT2C receptor were grown, cultured in 384-well plates, and incubated overnight at 37°C and 5% CO2. The assay was performed in a 1× dye loading buffer consisting of 1× dye, 1× additive A, and 2.5 mM probenecid in HBSS / 20 mM Hepes. Probenecid was freshly prepared. After loading the dye into the cells, they were tested and incubated at 37°C for 30–60 minutes. After dye loading, the cells were removed from the incubator and 10 μL of HBSS / 20 mM Hepes was added. A 3× vehicle was included in the assay buffer. The cells were incubated at room temperature in the dark for 30 minutes to equilibrate the plate temperature. Intermediate dilutions of the sample stock were performed to produce 4× samples in the assay buffer. Compound agonist activity was measured using FLIPR Tetra (MDS). Calcium recruitment was monitored for 2 minutes, and 5 seconds after the start of the assay, 4× sample in 10 μL of HBSS / 20 mM Hepes was added to the cells.

[0174] [Table 5]

[0175] Example 10. Effect on head spasm response (HTR) in mice The disclosed compounds were tested for their ability to induce a cerebral spasm response (HTR) in mice, and the results are summarized in Table 6. The maximum effect (less than 10 cerebral spasms / 20 mins) of the disclosed azetidinyl compounds was significantly less than that of the prototype 5-HT2A agonist 4-iodo-2,5-dimethoxyamphetamine (DOI) (35.6 cerebral spasms / 20 mins) and the prototype psychedelic tryptamine, 4-HO-MET (4-hydroxy-N-methyl-N-ethyltryptamine; 20.8 cerebral spasms / 20 mins). This observation is consistent with the far superior potency of compounds 1 and 2 as 5-HT1A agonists observed in vitro, as 5-HT1A agonism is known to suppress the maximum effect in HTR assays.

[0176] Animals. Mature 8-week-old male C57BL / 6 mice (body weight 20-25g) were used in these experiments. The animals were housed at a controlled temperature and in a 12-hour light / dark cycle (lights on from 07:00 to 19:00), and were given free access to food and water. The protocol was approved by the Animal Experimentation Committee of Eurofins Advinus. This study was conducted in strict accordance with the recommendations of the National Institutes of Health Guidelines for the Proper Conduct of Animal Experiments. Every effort was made to minimize suffering.

[0177] Drugs and drug administration. Compounds 1 and 2 were prepared as described above. All other compounds were commercially available. The test compounds were used as free base (2), fumarate (4-HO-MET and 1), or hydrochloride (DOI). The drugs were dissolved in a vehicle consisting of physiological saline (DOI, 4-HO-MET, and 1) or a mixture of 10% DMSO, 10% Tween 80, and 1 molar equivalent of HCl in physiological saline (2), and administered subcutaneously (SC) at a volume of 10 mL / kg. The test compounds were administered in 5 doses per compound (0.1 to 10 mg / kg, calculated based on the free base) to N=6 animals / group. The control compound DOI was administered in a 1 dose (3.16 mg / kg, calculated based on the HCl salt) to N=12 animals.

[0178] Procedure: Mice were administered a single dose of the test drug (or vehicle) via SC (Small-Coated Segmentation) and immediately placed in a small open field for behavioral observation. The animals were observed continuously for 20 minutes, and the HTR (Heat-to-Treat) count was coefficientd by an observer blinded to the treatment condition.

[0179] Statistical analysis. The data points shown in Table 6 represent the mean ± standard error (SEM). The analysis was performed using a graph pad prism 9.

[0180] [Table 6]

[0181] Example 11. Forced swimming test in rats Disclosed compound 2 induced an antidepressant-like effect in a forced swim test (FST) in rats after a 23.5-hour pre-treatment period (Figure 1). Specifically, the compound reduced immobility time compared to the vehicle control, indicating an antidepressant-like effect. This effect on immobility was highly potent, with a significant effect observed even at the lowest dose tested (0.1 mg / kg). Furthermore, the effect was observed 23.5 hours after single-compound administration, when most or all of the drug had been removed from systemic circulation, suggesting that compound 2 possesses both immediate and long-lasting antidepressant-like effects. In addition, the compound induced a significant increase in swimming behavior during the test (Figure 2). These effects on swimming were stronger than those induced by the control antidepressant desipramine.

[0182] Animals. Male Sprague Dolly rats aged 8-10 weeks were used in the experiments. The animals were housed in two groups under controlled temperature (22±3°C) and relative humidity (30-70%) conditions, in a 12-hour light / dark cycle, with free access to food and water. These studies were conducted in strict accordance with the requirements of the Commission for Control and Supervision of Animal Experiments in India (CPCSEA). Every effort was made to minimize suffering.

[0183] Drugs and drug administration. Compound 2 was prepared as described above. All other compounds were obtained commercially. The test compounds, saline vehicle, and positive control desipramine were administered subcutaneously (SC), and the doses were calculated based on the free base. Saline was used as the vehicle except for Compound 2, which was dissolved in a mixture of 10% DMSO, 10% Tween 80, and 1 molar equivalent of HCl in saline. All compounds were administered at a volume of 5 mL / kg. The test compounds and vehicle were administered 0.5 hours after the start of the training swim (Swim 1) and 23.5 hours before the test swim (Swim 2). Desipramine was administered 3 times at a dose of 20 mg / kg per time at 23.5 hours, 5 hours, and 1 hour before the test swim (Swim 2).

[0184] Forced swim test (FST). Animals were randomized based on body weight to ensure minimal variation between groups and that no group exceeded ±20% of the mean body weight of the entire group. The group size was N = 10, except for the vehicle and desipramine groups, which were N = 20 per treatment. Rats were handled daily for approximately 2 minutes for 5 days prior to the start of the experimental procedure. On the first day of the experiment (i.e., Day 0), after randomization, a training swim session (Swim 1) was conducted between 12:00 and 18:00, and all animals were used by placing the rats in individual glass cylinders (height 46 cm × diameter 20 cm) containing water at 23 - 25°C to a depth of 30 cm for 15 minutes. At the end of Swim 1, the animals were dried with a paper towel, placed in a heated drying cage for 15 minutes, and then returned to their home cages. The animals were then administered the appropriate drug or vehicle treatment as described above. For clarity, the compound administration time 23.5 hours before Swim 2 means 0.5 hours after the start of Swim 1 and 0.25 hours after the completion of Swim 1 (i.e., immediately after returning to the home cage). On Day 1 (i.e., 24 hours after the start of Swim 1), the animals performed a test swim (Swim 2) for 5 minutes under the same conditions as Swim 1, except that the water was changed between each animal during all swim sessions.

[0185] The locomotor scoring was performed by an observer blinded to the treatment group. During Swim 2, the animals were observed continuously and the total time spent engaging in the following behaviors was recorded: immobility, swimming, and climbing. A rat was judged to be immobile if it floated in the water without struggling and made only the movements necessary to keep its head above water. A rat was judged to be swimming if it made more active swimming movements than necessary to simply keep its head above water (e.g., moving around inside the cylinder). A rat was judged to be climbing if it made active movements inside and outside the water using its front paws that were normally directed towards the wall.

[0186] Statistical analysis. The data points shown in Figures 1 and 2 represent the mean ± standard error of the mean (SEM). The analysis was performed using GraphPad Prism 9. Intergroup comparisons were performed using one-way analysis of variance (ANOVA), followed by Dunnett's test for comparisons against the vehicle.

[0187] Example 12. Compound 4 is a prodrug of Compound 2. When administered to an animal, e.g., a human, the acetate ester of Compound 4 is rapidly hydrolyzed to give the phenolic Compound 2 as the active metabolite. Since Compound 4 is more stable to oxidation than Compound 2, it is a useful prodrug of Compound 2 that is more easily stored and handled. Other esters of Compound 2 (in the phenol) have similar useful properties as prodrugs.

[0188] Example 13. Microsomal stability of additional compounds. Additional disclosed compounds are tested for stability in human liver microsomes as described in Example 5. The compounds exhibit good stability in this preparation and are more stable than their N,N-dimethyl counterparts.

[0189] Example 14. Stability of additional compounds in the presence of monoamine oxidase Additional disclosed compounds are tested using liver mitochondrial preparations as described in Example 6 to determine their stability in the presence of monoamine oxidase. The compounds exhibit good stability in this preparation and are more stable than their N,N-dimethyl counterparts.

[0190] Example 15. Agonist activity of additional compounds in 5-HT1A and 5-HT2A receptors The additional disclosed compounds were tested as described in Example 9 to determine their agonist activity in the 5-HT2A and 5-HT1A receptors. The compounds exhibited potent and effective agonist activity in both receptors, and were more potent in 5-HT1A compared to their nearest acyclic amine analogues.

[0191] Example 16. Effect of additional compounds in HTR assay Additional disclosed compounds are tested as described in Example 10 to determine their ability to induce a cerebral spasm response (HTR) in mice. The compounds induce low to moderate maximum effects compared to other 5-HT2A agonists, e.g., DOI and 4-HO-MET.

[0192] Example 17. Effect of additional compounds in forced swimming tests in rats The additional disclosed compounds were tested in a forced swimming test (FST) in rats, as described in Example 11. The compounds reduced immobility in a dose-dependent manner in this test, consistent with an antidepressant-like effect.

[0193] Example 18. Synthesis of additional compounds Additional disclosed compounds may be prepared by standard methods known to those skilled in the art of organic synthesis, such as those presented in Examples 1-4 and described elsewhere in this Specified

[0194] Example 19. Preparation of Compound 5 Method 1: [ka]

[0195] Step 1: Preparation of benzyl(3-(2-(1-benzylazetidine-1-ium-1-yl)ethyl)-1H-indole-4-yl)phosphate. To a mixture of 3-(2-(azetidine-1-yl)ethyl)-1H-indole-4-ol (2,1 equivalent) in anhydrous THF (8.3 mL per 1 mmol of 2) at -78°C, a solution of 2.5 M nBuLi in hexane (1.2 equivalents) is added dropwise over several minutes while maintaining the internal temperature below -60°C. The reaction mixture is stirred for 10 minutes, then tetrabenzyl pyrophosphate (1.1 equivalents) is added all at once, and stirring is continued at -78°C for 1.5 hours. At this point, the cooling bath is removed, and the temperature is slowly raised to -25°C over approximately 2 hours. Completion of the reaction is confirmed by LC-MS. With the reaction mixture still at -25°C, amino-bonded silica gel (0.5 g per 1 mmol of 2) is added all at once, and the reaction mixture is diluted with siRNA (10 mL per 1 mmol of 2). The mixture is filtered through a Celite pad and washed with siRNA (6.7 mL per 1 mmol of 2). The filtered cake is re-slurried with an additional siRNA (6.7 mL per 1 mmol of 2) for 10 minutes and filtered again. The combined filtrate is concentrated, the residue is redissolved in DCM (1.7 mL per 1 mmol of 2), and the solution is heated with a heat gun until boiling for 5 minutes. The mixture is then allowed to cool to room temperature, then further cooled to 4°C and kept at that temperature overnight. The resulting precipitate is collected by filtration and triturated with DCM (4 × 1.7 mL per 1 mmol of 2), with the supernatant removed each time, and then thoroughly dried to obtain benzyl(3-(2-(1-benzylazetidine-1-ium-1-yl)ethyl)-1H-indole-4-yl) phosphate.

[0196] Step 2: Preparation of 3-(2-(azetidine-1-yl)ethyl)-1H-indole-4-yl dihydrogen phosphate (5). Under N2 conditions, 10% Pd / C (30.9 mg per mmol of substrate) is added to a mixture of benzyl (3-(2-(1-benzylazetidine-1-ium-1-yl)ethyl)-1H-indole-4-yl) phosphate (1 equivalent) in MeOH (33.7 mL per mmol of substrate). The atmosphere is evacuated, and H2 is refilled at 1 atm through the balloon. The reaction mixture is then stirred overnight at room temperature. Completion of the reaction is confirmed by LC-MS. The flask is then evacuated, N2 is refilled, and the suspension is filtered through a Celite pad. The filter pad is washed with MeOH (14 mL per mmol of substrate), and the combined filtrate is concentrated to obtain the crude product. The crude solid is suspended in iPrOH (5.6 ml per mmol of substrate), boiled for 30 minutes, filtered while hot (50 to 60°C), and the collected solid is washed with acetone. Next, this material is suspended in 25% MeOH in iPrOH, boiled for 30 minutes, filtered while hot, and the collected solid is washed with 25% MeOH in iPrOH. Finally, the solid is recrystallized from 30% water in acetone to obtain pure 3-(2-(azetidine-1-yl)ethyl)-1H-indole-4-yl dihydrogen phosphate (5). The product can be further recrystallized from 30% water in acetone or pure water to obtain a higher purity material if desired.

[0197] Method 2: [ka]

[0198] Step 1: Preparation of 3-(2-(azetidine-1-yl)ethyl)-1H-indole-4-yl dihydrogen phosphate (5). Under N2 conditions, prepare a slurry of 3-(2-(azetidine-1-yl)ethyl)-1H-indole-4-ol (2, 1 equivalent) and Celite (equal mass of 2) in anhydrous THF (3.07 mL per 1 mmol of 2), stir at room temperature for at least 2 hours, and then cool the mixture to -15°C. Separately, prepare a solution of POCl3 (1.5 equivalents) under N2 conditions in anhydrous THF (1.36 mL per 1 mmol of POCl3), and cool to -15°C. Then, slowly add the 2 / Celite / THF slurry to the POCl3 solution while maintaining the internal temperature between -15 and 0°C, and stir the resulting mixture at -15°C for 1 hour. Prepare a quench solution of THF / H2O (70:30, 2.04 mL per 1 mmol of 2) and Et3N (6 equivalents), and cool to -20 to 0°C. Next, the reaction mixture is slowly added to the quench solution while maintaining an internal temperature between -20 and 0°C. The residue in the reaction flask is washed with ice-cold THF (2 × 0.41 mL per 1 mmol of 2) and water (0.61 mL per 1 mmol of 2) while maintaining an internal temperature between -20 and 0°C to obtain the quench mixture. The combined mixture is then stirred at -20 to 0°C for at least 1 hour. At this point, the mixture is filtered and the cake is washed with 5 to 10°C water (2 × 0.41 mL per 1 mmol of 2). The lower aqueous phase containing the product is separated and mixed with iPrOH (2.04 mL per 1 mmol of 2), and the mixture is concentrated at an internal temperature below 45°C to a volume of approximately 1.02 mL per 1 mmol of 2, from which only water is distilled (additional iPrOH is added as needed to assist azeotropic distillation of water to achieve the target volume). At this point, add additional water (1.02 mL per 1 mmol of 2) and stir the mixture at room temperature for at least 24 hours. Collect the resulting precipitate by filtration under an N2 atmosphere, wash the cake with cold water (2 × 0.41 mL per 1 mmol of 2), and dry the collected solid under vacuum at 35-45°C for at least 24 hours. Mix the crude product with MeOH (10 mL per 1 g of crude product) under N2 and stir at room temperature for at least 12 hours. Filter the mixture under N2 and rinse the cake with MeOH (2 × 1.5 mL per 1 g of crude product) at room temperature.The collected solid is mixed with water (10 mL per 1 g of the crude product) under N2 and stirred at 45 - 55 °C for at least 24 hours. Then, the mixture is cooled to room temperature over about 2 hours and further stirred at that temperature for an additional 2 hours. The solid is collected by filtration under N2, washed with water at room temperature (2 × 1 mL per 1 g of the crude product), and dried under vacuum at 35 - 45 °C for at least 24 hours to obtain pure 3-(2-(azetidin-1-yl)ethyl)-1H-indol-4-yl dihydrogen phosphate (5).

[0199] Example 20. Compound 5 is a prodrug of compound 2. When administered to animals, such as humans, the phosphate ester of compound 5 is rapidly hydrolyzed to give the phenolic compound 2 as the active metabolite. Since compound 5 is more stable than compound 2, it is a useful prodrug of compound 2 that can be more easily stored and handled.

[0200] It should be understood that the examples and embodiments provided herein are illustrative. Those skilled in the art will envision various modifications of the examples and embodiments that are consistent with the scope of the disclosure herein. Such modifications are intended to be encompassed by the claims.

Claims

1. The following: 【Chemistry 1】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

2. The following: 【Chemistry 2】 A compound according to claim 1 having the structure, or a pharmaceutically acceptable salt thereof.

3. The following: 【Transformation 3】 A compound according to claim 1 having the structure, or a pharmaceutically acceptable salt thereof.

4. The following: 【Chemistry 4】 A compound according to claim 1 having the structure, or a pharmaceutically acceptable salt thereof.

5. The following: 【Transformation 5】 A compound having the structure of, or a pharmaceutically acceptable salt thereof.

6. The following: 【Transformation 6】 A compound having the structure of, or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.

Images