Azetidinyl tryptamines and methods of treating mental disorders

Abstract

The present disclosure includes azetidinyl tryptamines and methods of using such compounds to treat psychiatric disorders. Also provided are pharmaceutical compositions comprising azetidinyl tryptamines.

Description

Technical Field

[0001] Novel azahexacyclic butyltryptamines and methods for treating mental disorders with such compounds are also provided. Pharmaceutical compositions comprising azahexacyclic butyltryptamines are also provided. Background Technology

[0002] Tryptophan is a diverse class of alkaloids containing the structural framework of the natural alkaloid tryptophan.

[0003]

[0004] A large number of tryptamine compounds exist, including naturally occurring compounds and synthetic and semi-synthetic chemical derivatives with similar structures. Tryptamines are known to have a variety of psychoactive and physiological effects. Some tryptamines are 5-HT2A receptor agonists and / or modulators of other 5-HT receptors, and are known to have psychoactive effects and / or induce vasoconstriction. In some cases, such compounds induce prolonged hallucinations. Other tryptamines are modulators of monoamine transporters. The most well-known tryptamines are psychedelic compounds, including compounds derived from entheogenic fungi (psilocybin and psilocin), DMT, LSD, 5-MeO-DMT, bufotalin, and ibogain. These compounds are known to have significant effects on thought, perception, and behavior. However, these compounds are currently classified as Schedule I drugs under the Controlled Substances Act because of their high potential for abuse, lack of accepted medical use, and lack of established safety profiles. In addition, tryptophan is metabolized through multiple pathways, including monoamine oxidase in some cases, which limits the oral bioavailability of some compounds.

[0005] Therefore, there is still a need for safe and effective tryptamine compounds that can be reliably used to treat mental disorders. Summary of the Invention

[0006] This disclosure provides compounds having the following general formula I:

[0007]

[0008] in

[0009] R 1 -R 6 Each is independently selected from H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynynyl, C1-C5 heteroalkyl, C2-C5 heteroalkenyl, C2-C5 heteroynyl and C1-C5 haloalkyl;

[0010] R7 -R 10 and R 12 Each is independently selected from H, F, Cl, Br, I, CF3, SF5, Cl-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Heteroalkyl, C2-C 10 Heterene group, C2-C 10 Heterynyl group, C1-C 10 Haloalkyl, -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 groups, -OP(O)(OH)(OH), NH2, -NH-(C1-C 10 Alkyl), -N(C1-C 10 Alkyl) (C1-C 10 Alkyl groups), NO2 and OCF3; and

[0011] R 11 Selected from H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C1-C5 heteroalkyl, C2-C5 heteroalkenyl, C2-C5 heteroynyl and C1-C5 haloalkyl;

[0012] Or its pharmaceutically acceptable salts or esters.

[0013] This disclosure further provides pharmaceutical compositions comprising one or more compounds disclosed herein.

[0014] This disclosure further provides a method for treating mental illness or disorder in patients who require it, the method comprising administering to the subject a composition comprising an effective amount of a compound of this disclosure. Attached Figure Description

[0015] Figure 1Resting time in FST. One-way ANOVA showed that treatment (F(5,54)=19.35, P<0.0001) had a significant major effect on the total resting time in FST. Dunnett's multiple comparison test was used to test whether a group was significantly different from the medium. All treatments were significantly different from the medium. ****P<.0001 relative to the medium.

[0016] Figure 2 Swimming time in FST. One-way ANOVA showed that treatment (F(5,54)=9.606, P<0.0001) had a significant major effect on the total swimming time in FST. Dunnett's multiple comparison test was used to test whether a group was significantly different from the medium. **P<.01, ****P<.0001 relative to the medium. Detailed Implementation

[0017] In the following detailed description, numerous specific details are set forth to provide a thorough understanding of this disclosure. However, those skilled in the art will understand that this disclosure may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure this disclosure.

[0018] This article describes novel azahexacyclic butyltryptamines and methods for treating mental disorders using such compounds. Pharmaceutical compositions comprising azahexacyclic butyltryptamines are also provided. The provided compounds, as 5-hydroxytryptamine 1A (5-HT1A) receptor agonists, exhibit greater potency compared to their acyclic counterparts, such as tryptamines with N,N-dimethyl substituents. Furthermore, they possess better metabolic stability than such N,N-dimethyl counterparts.

[0019] This disclosure provides compounds having the following general formula I:

[0020]

[0021] in

[0022] R 1 -R 6 Each is independently selected from -H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynynyl, C1-C5 heteroalkyl, C2-C5 heteroalkenyl, C2-C5 heteroynyl and C1-C5 haloalkyl;

[0023] R 7 -R 10 and R 12 Each is independently selected from -H, -F, -Cl, -Br, -I, -CF3, -SF5, Cl-C 10 Alkyl, C2-C10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Heteroalkyl, C2-C 10 Heterene group, C2-C 10 Heterynyl group, C1-C 10 Haloalkyl, -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 groups, -OP(O)(OH)(OH), NH2, -NH-(C1-C 10 Alkyl), -N(C1-C 10 Alkyl) (C1-C 10 Alkyl groups), -NO2 and -OCF3; and

[0024] R 11 Selected from -H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C1-C5 heteroalkyl, C2-C5 heteroalkenyl, C2-C5 heteroynyl, and C1-C5 haloalkyl;

[0025] Or its pharmaceutically acceptable salts or esters.

[0026] In the implementation plan,

[0027] R 1 -R 6 Each is independently selected from -H, -Me, -Et, -n-Pr, -i-Pr, cyclopropyl, -CH=CH2 (vinyl), -C≡CH (ethynyl), and -CH2CHCH2 (allyl);

[0028] R 7 -R 10 and R 12Each is independently selected from -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; and

[0029] R 11 Selected from -H, -Me, -Et, -n-Pr, -i-Pr, cyclopropyl and -CH2CHCH2 (allyl);

[0030] Or its pharmaceutically acceptable salts or esters.

[0031] In the implementation plan,

[0032] R 1 -R 6 Each can be independently selected from -H, -Me, and -Et;

[0033] R 7 -R 10 and R 12 Each is independently selected from -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; and

[0034] R 11 Selected from -H, -Me, and -Et;

[0035] Or its pharmaceutically acceptable salts or esters.

[0036] In the implementation plan,

[0037] R 1 -R 6 Each can be independently selected from -H, -Me, and -Et;

[0038] R 7 -R 10 and R 12 Each is independently selected from -H, -F, -Cl, -Br, -I, -CF3, -Me, -CN, -OMe, -OH, -OAc, -C(O)-NH2, -OP(O)(OH)(OH) and -NH2; and

[0039] R 11-H;

[0040] Or its pharmaceutically acceptable salts or esters.

[0041] In some embodiments, the compound is represented by the following formula (Ia) or a pharmaceutically acceptable salt thereof:

[0042]

[0043] In some implementation schemes, R 7 Selected from -H, -OH, -O-(Cl-C) 10 Alkyl), -OC(O)-(C1-C 10 Alkyl groups and -OP(O)(OH)(OH). In some embodiments, R 7 Selected from -H, -OH, -OAc, and -OP(O)(OH)(OH). In some embodiments, R 8 Selected from -H, -OH, -O-(Cl-C) 10 Alkyl) and -OC(O)-(C1-C 10 Alkyl group). In some embodiments, R 8 Selected from -H, -OH, -OMe and -OAc.

[0044] In the implementation scheme, the compounds disclosed herein are selected from:

[0045]

[0046]

[0047]

[0048] Or its pharmaceutically acceptable salts or esters.

[0049] In the implementation scheme, the compounds disclosed herein are selected from:

[0050]

[0051]

[0052] Or its pharmaceutically acceptable salts or esters.

[0053] In the implementation scheme, the compounds disclosed herein are selected from:

[0054]

[0055]

[0056] Or its pharmaceutically acceptable salt.

[0057] In the implementation scheme, the compounds disclosed herein are selected from:

[0058]

[0059] Or its pharmaceutically acceptable salts or esters.

[0060] In the embodiments, the compounds disclosed herein have the following structures:

[0061] Or its pharmaceutically acceptable salt.

[0062] In the embodiments, the compounds disclosed herein have the following structures:

[0063] Or its pharmaceutically acceptable salt.

[0064] In the embodiments, the compounds disclosed herein have the following structures:

[0065]

[0066] Or its pharmaceutically acceptable salt.

[0067] In the embodiments, the compounds disclosed herein have the following structures:

[0068]

[0069] Or its pharmaceutically acceptable salt.

[0070] In the embodiments, the compounds disclosed herein have the following structures:

[0071]

[0072] Or its pharmaceutically acceptable salt.

[0073] This disclosure further provides pharmaceutical compositions comprising one or more compounds disclosed herein.

[0074] This disclosure further provides a method for treating mental illness or disorder in patients who require it, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound of this disclosure.

[0075] In the implementation plan, mental illness or disorder is selected from major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual anxiety disorder, seasonal affective disorder, psychotic depression, disruptive mood disorder, substance / drug-induced depressive disorder, and depressive disorder due to another medical condition.

[0076] In the implementation plan, mental illness or disorder is selected from bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / drug-induced bipolar and related disorders, and bipolar and related disorders due to another medical condition.

[0077] In the implementation plan, mental illness or disorder is defined as substance-related disorder or substance use disorder.

[0078] In the implementation plan, mental illness or disorder is selected from separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, panic attack, agoraphobia, generalized anxiety disorder, substance / drug-induced anxiety disorder, and anxiety disorder due to another medical condition.

[0079] In the implementation plan, mental illnesses or disorders are selected from obsessive-compulsive disorder and related disorders, trauma and stress-related disorders, feeding and eating disorders, borderline personality disorder, attention deficit / hyperactivity disorder, and autism spectrum disorder.

[0080] In the implementation plan, mental disorder is defined as neurocognitive disorder.

[0081] In the implementation plan, mental illness or disorder is defined as a treatment-resistant illness or disorder.

[0082] In the implementation plan, the method provides improvement in at least one of the following symptoms: sadness or drowsiness or fatigue, depressed mood, inability to feel, anxious feelings of worry, fear, feeling tense, feeling uneasy, decreased interest in all or almost all activities, difficulty initiating activities, significant increase or decrease in appetite leading to weight gain or loss, insomnia, irritability, fatigue, feelings of worthlessness or low self-esteem, strongly held negative beliefs or pessimistic thoughts about oneself, others, or the world, feelings of helplessness, inability to concentrate or be distracted, recurrent thoughts of death or suicide, feelings of guilt, memory disorders, difficulty experiencing positive feelings, feeling isolated or alienated from people, hypervigilance, risk-taking behavior, avoidance of thoughts about stressful or traumatic events, pain and aches, rumination and obsessive thoughts, compulsive behaviors, talking to people you don't know or strangers, becoming the center of attention, irritating intrusive thoughts, inability to get through a week without medication, guilt about medication use, problems with friends or family due to medication use, and withdrawal symptoms due to medication use.

[0083] This disclosure further provides a method for enhancing creativity or cognition in a subject, the method comprising administering the subject a composition comprising an effective amount of a compound of this disclosure.

[0084] In the implementation scheme, the methods and compositions can be used to treat mental disorders, including depressive disorders such as major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual anxiety disorder, seasonal affective disorder, psychotic depression, disruptive mood disorder, substance / drug-induced depressive disorder, and depressive disorder due to another medical condition.

[0085] This article also provides methods for treating treatment-resistant depression, such as in patients with depressive disorders who do not and / or have not responded to an appropriate course of treatment with at least one or more other antidepressant compounds or therapies. As used herein, “depressive disorder” includes treatment-resistant depression.

[0086] In the implementation scheme, the methods and compositions can be used to treat mental disorders, including bipolar and related disorders, such as bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / drug-induced bipolar and related disorders, and bipolar and related disorders due to another medical condition.

[0087] In the implementation methods, the methods and compositions can be used to treat mental disorders, including substance-related disorders, such as preventing substance use cravings, reducing substance use cravings, and / or promoting cessation or withdrawal of substance use. Substance use disorders include the abuse of psychoactive compounds such as alcohol, caffeine, cannabis, inhalers, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. As used herein, “substance” or “substances” refers to psychoactive compounds that may be addictive, such as alcohol, caffeine, cannabis, hallucinogens, inhalers, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. For example, the methods and compositions can be used to promote smoking cessation or cessation of opioid use.

[0088] In the implementation scheme, the methods and compositions can 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 / drug-induced anxiety disorder, and anxiety disorder due to another medical condition.

[0089] In the implementation scheme, the methods and compositions can be used to treat mental disorders, including obsessive-compulsive and related disorders, such as obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair-pulling disorder), skin-picking disorder, substance / drug-induced obsessive-compulsive and related disorders, and obsessive-compulsive and related disorders due to another medical condition.

[0090] In the implementation scheme, the methods and compositions can be used to treat mental disorders, including trauma and stress-related disorders such as reactive attachment disorder, disinhibitionary social participation disorder, post-traumatic stress disorder, acute stress disorder, and adjustment disorder.

[0091] In the implementation scheme, the methods and compositions can be used to treat mental disorders, including feeding and eating disorders such as anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, and avoidance / restriction eating disorder.

[0092] In the implementation scheme, the methods and compositions can be used to treat mental disorders, including neurocognitive disorders such as delirium, severe neurocognitive disorder, mild neurocognitive disorder, severe or mild neurocognitive disorder due to Alzheimer's disease, severe or mild frontotemporal neurocognitive disorder, severe or mild neurocognitive disorder with Lewy body, severe or mild vascular neurocognitive disorder, severe or mild neurocognitive disorder due to traumatic brain injury, substance / drug-induced severe or mild neurocognitive disorder, severe or mild neurocognitive disorder due to HIV infection, severe or mild neurocognitive disorder due to prions, severe or mild neurocognitive disorder due to Parkinson's disease, severe or mild neurocognitive disorder due to Huntington's disease, severe or mild neurocognitive disorder due to another medical condition, and severe or mild neurocognitive disorder due to multiple etiologies.

[0093] In the implementation scheme, the methods and compositions can be used to treat mental disorders, including neurodevelopmental disorders such as autism spectrum disorder, attention deficit / hyperactivity disorder, stereotyped movement disorder, tic disorder, Tourette's disorder, persistent (chronic) motor or vocal tic disorder, and transient tic disorder.

[0094] In the implementation scheme, the method and composition can be used to treat mental disorders, including personality disorders such as borderline personality disorder.

[0095] In the implementation scheme, the methods and compositions can be used to treat mental disorders, including sexual dysfunctions such as delayed ejaculation, erectile dysfunction, female orgasmic disorder, female sexual interest / arousal disorder, genital-pelvic pain / penetration disorder, male hypoactive sexual desire disorder, premature (early) ejaculation, and substance / drug-induced sexual dysfunction.

[0096] In the implementation scheme, the method and composition can be used to treat mental disorders, including gender dysphoria, for example, gender dysphoria.

[0097] In other embodiments, methods and compositions are provided for treating migraines or cluster headaches by administering the disclosed compounds to patients in need of them.

[0098] In the implementation plan, the term "effective amount" or "therapeutic effective amount" refers to the amount of a compound, material, composition, drug, or other material that effectively achieves a specific pharmacological and / or physiological effect, including but not limited to reducing sadness or somnolence, depressive mood, feelings of anxiety or grief, decreased interest in all or almost all activities, significant increase or decrease in appetite leading to weight gain or loss, insomnia, irritability, fatigue, feelings of worthlessness, helplessness, inability to concentrate, and the frequency or severity of recurrent thoughts of death or suicide; or providing the desired pharmacological and / or physiological effect, such as alleviating, inhibiting, or reversing one or more underlying pathophysiological mechanisms of 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 connectivity or neurogenesis in certain brain regions, or combinations thereof. The precise dosage will vary depending on a number of factors, such as subject dependence variables (e.g., age, immune system health, clinical symptoms, etc.), the disease or disorder being treated, and the route of administration and the pharmacokinetics of the administered drug.

[0099] In an embodiment, the method includes treating mental disorders, such as depressive disorders, by administering a pharmaceutical composition comprising about 0.01 mg to about 400 mg of the disclosed compound to a patient in need. In an embodiment, the dosage may be, for example, in the range of about 0.01-400 mg, 0.01-300 mg, 0.01-250 mg, 0.01-200 mg, 0.01-150 mg, 0.01-100 mg, 0.01-75 mg, 0.01-50 mg, 0.01-25 mg, 0.01-20 mg, 0.01-15 mg, 0.01-10 mg, 0.01-5 mg, 0.01-1 mg, 0.01-0.5 mg, 0.01-0.01, 0.1-400 mg, 0.1-300 mg. mg, 0.1-250mg, 0.1-200mg, 0.1-150mg, 0.1-100mg, 0.1-75mg, 0.1-50mg, 0.1-25mg, 0.1-20mg, 0.10-15mg, 0.1-10mg, 0.1-5mg, 0.1-1mg, 10-400mg, 10-300mg, 10-250mg, 10-200mg, 10-150mg, 10-100mg, 10-50mg, 10-25mg, 10-15mg, 20-40 Within the range of 0 mg, 20-300 mg, 20-250 mg, 20-200 mg, 20-150 mg, 20-100 mg, 20-50 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-150 mg, 50-100 mg, 100-400 mg, 100-300 mg, 100-250 mg, and 100-200 mg, examples are, for example, about 0.01 mg, 0.025 mg, 0.05 mg, 0.1 mg, 0.15 mg, Doses of 0.25mg, 0.5mg, 0.75mg, 1mg, 1.25mg, 1.5mg, 1.75mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 4.5mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, and 400mg.

[0100] In specific embodiments, the dosage may include an amount of the disclosed compound or a pharmaceutically acceptable salt thereof in the range of, for example, 1 mg-50 mg, 1 mg-40 mg, 1 mg-30 mg, 1 mg-20 mg, 1 mg-15 mg, 1 mg-10 mg, 0.1 mg-10 mg, 0.1-5 mg, or 0.1-1 mg, with specific examples of dosages being 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, 1.5 mg, etc. Doses of 1.0 mg, 1.75 mg, 2 mg, 2.5 mg, 2.75 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 10 mg, 11 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 35 mg, 40 mg, 45 mg, and 50 mg.

[0101] Generally, the compounds of this disclosure or pharmaceutically acceptable salts thereof are given to patients in need 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 approximately, for example, 0.1-400 mg / day, 0.1-300 mg / day, 0.1-250 mg / day, 0.1-200 mg / day, 0.1-100 mg / day, 0.1-50 mg / day, or 0.1-25 mg / day, such as 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 the implementation plan, the above-mentioned example dose range can be delivered at intervals longer than one day, for example, 0.1-400 mg / week.

[0102] In the embodiments, pharmaceutical compositions for parenteral or inhalation (e.g., sprays or nebulizers) administration of the disclosed compound or a pharmaceutically acceptable salt thereof have a concentration of about 0.005 mg / mL to about 500 mg / mL. In embodiments, the composition comprises, for example, compounds of the present disclosure or pharmaceutically acceptable salts thereof at concentrations of, 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.

[0103] In embodiments, the composition comprises, for example, a compound of the present disclosure or a pharmaceutically acceptable salt thereof at concentrations of 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 embodiments, the pharmaceutical composition is formulated to a total volume of, for example, 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.

[0104] Generally, the dosage may be given to the subject once, twice, three or four times daily, every other day, every three days, twice weekly, once weekly, twice monthly, once monthly, three times a year, twice a year, or once a year. In one embodiment, the compound of this disclosure or a pharmaceutically acceptable salt thereof is given to the subject once in the morning or once in the evening. In another embodiment, the compound of this disclosure or a pharmaceutically acceptable salt thereof is given to the subject once in the morning and once in the evening. In yet another embodiment, the compound of this disclosure or a pharmaceutically acceptable salt thereof is given to the subject three times a day (e.g., at breakfast, lunch, and dinner) at a dose of, for example, 0.5 mg / administered (e.g., 1.5 mg / day).

[0105] In one embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 0.5 mg / day or one or more doses. In another embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 1 mg / day or one or more doses. In another embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 2.5 mg / day or one or more doses. In another embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 5 mg / day or one or more doses. In another embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 10 mg / day or one or more doses. In another embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 15 mg / day or one or more doses. In another embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 20 mg / day or one or more doses. In another embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 25 mg / day or one or more doses. In another embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 30 mg / day or one or more doses. In one embodiment, the compound of this disclosure or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 40 mg / day or one or more doses. In another embodiment, the compound of this disclosure or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 50 mg / day or one or more doses.

[0106] In the embodiments, the dosage of the disclosed compound or its pharmaceutically acceptable salt is 0.0005-5 mg / kg, 0.001-1 mg / kg, 0.01-1 mg / kg, or 0.1-5 mg / kg, once, twice, three times, or four times daily. For example, in the 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 times, or four times daily. In the embodiments, the subject is given a total daily dose of 0.01 mg to 500 mg of the disclosed compound or its pharmaceutically acceptable salt, once, twice, three times, or four times daily. In the implementation plan, the total dose administered to the subject over a 24-hour period 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, or 500 mg. In the implementation plan, the subject may start with a low dose and gradually increase the dose. In the implementation plan, the subject may start with a high dose and gradually decrease the dose.

[0107] In the implementation plan, the compounds of this disclosure or pharmaceutically acceptable salts thereof are administered to patients under the supervision of a healthcare provider.

[0108] In the implementation scheme, the compounds of this disclosure or pharmaceutically acceptable salts thereof are administered to patients under the supervision of a healthcare provider in a clinic specializing in the delivery of neuroactive therapies.

[0109] In the implementation, the compounds of this disclosure are administered to patients under the supervision of a healthcare provider at a high dose intended to induce psychedelic experiences in subjects, 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.

[0110] In the implementation plan, high doses are administered to patients periodically under the supervision of a healthcare provider to maintain the therapeutic effect in patients, such as 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.

[0111] In the implementation plan, the compounds of this disclosure or their pharmaceutically acceptable salts are administered by the patient himself at home or otherwise away from the supervision of a healthcare provider.

[0112] In the implementation, the compounds of this disclosure or pharmaceutically acceptable salts thereof are administered by the patient himself at home or otherwise away from the supervision of a healthcare provider in a low dose intended to induce a subconscious or threshold psychoactive effect, said dose being, for example, 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.

[0113] In the implementation plan, low doses are administered periodically by the patient to maintain the therapeutic effect, such as daily, every other day, every three days, twice a week, once a week, twice a month, or once a month.

[0114] In the embodiments, the compounds of this disclosure or their pharmaceutically acceptable salts may be administered, for example, by inhalation or oral administration at prescribed intervals. For example, during treatment, a patient may administer the compounds of this disclosure at intervals such as 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.

[0115] Suitable dosage forms for the compounds of this disclosure or their pharmaceutically acceptable salts 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, buccal, tracheal, intraocular, or nasal forms, forms suitable for inhalation, local forms, transdermal or parenteral forms, such as forms suitable for intravenous, intra-arterial, intraperitoneal, intrathecal, intracardiac, intramuscular, or subcutaneous administration. In embodiments, for such parenteral administration, the pharmaceutical composition may be in the form of a sterile aqueous solution, which may contain other substances, such as sufficient salts or glucose, to make the solution isotonic with blood. If necessary, the aqueous solution should be appropriately buffered (preferably to a pH of 3-9). The preparation of suitable parenteral formulations under sterile conditions can be readily achieved by standard pharmaceutical techniques well known to those skilled in the art.

[0116] The pharmaceutical compositions described herein may provide immediate release, delayed release, extended release, or modified release profiles. In embodiments, pharmaceutical compositions with different drug release profiles may be combined to produce two-phase or three-phase release profiles. For example, the pharmaceutical compositions may provide immediate and extended release profiles. In embodiments, the pharmaceutical compositions may provide extended and delayed release profiles. Such compositions may be provided as pulsatile formulations, multilayer tablets, or capsules containing tablets, beads, granules, etc. The compositions may be prepared using pharmaceutically acceptable “carriers” composed of materials considered safe and effective. A “carrier” includes all components present in a pharmaceutical formulation other than one or more active ingredients. The term “carrier” includes, but is not limited to, diluents, binders, lubricants, gliding agents, disintegrants, fillers, and coating compositions.

[0117] As used herein, the term "pharmaceuticalally acceptable" means a molecular entity or composition that is "generally considered safe," for example, that is physiologically tolerable when administered to humans and generally does not produce allergic or similar undesirable reactions. In the implementation details, the term refers to a molecular entity or composition that has been approved by a federal or state regulatory agency, such as being on the GRAS list or similar under Sections 204 and 409 of the Federal Food, Drug and Cosmetic Act (which is subject to pre-market review and approval by the FDA), the United States Pharmacopeia, or another generally recognized pharmacopoeia, for use in animals, and more particularly in humans.

[0118] As used herein, the term "pharmaceutically acceptable salt" includes acid addition salts and free base addition salts, wherein the compound is modified by preparing its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and bases or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts 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, aminosulfonic 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, dihydroxynaphthyl acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, maleic acid, toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, and oxalic acid. Pharmaceutically acceptable salts of the disclosed compounds can be synthesized by conventional chemical methods from parent compounds containing basic or acidic moieties.

[0119] As used herein, the terms “approximately” or “roughly” mean within an acceptable margin of error for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “approximately” may mean within three or more standard deviations according to practice in the art. Alternatively, “approximately” may mean a range of up to 20%, up to 10%, up to 5%, and / or up to 1% of a given value. Or, particularly with respect to biological systems or processes, the term may mean within an order of magnitude of the numerical value, such as within 5 times or 2 times. “Approximately” and “roughly” are used interchangeably herein.

[0120] In the context of this disclosure, the term "5-HT2A receptor agonist" is intended to refer to any compound or substance that activates the 5-HT2A receptor. The agonist may be a partial or complete agonist.

[0121] In the context of this disclosure, the term "5-HT1A receptor agonist" is intended to refer to any compound or substance that activates the 5-HT1A receptor. The agonist may be a partial or complete agonist.

[0122] Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including percutaneous, buccal, and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration or via implantation. The compositions may be prepared by any method well known in the pharmaceutical field.

[0123] Such methods include the step of associating the compounds or combinations thereof used in this disclosure with any excipients. Excipients, also known as auxiliary ingredients, include those conventional in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, antioxidants, and humectants. Such excipients are appropriately selected taking into account the intended form and route of administration and in accordance with conventional pharmaceutical practice.

[0124] Pharmaceutical compositions suitable for oral administration may be presented as discrete dosage units, such as pills, tablets, sugar-coated pills, or capsules, or as powders or granules, or as solutions or suspensions. The active ingredient may also be presented as a pill or paste. The composition may be further processed into suppositories or enemas for rectal administration.

[0125] Tablets may contain active ingredient compounds and suitable binders, lubricants, disintegrants, colorants, flavoring agents, flow inducers, and solubilizers. Gelatin capsules may contain active ingredient compounds and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents may be used to manufacture compressed tablets. Compressed tablets may be sugar-coated or film-coated to mask any unpleasant tastes and protect the tablets from atmospheric effects, or may be enteric-coated for selective disintegration in the gastrointestinal tract. For example, for oral administration in tablet or capsule dosage units, the active pharmaceutical ingredient may be combined with an orally viable, 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 gum arabic, tragacanth, or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. Lubricants used in these formulations include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, etc.

[0126] For oral administration in liquid dosage forms, the oral drug component is combined with any orally administered, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, etc. Examples of suitable liquid dosage forms include solutions or suspensions, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent formulations reconstituted from effervescent granules, in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents (including esters). 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 coloring and flavoring agents to improve patient acceptability.

[0127] For parenteral administration, suitable compositions include aqueous and non-aqueous sterile solutions. Typically, water, suitable oils, saline solutions, aqueous dextrose (glucose) and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. Parenteral solutions 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, alone or in combination, are suitable stabilizers. Citric acid and its salts, and sodium EDTA are also used. Additionally, parenteral solutions may contain preservatives such as benzalkonium chloride, methylparaben or propylparaben, and chlorobutanol. The compositions may be presented in single-dose or multi-dose containers such as sealed vials and ampoules and may be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier such as water before use. For transdermal administration, gels, patches, or sprays may be considered. Compositions or formulations suitable for pulmonary administration, such as through nasal inhalation, include fine powders or nebulizers that can be generated by metered-dose pressurized aerosols, nebulizers, or blowpipes. Parenteral and intravenous forms may also include minerals and other materials to ensure compatibility with the type of injection or delivery system chosen.

[0128] The compounds used in the methods disclosed herein can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearamine, or phosphatidylcholine. The compounds can be administered as components of tissue-targeted emulsions.

[0129] The compounds used in the methods disclosed herein may also be coupled to soluble polymers that serve as targeted drug carriers or as prodrugs. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparagine-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers that can be used to achieve controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0130] The pharmaceutical compositions described herein can provide immediate release, delayed release, extended release, or modified release profiles. In some embodiments, pharmaceutical compositions with different drug release profiles can be combined to produce two-phase or three-phase release profiles. For example, the pharmaceutical compositions can provide immediate and extended release profiles. In some embodiments, the pharmaceutical compositions can provide extended and delayed release profiles. Such compositions can be provided as pulsatile formulations, multilayer tablets, or capsules containing tablets, beads, granules, etc.

[0131] The pharmaceutical compositions described herein can provide abuse-proof features using techniques known in the art, such as by preparing tablets that are difficult to pulverize or dissolve in water.

[0132] This disclosure further includes the pharmaceutical compositions as described above, combined with packaging materials, and includes instructions for use of the compositions for the purposes described above.

[0133] The exact dosage and administration regimen of the composition will necessarily 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, formulation, route of administration, or the age and condition of the individual subject to be given the composition.

[0134] The compounds used in the methods disclosed herein can be administered in various forms, including those detailed herein. Treatment with the compounds can be part of a combination therapy or adjunctive therapy, i.e., a subject or patient requiring the drug is treated or given another drug for the disease in combination with one or more of the compounds of the present invention. Such combination therapy can be a sequential therapy, wherein the patient is treated first with one drug and then with another, or two drugs are administered simultaneously. Depending on the dosage form used, these can be administered independently via the same route or via two or more different routes of administration.

[0135] In embodiments, deuterium-rich azahexacyclic butyltryptamines and their uses are considered and are within the scope of the methods and compositions described herein. Deuterium can be incorporated at any position to replace hydrogen (protium) according to synthetic procedures known in the art. For example, deuterium can be incorporated into various positions having exchangeable protons, such as amines (NH), via proton-deuterium equilibrium exchange. Therefore, deuterium can be selectively or non-selectively incorporated by methods known in the art. Exemplary deuterium-rich azahexacyclic butyltryptamines include:

[0136]

[0137]

[0138] Or a pharmaceutically acceptable salt thereof, wherein D represents a deuterium-rich -H site.

[0139] In the implementation scheme, each D represents a deuterium-rich -H site and the deuterium level at each deuterium-rich -H site of the compound is 0.02%-100%.

[0140] In the embodiments, each D represents a deuterium-rich -H site and the deuterium level at each deuterium-rich -H site of the compound is 50%-100%, 70%-100%, 90%-100%, 95%-100%, 96%-100%, 97%-100%, 98%-100%, or 99%-100%.

[0141] Tryptamines can be racemic and / or optically active isomers thereof. In this respect, some of these compounds may have asymmetric carbon atoms and thus may exist as racemic mixtures or as individual optical isomers (enantiomers). Compounds containing a chiral center described herein include all possible stereoisomers of the compound, including compositions comprising: racemic mixtures of two enantiomers, scalemic mixtures of two enantiomers, or mixtures comprising each enantiomer individually and substantially free of the other enantiomer. Thus, for example, compositions comprising, as an example, the S enantiomer of a compound substantially free of the R enantiomer, or the R enantiomer substantially free of the S enantiomer. If the specified compound comprises more than one chiral center, the scope of this disclosure also includes compositions comprising mixtures comprising diastereomers in varying proportions, and compositions comprising one or more diastereomers substantially free of one or more other diastereomers. “Substantially free” means that the composition contains less than 25%, 15%, 10%, 8%, 5%, 3%, or less than 1% of (one or more) minor enantiomers or diastereomers.

[0142] Methods for synthesizing, separating, preparing, and administering various stereoisomers are known in the art. Separation of diastereomers or cis and trans isomers can be achieved by conventional techniques, such as stepwise crystallization of stereoisomeric mixtures of the substance or suitable salts or derivatives, chromatography, or high-performance liquid chromatography (HPLC). Where appropriate, individual enantiomers of the disclosed compounds can also be prepared from the corresponding optically pure intermediates, or by resolution, for example by HPLC using the corresponding racemic mixture with a suitable chiral support, or by stepwise crystallization of the diastereomer formed by reacting the corresponding racemic mixture with a suitable optically active acid or base.

[0143] This disclosure further provides pharmaceutical compositions comprising compounds of this disclosure and pharmaceutically acceptable carriers.

[0144] In the context of this disclosure, the term "alkyl" should be understood to mean a straight, branched, or possibly cyclic hydrocarbon chain containing the indicated number of carbon atoms, wherein all bonds connecting the atoms are σ bonds.

[0145] In the context of this disclosure, the term "alkenyl" should be understood to mean a straight, branched, or possibly cyclic hydrocarbon chain containing the indicated number of carbon atoms, wherein at least one bond between two carbons in the chain is a double (π) bond.

[0146] In the context of this disclosure, the term "alkynyl" should be understood to mean a straight, branched, or possibly cyclic hydrocarbon chain containing the number of carbon atoms indicated, wherein at least one bond connecting the two carbon atoms of the chain is a triple bond.

[0147] In the context of this disclosure, the term "haloalkyl" should be understood to mean a straight, branched, or possibly cyclic hydrocarbon chain containing the indicated number of carbon atoms, wherein all bonds connecting the atoms are σ bonds, and at least one hydrogen atom in the chain is replaced by a halogen atom selected from F, Cl, Br, and I.

[0148] In the context of this disclosure, the term "heteroalkyl" should be understood to mean a straight, branched, or possibly 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, S), and all bonds connecting the atoms are σ bonds.

[0149] In the context of this disclosure, the term "heterene" should be understood to mean a straight, branched, or possibly 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, S), and at least one bond between two carbons of the chain is a double (π) bond.

[0150] In the context of this disclosure, the term "heterynyl" should be understood as referring to a straight, branched, or possibly 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, S), and at least one bond connecting the two carbon atoms of the chain is a triple bond.

[0151] This disclosure also contemplates including all isotopes of atoms present in the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By general example and not limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include... 13 C and 14 C.

[0152] It will be noted that throughout this application, when used without further notation, any symbol for carbon in the structure is expected to represent all isotopes of carbon, such as 12 C 13 C or 14 C. In addition, it contains 13 C or 14 Any compound of C may specifically have the structure of any compound disclosed herein.

[0153] It will also be noted that throughout this application, any symbol for hydrogen in the structure, when used without further notation, is intended to represent all isotopes of hydrogen, such as 1 H, 2 H or 3 H. In addition, containing 2 H or 3 Any compound of H may specifically have the structure of any compound disclosed herein.

[0154] Isotope-labeled compounds can typically be prepared using conventional techniques known to those skilled in the art, employing appropriate isotope-labeling reagents instead of the unlabeled reagents used.

[0155] Each embodiment disclosed herein is to be considered applicable to each of the other disclosed embodiments. Therefore, all combinations of the various elements described herein are within the scope of this disclosure.

[0156] General methods for the synthesis of compounds

[0157] The compounds disclosed herein can be prepared using techniques well known in organic synthesis and familiar to those skilled in the art. For example, the compounds can be prepared by the synthetic transformations shown in Schemes 1-4 and the subsequent specific examples. However, these may not be the only means of synthesizing or obtaining the desired compounds.

[0158] Scheme 1. A general method for synthesizing nitrogen-containing heterocyclic butyl tryptamines via alkylation.

[0159]

[0160] Scheme 2. A general method for synthesizing nitrogen-containing butyl tryptamines from 2-oxoacetamide obtained by acylation followed by reduction.

[0161]

[0162] Option 3. An example of nitrogen-containing heterocyclic butyl tryptamine is later converted to provide another analog.

[0163]

[0164] Example preparation of Scheme 4.3-(2-bromoethyl)indole intermediate.

[0165]

[0166] Example 1. Preparation of Compound 1

[0167]

[0168] Step 1: Preparation of 1-(azacyclobutane-1-yl)-2-(1H-indol-3-yl)ethyl-1-one.

[0169] 2-(1H-indol-3-yl)acetic acid (7 g, 39.96 mmol, 1 eq) was added in a single step to a mixture of aziridine hydrochloride (5.61 g, 59.94 mmol, 1.5 eq) and triethylamine (12.13 g, 119.87 mmol, 16.68 mL, 3 eq) in DCM (70 mL) at 0 °C under N2. HATU (22.79 g, 59.94 mmol, 1.5 eq) was added in a single step to the solution at 0 °C under N2, and the mixture was heated to 20 °C and stirred for 2 h. After completion, the reaction mixture was quenched at 20 °C by adding aqueous NH4Cl (50 mL), and then extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (column = Phenomenex C18 (250*100mm, 10μm); mobile phase = water (NH4HCO3)-ACN, B% = 15%-50%; 20 min run time) to provide 1-(azacyclobutan-1-yl)-2-(1H-indol-3-yl)ethyl-1-one (3 g, 14.00 mmol, 35% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ10.85(br s,1H),7.49(d,J=8.0Hz,1H),7.30(d,J=8.4Hz,1H),7.15(s,1H),7.03(t,J=7.6Hz,1H),6.97-6 .90(m,1H),4.11(t,J=7.6Hz,2H),3.79(t,J=7.6Hz,2H),3.42(s,2H),2.11(quin,J=7.6Hz,2H).

[0170] Step 2: Preparation of 3-(2-(azacyclobutane-1-yl)ethyl)-1H-indole fumarate (1).

[0171] A solution of 1-(azacyclobutan-1-yl)-2-(1H-indol-3-yl)ethyl-1-one (1 g, 4.67 mmol, 1 eq) in 50 mL of THF was cooled to 0 °C. Then, LAH (265.68 mg, 7.00 mmol, 1.5 eq) was added, and the mixture was heated to 20 °C and stirred for 2 h. After this, the mixture was cooled to 0 °C, the reaction was quenched with Na₂SO₄·10H₂O until bubbling stopped, and the mixture was filtered and concentrated. The residue was purified by preparative HPLC (column = Waters Xbridge C18 (150*50mm, 10μm); mobile phase = water (NH4HCO3)-ACN, B% = 1%-40%; 10 min run time) to provide a solution of 3-(2-(azacyclobutan-1-yl)ethyl)-1H-indole in a mixture of water (800 mL) and MeCN (50 mL). A solution of fumaric acid (231.82 mg, 2.00 mmol) in MeCN (2 mL) was added in a single addition to this solution at 20 °C under N2. The solution was then lyophilized to provide 3-(2-(azacyclobutan-1-yl)ethyl)-1H-indole fumarate (1) (550 mg, 1.90 mmol, 41% yield, 1:fumarate = 1:0.77) as a brown solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 10.86 (br s, 1H), 7.53 (d, J = 7.6Hz, 1H), 7.34 (d, J = 8.0Hz, 1H), 7.15 (d, J = 2.4Hz, 1H), 7.07 (dt, J = 1.2, 7.6Hz, 1H), 6.98 (dt, J = 1.2, 7.6Hz, 1H), 6.48 (s, 1.54H = fumarate, 0.77 mol eq), 3.46 (t, J = 7.6Hz, 4H), 2.93–2.86 (m, 2H), 2.78–2.71 (m, 2H), 2.15–2.04 (m, 2H); 13 C NMR (101MHz, DMSO-d6) δ168.56,136.68,135.77,127.48,123.32,121.41,118.72,111.88,111.54,58.16,54.27,22.38,17.21; LCMS(R T =1.334min,MS calc.:200.13,[M+H] + =201.1); qNMR = 89%.

[0172] Unsuccessful post-processing and purification methods for compound 1:

[0173] Several alternative methods for post-processing LAH reduction and purification of product 1 resulted in partial or complete decomposition and no pure product was obtained. These unsuccessful post-processing / purification methods are summarized below.

[0174] Method 1:

[0175] Post-processing: After completion, add H2O and 30% aqueous NaOH to the mixture, and then filter and concentrate the mixture.

[0176] purification: The residue was purified by preparative HPLC (column = Waters Xbridge BEH C18 (100*25mm, 5μm); mobile phase = water (NH4HCO3)-ACN, B% = 2%-40%; run time 10 min). After lyophilizing the eluent, 1 1H NMR showed that the product was impure.

[0177] Method 2:

[0178] Post-processing: After completion, the mixture was cooled to 0°C, the reaction was quenched with Na2SO4·10H2O, and the mixture was filtered and concentrated.

[0179] purification: The residue was purified by preparative HPLC (HCl) (column = Phenomenex luna C18 (80*40mm, 3μm); mobile phase = water (HCl)-ACN, B% = 1%-25%; run time 7 min). After lyophilization of the eluent, LCMS and 1 1H NMR showed that the product was impure.

[0180] Method 3:

[0181] Post-processing: Same as method 2.

[0182] purification: The residue was purified by preparative HPLC (column = Phenomenex luna C18 (250*70mm, 15μm); mobile phase = water (FA)-ACN, B% = 1%-30%; run time 20 min). After lyophilization of the eluent, LCMS and... 1 1H NMR showed that the product was impure.

[0183] Method 4:

[0184] Post-processing: Same as method 2.

[0185] purification: The residue was passed through a preparative HPLC (column = Phenomenex C18 (250*50mm, 10μm); mobile phase = water (NH3H2O+NH4HCO3)-ACN, B% = 3%-33%; run time 20 min). After lyophilization and eluent removal, the residue was ground with MTBE and the supernatant was removed, but the remaining solids were analyzed by LCMS and 1 1H NMR showed that the product was impure.

[0186] Method 5:

[0187] Post-processing: Same as method 2.

[0188] purification: The residue was purified by preparative TLC (DCM / MeOH = 5:1) and column chromatography (DCM / MeOH = 100 / 1-1:1). However, LCMS showed that the product was still impure.

[0189] Method 6:

[0190] Post-processing: Same as method 2.

[0191] purification: The residue was purified by preparative HPLC (column = Phenomenex C18 (250*50mm, 10μm); mobile phase = water (0.05% ammonium hydroxide)-ACN, B% = 5%-40%; run time 20 min). After lyophilization of the eluent, the product was impure. Fumaric acid (~0.5 eq) in a mixture of H2O and ACN was then added, the mixture was lyophilized again, and the residue was ground with diethyl ether and the supernatant was removed. However, LCMS and... 1 1H NMR showed that the product was still impure.

[0192] Example 2. Preparation of Compound 2

[0193]

[0194] Step 1: Preparation of 3-(2-chloro-2-oxoacetyl)-1H-indole-4-yl acetate. To a solution of 1H-indole-4-ylacetate (25 g, 142.71 mmol, 1 eq) in THF (250 mL) at 0 °C, (COCl)₂ (27.17 g, 214.06 mmol, 18.74 mL, 1.5 eq) was added. The mixture was then heated to 20 °C and stirred for 12 h. After completion, the reaction mixture was concentrated to provide 3-(2-chloro-2-oxo-acetyl)-1H-indole-4-ylacetate (37.91 g, 142.71 mmol, 100% yield) as a yellow solid.

[0195] Step 2: 3-(2-(azacyclobutane-1-yl)-2-oxoacetyl)-1H-indole-4-yl acetate. DIPEA (70.82 g, 547.94 mmol, 95.44 mL, 4 eq) was added to a solution of aziridine hydrochloride (19.22 g, 205.48 mmol, 1.5 eq) in DCM (100 mL), and the mixture was stirred at 20 °C for 30 min. The mixture was then cooled to 0 °C, and 3-(2-chloro-2-oxo-acetyl)-1H-indole-4-yl acetate (36.39 g, 136.99 mmol, 1 eq) was added to THF (100 mL). The mixture was then heated to 20 °C and stirred for 3 h. After this, aqueous NH4Cl (100 mL) was added, and the mixture was stirred for 5 min. The aqueous phase was extracted with DCM (50 mL x 3), and the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1-0 / 1) to provide 3-(2-(azacyclobutan-1-yl)-2-oxoacetyl)-1H-indole-4-yl acetate as a yellow solid (26 g, 90.82 mmol, 66% yield). 1 H NMR(400MHz,DMSO-d6)δ12.47(br s,1H),8.42(s,1H),7.48-7.39(m,1H),7.28(t,J=7.9Hz,1H),6.90(d,J=7.3Hz,1H),4 .16(t,J=7.7Hz,2H), 4.04(t,J=7.8Hz,2H), 2.34(s,3H), 2.27(pentet,J=7.8Hz,2H).

[0196] Step 3: Preparation of 3-(2-(azacyclobutane-1-yl)ethyl)-1H-indole-4-ol (2). LAH (5.30 g, 139.72 mmol, 10 eq) was added to a solution of 3-(2-(azacyclobutan-1-yl)-2-oxoacetyl)-1H-indole-4-yl acetate (4 g, 13.97 mmol, 1 eq) in THF (150 mL) at 0 °C. The mixture was then heated at 70 °C for 7 h. 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 / 1-0 / 1) to give 3-(2-(azacyclobutan-1-yl)ethyl)-1H-indole-4-ol (2) (1.1 g, 5.09 mmol, 36% yield) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ11.11(br s,1H),10.57(br s,1H),6.89(d,J=2.4Hz,1H),6.84-6.70(m,2H),6.28(dd,J=0.8,7.2Hz,1H),3.19(t,J=7.2Hz,4H),2.77-2.61(m,4H),2.06-1.93(m,2H); 13 C NMR (101MHz, DMSO-d6) δ152.37,139.27,122.33,121.70,117.36,113.05,104.11,103.13,61.83,54.93,25.13,17.46; LCMS(R T =2.021min,MS calc.:216.13,[M+H] + =217.1); qNMR = 93%.

[0197] Note: Product 2 is unstable and should be stored frozen, protected from light, and under an inert gas atmosphere. If stored properly, its stability has been confirmed by qNMR to be at least one month.

[0198] Preparation of 3-(2-(azacyclobutane-1-yl)ethyl)-1H-indole-4-ol fumarate (2-fumarate). A solution of fumaric acid (37.57 mg, 323.66 μmol, 0.7 eq) in H2O (20 mL) and MeCN (2 mL) was added in a single step to a solution of 3-(2-(azacyclobutan-1-yl)ethyl)-1H-indole-4-ol (2, 100 mg, 462.37 μmol, 1 eq) in MeCN (5 mL) at 20 °C under N2, and the mixture was lyophilized to provide 3-(2-(azacyclobutan-1-yl)ethyl)-1H-indole-4-ol fumarate (2 fumarate) (125 mg, 2: fumarate = 1:0.65) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),6.94(d,J=2.0Hz,1H),6.86-6.72(m,2H),6.51(s,1H),6.33(dd,J=0.8,7.2Hz,1H),3.69(t,J=7.6Hz,4H),3.10(br d, J=7.6Hz, 2H), 2.88 (s, 2H), 2.19 (br t, J=7.6Hz, 2H); qNMR=86%.

[0199] Unsuccessful post-processing and purification methods for compound 2:

[0200] Several alternative methods for post-processing LAH reduction and purification of product 2 resulted in partial or complete decomposition and no pure product was obtained. These unsuccessful post-processing / purification methods are summarized below.

[0201] Method 1:

[0202] Post-processing: After completion, H2O and 30% aqueous NaOH are added to the mixture, and the resulting slurry is filtered and concentrated.

[0203] purification: The residue was purified by preparative HPLC (Welch Ultimate C18 (250*70mm, 10μm); mobile phase: water (NH4HCO3)-ACN, B% = 5%-35%; run time 20 min). After lyophilization of the eluent, LCMS and... 1 ¹H NMR appears to show that the product is pure, but qNMR indicates only 62% purity, suggesting the presence of polymers or insoluble impurities that are not visible by LCMS or NMR.

[0204] Method 2:

[0205] Post-processing: After completion, add H2O and 30% aqueous NaOH to the mixture, filter the resulting slurry, add fumaric acid (~0.5-1 eq) to the filtrate, and concentrate the filtrate.

[0206] purification: The residue was then purified by preparative HPLC (column = Waters Xbridge Prep OBD C18 (150*40mm*10μm); mobile phase = water-ACN, B% = 0%-30%; 20 min run time), but the product decomposed during this purification attempt.

[0207] Method 3:

[0208] Post-processing: Same as method 1.

[0209] purification: The residue was purified by preparative HPLC (column = Welch Ultimate C18 (250*70mm, 10μm); mobile phase = water (NH4HCO3)-ACN, B% = 5%-35%, 20 min) to provide the product in H2O and CH3CN solution. A solution of fumaric acid (~0.5-1 eq) in H2O was added to this solution, and the mixture was lyophilized to provide the product, which was analyzed by LCMS and... 1The 1H NMR results showed it to be pure, but given the poor results of Method 1, qNMR was not performed to confirm this.

[0210] Example 3. Preparation of Compound 3

[0211]

[0212] Step 1: Preparation of 2-(5-methoxy-1H-indol-3-yl)-2-oxoacetyl chloride.

[0213] (COCl)₂ (6.47 g, 50.96 mmol, 4.46 mL, 1.5 eq) was added dropwise to a solution of 5-methoxy-1H-indole (5 g, 33.97 mmol, 1 eq) in THF (50 mL) at 0 °C. The mixture was then heated to 20 °C and stirred for 12 h. TLC (PE:EA = 3:1, Rf product = 0.1) showed good reaction performance. The mixture was concentrated to give crude 2-(5-methoxy-1H-indole-3-yl)-2-oxoacetyl chloride (8 g) as a brown solid, which was used directly in the next step without further purification.

[0214] Step 2: Preparation of 1-(azacyclobutane-1-yl)-2-(5-methoxy-1H-indol-3-yl)ethyl-1,2-dione.

[0215] DIPEA (17.40 g, 134.66 mmol, 23.46 mL, 4 eq) was added to a solution of aziridine hydrochloride (4.72 g, 50.50 mmol, 1.5 eq) in DCM (50 mL), and the mixture was stirred at 20 °C for 0.5 h. The solution was then cooled to 0 °C, and 2-(5-methoxy-1H-indol-3-yl)-2-oxoacetyl chloride (8 g, 33.66 mmol, 1 eq) in THF (100 mL) was added. The mixture was then heated to 20 °C and stirred for 12 h. TLC (PE:EA = 0:1, Rf product = 0.26) showed that the reaction was complete. The reaction mixture was quenched at 20 °C by adding saturated aqueous NH4Cl (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 by recrystallization from PE (50 mL) and DCM (20 mL) at 20 °C to provide 1-(azacyclobutan-1-yl)-2-(5-methoxy-1H-indol-3-yl)ethyl-1,2-dione (4.2 g, 16.26 mmol, 48% yield in two steps) as a white solid. 1H NMR (400MHz, DMSO-d6) δ12.13(br s,1H),8.42(br s,1H),7.68(br s,1H),7.42(br d,J=8.7Hz,1H),6.88(br d,J=7.8Hz,1H),4.33(br t,J=7.3Hz,2H),4.05(br t,J=7.4Hz,2H),3.79(s,3H),2.38-2.19(m,2H); LCMS(R T =1.226min, MS calc.:258.10, [M+H]+=259.1);

[0216] Step 3: Preparation of 3-(2-(azacyclobutane-1-yl)ethyl)-5-methoxy-1H-indolefumarate (3).

[0217] LAH (440.86 mg, 11.62 mmol, 3 eq) was added to a solution of 1-(azacyclobutan-1-yl)-2-(5-methoxy-1H-indol-3-yl)ethyl-1,2-dione (1 g, 3.87 mmol, 1 eq) in THF (50 mL) at 0 °C. The mixture was then heated at 70 °C for 8 h. After this, the mixture was cooled to 0 °C, and Na₂SO₄·10H₂O was added until bubbling stopped. The mixture was then filtered and concentrated. The residue was purified by preparative HPLC (column = Waters Xbridge Prep OBD C18 (150*40mm, 10μm); mobile phase = water (NH4HCO3)-ACN, B% = 5%-35%, 8 min run time) to provide a solution of 3-(2-(azacyclobutan-1-yl)ethyl)-5-methoxy-1H-indole in a mixture of H2O (400 mL) and MeCN (100 mL). A solution of fumaric acid (~1 eq) in MeCN (2 mL) was added in a single addition to this solution at 20 °C under N2. The mixture was stirred at 20 °C for 20 min and then lyophilized to provide 3-(2-(azacyclobutan-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), examined by LCMS (ET47030-21-P1A1, Rt = 1.543 min, M+H = 231.1). 1¹H NMR (400MHz, 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 eq), 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 (pent, J = 7.51 Hz, 2H); LCMS (R T =1.543min,MS calc.:230.14,[M+H] + =231.1).

[0218] Unsuccessful post-processing and purification methods for compound 3:

[0219] Several alternative methods for post-processing LAH reduction and purification of product 3 resulted in partial or complete decomposition and no pure product was obtained. These unsuccessful post-processing / purification methods are summarized below.

[0220] Method 1:

[0221] Post-processing: After completion, H2O and 30% aqueous NaOH are added to the mixture, and the resulting slurry is filtered and concentrated.

[0222] purification: The residue was passed through a preparative HPLC system (column = Waters Xbridge Prep OBD C18 (150*40mm, 10μm); mobile phase = water (NH4HCO3)-ACN, B% = 1%-25%; run time 8 min). After lyophilizing the eluent, 1 HNMR showed that the product was impure.

[0223] Method 2:

[0224] Post-processing: Same as method 1.

[0225] purification: The residue was purified by preparative HPLC (column = Phenomenex C18 (75*30mm, 3μm); mobile phase = water (NH3·H2O+NH4HCO3)-ACN, B% = 1%-30%; run time 8 min). After lyophilizing the eluent, 1 1H NMR showed that the product was impure.

[0226] Example 4. Preparation of Compound 4

[0227]

[0228] Step 1: Preparation of 3-(2-(azacyclobutane-1-yl)ethyl)-1H-indole-4-yl acetate (4).

[0229] A mixture of 3-(2-(azacyclobutan-1-yl)ethyl)-1H-indole-4-ol (2, 50 mg, 231.18 μmol, 1 eq) and pyridine (23.77 mg, 300.54 μmol, 24.26 μL, 1.3 eq) in DCM (1 mL) was cooled to 0 °C. Acetic anhydride (25.96 mg, 254.30 μmol, 23.82 μL, 1.1 eq) was then added dropwise at 0 °C, and the resulting mixture was stirred at 25 °C for 1 h. At this point, the solvent was removed and the residue was purified by preparative HPLC (column = Waters Xbridge BEH C18 (100*30mm, 10μm); mobile phase = water (NH4HCO3)-ACN, B% = 5%-40%; 10min run time) to provide 3-(2-(azacyclobutan-1-yl)ethyl)-1H-indole-4-yl acetate (4) (20 mg, 33% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.01(br s,1H),7.22(d,J=8.0Hz,1H),7.11(d,J=1.6Hz,1H),7.02(t,J=8.0Hz,1H),6.64(d,J=7.6 Hz,1H),3.09(t,J=6.8Hz,4H),2.57-2.54(m,4H),2.32(s,3H),1.96-1.90(m,2H); LCMS(R T =0.983min,MS calc.:258.14,[M+H] + =259.1).

[0230] Note: Product 4 is readily hydrolyzed, and hydrolysis was observed during LCMS and HPLC analysis using an aqueous mobile phase.

[0231] Example 5. Metabolic stability of human liver microsomes

[0232] The stability of the disclosed compounds in human liver microsomes (HLM) was tested, and the results are summarized in Table 1. Azacyclic butyl compounds 1, 2, and 3 exhibited greater metabolic stability than their dimethyl counterparts N,N-dimethyltryptamine (DMT), psilocybin, and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), respectively. Therefore, azacyclic butyl compounds are expected to have higher oral bioavailability than their dimethyl counterparts.

[0233] The test compound. Compounds 1, 2, and 3 were prepared as described above. All other compounds were commercially available.

[0234] HLM stability. Pooled HLMs from adult male and female donors (Corning 452117) were used. Microsomal incubation was performed in multi-well plates. The liver microsomal incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (1 mM), and NADPN (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. The reaction mixture was analyzed at six time points over 60 min, with 60 μL aliquots of the sample taken at each time point. The reaction 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), followed by shaking for 10 min and then precipitating the protein by centrifugation at 4,000 rpm for 20 min 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.

[0235] Data analysis. Using linear regression analysis, the elimination constant (k) is determined from the curve of ln(AUC) versus time. el ), half-life (t) 1 / 2 ) and inherent clearance rate (CL) int ).

[0236] Table 1. Inherent scavenging rate of compounds in the presence of HLM (CL) int ) and half-life (t 1 / 2 ).

[0237]

[0238]

[0239] Example 6. Stability in the presence of monoamine oxidase

[0240] The stability of the disclosed compounds in human liver mitochondrial formulations in the presence of monoamine oxidases A and B (MAO-A and MAO-B) was tested, and the results are summarized in Table 2. Azacyclic butyl compounds 1 and 3 exhibited greater stability than their dimethyl counterparts, N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), respectively. Therefore, azacyclic butyl compounds are expected to undergo reduced brain metabolism compared to their dimethyl counterparts. Azacyclic butyl compound 2 exhibited similar stability to its dimethyl counterpart, psilocybin, which was already stable in this formulation.

[0241] The test compound. Compounds 1, 2, and 3 were prepared as described above. All other compounds were commercially available.

[0242] Liver mitochondria incubation. Human liver mitochondria (Xenotech H0610.M) were used. Mitochondria were incubated in multi-well plates. The liver mitochondrial incubation medium consisted of PBS (100 mM, pH 7.4) containing 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 / well). Six time points within 60 minutes were analyzed. 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 (300 μL) in water, and the remaining parent compound was analyzed using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method suitable for the purpose.

[0243] Data analysis. Using linear regression analysis, the elimination constant (k) is determined from the curve of ln(AUC) versus time. el ), half-life (t) 1 / 2 ) and inherent clearance rate (CL) int ).

[0244] Table 2. Inherent clearance rate (CL) of compounds in the presence of monoamine oxidase (human mitochondrial formulation) int ), half-life (t) 1 / 2 ) and remaining percentage.

[0245]

[0246] Example 7. Stability in mouse brain homogenate

[0247] The stability of the disclosed compounds in mouse brain homogenate was tested (Table 3). Azacyclobutane compounds 1, 2, and 3 all exhibited good stability under the experimental conditions and were significantly more stable than N,N-dimethyltryptamine (DMT).

[0248] The test compound. Compounds 1, 2, and 3 were prepared as described above. All other compounds were commercially available.

[0249] Stability of brain homogenate. Immediately before use, frozen mouse brain homogenates (collected from male CD1 mice, Bioreclamation IVT, MSE00BRAINMZA) were thawed in a water bath at 37°C. Positive controls and test compounds (final concentrations in incubation medium = 1 μM test compound and 2 μM control, both containing 2% DMSO) were incubated in duplicate at 37°C in 100 μL of total reaction volume of mouse brain homogenate at each time point (0, 10, 30, 60, and 120 min). At the end of each incubation period, the reaction was immediately quenched with 400 μL of acetonitrile containing internal standards (200 ng / mL tolbutamine and 200 ng / mL labetalol) and thoroughly mixed. The plates were then sealed, shaken for 20 min, and centrifuged at 4,000 rpm and 4°C for 20 min. Aliquots of 50 μL of each supernatant were diluted in 100 μL of water, and the mixture was shaken again for 10 min. The resulting mixture was analyzed for the remaining parent compounds using an LC-MS / MS method appropriate for the purpose.

[0250] Table 3. Stability of the compounds in mouse brain homogenate.

[0251]

[0252] Example 8. Stability in rat brain homogenate

[0253] The stability of the disclosed compounds in rat brain homogenate was tested (Table 4). The azacyclobutane compounds 1, 2, and 3 all exhibited good stability under the experimental conditions and were more stable than their dimethyl counterparts N,N-dimethyltryptamine (DMT), psilocybin, and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), respectively.

[0254] The test compound. Compounds 1, 2, and 3 were prepared as described above. All other compounds were commercially available.

[0255] Brain homogenate stability. (The following is a continuation of the previous sentence.)Frozen rat brain homogenates (collected from male Sprague Dawley rats, Bioreclamation IVT, RAT00BRAINMZA) were thawed in a water bath at 37°C before use. Positive controls and test compounds (final concentrations in incubation medium = 1 μM test compound and 2 μM control, both containing 2% DMSO) were incubated in duplicate at 37°C in 100 μL of total reaction volume of rat brain homogenate at each time point (0, 10, 30, 60, and 120 min). At the end of each incubation period, the reaction was immediately quenched with 400 μL of acetonitrile containing internal standards (200 ng / mL tolbutamine and 200 ng / mL labetalol) and thoroughly mixed. The plates were then sealed, shaken for 20 min, and centrifuged at 4,000 rpm and 4°C for 20 min. Aliquots of 50 μL of each supernatant were diluted in 100 μL of water, and the mixture was shaken again for 10 min. The resulting mixture was analyzed for the remaining parent compounds using an LC-MS / MS method appropriate for the purpose.

[0256] Table 4. Stability of the compounds in rat brain homogenate.

[0257]

[0258]

[0259] Example 9. Functional activity on 5-hydroxytryptamine receptors

[0260] Using Ca 2+Flux function assays were performed to test the agonist activity of the disclosed compounds on several serotonin receptor subtypes (5-HT2A, 2-HT2B, 5-HT2C, and 5-HT1A), and the results are summarized in Table 5. All compounds exhibited potent agonist activity on 5-HT2A, suggesting potential hallucinogenic activity and possible therapeutic effects. However, azacyclic butyl compounds generally exhibited greater potency on 5-HT1A than closely related compounds. For example, compound 1 was >50-fold more potent on this receptor than its dimethyl and methylethyl counterparts, N,N-dimethyltryptamine (DMT) and N-methyl-N-ethyltryptamine (MET; N-ethyl-2-(1H-indol-3-yl)-N-methylethyl-1-amine). Similarly, compound 2 was >5 times more potent at 5-HT1A than its dimethyl and methyl ethyl counterparts, psilocybin and 4-hydroxy-N-methyl-N-ethyltryptamine (4-HO-MET; 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-4-ol). Finally, compound 3 was >10 times more potent at 5-HT1A than its dimethyl counterpart, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). These increases in the potency of azacyclic butyl compounds 1, 2, and 3 at 5-HT1A are associated with similar or slightly decreased potency at 5-HT2A, implying a relatively lower 5-HT2A selectivity for these compounds compared to their dimethyl and methyl ethyl counterparts. Given the known anxiolytic and antidepressant effects of 5-HT1A agonists, increased activity at this target is expected to enhance the therapeutic activity of azacyclic butyl compounds for treating mood disorders.

[0261] The test compound. Compounds 1, 2, and 3 were prepared as described above. All other compounds were commercially available.

[0262] Functional determination on 5-HT2A, 5-HT2B and 5-HT1A. According to its standard protocol, using WuXi AppTec (Hong Kong) Limited's FLIPR CA 2+ Throughput assays were used to determine agonist activity on 5-HT2A, 5-HT2B, and 5-HT1A. Briefly, stably transfected cells expressing the receptor of interest (HEK293 for 5-HT2A and 5-HT2B; CHO cells for 5-HT1A) were grown and plated in 384-well plates and incubated overnight at 37°C and 5% CO2. 250 mM probenecid solution was freshly prepared in 1 mL of FLIPR assay buffer. This solution was then reacted with the fluorescent dye (Fluo-4Direct). TMCombine the solutions to achieve a final assay concentration of 2.5 mM. Dilute the compound 1:3.16 at 10 spots and add 750 nL of ECHO with 30 μL of assay buffer to a 384-well compound plate. Then add the fluorescent dye with assay buffer to the assay plate to a final volume of 40 μL. Incubate the cell plate at 37 °C and 5% CO2 for 50 min and place it in a FLIPR Tetra along with the compound plate. Then transfer 10 μL of reference and compound from the compound plate to the cell plate and read the fluorescence signal.

[0263] Functional determination on 5-HT2C. Using Eurofins DiscoverX (Fremont, CA) FLIPR CAR 2+ The throughput assay, following its standard protocol, determined the agonist activity on 5-HT2C. In short, stably transfected cells expressing the human 5-HT2C receptor were grown and plated in 384-well plates and incubated overnight at 37°C and 5% CO2. The assay was performed in a 1x dye loading buffer consisting of 1x dye, 1x additive A, and 2.5mM probenecid in HBSS / 20mM Hepes. Probenecid was freshly prepared. Cells were dye-loaded and incubated at 37°C for 30–60 min prior to assay. After dye loading, cells were removed from the incubator and 10 μL of HBSS / 20mM Hepes was added. The assay buffer contained 3x mediator. Cells were incubated at room temperature in the dark for 30 min to equilibrate the plate temperature. Intermediate dilutions of the sample stock solution were performed to produce 4x samples in the assay buffer. The agonist activity of the compound was measured on a FLIPR Tetra (MDS). Calcium mobilization was monitored for 2 minutes and 10 μL of 4X sample in HBSS / 20 mM Hepes was added to the cells for 5 seconds for assay.

[0264] Table 5. Ca 2+ The agonist activity of compounds on the 5-hydroxytryptamine receptor in flux functional assays.

[0265]

[0266]

[0267] The * value is the average of two or more independent experiments.

[0268] Example 10. Effect on head twitching response (HTR) in mice

[0269] The ability of the disclosed compounds to induce head twitching response (HTR) in mice was tested, and the results are summarized in Table 6. The maximum effect of the disclosed azacyclic butyl compounds (<10 head twitches / 20 min) was much smaller than that of the prototype 5-HT2A agonist 4-iodo-2,5-dimethoxyphenylamphenicol (DOI) (35.6 head twitches / 20 min) and the prototype psychedelic tryptamine 4-HO-MET (4-hydroxy-N-methyl-N-ethyltryptamine; 20.8 head twitches / 20 min). This observation is consistent with the much greater potency of compounds 1 and 2 as 5-HT1A agonists observed in vitro, since 5-HT1A agonists are known to inhibit the maximum effect in HTR assays.

[0270] Animals. Eight-week-old (20–25 g) adult male C57BL / 6 mice were used in these experiments. Animals were housed under controlled temperature and a 12-hour light / dark cycle (lights on between 7:00 AM and 7:00 PM), with free access to food and water. This protocol was approved by the Eurofins Advinus Institutional Animal Care and Use Committee. The study was conducted strictly in accordance with the National Institutes of Health's Guide for the Care and Use of Laboratory Animals. All efforts were made to minimize suffering.

[0271] 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 medium 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 saline (2), and administered subcutaneously (SC) at a volume of 10 mL / kg. The test compounds were administered in N = 6 animals / group with 5 doses of each compound (0.1–10 mg / kg, calculated based on free base). The control compound DOI was administered in N = 12 animals with a single dose (3.16 mg / kg, calculated based on HCl salt).

[0272] Procedure: Mice were given a single dose of the test drug (or mediator) SC and immediately placed in a small, open area for behavioral observation. Animals were observed continuously for 20 minutes, and the number of HTRs was counted by an observer unaware of the treatment conditions.

[0273] Statistical analysis. The data points shown in Table 6 represent the mean ± standard error of the mean (SEM). Analysis was performed using GraphPad Prism 9.

[0274] Table 6. HTR of the compounds in mice.

[0275]

[0276] Example 11. Forced swimming test in rats

[0277] The disclosed compound 2 induced an antidepressant-like effect in a rat forced swimming test (FST) with a pretreatment time of 23.5 h. Figure 1 Specifically, compared to the mediator control, the compound reduced resting time, indicating an antidepressant-like effect. This effect on resting was highly potent, with significant effects observed even at the lowest tested dose (0.1 mg / kg). Furthermore, these effects were observed 23.5 hours after administration of the single compound, a time point at which most or all of the drug has been cleared from systemic circulation, indicating that compound 2 has a rapid and sustained antidepressant-like effect. Additionally, 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.

[0278] animal. Male Sprague Dawley rats aged 8–10 weeks were used in the experiments. Animals were housed in groups of two under controlled temperature (22±3℃) and relative humidity (30–70%) conditions, with a 12-hour light / dark cycle and unrestricted food and water. These studies were conducted strictly in accordance with the requirements of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), India. All efforts were made to minimize suffering.

[0279] Drugs and drug administration.Compound 2 was prepared as described above. All other compounds were commercially available. The test compound, saline medium, and positive control desipramine were administered subcutaneously (SC), with the dose calculated based on free base. Physiological saline was used as the medium, 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 compound and medium were administered 0.5 h after the start of training swim (Swim 1) and 23.5 h before test swim (Swim 2). Desipramine was administered three times at a dose of 20 mg / kg at 23.5 h, 5 h, and 1 h before test swim (Swim 2).

[0280] Forced swimming test (FST). Animals were randomly assigned to groups based on body weight, ensuring minimal differences between groups and no more than ±20% of the mean body weight between groups. Group size was N=10 / treatment, except for the mediator and desipramine groups (N=20). Rats were treated for approximately 2 minutes daily for 5 days prior to the start of the experimental procedure. On day 1 (day 0), after randomization, all animals underwent a training swimming phase (Swimming 1) between 12:00 and 18:00 by placing them in a single glass cylinder (46 cm high x 20 cm diameter) containing 30 cm deep water at 23–25°C for 15 minutes. At the end of Swimming 1, animals were dried with thick paper towels, placed in a heated drying cage for 15 minutes, and then returned to their rearing cages. Animals were then given appropriate drug or mediator treatment as described above. For clarity, the 23.5 h compound administration time prior to Swimming 2 refers to 0.5 h after the start of Swimming 1 and 0.25 h after the completion of Swimming 1 (i.e., immediately after returning to the rearing cage). On day 1 (24 hours after the start of Swimming 1), the animals underwent a test swim (Swimming 2) for 5 minutes, but were otherwise under the same conditions as Swimming 1. Water was changed between animals during all swimming phases.

[0281] Behavioral ratings were performed by observers unaware of the treatment group. Animals were continuously observed during Swimming 2, and the total time spent engaging in the following behaviors was recorded: stillness, swimming, and climbing. A rat was considered still when it remained afloat without struggling and performed only those movements necessary to keep its head above water. A rat was considered swimming when it engaged in active swimming movements exceeding those necessary to simply keep its head above water (e.g., moving around inside the cylinder). A rat was considered climbing when it actively moved its forepaws in and out of the water, typically pointing towards the cylinder wall.

[0282] Statistical analysis. Figure 1 and Figure 2The data points shown represent the mean ± standard error of the mean (SEM). Analysis was performed using GraphPad Prism 9. Between-group comparisons were performed using one-way ANOVA, followed by Dunnett's test for comparison with the medium.

[0283] Example 12. Compound 4 is a prodrug of compound 2.

[0284] When administered to animals, such as humans, the acetate of compound 4 undergoes rapid hydrolysis to yield phenolic compound 2 as the active metabolite. Because compound 4 is more stable to oxidation than compound 2, it is a useful prodrug for compound 2 that is easier to store and handle. Other esters of compound 2 (on the phenol) possess similar useful properties to the prodrug.

[0285] Example 13. Microparticle stability of another compound.

[0286] As described in Example 5, the stability of another disclosed compound in human liver microsomes was tested. The compound exhibited good stability in this formulation and was more stable than its N,N-dimethyl counterpart.

[0287] Example 14. Stability of other compounds in the presence of monoamine oxidase

[0288] As described in Example 6, another disclosed compound was tested using a liver mitochondrial formulation to determine its stability in the presence of monoamine oxidase. The compound exhibited good stability in this formulation and was more stable than its N,N-dimethyl counterpart.

[0289] Example 15. Agonistaltic activity of other compounds on 5-HT1A and 5-HT2A receptors.

[0290] As described in Example 9, other disclosed compounds were tested to determine their agonist activity on 5-HT2A and 5-HT1A receptors. The compounds exhibited potent and efficient agonist activity on both receptors, and were more potent on 5-HT1A compared to their closest acyclic amine analogs.

[0291] Example 16. Effects of other compounds in HTR assays

[0292] As described in Example 10, other disclosed compounds were tested to determine their ability to induce head twitching response (HTR) in mice. Compared to other 5-HT2A agonists such as DOI and 4-HO-MET, the compounds induced low to moderate maximum effects.

[0293] Example 17. Effects of other compounds in the forced swimming test in rats

[0294] As described in Example 11, another disclosed compound was tested in a rat forced swimming test (FST). The compound reduced rest in a dose-dependent manner in this test, consistent with antidepressant-like effects.

[0295] Example 18. Synthesis of other compounds

[0296] Other disclosed compounds can be prepared by standard methods known to those skilled in the art of organic synthesis, such as those presented in Examples 1-4 and elsewhere herein.

[0297] Example 19. Preparation of Compound 5

[0298] Method 1:

[0299]

[0300] Step 1: Benzyl(3-(2-(1-benzylazine-1-) -1-yl)ethyl)-1H-indol-4-yl)phosphate Preparation of .

[0301] Add 2.5 M nBuLi (1.2 eq) in hexane dropwise over several minutes to a mixture of 3-(2-(azacyclobutan-1-yl)ethyl)-1H-indo-4-ol (2, 1 eq) in anhydrous THF (8.3 mL per mmol of 2), maintained at -78 °C, while keeping the internal temperature below -60 °C. Stir the reaction mixture for 10 min, then add tetrabenzyl pyrophosphate (1.1 eq) in a single batch and continue stirring at -78 °C for 1.5 h. At this point, remove the cooling bath and allow the temperature to slowly rise to -25 °C over approximately ~2 h. The completion of the reaction is checked by LCMS. While the reaction is still at -25 °C, add amino-bound silica gel (0.5 g per mmol of 2) in a single batch and dilute the reaction mixture with EtOAc (10 mL per mmol of 2). Filter the mixture through a diatomaceous earth mat and wash with EtOAc (6.7 mL per mmol of 2). The filter cake was re-slurryed with another EtOAc (6.7 mL / mmol²) for 10 min and filtered again. The combined filtrates were concentrated, the residue was redissolved in DCM (1.7 mL / mmol²), and the solution was heated to boiling for 5 min using a hot gun. The mixture was then allowed to cool to room temperature and then further cooled to 4°C and held at that temperature overnight. The resulting precipitate was collected by filtration, milled with DCM (4 × 1.7 mL / mmol²), with the supernatant removed each time, and then thoroughly dried to provide benzyl(3-(2-(1-benzylazacyclobutane-1- -1-yl)ethyl)-1H-indole-4-yl)phosphate.

[0302] Step 2: Preparation of 3-(2-(azacyclobutane-1-yl)ethyl)-1H-indole-4-yl dihydrogen phosphate (5).

[0303] To benzyl(3-(2-(1-benzylazonylbutane-1-) under N2 1-(1-yl)ethyl)-1H-indol-4-yl)phosphate (1 eq) was added to a mixture of 10% Pd / C (30.9 mg / mmol substrate) in MeOH (33.7 mL / mmol substrate), and the atmosphere was purged and backfilled with hydrogen from a balloon at 1 atm. The reaction mixture was then stirred overnight at room temperature. The completion of the reaction was checked by LCMS. The flask was then purged, backfilled with N2, and the suspension was filtered through a diatomaceous earth pad. The filter pad was washed with MeOH (14 mL / mmol substrate), and the combined filtrates were concentrated to give the crude product. The crude solid was suspended in iPrOH (5.6 mL / mmol substrate), boiled for 30 min, hot filtered (50–60 °C), and the collected solid was washed with acetone. The product was then suspended in 25% MeOH in iPrOH, boiled for 30 min, hot filtered, and the collected solid was washed with 25% MeOH in iPrOH. Finally, the solid was recrystallized from 30% water in acetone to obtain pure 3-(2-(azacyclobutane-1-yl)ethyl)-1H-indole-4-yl dihydrogen phosphate (5). If desired, the product can be further recrystallized from 30% water in acetone or pure water to obtain a material of higher purity.

[0304] Method 2:

[0305]

[0306] Step 1: Preparation of 3-(2-(azacyclobutane-1-yl)ethyl)-1H-indole-4-yl dihydrogen phosphate (5).

[0307] A slurry of 3-(2-(azacyclobutan-1-yl)ethyl)-1H-indo-4-ol (2, 1 eq) and diatomaceous earth (2 by weight) in anhydrous THF (3.07 mL per mmol of 2) was prepared under N2 and stirred at room temperature for at least 2 h, and then the mixture was cooled to -15 °C. Separately, a solution of POCl3 (1.5 eq) in anhydrous THF (1.36 mL per mmol of POCl3) was prepared under N2 and cooled to -15 °C. The 2 / diatomaceous earth / THF slurry was then slowly added to the POCl3 solution while maintaining the internal temperature between -15 and 0 °C, and the resulting mixture was stirred at -15 °C for 1 h. A quenching solution of THF / H2O (70:30, 2.04 mL per mmol of 2) and Et3N (6 eq) was prepared and cooled to -20 to 0 °C. The reaction mixture was then slowly added to the quenching solution, maintaining the internal temperature at -20 to 0 °C. Ice-cold THF (2 x 0.41 mL / mmol²) and water (0.61 mL / mmol²) were used to wash the residue in the reaction flask into the quenching mixture, maintaining the internal temperature at -20 to 0 °C. The combined mixture was then stirred at -20 to 0 °C for at least 1 h. The mixture was then filtered, and the filter cake was washed with water (2 x 0.41 mL / mmol²) at 5–10 °C. The lower aqueous phase containing the product was separated, mixed with iPrOH (2.04 mL / mmol²), and the mixture was concentrated to a volume of approximately 1.02 mL / mmol² at an internal temperature <45 °C, from which only water was distilled (adding additional iPrOH as needed to facilitate azeotropic distillation of the water to achieve the target volume). Additional water (1.02 mL / mmol²) was then added, and the mixture was stirred at room temperature for at least 24 h. The precipitate was collected by filtration under a nitrogen atmosphere. The filter cake was washed with cold water (2 x 0.41 mL / g mmol) and the collected solid was dried under vacuum at 35–45 °C for at least 24 h. The crude product was mixed with MeOH (10 mL / g crude product) under nitrogen and stirred at room temperature for at least 12 h. The mixture was filtered under nitrogen and the filter cake was washed with MeOH (2 x 1.5 mL / g crude product) at room temperature. The collected solid was mixed with water (10 mL / g crude product) under nitrogen and stirred at 45–55 °C for at least 24 h. The mixture was then cooled to room temperature for ~2 h and stirred further at that temperature for another 2 h. The solid was collected by filtration under N2, washed with room temperature water (2 x 1 mL per g crude product) and dried under vacuum at 35-45 °C for at least 24 h to provide pure 3-(2-(azacyclobutan-1-yl)ethyl)-1H-indole-4-yl dihydrophosphate (5).

[0308] Example 20. Compound 5 is a prodrug of compound 2.

[0309] When administered to animals, such as humans, the phosphate ester of compound 5 undergoes rapid hydrolysis to yield phenolic compound 2 as the active metabolite. Because compound 5 is more stable than compound 2, it is a useful prodrug of compound 2 that is easier to store and handle.

[0310] It should be understood that the embodiments and implementations provided herein are exemplary. Those skilled in the art will contemplate various modifications to the embodiments and implementations consistent with the scope of this disclosure. Such modifications are intended to be included within the scope of the claims.

Claims

1. Compounds having the following general formula I: Formula I in R 1 -R 6 Each can be independently selected from -H, -Me, and -Et; R 7 and R 8 Each is independently selected from -H, -Me, -Et, -OMe, OEt, -OH, OC(O)-(Cl-C 10 Alkyl groups) and -OP(O)(OH)(OH); and R 9 -R 12 -H; Or its pharmaceutically acceptable salt.

2. The compound according to claim 1, wherein... R 1 -R 6 Each is independently selected from -H and -Me; R 7 and R 8 Each is independently selected from -H, -Me, -OMe, -OH, OC(O)-(Cl-C) 10 Alkyl groups) and -OP(O)(OH)(OH); and R 9 -R 12 -H; Or its pharmaceutically acceptable salt.

3. The compound according to claim 1, wherein the compound is represented by the following formula (Ia): (Ia), Or its pharmaceutically acceptable salt.

4. The compound according to claim 3, wherein R 7 Selected from -H, -OH, -OC(O)-(Cl-C 10 Alkyl groups) and -OP(O)(OH)(OH).

5. The compound according to claim 4, wherein R 7 Selected from -H and -OH.

6. The compound according to claim 3, wherein R 8 Selected from -H, -OH, Me, -OC(O)-(Cl-C) 10 Alkyl groups) and -OP(O)(OH)(OH).

7. The compound according to claim 6, wherein R 8 Selected from H, -OH and -OMe.

8. The compound according to claim 1, wherein the compound is selected from: Or its pharmaceutically acceptable salt.

9. The compound according to claim 1, wherein the compound is selected from: or Or its pharmaceutically acceptable salt.

10. The compound according to claim 1, having the following structure: Or its pharmaceutically acceptable salt.

11. The compound according to claim 1, having the following structure: Or its pharmaceutically acceptable salt.

12. The compound according to claim 1, having the following structure: Or its pharmaceutically acceptable salt.

13. The compound according to claim 1, having the following structure: Or its pharmaceutically acceptable salt.

14. The compound according to claim 1, having the following structure: Or its pharmaceutically acceptable salt.

15. A pharmaceutical composition comprising one or more compounds according to any one of claims 1-14.

16. Use of the compound of any one of claims 1-14 in the manufacture of a medicament as a 5-hydroxytryptamine 1A receptor agonist, wherein the medicament is used to treat mental illness or disorder in patients in need of it.

17. The use of claim 16, wherein the mental illness or disorder is selected from major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual anxiety disorder, seasonal affective disorder, psychotic depression, disruptive mood disorder, substance / drug-induced depressive disorder, and depressive disorder due to another medical condition.

18. The use of claim 16, wherein the mental illness or disorder is selected from bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / drug-induced bipolar and related disorders, and bipolar and related disorders due to another medical condition.

19. The use of claim 16, wherein the mental illness or disorder is a substance-related disorder or a substance use disorder.

20. The use of claim 16, wherein the mental illness or disorder is selected from separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, panic attack, agoraphobia, generalized anxiety disorder, substance / drug-induced anxiety disorder, and anxiety disorder due to another medical condition.

21. The use of claim 16, wherein the mental illness or disorder is selected from obsessive-compulsive disorder and related disorders, trauma and stress-related disorders, feeding and eating disorders, borderline personality disorder, attention deficit / hyperactivity disorder and autism spectrum disorder.

22. The use of claim 16, wherein the mental disorder is a neurocognitive disorder.

23. The use of claim 16, wherein the mental illness or disorder is a treatment-resistant illness or disorder.

24. The use of claim 16, wherein said use provides improvement in at least one symptom selected from the following: sadness or somnolence or fatigue, depressive mood, inability to feel, anxious feelings of worry, fear, feeling tense, feeling uneasy, decreased interest in all or almost all activities, difficulty initiating activity, significantly increased or decreased appetite leading to weight gain or loss, insomnia, irritability, fatigue, feelings of worthlessness or low self-esteem, strongly held negative beliefs or pessimistic thoughts about oneself, others, or the world, feelings of helplessness, inability to concentrate or be distracted, recurrent thoughts of death or suicide, feelings of guilt, memory disorders, difficulty experiencing positive feelings, feeling isolated or alienated from people, hypervigilance, risk-taking behavior, avoidance of thoughts about stressful or traumatic events, pain and aches, rumination and obsessive thoughts, compulsive behaviors, talking to people you don't know or strangers, becoming the center of attention, irritating intrusive thoughts, inability to get through a week without medication, guilt about medication use, problems with friends or family due to medication use, and withdrawal symptoms due to medication use.

25. Use of the compound of any one of claims 1-14 in the manufacture of a medicament as a 5-hydroxytryptamine 1A receptor agonist, wherein the medicament is used to enhance creativity or cognition in a subject.

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