Therapeutic phenethylamine compositions and methods of use thereof

Abstract

Serotonin 5-HT2 receptor agonist compounds and methods of treatment with said compounds are provided. Disclosed are deuterated 2C-X phenethylamine compounds, their use in treating diseases associated with the serotonin 5-HT2 receptor, pharmaceutical compositions, e.g., tablet compositions, and kits containing the compounds, methods for delivering the compounds in a mist via inhalation, and methods for treating diseases or disorders associated with the serotonin 5-HT2 receptor, e.g., central nervous system (CNS) disorders or psychological disorders, using the compounds of the invention.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 63 / 067,303, filed August 18, 2020. No. 63 / 131,974, filed December 30, 2020. No. 60 / 629,995, filed on Oct. 1, 2007, and claims the benefit of US Provisional Patent Application No. 2007 / 0109994, each of which is incorporated herein by reference in its entirety. .

[0002] The present disclosure relates generally to compounds, and in some embodiments, to serotonin 5-HT 2 receptor agonists and their use in the treatment of diseases associated with the 5-HT2 receptor - Patent application Regarding. [Background technology]

[0003] The "Background" statement provided herein generally presents the context of the present disclosure. The research of the inventors of this application is intended to and in a manner of description that could not qualify as prior art at the time of filing. to the extent that it is not admitted expressly or impliedly as prior art to the present invention. .

[0004] Serotonin 5-HT2 receptors (5-HT2Rs) contain 5-HT 2A , 5-HT 2B , and 5-HT 2C There are three closely related subtypes of the receptor: The major serotonergic hallucinogens lysergic acid diethylamide (LSD) and 2,5-dimethylaminobenzoates It is the primary target of thiazol-4-bromoamphetamine (DOB). Active hallucinogens and entactogens have been shown to alleviate many central nervous system (CNS) disorders. , and is being actively researched in the medical community (Reiff, C.M., Richman, E. E., Nemeroff, C.B., Carpenter, L.L., Widge, A. S., Rodriguez, C.I., Kalin, N.H., and McDonald d,WM,2020,Psychedelics and Psychedelic -Assisted Psychotherapy,Am J Psychiatry 177, 391-410). Such studies include, for example, (i) post-traumatic stress Post-traumatic stress disorder (PTSD) (Jerome, L., Feduccia, A.A., Wang, J. B., Hamilton, S., Yazar-Klosinski, B., Emers. on, A., Mithoefer, M. C., and Doblin, R., 2020, Long-term follow-up outcomes of MDMA-ass isted psychotherapy for treatment of PTS D:a longitudinal pooled analysis of six phase 2 trials,Psychopharmacology(Berl)2 37,2485-2497), (ii) major depressive disorder (MDD), and (iii) treatment resistance. Transgender Depression (TRD) (Goldberg, S.B., Pace, B.T., Nichol as,CR,Raison,CL,and Hutson,PR,2020 ,The experimental effects of psilocybin on symptoms of anxiety and depression:A meta-analysis,Psychiatry Res 284,112749) , (iv) Obsessive-compulsive disorder (OCD) (Moreno, FA, Wiegand, CB ,Taitano,EK,and Delgado,PL,2006,Safe. ty,tolerability,and efficacy of psilocyb in in 9 patients with obsessive-compulsi ve disorder,J Clin Psychiatry 67,1735-17 40), (v) social anxiety disorder (ClinicalTrials.gov, number NCT02008396), (vi) including but not limited to alcohol use disorder, opioid use disorder, Use Disorder, Amphetamine Use Disorder, Nicotine Use Disorder, and Cocaine Use Disorder (vii) anorexia nervosa; (viii) bulimia nervosa (Clinical Trials.gov, numbers NCT04454684 and NCT0405 2568), (ix) Alzheimer's disease (ClinicalTrials.gov,nu mber NCT04123314), and (x) cluster headache and migraine (Nich ols,DE,2016,Psychedelics,Pharmacol Rev 68,264-355;Johnson,MW,Hendricks,PS, Barrett, FS, and Griffiths, RR, 2019, Cl. assic psychedelics:An integrative review of epidemiology,therapeutics,mystical e xperience,and brain network function,Pha rmacol Ther 197,83-102;Sewell,RA,Halpe rn,JH,and Pope,HG,Jr.,2006,Response of cluster headache to psilocybin and LS D,Neurology 66,1920-1922;ClinicalTrials. gov, number NCT04218539).

[0005] These drugs are particularly effective in treating lung disorders (e.g., asthma and chronic obstructive pulmonary disease (COPD) and Alleviating conditions of the autonomic nervous system, including cardiovascular disorders (e.g., atherosclerosis) Studies have also been conducted on nd Nichols,CD,2017,Psychedelics as Med icines:An Emerging New Paradigm, Clin Pha rmacol Ther 101,209-219;Flanagan,TW,Se bastian, MN, Battaglia, DM, Foster, TP, Cormier,SA,and Nichols,CD,2019,5-HT2 receptor activation alleviates airway i nflammation and structural remodeling in a chronic mouse asthma model, Life Sci 2 36,116790;Flanagan,TW,Sebastian,MN,B attaglia,DM,Foster,TP,Maillet,EL,a nd Nichols,CD,2019,Activation of 5-HT2 Receptors Reduces Inflammation in Vascu lar Tissue and Cholesterol Levels in High h-Fat Diet-Fed Apolipoprotein E Knockout Mice,Sci Rep 9,13444;Sexton,JD,Nichol s,CD,and Hendricks,PS,2019,Populatio n Survey Data Informing the Therapeutic Potential of Classic and Novel Phenethyl amine, Tryptamine, and Lysergamide Psyched elics, Front Psychiatry 10,896).

[0006] For example, 3,4-methylenedioxymethamphetamine (MDMA) for the treatment of PTSD. Use of (Feduccia, A.A., Jerome, L., Yazar-Klosin ski, B., Emerson, A., Mithoefer, MC, and Dob. lin, R., 2019, Breakthrough for Trauma Trea tment:Safety and Efficacy of MDMA-Assist ed Psychotherapy Compared to Paroxetine and Sertraline, Front Psychiatry 10,650) Some studies have progressed to Phase III trials, including 3,4,5-trimethoxyphenethyl A Phase I trial of an amine (mescaline) has begun ( ClinicalTrials.go v,number NCT04227756).

[0007] Mechanistically, the therapeutic effects of the hallucinogen phenethylamine are due to the interaction of phenethylamine and serotonin ( 5-HT) receptors, especially 5-HT 2A It is thought to be mediated by interaction with receptors However, 5-HT 1A Other targets, including receptors, may also be involved (Nichol s,DE,2016,Psychedelics,Pharmacol Rev 6 8,264-355;Canal,CE,2018,Serotonergic P psychodelics:Experimental Approaches for Assessing Mechanisms of Action,Handb Exp Pharmacol 252,227-260). 5-HT 2C Receptor involvement is This may be responsible for the anti-addictive properties reported for classical hallucinogens (Canal ,CE,and Murnane,KS,2017,The serotoni n 5-HT2C receptor and the non-addictive nature of classic hallucinogens,J Psycho Pharmacol 31, 127-143). The effect of phenethylamine, an entactogen, The results are mainly monoamine transporters, especially serotonin (SERT) and dopamine (DA T) transporter (Jayanthi, LD ,and Ramamoorthy,S.,2005,Regulation of m. onoamine transporters:influence of psych ostimulants and therapeutic antidepressants nts,AAPS J 7,E728-738).

[0008] The safety of hallucinogens and entactogens remains a significant challenge for their clinical application. (Hasler, F., Grimberg, U., Benz, MA, Huber, T.,and Vollenweider,FX,2004,Acute psych. hological and physiological effects of p silocybin in healthy humans: a double-bli nd, placebo-controlled dose-effect study, Psychopharmacology (Berl) 172,145-156;Ca rbonaro,TM,Bradstreet,MP,Barrett,FS ., MacLean, K.A., Jesse, R., Johnson, M.W., and Griffiths, RR, 2016, Survey study of cha llenging experiences after ingesting psi locybin mushrooms: Acute and enduring pos itive and negative consequences,J Psycho pharmacol 30,1268-1278;Garcia-Romeu,A.,K ersgaard,B.,and Addy,PH,2016,Clinical applications of hallucinogens:A review,E xp Clin Psychopharmacol 24,229-268;Morga n,L.,2020,MDMA-assisted psychotherapy fo r people diagnosed with treatment-resist ant PTSD:what it is and what it isn't,An n Gen Psychiatry 19,33;Schenk, S., and New combe, D., 2018, Methylenedioxymethamphetam ine (MDMA) in Psychiatry:Pros, Cons, and S suggestions,J Clin Psychopharmacol 38,632 -638).

[0009] The safe therapeutic window for these drugs is clearly very narrow, and long-term serotonin release and 5- HT 2B Cardiovascular complications due to increased stimulation (Huang, X.-P., Setola, V., Yadav, P. N., Allen, J. A., Logan, S. C., Hans. on, B.J., Revankar, C., Robers, M., Doucette, C. .,and Roth,BL,2009,Parallel Functional. Activity Profiling Reveals Valvulopathy gens Are Potent 5-Hydroxytryptamine(2B)R eceptor Agonists: Implications for Drug S afety Assessment,Molecular Pharmacology 76,710-722;Rothman,RB,and Baumann,MH ,2009,Serotonergic drugs and valvular he art disease,Expert Opin Drug Saf 8,317-3 29), depressive sequelae due to decreased central serotonin levels (Parrott, AC, 2014,The potential dangers of using MDMA for psychotherapy,J Psychoactive Drugs 46,37-43), as well as anxiety, fear, tachycardia, hypertension, elevated body temperature, nausea, and vomiting. There are many other acute side effects, including vomiting, many of which are caused by rapid blood levels after oral administration. This is due to high drug concentrations (spikes) (Meyer, JS, 2013, 3, 4-m ethylenedioxymethamphetamine (MDMA):curr ent perspectives,Subst Abuse Rehabilitation 4,8 3-99;Baylen, CA, and Rosenberg, H., 2006, A review of the acute subjective effects of MDMA / ecstasy,Addiction 101,933-947;Sh ulgin, A., and Shulgin, Ann., 1991, Pihkal:a chemical love story,Transform Press,Berk eley, CA; Barrett, FS, Bradstreet, MP, Leo utsakos, JS, Johnson, MW, and Griffiths, RR,2016,The Challenging Experience Que stionnaire:Characterization of challenge ng experiences with psilocybin mushrooms ,J Psychopharmacol 30,1279-1295). Many hallucinogens and Entactogens are also long-acting, and given their narrow therapeutic window, full-day monitoring is required. is required, which is the main obstacle to clinical application.

[0010] One type of hallucinogen, phenethylamine, is the 2C-X family of phenethylamines ( It is a phenethylamine containing 2,4,5 substitution, and has methoxy groups at the 2nd and 5th positions of the phenyl group. For example, 2,5-dimethoxy-4-bromophenethylamine (2C-B), This class of substances is thought to be associated with sexual dysfunction (Shulgin, A., and Shulgin, A. nn.,1991,Pihkal:a chemical love story,Tr (Ansform Press, Berkeley, CA), as well as neuropsychiatric conditions. may be used to treat conditions that result in changes in perception, cognition, emotion, and mood. , which may underlie the reported benefits of neuropsychological treatment (Johnson, n, MW, Hendricks, PS, Barrett, FS, and G riffiths,RR,2019,Classic psychedelics: An integrative review of epidemiology,th erapeutics, mystical experience, and brain network function,Pharmacol Ther 197,83- 102).

[0011] However, extensive clinical testing of 2C-X compounds and the development of practical treatment protocols are needed. Finding a suitable colloid is difficult due to the following factors: 1) low oral bioavailability; 2) low brain penetration; 3) slow onset of action after oral administration; and 4) to achieve a therapeutic effect. requiring high doses; 5) acute psychopathological adverse events (AEs), e.g., fear, anxiety cardiovascular events including tachycardia and hypertension, and gastrointestinal effects including nausea. 6) toxicity. These properties are due to the activity of monoamine oxidase (MAO). Deamination / oxidation by MAO-A and MAO-B, and other pathways such as CYP2D6 Rapid first-pass metabolism via O-dealkylation by cytochrome P450 enzymes, and relatively hydrophilic (e.g., 2,4,5-trimethoxyphenethylamine (2C-O) It is thought that the presence of α-glucan in the cerebrospinal fluid (having a logP value of 0.98) may also be a cause of the brain damage. (Suzuki, O., Katsumata, Y., and Oy a, M., 1981, Oxidation of beta-phenylethyla mine by both types of monoamine oxidase: examination of enzymes in brain and live r mitochondria of eight species,J Neuroc hem 36,1298-1301;Monte,AP,Marona-Lewic ka, D., Parker, M.A., Wainscott, D.B., Nelson, DL, and Nichols, DE, 1996, Dihydrobenzof. uran analogues of hallucinogens.3.Models of 4-substituted (2,5-dimethoxyphenyl)a lkylamine derivatives with rigid me thoxy groups,J Med Chem 39,2953-2961;Mon te, A.P., Waldman, S.R., Marona-Lewicka, D., W. ainscott, DB, Nelson, DL, Sanders-Bush, E .,and Nichols,DE,1997,Dihydrobenzofura n analogues of hallucinogens.4.Mescaline derivatives, J Med Chem 40, 2997-3008). For example, 2,4,5-trimethoxyphenethylamine (2C-O) is inactive after oral administration. (Shulgin, AT, 1978, Psychotomimetic Dru gs:Structure-activity relationships.Chap ter 6,In Handbook of psychopharmacology, V.11-Stimulants, pp 243-333, Plenum Press, New York).

[0012] Current 2C-X compounds and their formulations, as well as other hallucinogens and entactogens The limitations of netylamine are clear, and it is necessary to control drug exposure and keep it within a safe and effective range. Maintaining drug concentrations has proven difficult. Summary of the Invention

[0013] In view of the above, the pharmacokinetic properties, i.e., bioavailability and brain penetration, are improved, and the onset is rapid. , short-acting, and exhibits strong activity while minimizing psychiatric adverse events and toxicity, Novel 2C-X phenethylamine compounds are needed. It is efficient, convenient, and does not produce (e.g., psychotomimetic) plasma concentrations. There is also a need for phenethylamine formulations that are controllable.

[0014] It is therefore an object of the present invention to provide novel compounds that meet these criteria.

[0015] It is another object of the present disclosure to provide novel pharmaceutical compositions containing the compounds.

[0016] The compound is used to treat a patient with a disease or disorder associated with the serotonin 5-HT2 receptor. It is another object of the present disclosure to provide a method of treating a subject.

[0017] Novel tablet compositions, such as single-layer oral tablet compositions containing the compounds, are also provided. , another object of this disclosure.

[0018] The provision of novel kits containing formulations of the compounds for use in therapy is also another aspect of the present disclosure. That is one purpose.

[0019] Inhalation of the mist, for example, for the treatment of central nervous system (CNS) or psychological disorders It is yet another object of the present disclosure to provide novel methods for delivering such compounds via the endothelial cell membrane.

[0020] Serotonin 5-HT2 receptor agonists, for example, in central nervous system (CNS) or psychological disorders The present invention also provides novel uses of compounds for treating subjects with diseases or disorders related to the body. This is yet another object of the invention.

[0021] These and other objects, which will become apparent in the detailed description below, are achieved by site-specific deuteration. / The novel compounds described herein having fluorination (e.g., compounds of formula (I) to formula (IV) compounds) to G protein-coupled receptors (GPCRs), such as the 5-HT2 receptor. Maintaining preferential binding and improved exposure (e.g., rapid increase observed after administration) prevention of high drug concentrations (spikes) and a favorable enzymatic degradation profile. The inventors have demonstrated improved bioavailability, brain penetration and prevention / reduction of toxic metabolite formation. This was achieved by the discovery of

[0022] Thus, the present invention provides the following:

[0023] (1) A compound having the structure of Formula I: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof. hand, During the ceremony, X 1 and X 2 are independently hydrogen or deuterium, Y 1 and Y 2 are independently hydrogen or deuterium, R 3 is hydrogen or deuterium, R 4 is halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, -OR b , or -SR b and Each R ais independently a substituted or unsubstituted C1-C6 alkyl, and R b is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, or substituted or is unsubstituted C3-C 10 is cycloalkyl, However, X 1 , X 2 , Y 1 , Y 2 , R 3 , R 4 , and R a At least one of , containing deuterium, and / or R 4 are -SCF3, -SCH2CH2CF3, -SC H2CH2CF2H, -SCH2CH2CFH2, -OCH2CH2CF3, -OCH2 A compound selected from the group consisting of -CH2CF2H, and -OCH2CH2CFH2.

[0024] (2) Y 1 and Y 2 is hydrogen.

[0025] (3)R 3 is hydrogen.

[0026] (4)X 1 and X 2 is hydrogen. .

[0027] (5)X 1 and X 2 is deuterium. thing.

[0028] (6)Each R a is -CH3 or -CD3, and is described in any one of (1) to (5). The compounds listed above.

[0029] (7)R 4 -SMe, -SCD 3、 -SCF 3、 -SCH2CH2CF3, -SC H2CH2CF2H, -SCH2CH2CFH2, -SEt, -Sn-Pr, -Me, - CD3, -CF3, -t-Bu, -C(CD3)3, -cyclopentyl, -OMe, -O CD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, -OCH2 CH2CFH2, -Cl, -I, or -Br, any one of (1) to (6) The compound described.

[0030] (8) A compound of (1) having the structure of formula (II): [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof. hand, During the ceremony, X 1 and X 2 are independently hydrogen or deuterium, Y 1 and Y 2 are independently hydrogen or deuterium, R 4 is halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, -OR b , or -SR b and R b is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, or substituted or is unsubstituted C3-C 10 A compound which is a cycloalkyl.

[0031] (9)X 1 and X 2 is hydrogen.

[0032] (10)R 4 -SMe, -SCD 3、 -SCF 3、 -SCH2CH2CF3, -S CH2CH2CF2H, -SCH2CH2CFH2, -SEt, -Sn-Pr, -Me, -CD3, -CF3, -t-Bu, -C(CD3)3, -cyclopentyl, -OMe, - OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, -OCH 2CH2CFH2, -Cl, -I, or -Br, Compound.

[0033] (11)R 4 -SMe, -Me, -OCD3, -CF3, -t-Bu, or -Si The compound according to any one of (8) to (10), which is clopentyl.

[0034] (12) A compound of (1) having the structure of formula (III): [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof. hand, During the ceremony, X 1 and X 2 are independently hydrogen or deuterium, Y 1 and Y 2 are independently hydrogen or deuterium, R 4 is C1-C6 alkyl substituted with one or more deuterium atoms, C3-C 10 Cycloalkyl, -OR b , or -SR b and Each R a is independently a substituted or unsubstituted C1-C6 alkyl, and R b is a C1-C6 alkyl substituted with one or more deuterium atoms, or C3-C substituted with 10 A compound which is a cycloalkyl.

[0035] (13)X 1 and X 2 is hydrogen, and each R a is -CH3, as described in (12) Compound.

[0036] (14)R 4 is -SCD3, -CD3, -C(CD3)3 or -OCD3; The compound according to (12) or (13).

[0037] (15) A compound of (1) having the structure of formula (IV): [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof. hand, During the ceremony, Y 1 and Y 2 are independently hydrogen or deuterium, R 4 is halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, -OR b , or -SR b and Each R a is independently a substituted or unsubstituted C1-C6 alkyl, and R b is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, or substituted or is unsubstituted C3-C 10 A compound which is a cycloalkyl.

[0038] (16) A compound according to any one of (1) to (15), selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or prodrug thereof. [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0039] (17) The compound is a serotonin 5-HT2 receptor agonist, (1) to ( 16). The compound according to any one of

[0040] (18) The compound is a serotonin 5-HT 2A (1) is an agonist of the receptor (17) The compound according to any one of (17).

[0041] (19) A compound according to any one of (1) to (18), and a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising an excipient.

[0042] (20) The compound is a compound having a total isotope ratio of the compound present in the pharmaceutical composition. The pharmaceutical composition according to (19), wherein the pharmaceutical composition is present in a purity of at least 50% by weight based on the amount of the compound. The pharmaceutical composition described above.

[0043] (21) Any position of the compound having deuterium is at least (19) or (20), both of which have a minimum deuterium incorporation of 50 atomic %. Finished product.

[0044] (22) The compound (19) to (20) is substantially free from other isotopologues of the compound. The pharmaceutical composition described in any one of the above.

[0045] (23) The pharmaceutical agent according to any one of (19) to (22), which is formulated for oral administration. composition.

[0046] (24) A method according to any one of (19) to (22) above, formulated for administration via inhalation. The pharmaceutical composition described above.

[0047] (25) Treating a subject with a disease or disorder associated with the serotonin 5-HT2 receptor A method of

[0048] A therapeutically effective amount of the compound according to any one of (1) to (18) is administered to the subject. and

[0049] (26) The disease or disorder associated with serotonin 5-HT2 receptor is a neuropsychiatric disorder. The method according to (25), wherein the disease or disorder is an inflammatory disease or disorder.

[0050] (27) A disease or disorder associated with serotonin 5-HT2 receptors is a central nervous system (CN) The method according to (25) or (26), wherein the disorder is a disorder of the serotonin receptor agonist (S).

[0051] (28) The central nervous system (CNS) disorder is post-traumatic stress disorder (PTSD), Major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, suicidal thoughts Major depressive disorder with suicidal thoughts or behavior, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders, cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), Social anxiety disorder, substance use disorder, anorexia nervosa, bulimia nervosa, binge eating disorder, Alzheimer's Marsh's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain, aphantasia Childhood-onset fluency, dementia, mild dementia, sexual dysfunction, chronic fatigue syndrome, Lyme disease The method according to (27), wherein the disease is selected from the group consisting of: diabetes, encephalopathy, and obesity.

[0052] (29) The central nervous system (CNS) disorder is pain, (27) or (28). The method described.

[0053] (30) The central nervous system (CNS) disorder is sexual dysfunction, (27) or (2 The method described in 8).

[0054] (31) Diseases or disorders associated with serotonin 5-HT2 receptors are associated with the autonomic nervous system (AN) The method according to (25) or (26), wherein the disorder is a disorder of the serotonin receptor agonist (S).

[0055] (32) The disorder of the autonomic nervous system (ANS) is a pulmonary disorder or a cardiovascular disorder. The method described in 1).

[0056] (33) The compound is administered orally, sublingually, bucally, topically, or by injection; The method according to any one of (25) to (32), wherein the compound is administered by inhalation.

[0057] (34) A single compound containing the compound according to any one of (1) to (18) and a polymer. A tablet composition for oral administration.

[0058] (35) The monolayer oral administration composition according to (34), wherein the composition is adapted for maximum sustained release. Tablet composition.

[0059] (36) The tablet composition comprises: (i) a water-insoluble, neutrally charged nonionic matrix; (ii) a polymer carrying one or more negatively charged groups, and (iii) the compound. The monolayer tablet composition for oral administration according to (34) or (35), comprising:

[0060] (37) The water-insoluble, neutrally charged nonionic matrix may be starch, Wax, neutral rubber, polymethacrylate, PVA, PVA / PVP mixtures, and the like and a mixture of the same with a component selected from the group consisting of: The monolayer tablet composition for oral administration according to (36), wherein the polymer is selected from a cellulose-based polymer.

[0061] (38) The cellulose-based polymer is hydroxypropyl methylcellulose (HPM The monolayer tablet composition for oral administration according to (37), wherein

[0062] (39) The polymer carrying one or more negatively charged groups is polyacrylic acid, polylactic acid, poly Glycolic acid, polymethacrylate carboxylate, cation exchange resin, clay, zeolite hyaluronic acid, anionic gums, salts thereof, and mixtures thereof. The monolayer tablet composition for oral administration according to any one of (36) to (38), which is selected from the group consisting of:

[0063] (40) The anionic rubber is selected from the group consisting of natural and semi-synthetic materials. 2. The monolayer tablet composition for oral administration according to (39).

[0064] (41) The natural substance is alginic acid, pectin, xanthan gum, carrageenan, - Castor bean gum, gum arabic, gum karaya, guar gum, and gum tragacanth The monolayer tablet composition for oral administration according to (40), selected from the group consisting of:

[0065] (42) The semi-synthetic material is composed of carboxymethyl-chitin and cellulose gum. The monolayer tablet composition for oral administration according to (40), selected from the group consisting of:

[0066] (43) A composition according to any one of (34) to (42) containing a therapeutically effective amount of the compound for the purpose of treating pain. The monolayer tablet composition for oral administration according to any one of the preceding claims.

[0067] (44) (34) to (42) containing a therapeutically effective amount of the compound for the treatment of brain trauma. 10. The monolayer tablet composition for oral administration according to claim 9, wherein the tablet composition is a monolayer tablet composition for oral administration.

[0068] (45) (34) to (42) containing a therapeutically effective amount of the compound for the treatment of depression. 10. The monolayer tablet composition for oral administration according to claim 9, wherein the tablet composition is a monolayer tablet composition for oral administration.

[0069] (46) Use in the treatment of diseases or disorders associated with serotonin 5-HT2 receptors The composition according to any one of (34) to (42), which contains a therapeutically effective amount of the compound. A monolayer tablet composition for oral administration.

[0070] (47) The disease or disorder is post-traumatic stress disorder (PTSD), major depressive disorder harm (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, suicidal ideation or suicide Major depressive disorder with behavioral effects, non-suicidal self-injury disorder (NSSID), bipolar disorder type I, bipolar disorder type II Bipolar disorder and related disorders, including bipolar disorder, cyclothymic disorder, obsessive-compulsive disorder (OCD), Generalized anxiety disorder (GAD), social anxiety disorder, alcohol use disorder, opioid use disorder, Substance use disorders, including amphetamine use disorder, nicotine use disorder, and cocaine use disorder Harm, anorexia nervosa, bulimia nervosa, binge eating disorder, Alzheimer's disease, cluster headaches and migraines Headache, Attention Deficit Hyperactivity Disorder (ADHD), Pain and Neuropathic Pain, Aphantasia, Minor Childhood-onset fluency, dementia, mild dementia, sexual dysfunction, chronic fatigue syndrome, Lyme disease, etc. and obesity, as described in (46). A single-layer tablet composition for oral administration.

[0071] (48) The method according to (46), wherein the disease or disorder is a condition of the autonomic nervous system (ANS). A single-layer tablet composition for oral administration.

[0072] (49) The monolayer according to (46) or (48), wherein the disease or disorder is a pulmonary disorder. A tablet composition for oral administration.

[0073] (50) The disease or disorder according to (46) or (48), wherein the disease or disorder is a cardiovascular disorder. A single-layer tablet composition for oral administration.

[0074] (51) The composition achieves a plasma integrated concentration of the compound in the range of 10 to 500 ng / ml. and maintaining this concentration throughout the release period. A tablet composition for oral administration.

[0075] (52) Any of (34) to (51), wherein the polymer contains one or more negatively charged groups. A single-layer tablet composition for oral administration according to one of the preceding claims.

[0076] (53) A method for manufacturing a pharmaceutical composition comprising the compound according to any one of (1) to (18) and a polymer. A tablet composition formulated for oral administration.

[0077] (54) The tablet composition according to (53), wherein the polymer contains one or more negatively charged groups.

[0078] (55) The tablet according to (53) or (54), wherein the polymer contains one or more acid groups. Agent composition.

[0079] (56) The polymer comprises a water-insoluble, neutrally charged nonionic matrix. (53) The tablet composition according to any one of (55).

[0080] (57) The water-insoluble, neutrally charged nonionic matrix may be starch, Wax, neutral rubber, polymethacrylate, PVA, PVA / PVP mixtures, and the like and a mixture of the same with a component selected from the group consisting of: The tablet composition according to (56), wherein the polymer is selected from a cellulose-based polymer.

[0081] (58) The cellulose-based polymer is hydroxypropyl methylcellulose (HPM C). The tablet composition according to (57).

[0082] (59) 1) The monolayer tablet composition for oral administration according to any one of (34) to (52). and 2) instructions for use in treating pain.

[0083] (60) The kit according to (59), wherein the polymer comprises one or more negatively charged groups.

[0084] (61) 1) The monolayer tablet composition for oral administration according to any one of (34) to (52). and 2) a kit for treating a subject, the kit including instructions for use in treating brain trauma. .

[0085] (62) The kit according to (61), wherein the polymer comprises one or more negatively charged groups.

[0086] (63) 1) The monolayer tablet composition for oral administration according to any one of (34) to (52). and 2) a kit for treating a subject, the kit including instructions for use in treating depression. .

[0087] (64) The kit according to (63), wherein the polymer comprises one or more negatively charged groups.

[0088] (65) 1) The monolayer tablet composition for oral administration according to any one of (34) to (52). and 2) for use in treating diseases or disorders associated with the serotonin 5-HT2 receptor. A kit for treating a subject, including instructions for the treatment.

[0089] (66) The kit according to (65), wherein the polymer comprises one or more negatively charged groups.

[0090] (67) The need for, including administering via inhalation, hallucinogens dissolved in the liquid phase of a mist. A method for delivering a hallucinogen to a patient, wherein the hallucinogen is any one of (1) to (18). a method comprising administering to a subject a compound according to any one of claims 1 to 4,

[0091] (68) The method according to (67), wherein the hallucinogen is delivered to the central nervous system of the patient.

[0092] (69) The hallucinogen is delivered with air, oxygen, or a mixture of helium and oxygen. , (67) or (68).

[0093] (70) The hallucinogen is delivered with a mixture of helium and oxygen. (67)-(69) ) A method according to any one of the preceding claims.

[0094] (71) The mixture of helium and oxygen is heated to about 50°C to about 60°C. (70) The method described below.

[0095] (72) The helium is present in a mixture of helium and oxygen at about 50-90%. The oxygen is present in a mixture of helium and oxygen at about 10-50% (70) or ( 71).

[0096] (73) Pretreatment inhalation therapy with a mixture of helium and oxygen, followed by administration of hallucinogens. The method according to any one of (70) to (72), further comprising:

[0097] (74) The pretreatment involves inhaling helium heated to approximately 90°C to approximately 120°C into the patient. The method of (73), comprising administering a mixture of acetone and oxygen.

[0098] (75)(i) Helium and oxygen heated to approximately 90°C to 120°C is delivered to the patient by inhalation. and (ii) administering the mixture to the patient by inhalation heated to about 50°C to 60°C. and administering a mist containing helium and oxygen and hallucinogens. (74) A method according to any one of (74).

[0099] (76) Further comprising repeating steps (i) and (ii) at least once, (7 The method described in 5).

[0100] (77) The hallucinogen has a drug bioavailability of at least 25% compared to oral delivery. Improvement in C by at least 25% compared to oral delivery max Increased serotonin levels compared to oral delivery T by at least 50%max or a combination thereof, The method according to any one of (67) to (76), wherein the compound is delivered to the central nervous system.

[0101] (78) Central nervous system disorders, including administering hallucinogens dissolved in a mist by inhalation. A method for treating a central nervous system (CNS) disorder or a psychological disorder, wherein the hallucinogen comprises: (1) A method comprising the compound according to any one of (18) to (19).

[0102] (79) The hallucinogen is delivered with air, oxygen, or a mixture of helium and oxygen. , (78).

[0103] (80) The hallucinogen is delivered with a mixture of helium and oxygen to provide a dose of the hallucinogen to the patient. The mixture of helium and oxygen is heated to about 50°C to about 60°C before administration. How to post.

[0104] (81) The CNS disorder is post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, suicidal ideation or suicide attempt Major depressive disorder with ataxia, non-suicidal self-injury disorder (NSSID), bipolar disorder type I, bipolar disorder type II Bipolar disorder and related disorders, including polarized disorders, cyclothymic disorder, obsessive-compulsive disorder (OCD), Generalized anxiety disorder (GAD), social anxiety disorder, alcohol use disorder, opioid use disorder, Substance use disorders, including amphetamine use disorder, nicotine use disorder, and cocaine use disorder , anorexia nervosa, bulimia nervosa, binge eating disorder, Alzheimer's disease, cluster headaches and hemiplegia Pain, Attention Deficit Hyperactivity Disorder (ADHD), Pain and Neuropathic Pain, Aphantasia, Children Early-onset fluency, dementia, mild dementia, sexual dysfunction, chronic fatigue syndrome, Lyme disease or The method according to any one of (78) to (80), wherein the patient is obese.

[0105] (82) A transdermal patch comprising the compound according to any one of (1) to (18).

[0106] (83) Further comprising a pressure-sensitive adhesive layer, a backing, and a release liner; (82) The transdermal patch described in

[0107] (84) The process according to (83), wherein the compound is uniformly distributed throughout the pressure-sensitive adhesive layer. Skin patch.

[0108] (85) Any one of (82) to (84) containing 5 mg to 25 mg of the compound. The transdermal patch described.

[0109] (86) A method for treating a subject having a disease or disorder associated with the serotonin 5-HT2 receptor. A method of

[0110] A therapeutically effective amount of the compound is administered via a transdermal patch of any one of (82) to (85). administering to said subject.

[0111] (87) Diseases or disorders associated with serotonin 5-HT2 receptors are neuropsychiatric disorders. The method according to (86), wherein the disease or disorder is an inflammatory disease or disorder.

[0112] (88) Diseases or disorders associated with serotonin 5-HT2 receptors are associated with the central nervous system (CN The method according to (86) or (87), wherein the disorder is a disorder of the serotonin receptor agonist (S).

[0113] (89) The central nervous system (CNS) disorder is post-traumatic stress disorder (PTSD), Major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, suicidal thoughts Major depressive disorder with suicidal thoughts or behavior, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders, cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), Social anxiety disorder, substance use disorder, anorexia nervosa, bulimia nervosa, binge eating disorder, Alzheimer's Marsh's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain, aphantasia Childhood-onset fluency, dementia, mild dementia, sexual dysfunction, chronic fatigue syndrome, Lyme disease The method according to (88), wherein the disease is selected from the group consisting of: diabetes, encephalopathy, and obesity.

[0114] (90) Diseases or disorders associated with serotonin 5-HT2 receptors are associated with the autonomic nervous system (AN) The method according to (86) or (87), wherein the disorder is a disorder of the serotonin receptor agonist (S).

[0115] (91) The disorder of the autonomic nervous system (ANS) is a pulmonary disorder or a cardiovascular disorder. 0).

[0116] (92) 5 mg to 25 mg of the compound is administered to the subject over a period of 4 to 72 hours. The method according to any one of (86) to (91),

[0117] (93) Serotonergic, but subpsychoactive concentrations of the compound are administered. The method according to any one of (86) to (92),

[0118] (94) A method for treating a subject having a disease or disorder associated with the serotonin 5-HT2 receptor. A method of A compound according to any one of (1) to (18) is administered to the subject via an automatic injection device. administering a therapeutically effective amount of the compound transdermally, subcutaneously, or intramuscularly. [Brief explanation of the drawings]

[0119] The preceding paragraphs are provided by way of general introduction and are not intended to limit the scope of the claims that follow. The described embodiments should be considered in conjunction with the accompanying drawings. The present invention is best understood with further advantage by reference to the detailed description below. It will be done.

[0120] [Figure 1] FIG. 1 shows a synthetic route for making compound II-1. [Figure 2] FIG. 2 shows a synthetic route for making compound II-2. [Figure 3] FIG. 3 shows a synthetic route for making compound II-3. [Figure 4] FIG. 4 shows a synthetic route for making compound II-4. [Figure 5] FIG. 5 shows a synthetic route for making compound II-14. [Figure 6] FIG. 6 shows a synthetic route for making compound III-1. [Figure 7] FIG. 7 shows a synthetic route for making compound III-2. [Figure 8] FIG. 8 shows a synthetic route for making compound IV-1. [Figure 9] FIG. 9 shows a synthetic route for making compound IV-2. [Figure 10] FIG. 10 shows a synthetic route for making compound IV-3. [Figure 11] FIG. 11 shows a synthetic route for making compound IV-5. [Figure 12] FIG. 12 shows a synthetic route for making compound IV-12. [Figure 13] FIG. 13 shows a synthetic route for making compound I-1. [Figure 14] FIG. 14 shows synthetic routes for making compounds of formula (I) containing a fluoropropoxy or fluorothiopropoxy substituent as R4, such as compounds I-2, I-3, I-4, I-5-I-6, I-7, II-16, II-17, II-18, II-19, II-20, and II-21. [Figure 15] FIG. 15 shows a synthetic route for making Reference Compound 1. [Figure 16] Figure 16 shows the effects of CYB2108 (Compound I-1, 3 mg / kg) and CYB2108D (Compound II-10, 3 mg / kg) compared to vehicle (Veh) control and the positive control serotonergic hallucinogen (±)2,5-dimethoxy-4-iodoamphetamine (DOI, 1 mg / kg) on ​​serotonin 5-HT2A receptor-dependent head-twitch response (HTR) in adult male C57BL / 6J mice. Data for each test compound are best fitted to a two-site model (GraphPad Prism 9). [Figure 17] FIG. 17 is a graph of radioligand competitive binding of antagonist-labeled human serotonin 5-HT2A receptors using CYB2108 (compound I-1) and CYB2108D (compound II-10). DETAILED DESCRIPTION OF THE INVENTION

[0121] A complete understanding of the embodiments of the present disclosure is provided in the following detailed description of the embodiments of the present disclosure. Numerous specific details are set forth to provide a thorough understanding of the present disclosure. It will be apparent to one skilled in the art that the present invention may be practiced without these specific details. , known methods, procedures, components, and elements as described above so as not to unnecessarily obscure aspects of the embodiments of the present disclosure. The elements and circuits are not described in detail.

[0122] definition Unless otherwise defined, all technical and scientific terms used herein are within the meaning of the present disclosure. has the same meaning as commonly understood by a person skilled in the art to which it pertains.

[0123] "Alkyl" means an alkyl group having 1 to 10 carbon atoms, for example, 1 to 6 carbon atoms, or 1 to 5 carbon atoms. Monovalent saturated fats having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 3 This term refers to an aliphatic hydrocarbyl group. Examples of such groups include methyl (CH3-), ethylene (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((C H3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3 )2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl butyl (t-Bu) ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2 -), and neopentyl ((CH3)3CCH2-), It includes a locarbyl group.

[0124] The term "substituted alkyl" refers to an alkyl chain in which one or more carbon atoms are optionally substituted, such as - O-, -N-, -S-, -S(O) n - (wherein n is 0 to 2), -NR- (wherein R is The present invention provides a compound substituted with a heteroatom such as hydrogen or alkyl, and having 1 to 10 substituents. The term "alkyl" refers to an alkyl group as defined in the specification, and the substituents include deuterium, alkoxy, substituted alkoxy, and the like. cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, Acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, o Aminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, chlorine carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thi heterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, Aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclo Oxy, hydroxyamino, alkoxyamino, nitro, SO-alkyl, -SO-aryl -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2- Heteroaryl, and -NR ’ R″, wherein R′ and R′ ' may be the same or different and are selected from hydrogen, optionally substituted alkyl, cycloalkyl, alkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and and heterocycle.

[0125] "Alkylene" refers to a divalent aliphatic alkyl group having 1 to 6, for example 1 to 3, carbon atoms. refers to a dihydrocarbyl group, which may be linear or branched, and optionally includes -O-, -NR 10 -, -NR 10 C(O)-, -C(O)NR 10 -, etc. Examples of such terms include methylene (-CH2-), ethylene (-CH2C H2-), n-propylene (-CH2CH2CH2-), iso-propylene (-CH2C H(CH3)-), (-C(CH3)2CH2CH2-), (-C(CH3)2CH2C (O)-), (-C(CH3)2CH2C(O)NH-), (-CH(CH3)CH2- ) etc.

[0126] "Substituted alkylene" refers to any group defined with respect to carbon in the definition of "substituted" below. It refers to an alkylene group in which 1 to 3 hydrogen atoms have been substituted with a substituent, as shown in the following formula:

[0127] The term "alkane" refers to alkyl and alkylene groups as defined herein. vinegar.

[0128] "Alkylaminoalkyl", "alkylaminoalkenyl", and "alkylamino" The term "alkynyl" refers to the group R'NHR'', where R' is defined herein. R' is an alkyl group, as defined herein, alkenylene, group, or an alkynylene group.

[0129] The term "alkaryl" or "aralkyl" refers to -alkylene-aryl and - It refers to the group substituted alkylene-aryl, in which alkylene, substituted alkylene, and aryl are defined herein.

[0130] "Alkyloxy" refers to an -O-alkyl group, where alkyl is an alkyl group of the present invention. Alkoxy includes, for example, methoxy, ethoxy, n-propyl, propyl alkoxy ... propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy The term "alkoxy" includes alkenyl-O-, cycloalkoxy, and the like. The term also refers to the groups cycloalkenyl-O-, cycloalkenyl-O-, and alkynyl-O-, in which As used herein, alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are defined as As defined.

[0131] The term "substituted alkoxy" refers to substituted alkyl-O-, substituted alkenyl-O-, substituted Cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- groups In this case, it refers to substituted alkyl, substituted alkenyl, substituted cycloalkyl ... Chloroalkenyl, and substituted alkynyl are as defined herein.

[0132] The term "alkoxyamino" refers to the group -NH-alkoxy, in which Alkoxy is defined herein.

[0133] The term "haloalkoxy" refers to an alkyl-O- group, in which alkyl One or more hydrogen atoms on the alkyl group may be replaced by a halo group, for example, trifluoromethoxy. Examples of the group include the following.

[0134] The term "haloalkyl" refers to a substituted alkyl group as defined above, in which case alkoxy is substituted with alkoxy. One or more hydrogen atoms on the alkyl group may be replaced by a halo group. Examples of such groups include: Examples include, but are not limited to, trifluoromethyl, difluoromethyl, and trifluoroethyl. Examples of fluoroalkyl groups include:

[0135] The term "alkylalkoxy" refers to -alkylene-O-alkyl, alkylene-O -substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl alkyl, in which alkyl, substituted alkyl, alkylene, and substituted alkyl are included. Alkylene is as defined herein.

[0136] The term "alkylthioalkoxy" refers to -alkylene-S-alkyl, alkylene -S-substituted alkyl, substituted alkylene-S-substituted alkyl, and substituted alkylene-S- substituted alkyl groups, in which alkyl, substituted alkyl, alkylene, and and substituted alkylene are as defined herein.

[0137] "Alkenyl" means an alkyl group having 2 to 6 carbon atoms, for example, 2 to 4 carbon atoms, straight-chain or branched hydrocarbons each having one, e.g., one to two, double bond unsaturation sites; The term refers to alkyl groups, such as bi-vinyl, allyl, and but-3-ene-. The term includes cis and trans isomers, or any combination thereof. Mixtures of isomers are included.

[0138] The term "substituted alkenyl" refers to an alkenyl group having 1 to 5 substituents, or 1 to 3 substituents. and the substituents include alkoxy, substituted ... cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, Acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyl hydroxyl, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thio Oketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryl thioloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, Heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl , -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-aryl alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl are selected.

[0139] "Alkynyl" means an alkyl group having 2 to 6 carbon atoms, for example, 2 to 3 carbon atoms, A linear or branched monovalent alkyl group having one, for example, one to two triple bond unsaturated sites. refers to a hydrocarbyl group. Examples of such alkynyl groups include acetylenyl (-C≡ CH), and propargyl (-CHC≡CH).

[0140] The term "substituted alkynyl" refers to an alkynyl group having 1 to 5 substituents, or 1 to 3 substituents. alkynyl groups as defined herein, wherein the substituents include deuterium, alkoxy, substituted Alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl phenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, acyl aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, o oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thiohetero aryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy koxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyano Acrylic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO- Alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2-Alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl Selected from the reels.

[0141] "Alkynyloxy" refers to the group -O-alkynyl, in which case alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy. Examples of alkoxy include oxy and propynyloxy.

[0142] "Acyl" means HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)- , alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted Substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O )-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl- C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl Heterocyclyl-C(O)-, heterocyclyl-C(O)-, and substituted heterocyclyl-C(O) - refers to the group of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkene aryl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl Aryl, heterocycle and substituted heterocycle are as defined herein. The alkyl group contains the "acetyl" group CH3C(O).

[0143] "Acylamino" means -NR 20 C(O) alkyl, -NR 20 C(O) substituted alkyl Le, NR 20 C(O)cycloalkyl, -NR 20 C(O)-substituted cycloalkyl, -NR 20 C(O)cycloalkenyl, -NR 20 C(O)-substituted cycloalkenyl, -NR 20 C(O)alkenyl, -NR 20 C(O) substituted alkenyl, -NR 20 C(O) Alkini Le, -NR 20 C(O) substituted alkynyl, -NR 20 C(O)aryl, -NR 20 C( O) substituted aryl, —NR20 C(O)heteroaryl, -NR 20 C(O) substituted hetero Aryl, -NR 20 C(O) heterocycle, and -NR 20 C(O) refers to a substituted heterocyclic group , in this case R 20 is hydrogen or alkyl, and alkyl, substituted alkyl, alkyl alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cyclo Alkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, hetero Aryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. This is the case.

[0144] The term "aminocarbonyl" or "aminoacyl" refers to -C(O)NR 21 R 2 2 In this case, R 21 and R 22 are independently hydrogen, alkyl, substituted Alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted Aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkene and n is selected from the group consisting of aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic. Selected, R 21 and R 22 are optionally joined together with the nitrogen to which they are attached to form a heterocycle or or a substituted heterocyclic group, in which case alkyl, substituted alkyl, alkenyl , substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl , cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl , substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein .

[0145] "Aminocarbonylamino" means -NR 21 C(O)NR 22 R 23 R refers to the group 2 1 , R 22 , and R 23 are independently hydrogen, alkyl, aryl or cycloalkyl or two R groups joined to form a heterocyclyl group.

[0146] The term "alkoxycarbonylamino" refers to the group -NRC(O)OR, where wherein each R is independently hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl. or heterocyclyl, in which case alkyl, substituted alkyl, aryl, Heteroaryl, and heterocyclyl are as defined herein.

[0147] The term "acyloxy" includes alkyl-C(O)O-, substituted alkyl-C(O)O -, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C (O)O-, heteroaryl-C(O)O-, and heterocyclyl-C(O)O- groups In this case, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl Aryl, aryl, heteroaryl, and heterocyclyl are as defined herein. is.

[0148] "Aminosulfonyl" means -SO2NR 21 R 22 refers to the group, in which case R 2 1 and R 22 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl Alkyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl R is selected from the group consisting of aryl, heterocycle, and substituted heterocycle; 21 and R 22 is optional together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group; alkyl, Substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkenyl alkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted Aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are defined herein. As defined in

[0149] "Sulfonylamino" means -NR 21 SO2R 22 refers to the group, in which case R 2 1 and R 22 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl Alkyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl R is selected from the group consisting of aryl, heterocycle, and substituted heterocycle; 21 and R 22 is optional They may be joined together with the atoms to which they are attached to form a heterocyclic or substituted heterocyclic group, in which case In this case, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkenyl Alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkene aryl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted Substituted heterocycle is as defined herein.

[0150] "Aryl" or "Ar" refers to an aryl group having one ring (e.g., the aryl group present in a phenyl group). or having a ring system with multiple fused rings (examples of such aromatic ring systems include: naphthyl, anthryl, and indanyl), monovalent aromatic rings of 6 to 18 carbon atoms refers to an aromatic carbocyclic group, the fused rings of which may or may not be aromatic, provided that the fused rings are bonded together. The bond is via an atom in an aromatic ring. The term includes, by way of example, phenyl and naphthalene. Unless otherwise constrained by the definition of an aryl substituent, such The aryl group may be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents, The substituents are acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkoxy, alkoxy, hydroxy, hydroxy, thiol, acyl, hydroxy ... cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy thio, azido, carboxyl, carboxyl alkyl, cyano, halogen, nitro, hetero Aryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyl Oxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-a Aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -S It is selected from O2-aryl, -SO2-heteroaryl, and trihalomethyl.

[0151] "Aryloxy" refers to the group -O-aryl, where aryl is an alkyl group of the present invention. as defined in the specification, including, by way of example, optionally substituted aryl; hydroxy, naphthoxy, and the like, as defined herein.

[0152] "Amino" refers to the group -NH2.

[0153] The term "substituted amino" refers to the group -NRR, where each R is independently hydrogen, alkyl, Substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkyl Cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heterocyclic and heterocyclyl, provided that at least one R is not hydrogen.

[0154] The term "azido" refers to the group -N3.

[0155] "Carboxyl", "carboxy" or "carboxylate" means -CO2H or its derivatives. It refers to the salt of

[0156] "Carboxyl ester" or "carboxy ester" or "carboxy alkyl" " or "carboxyalkyl" refers to -C(O)O-alkyl, -C(O)O -substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O )O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O )O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(O )O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocycle, and and -C(O)O-substituted heterocyclic groups, in which alkyl, substituted alkyl, Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl alkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, hetero Heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein. This is the case.

[0157] "(Carboxy ester)oxy" or "carbonate" means -OC(O)O-alkyl -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O) O-substituted alkenyl, -OC(O)O-alkynyl, -OC(O)O-substituted alkynyl Aryl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O -cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-cyclo Alkenyl, -OC(O)O-substituted cycloalkenyl, -OC(O)O-heteroaryl -OC(O)O-substituted heteroaryl, -OC(O)O-heterocycle, and -O -C(O)O- refers to the group of substituted heterocycles, in which alkyl, substituted alkyl, alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkynyl alkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl Aryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein. is.

[0158] "Cyano" or "nitrile" refers to the group --CN.

[0159] "Cycloalkyl" refers to one or more rings, including fused, bridged, and spiro ring systems. The preferred cycloalkyl groups are cyclic alkyl groups having 3 to 10 carbon atoms and a ring of the formula: Examples include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, Examples of such cycloalkyl groups include cyclohexyl and cyclooctyl. is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl or multiple ring structures such as, for example, adamantanyl.

[0160] The term "substituted cycloalkyl" refers to a group containing 1 to 5 substituents, or 1 to 3 substituents. The term "cycloalkyl group" refers to a cycloalkyl group having a deuterium, alkyl, substituted alkyl, alkoxy, or cycloalkyl, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkyl Chloroalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoa Cyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxy Sil, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, Thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-Alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl , -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2- heteroaryl.

[0161] "Cycloalkenyl" means a group having one or more rings and at least one double bond, For example, it refers to a non-aromatic cyclic alkyl group having 3 to 10 carbon atoms and having 1 or 2 double bonds.

[0162] The term "substituted cycloalkenyl" refers to cycloalkenyl groups containing 1 to 5 substituents, or 1 to 3 substituents. and the cycloalkenyl group may be substituted with deuterium, alkoxy, substituted alkoxy, Cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acylate aryl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacylo Oxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, keto, thioketo , carboxyl, carboxyl alkyl, thioaryloxy, thioheteroaryloxy thio, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, hetero Cyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -S O-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, Selected from -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl will be done.

[0163] "Cycloalkynyl" refers to a group having one or more rings and at least one triple bond. It refers to a non-aromatic cycloalkyl group having 5 to 10 carbon atoms.

[0164] "Cycloalkoxy" refers to -O-cycloalkyl.

[0165] "Cycloalkenyloxy" refers to -O-cycloalkenyl.

[0166] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0167] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0168] "Heteroaryl" refers to a heteroaryl group having 1 to 15 carbon atoms, for example, 1 to 10 carbon atoms and an acid. an aromatic group having 1 to 10 ring heteroatoms selected from the group consisting of hydrogen, nitrogen, and sulfur; Such heteroaryl groups may have only one ring (e.g., pyridinyl, imidazoline) in the ring system. aryl, or furyl), or multiple condensed rings (e.g., indolizinyl, quinolinyl, benzoyl, The compound may have a substituent such as benzofuran, benzimidazolyl, or benzothienyl. In this case, at least one ring in the ring system is aromatic and at least The other ring is aromatic, provided that the point of attachment is through an atom of the aromatic ring. In certain embodiments, the nitrogen and / or sulfur ring atoms of a heteroaryl group are optionally Oxidized to an N-oxide (N→O) moiety, a sulfinyl moiety, or a sulfonyl moiety The term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl and furanyl. Unless otherwise specified, such heteroaryl groups may optionally have 1 to 5 substituents, or 1 to 3 substituents. The substituents may be acyloxy, hydroxy, thiol, acyl, alkoxy ... alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted Alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, Aryl, aryloxy, azido, carboxyl, carboxyl alkyl, cyano, ha aryl, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyl oxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy oxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted Substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO 2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and trihalome Selected from chill.

[0169] The term "heteroaralkyl" refers to the group -alkylene-heteroaryl, where where alkylene and heteroaryl are defined herein. Examples include pyridylmethyl, pyridylethyl, indolylmethyl, and the like.

[0170] "Heteroaryloxy" refers to -O-heteroaryl.

[0171] "Heterocycle," "heterocyclic," "heterocycloalkyl," and "heterocyclyl" refers to saturated or unsaturated groups having one ring or multiple fused rings, including fused and bridged ring systems. and spiro ring systems, having 3 to 20 ring atoms, including 1 to 10 heteroatoms. The ring atoms are selected from the group consisting of nitrogen, sulfur, or oxygen, wherein In fused ring systems, one or more of the rings may be cycloalkyl, aryl, or heteroaryl. provided that the point of attachment is through the non-aromatic ring. The nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to form an N-oxide moiety. , -S(O)- moiety, or -SO2- moiety.

[0172] Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, benzophenone, benzophenone, benzophenone-1, benzophenone-2, benzophenone-3, benzophenone-4, benzophenone-5, benzophenone-6, benzophenone-7, benzophenone-8, benzophenone-9, benzophenone-11, benzophenone-12, benzophenone-13, benzophenone Midazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine , isoindole, indole, dihydroindole, indazole, purine, quinolidine quinoxaline, quinazolidinone, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazolidinone cinnoline, pteridine, carbazole, carboline, phenanthridine, acridin phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine , phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indole phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydroisoquinoline Hydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b ]thiophene, morpholinyl, thiomorpholinyl (also called thiomorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, tetrahydrofuranyl , benzo[b][1,3]oxathiol, benzo[b][1,3]dioxole, etc. Examples include:

[0173] Unless otherwise constrained by a definition for a heterocyclic substituent, such a heterocyclic group is optionally The substituents may be substituted with 1 to 5 substituents, or 1 to 3 substituents, and the substituents may be deuterium, a alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, Substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, a aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxybenzoate Hydroxyl, oxo, thioketo, carboxyl, carboxyl alkyl, thioaryl oxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy , substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy oxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl Aryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2 -heteroaryl, and fused heterocycle.

[0174] "Heterocyclyloxy" refers to the group --O-heterocyclyl.

[0175] The term "heterocyclylthio" refers to the group heterocycle-S-.

[0176] The term "heterocyclene" refers to a heterocycle formed from a heterocycle, as defined herein. It refers to a diradical group.

[0177] The term "hydroxyamino" refers to the group --NHOH.

[0178] "Nitro" refers to the -NO2 group.

[0179] "Oxo" refers to the atom (=O).

[0180] "Sulfonyl" refers to SO2-alkyl, SO2-substituted alkyl, SO2-alkenyl , SO2-substituted alkenyl, SO2-cycloalkyl, SO2-substituted cycloalkyl, S O2-cycloalkenyl, SO2-substituted cycloalkenyl, SO2-aryl, SO2- Substituted aryl, SO2-heteroaryl, SO2-substituted heteroaryl, SO2-heterocycle and SO2-substituted heterocyclic groups, in which alkyl, substituted alkyl, alkyl alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cyclo Alkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, hetero Aryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein. Examples of sulfonyl include methyl-SO2-, phenyl-SO2-, and Contains 4-methylphenyl-SO2-.

[0181] "Sulfonyloxy" refers to -OSO2-alkyl, OSO2-substituted alkyl, OSO 2-Alkenyl, OSO2-substituted alkenyl, OSO2-cycloalkyl, OSO2-substituted Substituted cycloalkyl, OSO2-cycloalkenyl, OSO2-substituted cycloalkenyl, O SO2-aryl, OSO2-substituted aryl, OSO2-heteroaryl, OSO2-substituted substituted heteroaryl, OSO2-heterocycle, and OSO2-substituted heterocycle groups, In this case, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkenyl Alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkene aryl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted Substituted heterocycle is as defined herein.

[0182] The term "aminocarbonyloxy" refers to the group -OC(O)NRR, where wherein each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or or heterocyclic ring, in which case alkyl, substituted alkyl, aryl, heteroaryl The rings, rings, and heterocycles are as defined herein.

[0183] "Thiol" refers to the group --SH.

[0184] The term "thioxo" or "thioketo" refers to the atom (=S).

[0185] The term "alkylthio" or "thioalkoxy" refers to an -S-alkyl group, In this instance, alkyl is as defined herein. In certain embodiments, Sulfur may be oxidized to -S(O)-. Sulfoxides may exist as one or more stereoisomers. It can exist.

[0186] The term "substituted thioalkoxy" refers to the group --S-substituted alkyl.

[0187] The term "thioaryloxy" refers to the group aryl-S-, in which Aryl groups are as defined herein, including optionally substituted aryl, Also defined herein.

[0188] The term "thioheteroaryloxy" refers to the group heteroaryl-S-, where wherein the heteroaryl group is as defined herein and is optionally substituted. Includes aryl, also defined herein.

[0189] The term "thioheterocyclooxy" refers to a heterocyclyl-S- group, in which wherein the heterocyclyl group is as defined herein and is an optionally substituted heterocyclyl group. This includes terocyclyl groups, which are also defined herein.

[0190] In addition to the disclosure herein, when used to modify a particular group or radical, The term "substituted" means that one or more hydrogen atoms of a specified group or radical has been substituted with each independently substituted with the same or different substituents as defined below. It can also mean:

[0191] In addition to the groups disclosed for each individual term herein, the term may be used in any group or radical specified. One or more hydrogens on saturated carbon atoms (any two hydrogens on one carbon atom are ═O, ═NR 70 , =N-OR 70 , =N2 or =S) are Deuterium, -R, unless otherwise specified 60 , halo, =O, -OR 70 , -SR 70 , -N R 80 R 80 , trihalomethyl, -CN, -OCN, -SCN, -NO, -NO2, =N 2, -N3, -SO2R 70 , -SO2O - M + , -SO2OR 70 , -OSO2R 70 , -OSO2O - M + , -OSO2OR 70 , -P(O)(O - )2(M + )2, -P( O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S) R 70 , -C(NR 70 )R 70 , -C(O)OM + , -C(O)OR 70 , -C(S ) OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O )R 70 , -OC(S)R 70 , -OC(O)O - M + , -OC(O)OR 70 , -OC (S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 C O2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O )NR 80 R 80 , -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )N R 80 R 80 In this case, R 60 is an optionally substituted alkyl, cycloalkyl alkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, alkyl the group consisting of aryl, arylalkyl, heteroaryl, and heteroarylalkyl; Each R 70 are independently hydrogen or R 60 and each R 80 is independently R 7 0 Or two R 80 together with the nitrogen atom to which they are attached, and forming a heterocycloalkyl of the formula: and optionally containing 1 to 4 additional heteroatoms, which may be the same or different, selected from the group consisting of: wherein N may have —H or C1-C3 alkyl substitution, and each M + teeth, There is one net positive charge and a counter ion. + are independently, for example, alkali ions, For example, K + , Na + , Li + ammonium ions, e.g. + N(R 60 )4; or Alkaline earth ions, such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2 + ] 0.5 (The subscript 0.5 indicates one of the counterions of such divalent alkaline earth ions. One is the ionized form of the compound of the present disclosure, and the other is a typical counter form, e.g., chloride. ions, or that the two ionized compounds disclosed herein may be such two may serve as a counter ion for the valent alkaline earth ion, or The doubly ionized compounds of the formula (I) serve as counter ions for such divalent alkaline earth ions. A specific example is -NR 80 R 8 0 -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl It is intended to include N-piperazin-1-yl, and N-morpholinyl.

[0192] In addition to the disclosure herein, "substituted" alkene, alkyne, aryl and Substituents for hydrogen atoms on unsaturated carbon atoms in heteroaryl and heteroaryl groups are defined as follows unless otherwise specified: As long as deuterium, -R 60 , halo, -O - M + , -OR 70 , -SR 70 , -S - M + ,- NR 80 R 80 , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, - NO2, -N3, -SO2R 70 , -SO3 - M + , -SO3R 70 , -OSO2R 70 , -OSO3 - M + , -OSO3R 70 , -PO3 -2 (M + )2, -P(O)(OR 7 0 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C (NR 70 )R 70 , -CO2 - M + , -CO2R 70 , -C(S)OR 70 , -C(O )NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S )R 70 , -OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C (O)R70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2 R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 In this case, In R 60 , R 70 , R 80 and M + is as defined above, but However, in the case of a substituted alkene or substituted alkyne, the substituent is -O - M + , -OR 70 , -S R 70 , or -S - M + isn't it.

[0193] In addition to the groups disclosed for each individual term herein, "substituted" heteroalkyl The substituents for the hydrogens on the nitrogen atoms in the cycloheteroalkyl groups and cycloalkyl groups are Unless -R 60 , -OM + , -OR 70 , -SR 70 , -SM + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R 70 ,- S(O)2O-M + , -S(O)2OR 70, -OS(O)2R 70 , -OS(O)2O -M + , -OS(O)2OR 70 , -P(O)(O-)2(M + )2, -P(O)(OR 70 )OM + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 , -C(S) R 70 , -C(NR 70 )R 70 , -C(O)OR 70 , -C(S)OR 70 , -C(O )NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S )R 70 , -OC(O)OR 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 C(O)OR 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 and -NR 7 0 C(NR 70 )NR 80 R 80 In this case, R 60 , R 70 , R 80 Oh BiM + is as defined above.

[0194] Further to the disclosure herein, in certain embodiments, a substituted group may have 1, 2, 3 or or 4 substituents, 1, 2 or 3 substituents, 1 or 2 substituents, or 1 has the following substituents:

[0195] In all of the above defined substituents, the substituent may be separated by a further substituent to itself. The polymer obtained by defining (for example, a substituted aryl having a substituted aryl as a substituent) A substituted aryl is itself substituted with a substituted aryl group and is further substituted with a substituted aryl group. Unless otherwise specified, the inclusion of In such cases, the maximum number of such substitutions is three. The contiguous substitution of the substituted aryl group contemplated is substituted aryl-(substituted aryl)-substituted aryl. However, substituents defined as, for example, polyethers may be substituted more than three times. It may also include any successive substitutions, for example, -O-(CH2CH2O) n -H, n is 1 , 2, 3 or more.

[0196] Unless otherwise indicated, the naming of substituents not explicitly defined herein refers to functional groups. This is done by naming adjacent functional groups from the terminal portion of the For example, the substituent "arylalkyloxycarbonyl" means (aryl)-(alkyl) -OC(O)-.

[0197] It is understood that any of the groups disclosed herein that contain one or more substituents However, such groups are sterically impractical and / or synthetically impractical. It is understood that this does not include any substitution or substitution pattern in which the subject compounds are The compounds include all stereochemical isomers resulting from the substitution of these compounds.

[0198] When a substituent or group is defined as "deuterium-containing" or "containing deuterium," The substituent or group may itself be deuterium, or the substituent or group may be deuterium-containing. It is understood that the substituent may contain at least one deuterium substitution. If "-R" is defined to include deuterium, -R can be -D (-deuterium) or a group meeting the other requirements described for -R, such as -CD3. It should be understood that this is also acceptable.

[0199] The term "pharmaceutically acceptable salt" refers to a compound that is acceptable for administration to a patient, e.g., a mammal. "Acceptable salts" means salts that have acceptable mammalian safety for a given administration regimen. Such salts may be prepared by the addition of pharmaceutically acceptable inorganic or organic bases. and may be derived from a pharmaceutically acceptable inorganic or organic acid. "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of a compound, , derived from a variety of organic and inorganic counterions known in the art, examples of which include naphthalene, ... Thorium, potassium, calcium, magnesium, ammonium, tetraalkylammonium When the molecule contains a basic functional group, salts such as hydrochloride, bromide, etc. Hydrogen salts, formates, tartrates, besylates, mesylates, acetates, maleates, oxalates Examples of the salts include salts of organic or inorganic acids such as acid salts.

[0200] The term "salts thereof" refers to salts in which the protons of the acid are bonded to, for example, a metal cation or an organic cation. means a compound formed when a cation such as benzophenone is substituted by a cation, where appropriate. is an intermediate compound that is not intended for administration to a patient, although the salt is a pharmaceutically acceptable salt. For example, salts of the compounds of the present invention may be prepared by reacting the compounds with inorganic acids or or as the anionic component of the salt when protonated by an organic acid to form a cation. Examples include those containing a conjugate base of an inorganic or organic acid.

[0201] A "solvate" is a compound formed by the combination of solvent molecules and solute molecules or ions. A solvent can be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, methylformamide, tetrahydrofuran, dimethyl sulfoxide, and water When the solvent is water, the solvate formed is a hydrate.

[0202] "Stereoisomers" are compounds that have the same atomic connectivity but different arrangements of atoms in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, For example, racemic and optically pure forms of the compounds are also included. All forms are contemplated herein, including pure stereoisomers. Chemical formulas and compounds that have a racemic center but are drawn without consideration of stereochemistry are racemic. compounds, as well as the individual stereoisomers, e.g., R and / or S stereoisomers; As long as the diastereomers are geometrically feasible, It is intended to be all-inclusive.

[0203] "Tautomers" are compounds that differ only in the electronic bonding of atoms and / or the arrangement of protons. refers to alternative forms of a molecule, such as enol-keto tautomers and imine-enamine tautomers. tautomers, or other tautomers such as pyrazole, imidazole, benzimidazole, thiazole, Heteroazoles containing the -N=C(H)-NH- ring atom configuration, such as thiazole and tetrazole Tautomeric forms of the aryl group are possible. Those skilled in the art will recognize that other tautomeric ring atom arrangements are also possible. You will realize that.

[0204] The compounds herein may exist in different salt, solvate and stereoisomeric forms. The present disclosure also provides solvates of pharmaceutically acceptable salts of stereoisomers of the subject compounds. It is recognized that the present invention is intended to include all permutations of the compounds, salts, solvates and stereoisomers. sea ​​bream.

[0205] As used herein, the phrase "maximum sustained release" refers to increasing the release period to a maximum value. describes the release window for certain formulations of the present disclosure formulated to add The time limit is ultimately reached when the digestive tract naturally eliminates all of the drug with food.

[0206] The term "tamper evident" refers to the drug product being withdrawn for intravenous use. It is recognized in the art that this describes an aspect of a drug that is difficult to use in a pharmaceutical formulation, such as abusing the drug. , which reduces the risk of drug abuse.

[0207] As used herein, the term "steady state" refers to a molecular concentration, e.g., Describes the stable or steady-state level of concentration of any compound placed on the .

[0208] As used herein, the term "composition" is equivalent to the term "formulation." do.

[0209] As used herein, the term "administration event" refers to a period of time, e.g., less than 10 minutes, describes the administration of a given dose in the form of one or more pills to a subject within a short time frame. This is what is done.

[0210] As used herein, the phrase "release period" refers to any of the release periods described herein. The compound is released from the matrix to provide a plasma concentration of the compound described herein. The start of the release period is defined as the time from the time of oral administration to the subject. This is defined as roughly equivalent to the gastric flow and initial dissolution by gastric enzymes and acids. do.

[0211] As used herein, the term "treating" or "treatment" refers to, for example, Treating a disease or medical condition in a patient (especially a human), such as a mammal, and means to treat, e.g., to cause a disease or medical condition to disappear in a patient. causing regression or slowing the onset of a disease or medical condition in a patient. inhibiting a disease or medical condition by inhibiting or halting the progression of the disease or medical condition in a patient; Ameliorating a disease or medical condition, such as alleviating the symptoms of the disease or medical condition In some embodiments, prophylactic treatment includes preventing a disease or medical condition in a subject. It may be to prevent the occurrence.

[0212] "Patient" refers to human and non-human subjects, and particularly to mammalian subjects.

[0213] As used herein, unless otherwise specified, "prevent" and "preventing" and the term "prevention" means preventing the onset, recurrence, or spread of a disease, disorder, or condition. The term refers to the prevention of a particular disease, disorder, or one or more symptoms thereof. This includes inhibiting or reducing the symptoms of a disease, disorder or condition, particularly in patients with a family history of the disease, disorder or condition. In certain embodiments, subjects with recurrent disease are candidates for a preventative regimen. Subjects with a history of the condition are also potential candidates for prevention. The term may be used interchangeably with "prophylactic treatment."

[0214] As used herein, unless otherwise specified, "manage" and "managing" and the term "management" refers to the management of a disease, disorder, or condition, or one or more symptoms thereof. It refers to preventing or slowing the progression, spread or worsening of a disease. The beneficial effects resulting from a preventative and / or therapeutic agent may be indicative of a cure for a disease, disorder, or condition. In this context, the term "manage" does not mean to treat a disease, disorder, or condition. Treatment of a particular disease, disorder, or condition in an attempt to prevent or minimize the recurrence of the harm or condition includes treating a subject suffering from a condition.

[0215] "Pharmaceutically effective amount" and "therapeutically effective amount" refer to a dose that is effective to treat a particular disorder or disease, or Treating one or more of the symptoms of and / or preventing the occurrence of a disease or disorder refers to an amount of a compound sufficient to

[0216] As used herein, and unless otherwise specified, a "prophylactically effective amount" of an active agent is , in an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition The term "prophylactically effective amount" refers to an amount that improves the overall prophylactic benefit of, or enhances the prophylactic benefit of, another prophylactic agent. It may include both of these to enhance the therapeutic effect.

[0217] The term "neurotoxic spikes" is used herein to refer to, for example, hallucinations, The compounds described herein may produce sedative or psychotomimetic side effects, such as dizziness, nausea, and vomiting. It is used to describe a spike in the concentration of any compound that is causing an immediate side effect. This can affect not only the effects of the drug but also treatment compliance. This can be even more pronounced at blood concentration levels above 1000 g / L.

[0218] As used herein, and unless otherwise specified, "neuropsychiatric disorders or "Disorder" means a behavioral or psychological problem associated with a known neurological condition, Typically defined as a cluster of coexisting symptoms, it is an example of a neuropsychiatric disorder. Including, but not limited to, schizophrenia, cognitive impairment in schizophrenia, attention deficit disorder, attention deficit hyperactivity disorder disorders, bipolar disorders and mania, depression or any combination thereof.

[0219] As used herein, "inflammatory condition or disease" refers broadly to any chronic or Refers to acute inflammatory conditions and diseases, including but not limited to rheumatoid arthritis. diseases (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthritis), spondyloarthropathies (e.g., , ankylosing spondylitis, reactive arthritis, Reiter's syndrome), crystal arthropathy (e.g., gout, pseudodynia) Colds, calcium pyrophosphate deposition disease), multiple sclerosis, Lyme disease, polymyalgia rheumatica, Connective tissue diseases (e.g., systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis) , Sjögren's syndrome), vasculitis (e.g., polyarteritis nodosa, Wegener's granulomatosis, Jurgen-Strauss syndrome), inflammatory conditions including those resulting from trauma or ischemia, sarcoidosis , atherosclerotic vascular disease, including atherosclerosis and vascular occlusive disease vascular diseases (e.g., atherosclerosis, ischemic heart disease, myocardial infarction, stroke, peripheral Vascular disease), and vascular stent restenosis, uveitis, corneal disease, iritis, iridocyclitis and eye diseases, including cataracts.

[0220] As used herein, the term "and / or" means any or all of the associated listed items. This includes any and all combinations of one or more of the above. As used throughout the claims below, unless the context clearly suggests otherwise: The meanings of "a," "an," and "the" include the plural as well as the singular. The term "about" means that the value may vary up or down by up to 5%. For example, about 10 A value of 0 means 95 to 105 (or any value between 95 and 105) .

[0221] compound

[0222] The inventors have developed a method for the treatment of G protein-coupled receptors (GPCRs), such as the 5-HT2 receptor. exhibits preferential binding to, is bioavailable (e.g., orally bioavailable), and The drug was distributed in a wide range of doses, improving exposure (i.e., preventing a sudden spike in drug concentration after administration). ) and a novel compound with a favorable enzymatic degradation profile and clearance. As a result, the compounds of the present disclosure have been found to have no side effects. low cost and / or toxicity, low interpatient variability, rapid onset, and relatively short duration of action This allows for practical use in clinical settings. Additionally, these new compounds may be administered via inhalation or transdermal routes, for example in the form of a transdermal patch. The novel 2C-X compounds may also have desirable properties such as lipophilicity that allows for specific sites, including deuteration and / or fluorination, which slow or short-circuit enzymatic degradation at specific sites. These are based on specific molecular modifications, often introducing / maintaining metabolic soft spots at other sites. It is based on molecular modifications that lead to the development of HIV-1, which can only be identified after significant research. there were.

[0223] Formula (I) As used herein, a compound according to formula (I): [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof And, During the ceremony, X 1 and X 2 are independently hydrogen or deuterium, Y 1 and Y 2 are independently hydrogen or deuterium, R 3 is hydrogen or deuterium, R 4 is halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, -OR b , or -SR band Each R a is independently a substituted or unsubstituted C1-C6 alkyl, and R b is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, or substituted or is unsubstituted C3-C 10 is cycloalkyl, However, X 1 , X 2 , Y 1 , Y 2 , R 3 , R 4 , and R a At least one of , containing deuterium, and / or R 4 are -SCF3, -SCH2CH2CF3, -SC H2CH2CF2H, -SCH2CH2CFH2, -OCH2CH2CF3, -OCH2 A compound selected from the group consisting of -CH2CF2H, and -OCH2CH2CFH2.

[0224] X 1 and X 2 may be the same or different. In some embodiments, X 1 and X 2 are the same. In some embodiments, X 1 and X 2 is hydrogen. In some embodiments, X 1 and X 2 is deuterium.

[0225] Y 1 and Y 2 may be the same or different. In some embodiments, Y 1 and Y 2 are the same. In some embodiments, Y 1 and Y 2 is hydrogen. In some embodiments, Y 1 and Y 2is deuterium.

[0226] In some embodiments, R 3 is deuterium. In some embodiments, R 3 is hydrogen do.

[0227] In some embodiments, R 4 is a halogen, e.g., -Br, -F, -Cl, or -I be.

[0228] In some embodiments, R 4 is a substituted or unsubstituted C1-C6 alkyl. In embodiments, R 4 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to: However, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Preferred are n-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. Preferred unsubstituted alkyl groups are methyl and t-butyl. In some embodiments, R 4 is a substituted C1-C6 alkyl. Preferred substituents include, but are not limited to, deuterium, Halogens (e.g., fluorine), such as hydroxyl or polyether substituents Examples of polar substituents include the following: The alkyl group may contain one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), then the substituted C1 alkyl group may be The alkyl groups are -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. It's okay to have it.

[0229] In some embodiments, R 4 is a substituted or unsubstituted C3-C 10 Cycloalkyl In some embodiments, R 4 is unsubstituted C3-C10 Cycloalkyl, examples of which include Examples include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R 4 is placed Exchange C3-C 10 Preferred substituents include, but are not limited to, alkyl. hydrogen, deuterium, halogen (e.g., fluorine), e.g., hydroxyl substituents or polyethers The cycloalkyl group may have one or more substituents. It may contain a group.

[0230] In some embodiments, R 4 -OR b where R b hydrogen, deuterium, and substitution or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C 10 Cycloa alkyl, preferably substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted Conversion C3-C 10 Cycloalkyl, such as substituted C1-C6 alkyl as defined and exemplified above. alkyl groups, unsubstituted C1-C6 alkyl groups, substituted C3-C 10 Cycloalkyl groups, or non- Substitution C3-C 10 cycloalkyl groups and the like.

[0231] In some embodiments, R 4 -SR b where R b hydrogen, deuterium, and substitution or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C 10 Cycloa alkyl, preferably substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted Conversion C3-C10 Cycloalkyl, such as substituted C1-C6 alkyl as defined and exemplified above. alkyl groups, unsubstituted C1-C6 alkyl groups, substituted C3-C 10 Cycloalkyl groups, or non- Substitution C3-C 10 cycloalkyl groups and the like.

[0232] In some embodiments, R 4 -SMe, -SCD 3、 -SCF 3、 -SCH2CH2 CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -SEt, -Sn-P r, -Me, -CD3, -CF3, -t-Bu, -C(CD3)3, -cyclopentyl, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2 selected from the group consisting of H, -OCH2CH2CFH2, -Cl, -I, or -Br In some embodiments, R 4 -SMe, -Me, -OCD3, -CF 3、 -t-Bu In some embodiments, R is selected from the group consisting of: 4 teeth,- SCF3, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CF H2, -OCH2CH2CF3, -OCH2CH2CF2H, and -OCH2CH2C FH2. 4 However, -SCF3, -SCH2CH2CF3, -S CH2CH2CF2H, -SCH2CH2CFH2, -OCH2CH2CF3, -OCH 2CH2CF2H, or -OCH2CH2CFH2, other substituents (i.e. , X 1 , X 2 , Y 1 , Y 2 , R 3 , and R a) may or may not contain deuterium. stomach.

[0233] Each R a may be the same or different. In some embodiments, each R a teeth, The same for each R a are independently substituted or unsubstituted C1-C6 alkyl, preferably substituted substituted or unsubstituted C1-C3 alkyl, preferably substituted or unsubstituted C1 alkyl. Examples include, but are not limited to, -CH3, -CDH2, -CD2H, -C In some embodiments, each R a teeth , -CH3. In some embodiments, each R a is -CD3. is each R a are different, for example, one R a is -CH3 and the other is -CD3 be.

[0234] In some embodiments, Y 1 and Y 2 are hydrogen or deuterium, and R 3 is hydrogen X 1 and X 2 are hydrogen or deuterium, and each R a is -CH3 or -CD3 and R 4 -SMe, -SCD 3、 -SCF 3、 -SEt, -Sn-Pr , -Me, -CD3, -CF3, -t-Bu, -C(CD3)3, -Cyclopentyl, - -OMe, -OCD3, -OCF3, or -Br.

[0235] As noted above, any of the above embodiments of compounds of formula (I) may also include X 1 , X2 , Y 1 , Y 2 , R 3 , R 4 , and R a At least one of the atoms contains deuterium, and / or is R 4 are -SCF3, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH 2CH2CFH2, -OCH2CH2CF3, -OCH2CH2CF2H, and -OC H2CH2CFH2.

[0236] Formula (II) In some embodiments, the compound has formula (II): [ka] or the structure of a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof and During the ceremony, X 1 and X 2 are independently hydrogen or deuterium, Y 1 and Y 2 are independently hydrogen or deuterium, R 4 is halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, -OR b , or -SR b and R b is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, or substituted or is unsubstituted C3-C 10 A compound which is a cycloalkyl.

[0237] X 1 and X 2 may be the same or different. In some embodiments, X 1 and X 2 are the same. In some embodiments, X 1 and X 2 is hydrogen. In some embodiments, X 1 and X 2 is deuterium.

[0238] Y 1 and Y 2 may be the same or different. In some embodiments, Y 1 and Y 2 are the same. In some embodiments, Y 1 and Y 2 is hydrogen. In some embodiments, Y 1 and Y 2 is deuterium.

[0239] In some embodiments, R 4 is a halogen, e.g., -Br, -F, -Cl, or -I be.

[0240] In some embodiments, R 4 is a substituted or unsubstituted C1-C6 alkyl. In embodiments, R 4 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to: However, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Preferred are n-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. Preferred unsubstituted alkyl groups are methyl and t-butyl. In some embodiments, R 4 is a substituted C1-C6 alkyl. Preferred substituents include, but are not limited to, deuterium, Halogens (e.g., fluorine), such as hydroxyl or polyether substituents Examples of polar substituents include the following: The alkyl group may contain one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), then the substituted C1 alkyl group may be The alkyl groups are -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. It's okay to have it.

[0241] In some embodiments, R 4 is a substituted or unsubstituted C3-C 10 Cycloalkyl In some embodiments, R 4 is unsubstituted C3-C 10 Cycloalkyl, examples of which include Examples include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R 4 is placed Exchange C3-C 10 Preferred substituents include, but are not limited to, alkyl. hydrogen, deuterium, halogen (e.g., fluorine), e.g., hydroxyl substituents or polyethers The cycloalkyl group may have one or more substituents. It may contain a group.

[0242] In some embodiments, R 4 -OR b where R b hydrogen, deuterium, and substitution or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C 10 Cycloa alkyl, preferably substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted Conversion C3-C 10 Cycloalkyl, such as substituted C1-C6 alkyl as defined and exemplified above. alkyl groups, unsubstituted C1-C6 alkyl groups, substituted C3-C 10Cycloalkyl groups, or non- Substitution C3-C 10 cycloalkyl groups and the like.

[0243] In some embodiments, R 4 -SR b where R b hydrogen, deuterium, and substitution or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C 10 Cycloa alkyl, preferably substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted Conversion C3-C 10 Cycloalkyl, such as substituted C1-C6 alkyl as defined and exemplified above. alkyl groups, unsubstituted C1-C6 alkyl groups, substituted C3-C 10 Cycloalkyl groups, or non- Substitution C3-C 10 cycloalkyl groups and the like.

[0244] In some embodiments, R 4 -SMe, -SCD 3、 -SCF 3、 -SCH2CH2 CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -SEt, -Sn-P r, -Me, -CD3, -CF3, -t-Bu, -C(CD3)3, -cyclopentyl, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2 selected from the group consisting of H, -OCH2CH2CFH2, -Cl, -I, or -Br In some embodiments, R 4 -SMe, -Me, -OCD3, -CF 3、 -t-Bu or -cyclopentyl.

[0245] In some embodiments, Y 1 and Y 2 are hydrogen or deuterium, respectively, and X1 and X 2 are hydrogen or deuterium, and R 4 -SMe, -SCD 3、 -SCF 3、 -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -S Et, -Sn-Pr, -Me, -CD3, -CF3, -t-Bu, -C(CD3)3, - Cyclopentyl, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OC H2CH2CF2H, -OCH2CH2CFH2, -Cl, -I, or -Br; Preferably R 4 -SMe, -Me, -OCD 3、 -CF3, -t-Bu, or -Si It is clopentyl.

[0246] Formula (II) containing deuteration in the form of -OCD3 groups at the 2- and 5-positions of the phenyl ring The compounds are O-demethylated at these positions (primarily mediated by the CYP2D6 enzyme). ) can have a beneficial effect by slowing down or shorting the Improved pharmacokinetics, particularly bioavailability, and reduced exposure to toxic metabolites results in increased safety Safety is improved.

[0247] Formula (III) In some embodiments, the compound has formula (III): [ka] or the structure of a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof and During the ceremony, X 1 and X 2 are independently hydrogen or deuterium, Y 1 and Y2 are independently hydrogen or deuterium, R 4 is C1-C6 alkyl substituted with one or more deuterium atoms, C3-C 10 Cycloalkyl, -OR b , or -SR b and Each R a is independently a substituted or unsubstituted C1-C6 alkyl, and R b is a C1-C6 alkyl substituted with one or more deuterium atoms, or C3-C substituted with 10 A compound which is a cycloalkyl.

[0248] X 1 and X 2 may be the same or different. In some embodiments, X 1 and X 2 are the same. In some embodiments, X 1 and X 2 is hydrogen. In some embodiments, X 1 and X 2 is deuterium.

[0249] Y 1 and Y 2 may be the same or different. In some embodiments, Y 1 and Y 2 are the same. In some embodiments, Y 1 and Y 2 is hydrogen. In some embodiments, Y 1 and Y 2 is deuterium.

[0250] In some embodiments, R 4 is C1-C6 alkyl substituted with one or more deuterium atoms. Examples include, but are not limited to, methyl, ethyl, and methyl groups containing one or more deuterium substituents. , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl , n-pentyl, neopentyl, and hexyl groups. or may contain multiple deuterium substituents, e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9 deuterium substituents. Examples of alkyl groups include, but are not limited to, -CD3 and -C(CD3)3.

[0251] In some embodiments, R 4 is a C3-C bond substituted with one or more deuterium atoms. 10 Cycloal cyclopropyl, adamantyl, cyclopropyl ... Examples of the cycloalkyl group include cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl groups. The cycloalkyl group may contain one or more substituents, for example, 1, 2, 3, 4 , 5, 6, 7, 8, or 9 deuterium substituents.

[0252] In some embodiments, R 4 -OR b where R b is substituted with one or more deuterium atoms. C1-C6 alkyl substituted with one or more deuterium atoms, or C3-C 10 Cyclo Alkyl, for example, C1-C6 substituted with one or more deuterium atoms as defined and exemplified above. Alkyl groups or C3-C substituted with one or more deuterium atoms 10 is a cycloalkyl group In some embodiments, R 4 is -OCD3.

[0253] In some embodiments, R4 -SR b where R b is substituted with one or more deuterium atoms. C1-C6 alkyl substituted with one or more deuterium atoms, or C3-C 10 Cyclo Alkyl, for example, C1-C6 substituted with one or more deuterium atoms as defined and exemplified above. Alkyl groups or C3-C substituted with one or more deuterium atoms 10 is a cycloalkyl group In some embodiments, R 4 is -SCD3.

[0254] In some embodiments, R 4 -SCD 3、 -CD3, -C(CD3)3, and -O CD3.

[0255] Each R a may be the same or different. In some embodiments, each R a teeth, The same for each R a are independently substituted or unsubstituted C1-C6 alkyl, preferably substituted substituted or unsubstituted C1-C3 alkyl, preferably substituted or unsubstituted C1 alkyl. Examples include, but are not limited to, -CH3, -CDH2, -CD2H, -C In some embodiments, each R a teeth , -CH3. In some embodiments, each R a is -CD3. is each R a are different, for example, one R a is -CH3 and the other is -CD3 be.

[0256] In some embodiments, X 1 and X 2are hydrogen or deuterium, respectively, and Y 1 and Y 2 are hydrogen or deuterium, and each R a is -CH3 and R 4 -SCD3 、 -CD3, -C(CD3)3, or -OCD3.

[0257] R on the phenyl ring 4 The compounds of formula (I) containing alkyl / cycloalkyl groups deuterated at position Compounds II) may be beneficially formulated by incorporating lipophilic groups for improved brain penetration. However, at the same time, metabolism at the site is slowed down or shunted, resulting in poor pharmacokinetics, especially bioavailability. The rate can be improved.

[0258] Formula (IV) In some embodiments, the compound has formula (IV): [ka] or the structure of a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof and During the ceremony, Y 1 and Y 2 are independently hydrogen or deuterium, R 4 is halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, -OR b , or -SR b and Each R a is independently a substituted or unsubstituted C1-C6 alkyl, and R b is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, or substituted or is unsubstituted C3-C 10 A compound which is a cycloalkyl.

[0259] Y 1 and Y 2 may be the same or different. In some embodiments, Y 1 and Y 2 are the same. In some embodiments, Y 1 and Y 2 is hydrogen. In some embodiments, Y 1 and Y 2 is deuterium.

[0260] In some embodiments, R 4 is a halogen, e.g., -Br, -F, -Cl, or -I be.

[0261] In some embodiments, R 4 is a substituted or unsubstituted C1-C6 alkyl. In embodiments, R 4 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to: However, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Preferred are n-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. Preferred unsubstituted alkyl groups are methyl and t-butyl. In some embodiments, R 4 is a substituted C1-C6 alkyl. Preferred substituents include, but are not limited to, deuterium, Halogens (e.g., fluorine), such as hydroxyl or polyether substituents Examples of polar substituents include the following: The alkyl group may contain one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), then the substituted C1 alkyl group may be The alkyl groups are -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. It's okay to have it.

[0262] In some embodiments, R 4 is a substituted or unsubstituted C3-C 10 Cycloalkyl In some embodiments, R 4 is unsubstituted C3-C 10 Cycloalkyl, examples of which include Examples include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R 4 is placed Exchange C3-C 10 Preferred substituents include, but are not limited to, alkyl. hydrogen, deuterium, halogen (e.g., fluorine), e.g., hydroxyl substituents or polyethers The cycloalkyl group may have one or more substituents. It may contain a group.

[0263] In some embodiments, R 4 -OR b where R b hydrogen, deuterium, and substitution or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C 10 Cycloa alkyl, preferably substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted Conversion C3-C 10 Cycloalkyl, such as substituted C1-C6 alkyl as defined and exemplified above. alkyl groups, unsubstituted C1-C6 alkyl groups, substituted C3-C 10 Cycloalkyl groups, or non- Substitution C3-C 10 cycloalkyl groups and the like.

[0264] In some embodiments, R 4 -SR b where R b hydrogen, deuterium, and substitution or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C 10 Cycloa alkyl, preferably substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted Conversion C3-C 10 Cycloalkyl, such as substituted C1-C6 alkyl as defined and exemplified above. alkyl groups, unsubstituted C1-C6 alkyl groups, substituted C3-C 10 Cycloalkyl groups, or non- Substitution C3-C 10 cycloalkyl groups and the like.

[0265] In some embodiments, R 4 -SMe, -SCD 3、 -SCF 3、 -SCH2CH2 CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -SEt, -Sn-P r, -Me, -CD3, -CF3, -t-Bu, -C(CD3)3, -cyclopentyl, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2 selected from the group consisting of H, -OCH2CH2CFH2, -Cl, -I, or -Br In some embodiments, R 4 -SMe, -Me, -OCD3, -CF 3、 -t-Bu or -cyclopentyl.

[0266] Each R a may be the same or different. In some embodiments, each R a teeth, The same for each R a are independently substituted or unsubstituted C1-C6 alkyl, preferably substituted substituted or unsubstituted C1-C3 alkyl, preferably substituted or unsubstituted C1 alkyl. Examples include, but are not limited to, -CH3, -CDH2, -CD2H, -C In some embodiments, each R a teeth , -CH3. In some embodiments, each R a is -CD3. is each R a are different, for example, one R a is -CH3 and the other is -CD3 be.

[0267] In some embodiments, Y 1 and Y 2 are hydrogen or deuterium, and each R a teeth- CH3 or -CD3, and R 4 -SMe, -SCD 3、 -SCF 3、 -SEt,- Sn-Pr, -Me, -CD3, -CF3, -t-Bu, -C(CD3)3, -Cyclopentanol -O-, ...

[0268] Deuterium in the ethylene fragment connecting the amino group and the benzene ring in phenethylamine Compounds of formula (IV) containing deuteration, e.g., deuteration at the α-carbon, are also susceptible to MAO-mediated deamination. / Beneficially slows down enzymatic degradation compared to compounds that may be susceptible to oxidative processes, This effectively reduces the therapeutic dose and prevents the rapid high drug concentration (spike) observed after administration. Improved bioavailability and brain levels of the active compound for the prevention of rheumatoid arthritis (rheumatoid arthritis) As a result, such compounds may have adverse effects such as anxiety, fear, tachycardia, hypertension, and hyperthermia. acute adverse effects such as elevated 5-HT2 cholesterol, nausea and vomiting, and valvular heart disease B This may reduce side effects and toxicity, such as toxicity caused by receptor activation.

[0269] The compounds of formulae (I) to (IV) may contain a stereocenter. IV) Even if the compound is drawn without considering the stereochemistry, it may exist in various stereoisomeric forms. Therefore, the present disclosure includes all possible stereoisomers, including racemic forms. Not only the individual enantiomers (enantiomerically pure compounds) but also the individual enantiomers and Non-racemic mixtures are included as well. If a compound as a single enantiomer is desired, by site-specific synthesis, by resolution of the final product or any suitable intermediate, and The compounds may also be obtained by chiral chromatography methods, which are currently Resolution of the final product, an intermediate, or a starting material may be carried out by any suitable method known in the art. This may be done by any appropriate method.

[0270] In some embodiments, a compound described herein, e.g., a compound of Formula (I)-(IV) In some embodiments, the compounds described herein, e.g., those of formula (I) to Compound (IV) is enantiomerically pure.

[0271] In some embodiments, the compound is an agonist of the serotonin 5-HT2 receptor.

[0272] In some embodiments, the compound is serotonin 5-HT 2A Agonists of the receptor Good too.

[0273] In some embodiments, the compounds, e.g., compounds of Formulas (I)-(IV), consist of Selected from the group: [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0274] Table 1 lists the compound numbers, IUPAC names, and substituents for the compounds identified above. show. [Table 1] [Table 2] [Table 3]

[0275] Therapeutic Uses and Methods As used herein, the compounds disclosed herein (e.g., compounds of formulas (I) to (IV)) 2. A method for treating a subject having a disease or disorder, comprising administering to the subject a therapeutically effective amount of The law is also revealed.

[0276] The dose and frequency (single or multiple administrations) of the compound administered will depend on a variety of factors. These factors may vary depending on factors including, but not limited to, the disease / condition being treated, administration, route, size, age, sex, health status, weight, body mass index, and diet of the recipient, treatment the nature and severity of the disease being treated, the presence of other diseases or other health-related problems; Include types of concomitant therapy, as well as complications from any disease or treatment regimen. Other therapeutic regimens or agents may be used in combination with the methods and compounds disclosed herein. It can be used.

[0277] Therapeutically effective amounts for use in humans may be determined from animal models. Doses for steroids are formulated to achieve concentrations found to be effective in animals. Dosage in humans may be adjusted upward or downward based on monitoring response to treatment. It can be adjusted by adjusting.

[0278] Dosages may vary depending on the requirements of the subject and the compound employed. In the context of a pharmaceutical composition, the dose administered to a subject is sufficient to provide a long-term beneficial effect in the subject. The amount must be sufficient to produce a satisfactory therapeutic response. The presence, nature, and severity of side effects will determine treatment. Treatment is generally initiated with a low dose. The starting dose is less than the optimal dose of the compound, and then the optimal effect is achieved under the circumstances. The dose is increased in small increments until adequate treatment is achieved.

[0279] The dosage and interval of administration will determine the level of the administered compound that is effective for the particular clinical indication being treated. This allows for individualized delivery of the appropriate dose based on the severity of the individual's disease state. A tailored treatment regimen is provided.

[0280] Dosing schedules may vary depending on the compound employed, the condition being treated, etc. For example, administration may be once daily (QD), or may be twice daily (BID), for example. In divided doses throughout the day, such as three times a day (TID) or four times a day (QID) In some embodiments, administration may be performed every night (QHS). In embodiments, the compounds / pharmaceutical compositions may be administered as needed (PRN).

[0281] In some embodiments, the pharmaceutical uses of the present disclosure may be used as the sole treatment. In some embodiments, the pharmaceutical uses of the present disclosure are used as adjuvant / combination therapy. That's fine.

[0282] By utilizing the teachings provided herein, it is possible to produce less toxic and However, there are highly effective preventive or therapeutic regimens for treating the clinical symptoms presented by certain patients. A therapeutic regimen can be designed, which may include, for example, determining the efficacy of the compounds, their relative bioavailability, and utilization, patient weight, the presence and severity of adverse side effects, preferred method of administration, and Careful activation of the drug is ensured by considering factors such as the toxicity profile of the selected drug. It must involve choosing an object.

[0283] The subjects treated herein are those suffering from a disease or conditions associated with the serotonin 5-HT2 receptor. may have a disability.

[0284] In some embodiments, the disease or disorder is a neuropsychiatric disease or disorder, or In some embodiments, the disease or disorder is an inflammatory disease or disorder of the central nervous system. (CNS) disorders, including post-traumatic stress disorder (PTSD), major aspiration disorder (MAA), MDD, Treatment-Resistant Depression (TRD), Suicidal Ideation, Suicidal Behavior, Suicidal Ideation or Major depressive disorder with or without suicidal behavior, non-suicidal self-injury disorder (NSSID), bipolar disorder type I , bipolar disorder and related disorders, including type II bipolar disorder, cyclothymic disorder, obsessive-compulsive disorder (OCD) CD), generalized anxiety disorder (GAD), social anxiety disorder, alcohol use disorder, opioid use disorder Use Disorder, Amphetamine Use Disorder, Nicotine Use Disorder, and Cocaine Use Disorder Quality use disorder, anorexia nervosa, bulimia nervosa, binge eating disorder, Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasy Diarrhea, childhood onset dysphagia, dementia, mild dementia, sexual dysfunction (e.g., low libido), chronic In some embodiments, the disease or The disorder may include a condition of the autonomic nervous system (ANS). These may include pulmonary disorders (e.g., asthma and chronic obstructive pulmonary disorder (COPD)). In embodiments, the disease or disorder includes a cardiovascular disorder (e.g., atherosclerosis). It can be seen.

[0285] In some embodiments, the present disclosure provides a method for treating, but not limited to, cancer pain, including refractory cancer pain. Pain; neuropathic pain; postoperative pain; opioid-induced hyperalgesia and opioid-related tolerance; Neuropathic pain; Post-operative / post-surgical pain; Complex Regional Pain Syndrome (CRPS); Shock; Hand foot amputations; severe chemical burns and scalds; sprains, ligament tears, fractures, injuries, and other tissue damage Wounds; dental surgery, procedures and illnesses; childbirth; physical therapy; radiation poisoning; acquired immune deficiency syndrome AIDS; epidural fibrosis; orthopedic pain; back pain; post-spine surgery pain and vertebral arch Post-operative pain; sciatica; painful sickle cell crisis; arthritis; autoimmune disease; intractable Recurring bladder pain; pain associated with certain viruses, such as shingles pain or herpes Pain; acute nausea, e.g., abdominal pain that can cause nausea or frequent severe nausea pain; migraine, e.g., migraine with aura; and depression (e.g., acute depression or chronic depression), depression accompanied by pain, alcoholism, sudden excitement, intractable asthma, acute asthma ( For example, an unrelated pain state may trigger asthma), epilepsy, acute brain trauma, and various types of other conditions, including stroke, Alzheimer's disease, and other disorders Provides pain management. Pain can be persistent or chronic, lasting from weeks to years. In some cases, the injury or illness that caused the pain may have healed or subsided. In some cases, the patient has received prior medication and / or treatment. Including the treatment / management of any combination of these types of pain or conditions.

[0286] In some embodiments, the pain being treated / managed is acute breakthrough pain or chronic pain. In some embodiments of the present disclosure, the treatment is a pain associated with tightening that can occur in painful conditions. The pain to be treated / managed is cancer pain, for example, intractable cancer pain. In embodiments, the pain being treated / managed is post-operative pain. In some embodiments of the present disclosure, the pain being treated / managed is orthopedic pain. In some embodiments of the present disclosure, the pain being treated / managed is back pain. In some embodiments of the present disclosure, the pain to be treated / managed is neuropathic pain. In some embodiments of the present disclosure, the condition being treated / managed is depression. In some embodiments of the present disclosure, the pain treated / managed is pain in opioid-tolerant patients. It is a chronic pain that occurs.

[0287] In some embodiments, the present disclosure provides for management of sexual dysfunction, Sexual desire disorders, including but not limited to: sexual desire disorders, e.g., hypoactive sexual desire; sexual arousal disorders, e.g., lack of desire; These can cause orgasmic disorders such as lack of arousal, pain during intercourse, and anorgasmia. sexual dysfunction, especially those due to psychological factors.

[0288] In embodiments, the present disclosure provides a method for treating N-methyl-D-aspartate (NMDA) activity. The present invention relates to a method for treating a disease or condition by modulating Any of the compounds described herein (e.g., compounds of Formula (I) (IV) to (IV) In some embodiments, the disease or condition is levodopa-induced movement disorder; dementia (e.g., , Alzheimer's disease), tinnitus, treatment-resistant depression (TRD), major depressive disorder, Neuropathic pain, Alzheimer's disease-related or related agitation, pseudobulbar paralytic effects ( pseudobulbar effect, autism, bulbar function ction), generalized anxiety disorder, Alzheimer's disease, schizophrenia, diabetic neuropathy, acute sexual pain, depression, bipolar depression, suicidal tendencies, neuropathic pain, or post-traumatic stress disorder ( In some embodiments, the disease or condition is selected from psychiatric disorders (PTSD). For example, schizophrenia, mood disorders, substance-induced psychosis, major depressive disorder (MDD), bipolar disorder Disorder, bipolar depression (BDep), post-traumatic stress disorder (PTSD), suicidal ideation, Other examples include: anxiety, obsessive-compulsive disorder (OCD), and treatment-resistant depression (TRD). In this context, the disease or condition may be a neurological disorder (e.g., Huntington's disease (HD), Alzheimer's disease (AD), or a combination of these. Alzheimer's disease (AD), or systemic lupus erythematosus (SLE).

[0289] For example, in some embodiments, the present disclosure provides compounds described herein (e.g., compounds of formula (I) ) to (IV)) or a pharmaceutically acceptable salt thereof. The present invention provides a method for treating a pulmonary artery disease, the method comprising administering to a subject a compound described herein (e.g., Oral administration of any of the compounds of formula (I) to (IV) or a pharmaceutically acceptable salt thereof administering a therapeutic tablet composition, e.g., a matrix composition, to a subject to treat the subject. include.

[0290] The administering physician should be aware of the compounds described herein (e.g., compounds of Formulas (I)-(IV)). The amount and timing of administration of either the compound or a pharmaceutically acceptable salt thereof to the patient to be treated preventative or therapeutic use by adjusting based on the findings of one or more symptoms of a disorder or condition It is possible to provide a therapeutic method of treatment.

[0291] In some embodiments of the present disclosure, the subject is a mammal.

[0292] In some embodiments of the present disclosure, the mammal is a human.

[0293] In some embodiments, the present disclosure provides a compound described herein (e.g., Formula (I)-( IV) or a pharmaceutically acceptable salt thereof. Any of the compounds described herein (e.g., compounds of formulas (I) to (IV)) is provided. or a pharmaceutically acceptable salt thereof is formulated into a tablet composition, e.g., a monolayer tablet. The tablet may contain a compound described herein (e.g., a compound of formula (I) to (IV)). or a pharmaceutically acceptable salt thereof, Completely without neurological toxic spikes, such as sexual or psychotic toxic spikes. The tablet composition steadily releases a therapeutically effective concentration of the compound over the release period. (e.g., compounds of formulas (I) to (IV)), or a drug thereof orally administering to a subject a continuous therapeutically effective concentration of a physiologically acceptable salt thereof to the subject. This may be done.

[0294] The compounds of the present disclosure have beneficial metabolic degradation profiles that This enhances brain levels of the active compound while preventing the rapid rise in drug concentrations observed after administration. As a result, the compound may have adverse effects on, for example, the heart. 5-HT associated with valvular heart disease 2B Reduced toxicity, including that associated with receptor activation and may be amenable to microdosing for long-term therapeutic benefit (Rothman, R. B.,and Baumann,MH,2009,Serotonergic dr. ugs and valvular heart disease,Expert Op in Drug Saf 8,317-329).

[0295] Pharmaceutical Composition

[0296] The compounds disclosed herein (e.g., compounds of Formulas (I)-(IV)), or pharmaceutical Also disclosed herein are pharmaceutical compositions comprising an acceptable excipient.

[0297] The compound may comprise at least 100 isotopes of the compound, based on the total weight of the compound's isotopologues present in the pharmaceutical composition. At least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight , at least 90% by weight, at least 95% by weight, at least 99% by weight purity. In preferred compounds and compositions, deuterium-containing compounds Any position may be at least 10 atomic %, at least 20 atomic %, at least at least 25 atomic %, at least 30 atomic %, at least 40 atomic %, at least 45 atomic %, At least 50 atomic %, at least 60 atomic %, at least 70 atomic %, at least 80 atomic %, at least 90 atomic %, at least 95 atomic %, at least 99 atomic % In a preferred embodiment, the composition has a hydrogen incorporation. For example, the composition may be substantially free of 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or less than 0.5 mole percent of other isotopologues of the compound.

[0298] Pharmaceutical compositions include, for example, enantiomeric compounds of the present disclosure, such as compounds of Formulas (I)-(IV). The compounds may be formulated using pure compounds or racemic mixtures of the compounds. As described, the racemic compounds of formulas (I)-(IV) may be prepared in a molar ratio of one of the isomers. (about 48 to about 52 mole %, or about a 1:1 ratio), based on about 50% R and S stereochemistry In some embodiments, the composition, medicament, or method of treatment may contain distinct isomers. The R and S stereoisomers of the compound were prepared in approximately equal molar ratios (approximately 48-52%). In some embodiments, the agent or pharmaceutical composition may be combined with The compound may contain a mixture of separate compounds of R and S stereoisomers in varying proportions. In the form, the pharmaceutical composition contains an excess (greater than 50%) of the R-enantiomer. Suitable molar ratios of HCl / S are about 1.5:1, 2:1, 3:1, 4:1, 5:1, 10:1, or In some embodiments, the pharmaceutical composition may contain an excess of S-enantiomers. The ratio of R / S may be reversed. For example, the R-enantiomer may be at least about 55% to 100%, or at least at least 65%, at least 75%, at least 80%, at least 85%, at least 9 It may be present in an amount of 0%, about 95%, about 98%, or 100%. The S-enantiomer may be present in a large proportion, for example at least about 55% to 100%. % amount, or at least 65%, at least 75%, at least 80%, at least 8 It may be present in an amount of 5%, at least 90%, about 95%, about 98%, or 100%. All of these exemplary embodiments, and larger and smaller The composition comprises a hydroxyl group having a formula (I) to a formula (IV) and a hydroxyl group having a formula (I) to a hydroxyl group having ...IV) Mixtures of semiconducting compounds and separate compounds in free base form and / or salt form. Good too.

[0299] The term "excipient" refers to a diluent, adjuvant, vehicle, or carrier, The compounds of the present disclosure are formulated for administration to mammals. "Excipients" are those approved by federal or state regulatory agencies or that are approved for use in, e.g., human Listed in the United States Pharmacopoeia or generally recognized for use in any mammal diluents, adjuvants, vehicles or carriers listed in other pharmacopoeias Such pharmaceutically acceptable excipients may be solid or liquid, e.g. , petroleum, animal, vegetable, or synthetic oils, for example, peanut oil, soybean oil, The pharmaceutically acceptable excipient may be water or an oil, such as mineral oil, sesame oil, etc. Acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea In addition, auxiliary agents, stabilizers, disintegrants, thickeners, lubricants, flavoring agents, buffering agents, etc. , and colorants may also be used.

[0300] When administered to a mammal, the compounds and compositions of the present disclosure may be sterile. In some cases, when the subject compounds are administered intravenously or via inhalation, e.g., water, Aqueous media such as saline, and aqueous dextrose and glycerol solutions are used as vehicles. He is employed as a kuru.

[0301] The pharmaceutical compositions may be in the form of capsules, tablets, pills, pellets, lozenges, powders, granules, syrups, Elixirs, solutions, suspensions, emulsions, suppositories, or sustained-release formulations thereof; can take the form of any other suitable form for administration to a mammal. The pharmaceutical composition is a pharmaceutical composition adapted for oral or intravenous administration to humans and is used routinely. Examples of suitable pharmaceutical vehicles and their formulations The method is described in Remington: The Science and Practice f Pharmacy,Alfonso R.Gennaro ed.,Mack Pu blishing Co. Easton, Pa., 19th ed., 1995, chap. 86, 87, 88, 91 and 92, which are incorporated herein by reference. The choice of excipient will depend on the particular compound and the method used to administer the composition. The specific method for preparing the pharmaceutical composition is determined in part by the method. There are a variety of suitable formulations.

[0302] Administration of the subject compounds may be systemic or local. In certain embodiments, mammals Upon administration to the body, the compounds of the present disclosure are released systemically (e.g., into the bloodstream). Administration methods include enteral routes, such as oral, buccal, sublingual, and rectal; Topical administration, such as dermal (e.g., using a skin patch formulation of the compounds herein) and intradermal administration by inhalation, e.g., via a nebulizer or inhaler, and parenteral administration (e.g., In addition to intravenous injection, other injection routes of administration include, but are not limited to: Although not limited to these, other routes of administration include transdermal, subcutaneous, and intramuscular administration using autoinjector devices. In some preferred embodiments, the pharmaceutical compositions herein are formulated for oral administration. In some preferred embodiments, the pharmaceutical compositions herein are formulated for administration by inhalation. In some preferred embodiments, the pharmaceutical compositions herein are in the form of a skin patch for transdermal administration. It is formulated in this form.

[0303] In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure and a polymer. In embodiments, the pharmaceutical composition comprises (i) a water-insoluble, neutrally charged non-ionic matrix; and (ii) a polymer carrying one or more negatively charged groups.

[0304] In some embodiments, the water-insoluble, neutrally charged non-ionic matrix may be a single or derivative. Starch, wax, neutral rubber, polymethacrylate, PVA, PVA / PVP mixture, and and mixtures thereof. In some embodiments, the polymer is selected from a cellulosic polymer, such as HPMC. The cellulosic polymer is hydroxypropyl methylcellulose (HPMC).

[0305] In some embodiments, the polymer carrying one or more negatively charged groups is polyacrylic acid, poly(ethylene glycol). Polylactic acid, polyglycolic acid, polymethacrylate carboxylate, cation exchange resin, clay , zeolites, hyaluronic acid, anionic gums, their salts, and mixtures thereof is selected from the group consisting of:

[0306] In some embodiments, the anionic gum is a natural or semi-synthetic material. In embodiments, the natural substances include alginic acid, pectin, xanthan gum, carrageenan, lauric acid, and the like. Castor bean gum, gum arabic, gum karaya, guar gum, and gum tragacanth In some embodiments, the semi-synthetic material is selected from the group consisting of carboxymethyl-chichiazone. and cellulose gums.

[0307] In some embodiments, a modified release oral formulation is provided. The agent is for low-dose maintenance therapy, which can be established using the compounds described herein, The ability of the phenethylamine-type compounds described herein to bind to anionic polymers is demonstrated. I am using it.

[0308] In some embodiments, the formulations are used to treat pulmonary disorders (e.g., asthma) and cardiovascular disorders (e.g., orally active anti-inflammatory drug for the treatment of autonomic nervous system disorders, including atherosclerosis , containing compounds of the present disclosure that are locally restricted 5-HT2 agonists.

[0309] The pharmaceutical compositions may be prepared and administered in a variety of dosage formulations. Administered orally, topically (cream or patch), rectally, via inhalation, or by injection administered by injection (e.g., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally) In some embodiments, the compounds described herein may be administered via an autoinjector device. It may be administered as follows.

[0310] Autoinjection devices provide a method for delivering the compositions disclosed herein to a patient. The compositions disclosed herein can be administered via a number of known devices, including auto-injection devices. The device may be administered to the patient using a non-limiting list of such devices: These include transdermal, subcutaneous, and intramuscular delivery.

[0311] In some transdermal, subcutaneous, or intramuscular applications, the compositions disclosed herein comprise: Passive transdermal patch devices are often placed on the outer layer of the skin. The membrane typically comprises an absorbent layer or membrane that is applied to the skin to deliver the composition to the patient. It contains a dose of a substance that allows it to be absorbed through the outer layer of the skin. Only substances that are readily absorbed can be delivered in such transdermal patch devices.

[0312] Other autoinjector devices disclosed herein enhance skin permeability to deliver the disclosed compositions configured to improve delivery of, for example, Non-limiting examples of structures that may be used to improve the transfer of compositions into the muscle include: In some embodiments, the microneedles may be any of the microneedles disclosed herein. Alternatively, hollow microneedles may be used to deliver the composition beneath the outer layer of the skin. Fluid channels may be provided for delivery of the disclosed compositions. The devices include iontophoresis, sonophoresis, and reverse iontophoresis. transdermal delivery by laser, or a combination thereof, as well as by increasing skin permeability Other techniques known in the art to enhance drug delivery include:

[0313] For the preparation of pharmaceutical compositions from the compounds described herein, pharmaceutically acceptable excipients are used. The vehicle may be either solid or liquid. Solid preparations include powders, tablets, Solid carriers include pills, capsules, cachets, suppositories, and dispersible granules. It may also function as a flavoring agent, binder, preservative, tablet disintegrant, or encapsulating material. There may be more than one substance.

[0314] In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions. , may be compressed into a desired shape and size.

[0315] Powders and tablets: about 5% to about 70% by weight, or about 10% to about 60% by weight, or about 20% to about 50%, or about 30% to about 40% by weight of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, Sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl Cellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter The term "preparation" includes encapsulating materials as carriers to provide capsules. It is intended to include formulations of the active compound containing the active ingredient together with other carriers, or or other carriers, but is surrounded by the carrier, so that the carrier and the active ingredient are associated Also included are cachets and lozenges. Tablets, powders, capsules, Pills, cachets, and lozenges are available as solid dosage forms suitable for oral administration. Cut.

[0316] For the preparation of suppositories, low-calorie glycerides, such as mixtures of fatty acid glycerides or cocoa butter, are used. The melting point wax is first melted and then stirred to evenly distribute the active ingredient within it. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify. Can.

[0317] Liquid form preparations include solutions, suspensions, and emulsions, e.g., water, or water / water mixtures. For parenteral injection, liquid preparations may be prepared in aqueous polypropylene glycol or in solutions in propylene glycol. The formulation may be made into a solution in aqueous ethylene glycol.

[0318] Aqueous solutions suitable for oral use may be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, or other additives, if desired. It may be prepared by adding additives, stabilizers, and thickeners. Suspensions are prepared by dissolving the finely divided active ingredient in a viscous substance, such as natural or synthetic rubber, resin, Methylcellulose, sodium carboxymethylcellulose, and other known suspending agents It may also be prepared by dispersing the compound in water together with the above.

[0319] Also, solid preparations intended to be converted, shortly before use, into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, etc. It may also contain buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0320] The pharmaceutical preparation may be in unit dosage form. In unit dosage form, the preparation contains an appropriate amount of active The formulation is divided into unit doses containing the ingredients. The unit dose forms are, for example, packaged tablets, capsules, etc. and packages containing individual quantities of the preparation, such as powders in vials or ampoules. The unit dosage form may also be a packaged preparation, such as a capsule, tablet, cachet, or the like. or a lozenge or the like on its own, or a suitable number of such in a packaged form. It may be any of the above.

[0321] The amount of active ingredient in a unit dose preparation may be, for example, 0.001 mg to 100 mg, or 0. 0.001mg to 75mg, or 0.001mg to 50mg, or 0.001mg to 2 5 mg, or 0.001 mg to 10 mg, or 0.01 mg to 8 mg, or 0.1 It may be varied or adjusted to mg to 5 mg, or 1 mg to 3 mg, or a specific Varies as deemed appropriate using reasonable medical judgment according to use and potency of active ingredient The compositions may, if desired, also contain other compatible therapeutic agents. good.

[0322] Some compounds may have limited solubility in water and therefore may need to contain surfactants or Other suitable co-solvents may be required. Such co-solvents include: Polysorbates 20, 60, and 80; Pluronic F-68, F-84, and and P-103; cyclodextrin; and polyoxyl 35 castor oil. Co-solvents are typically employed at levels of about 0.01% to about 2% by weight. To reduce variability in the administration of the suspension or emulsion components of the formulation, To reduce separation and / or otherwise improve formulation, simple water In some cases, a viscosity higher than that of the solution is desired. Such viscosity-increasing agents include, for example: , polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy Hydroxypropyl cellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts Such media typically have a pH of about 0.05 or higher. It is employed at a level of 1% to about 2% by weight.

[0323] The pharmaceutical composition may additionally contain ingredients to provide sustained release and / or comfort. Such ingredients include high molecular weight anionic mucus-like polymers, gelling polysaccharides, and a micronized drug carrier substrate. These components are described in U.S. Pat. Nos. 11,920, 5,403,841, 5,212,162, and 4,86 The entire contents of these patents are hereby incorporated by reference. No. 6,023,499, filed Dec. 16, 2003, which is incorporated herein in its entirety for all purposes.

[0324] The pharmaceutical composition may also be intended for intravenous use. Examples of suitable buffers include buffers to adjust the pH to a desired range for intravenous use. Many buffering agents are known, including salts of inorganic acids such as phosphates, borates, and sulfates. do.

[0325] A pharmaceutical composition contains an active ingredient in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular application may include, among other things, the amount of the composition contained therein. Depends on the condition being treated.

[0326] Tablet compositions (e.g., monolayer oral tablet compositions)

[0327] Also referred to herein are tablet compositions, i.e. pharmaceutical compositions formulated for oral administration, For example, any of the compounds described herein (e.g., compounds of formulas (I)-(IV)): or a pharmaceutically acceptable salt thereof, e.g., a pill, capsule, caplet, lozenge , medicinal candy, cachet, gel capsule, capsule (caps), pellet, ball Tablets, such as single-layer tablet compositions, are disclosed. The pharmaceutical composition does not produce sedative or psychotomimetic toxic spikes in plasma concentrations. The compound may be formulated to provide a steady release of a therapeutically effective amount of the compound described herein without any need for a therapeutically effective amount. Such spikes in plasma concentrations have been shown to have severe psychotomimetic side effects. These side effects are well documented and include, but are not limited to, hallucinations, dizziness, and nausea, which not only have immediate effects but also affect treatment compliance. In this regard, the present disclosure provides a method for reducing sedative and psychotomimetic side effects. While maintaining the above, any of the compounds of formula (I) to (IV) or a pharmaceutically acceptable salt thereof A novel oral formulation containing an optimized matrix that has been shown to provide long-term stable release Inventive formulations are provided.

[0328] In some embodiments, the pharmaceutical composition (e.g., a monolayer tablet composition formulated for oral administration) The tablet composition) can be prepared by administering to a subject a compound described herein (e.g., a compound of Formulas (I) to (IV) or a pharmaceutically acceptable salt thereof, and a polymer.

[0329] In some embodiments of the present disclosure, the tablet composition is suitable for sustained release, preferably maximum sustained release. It is a modified-release tablet containing

[0330] In some embodiments of the present disclosure, the tablet composition is adapted to be tamper-evident. In the form of a tablet composition, the tablet composition may be, for example, in combination with HPMC, from about 2,000 to about 7,000 In some embodiments, the tablet composition comprises polyethylene oxide (PEO) of MW 0 kDa. The composition may further include polyethylene glycol (PEG), for example, PEG 8K. In some embodiments, the tablet composition may comprise one or more negatively charged groups, e.g., polyacrylic acid In certain embodiments, the tablet composition may further comprise a polymer carrying PEO. The article may be further subjected to heating / annealing, for example extrusion.

[0331] In some embodiments of the present disclosure, the pharmaceutical composition comprises: (i) a water-insoluble, neutrally charged, non-ionic matrix; (ii) a polymer bearing one or more negatively charged groups; and (iii) a polymer as defined herein. Any of the compounds described (e.g., compounds of formula (I)-(IV)) or pharmaceutical compositions thereof and combinations of physiologically acceptable salts.

[0332] In some embodiments of the present disclosure, the polymer carrying one or more negatively charged groups is a polyacrylic Polylactic acid, polyglycolic acid, polymethacrylate carboxylate, cation exchange resin Fats, clays, zeolites, hyaluronic acid, anionic gums, their salts, and mixtures thereof In some embodiments, the anionic gum is selected from the group consisting of natural materials and In some embodiments, the natural material is selected from the group consisting of alginate and semi-synthetic materials. , pectin, xanthan gum, carrageenan, locust bean gum, gum arabic, The gum is selected from the group consisting of raya gum, guar gum, and tragacanth gum. In an embodiment, the semi-synthetic material consists of carboxymethyl-chitin and cellulose gum. is selected from the group.

[0333] Furthermore, without wishing to be bound by theory, in some embodiments, one or more negatively charged groups, e.g., polymers bearing acidic moieties such as portions of the acidic polymers described herein. Thus, it is surprisingly possible to incorporate compounds described herein (e.g., compounds of formula (I)) into the matrix. (IV)) or a pharmaceutically acceptable salt thereof is significantly retained. In some embodiments, this negative charge can be determined, for example, by the pKa and the proton under certain pH conditions. Generated in situ based on ion emission or via electrostatic interaction / generation of negative charges Additionally, the acidic polymer may be a salt of the corresponding weak acid, which may be used to release the associated protons in the stomach. Without wishing to be bound by theory, this neutralizes the charge and any of the compounds described in the document (e.g., compounds of formula (I) to (IV)), or The interaction of the pharmaceutically acceptable salt with the matrix may be reduced. Suitable additives include, for example, fillers, disintegrants, flow improvers, lubricants, colorants, taste masking agents, etc. The composition may be further complemented by other inactive pharmaceutical ingredients that aid in the preparation of suitable solid dosage forms.

[0334] In some embodiments of the present disclosure, the tablet composition is adapted to be tamper-evident. In the form of a tablet composition, the tablet composition may be, for example, polyethylene having a MW of about 2,000 to about 7,000 KDa. In certain embodiments, the tablet composition comprising PEO may further comprise, for example, Further heating / annealing such as extrusion may be performed.

[0335] In some embodiments of the present disclosure, the non-ionic matrix may be a starch, a water-soluble polymer, or a mixture of starch, water, and the like. Polyvinyl alcohol, neutral rubber, polymethacrylate, PVA, PVA / PVP mixtures, and their fortified by mixing with a component selected from the group consisting of a mixture of It is selected from cellulosic polymers such as HPMC.

[0336] In some embodiments of the present disclosure, the cellulosic polymer is hydroxypropyl methylcellulose. In some embodiments, the tablet composition comprises about 20-60% by weight of HPMC. or about 30 to 50% by weight of hydroxypropyl methylcellulose, about 10 to 30% by weight % or about 15-20% by weight starch, or any combination thereof.

[0337] In some embodiments, the tablet composition comprises a compound described herein for the treatment of pain. In some embodiments, the pain being treated includes a therapeutically effective amount of any of the following: cancer pain, For example, intractable cancer pain. In some embodiments, the pain being treated is post-operative pain. In some embodiments, the pain being treated is orthopedic pain. In some embodiments, the pain treated is back pain. In some embodiments, the pain being treated is dental pain. In some embodiments, the pain being treated is chronic pain. The pain is chronic in opioid-tolerant patients.

[0338] In some embodiments, the tablet composition comprises a compound described herein for the treatment of depression. The present invention includes a therapeutically effective amount of any of the following:

[0339] In some embodiments, the tablet composition comprises a compound described herein for the treatment of brain trauma. The present invention includes a therapeutically effective amount of any of the following:

[0340] In some embodiments, the tablet composition contains a compound described herein for the treatment of stroke. The present invention includes a therapeutically effective amount of any of the following:

[0341] In some embodiments, the tablet composition is for use in treating migraine headaches, such as migraine headaches with aura. The intended therapeutically effective amount includes any of the compounds described herein.

[0342] In some embodiments, the tablet composition comprises a compound as described herein for use in refractory asthma. It includes a therapeutically effective amount of any of the compounds described.

[0343] In some embodiments, the tablet composition is intended for use in the treatment of alcoholism. and a therapeutically effective amount of any of the compounds described herein.

[0344] In some embodiments, the tablet composition is useful in the treatment of post-traumatic stress disorder (PTSD). The present invention includes a therapeutically effective amount of any of the compounds described herein for use in

[0345] In some embodiments, the tablet composition is for treating depression (e.g., treatment-resistant depression (TRD) or any of the compounds described herein for use in the treatment of steroids or bipolar depression A therapeutically effective amount of

[0346] In some embodiments, the tablet composition is for use in the treatment of major depressive disorder (MDD). The intended therapeutically effective amount includes any of the compounds described herein.

[0347] In some embodiments, the tablet composition is for use in the treatment of anxiety (e.g., generalized anxiety disorder). It includes a therapeutically effective amount of any of the compounds described herein for its intended use.

[0348] In some embodiments, the tablet composition comprises a tablet according to the present invention for use in the treatment of schizophrenia. The present invention includes a therapeutically effective amount of any of the compounds described herein.

[0349] In some embodiments, the tablet composition comprises a tablet composition according to the present invention for use in the treatment of bipolar disorder. The present invention includes a therapeutically effective amount of any of the compounds described herein.

[0350] In some embodiments, the tablet composition is intended for use in the treatment of suicidal tendencies or suicidal ideation. The present invention includes a therapeutically effective amount of any of the compounds described herein.

[0351] In some embodiments, the tablet composition is a composition as described herein for use in the treatment of autism. The compound of claim 1, wherein the compound is a compound selected from the group consisting of benzodiazepines, ...

[0352] In some embodiments, the tablet composition is intended for use in the treatment of diabetic neuropathy. and a therapeutically effective amount of any of the compounds described herein.

[0353] In some embodiments, the tablet composition is a composition of the present invention for use in the treatment of neuropathic pain. It includes a therapeutically effective amount of any of the compounds described herein.

[0354] In some embodiments, the tablet composition is for use in the treatment of acute pain (e.g., acute trauma pain). It includes a therapeutically effective amount of any of the compounds described herein for its intended use.

[0355] In some embodiments, the tablet composition is a composition as described herein for use in the treatment of chronic pain. The present invention includes a therapeutically effective amount of any of the compounds described herein.

[0356] In some embodiments, the tablet composition is for use in treating levodopa-induced movement disorders. The present invention includes a therapeutically effective amount of any of the compounds described herein.

[0357] In some embodiments, the tablet composition provides a pseudobulbar e for the treatment or regulation of the medullary effect or bulbar function The present invention includes a therapeutically effective amount of any of the compounds described herein for use in the treatment of rheumatoid arthritis.

[0358] In some embodiments, the tablet composition is a composition for treating Alzheimer's disease or an Alzheimer's disease-related condition. in the treatment of conditions (e.g., Alzheimer's dementia or agitation due to Alzheimer's disease) The present invention includes a therapeutically effective amount of any of the compounds described herein for use in treating a variety of conditions.

[0359] In some embodiments, the tablet composition is a composition as described herein for use in the treatment of tinnitus. The compound of claim 1, wherein the compound is a compound selected from the group consisting of benzodiazepines, ...

[0360] In some embodiments, the tablet composition is used to treat a disease or condition associated with the serotonin 5-HT2 receptor. is a therapeutically effective amount of any of the compounds described herein for use in treating a disorder Includes.

[0361] In some embodiments, the disease or disorder is selected from the group consisting of disorders of the central nervous system (CNS). Selected, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment resistance Transsexual depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or behavior Bipolar disorder, including non-suicidal self-injury disorder (NSSID), bipolar disorder type I, and bipolar disorder type II and related disorders, cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD) ), social anxiety disorder, alcohol use disorder, opioid use disorder, amphetamine use disorder substance use disorders, including nicotine use disorder, and cocaine use disorder; anorexia nervosa; Bulimia, binge eating disorder, Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder ADHD, pain and neuropathic pain, aphantasia, childhood onset dysphagia, cognitive impairment These include dementia, mild dementia, sexual dysfunction, chronic fatigue syndrome, Lyme disease, and obesity. .

[0362] In some embodiments, the disease or disorder comprises a condition of the autonomic nervous system (ANS).

[0363] In some embodiments, the disease or disorder includes asthma and chronic obstructive pulmonary disorder (COPD). Including lung disorders.

[0364] In some embodiments, the disease or disorder is a cardiovascular disorder, including atherosclerosis. Includes.

[0365] In some embodiments, the tablet composition is 0.05 wt. 12 to 24 hours, e.g., 24 hours. The amount of the compound described herein released from the matrix at a rate of 0.05 to 2 mg / kg / hr. The compound includes any of the compounds.

[0366] In some embodiments of the present disclosure, the composition comprises a soluble form of the compound described herein in a range of about 10-500 ng / ml. any of the compounds described in the document (e.g., compounds of formula (I) to (IV)) or pharmaceutical compositions thereof Achieve a substantially acceptable plasma concentration of the salt and maintain this concentration for the duration of the release period. In embodiments, the composition contains a compound described herein in the range of about 10-300 ng / ml. (e.g., any of the compounds of formulas (I) to (IV)) or a pharmaceutically acceptable salt thereof In some embodiments, the composition achieves a plasma integrated concentration of 0.1% of the active ingredient and maintains this concentration for the duration of the release period. The composition is in the range of about 10 to 100 ng / ml or about 50 to 100 ng / ml, as defined herein. (e.g., compounds of formula (I) to (IV)), or pharmaceutical compositions thereof Achieve a plasma integrated concentration of the salt that is acceptable to the patient and maintain this concentration throughout the release period. In embodiments, the composition contains a compound described herein (e.g., a compound or compound-containing compound) in the range of about 10-20 ng / ml. For example, a compound of any of formulas (I) to (IV) or a pharmaceutically acceptable salt thereof A plasma integrated concentration is achieved and maintained for the duration of the release period.

[0367] In some embodiments of the present disclosure, a compound described herein (e.g., a compound of formula The release period of any of the compounds (I) to (IV) or a pharmaceutically acceptable salt thereof is , over four hours.

[0368] In some embodiments of the present disclosure, a compound described herein (e.g., a compound of formula The release period of any of the compounds (I) to (IV) or a pharmaceutically acceptable salt thereof is , about 8 hours or more.

[0369] In some embodiments of the present disclosure, a compound described herein (e.g., a compound of formula The release period of any of the compounds (I) to (IV) or a pharmaceutically acceptable salt thereof is , approximately over 12 hours.

[0370] In some embodiments of the present disclosure, a compound described herein (e.g., a compound of formula The release period of any of the compounds (I) to (IV) or a pharmaceutically acceptable salt thereof is , approximately over 16 hours.

[0371] In some embodiments of the present disclosure, a compound described herein (e.g., a compound of formula The release period of any of the compounds (I) to (IV) or a pharmaceutically acceptable salt thereof is , about 20 hours or more.

[0372] In some embodiments of the present disclosure, a compound described herein (e.g., a compound of formula The release period of any of the compounds (I) to (IV) or a pharmaceutically acceptable salt thereof is , for about 24 hours or more.

[0373] In some embodiments of the present disclosure, a compound described herein (e.g., a compound of formula The release period of any of the compounds (I) to (IV) or a pharmaceutically acceptable salt thereof is , approximately 28 hours or more.

[0374] In some embodiments of the present disclosure, a compound described herein (e.g., a compound of formula The release period of any of the compounds (I) to (IV) or a pharmaceutically acceptable salt thereof is , approximately 32 hours or more.

[0375] In some embodiments of the present disclosure, a compound described herein (e.g., a compound of formula The release period of any of the compounds (I) to (IV) or a pharmaceutically acceptable salt thereof is , approximately 36 hours or more.

[0376] In some embodiments of the present disclosure, a compound described herein (e.g., a compound of formula The release period of any of the compounds (I) to (IV) or a pharmaceutically acceptable salt thereof is , less than about 48 hours.

[0377] In some embodiments of the present disclosure, a compound described herein (e.g., a compound of formula The release period of any of the compounds (I) to (IV) or a pharmaceutically acceptable salt thereof is , less than about 36 hours.

[0378] In some embodiments of the present disclosure, the tablet compositions of the present disclosure are administered twice daily (BID), three times daily (TID), or both. (TID) or four times daily (QID) applications.

[0379] In some embodiments of the present disclosure, the tablet compositions of the present disclosure are administered as a once-daily (QD) application. It will be used.

[0380] In some embodiments of the present disclosure, the tablet compositions of the present disclosure are utilized as a nightly (QHS) application. It is used.

[0381] In some embodiments of the present disclosure, the tablet compositions of the present disclosure are administered as needed (PRN). It is used as.

[0382] In some embodiments of the present disclosure, the oral pharmaceutical composition is fortified. Due to the efficacy of the administration, pharmaceutical compositions can be used to treat a small amount of an active compound (e.g., a compound of formula (I) ) to (IV), or a pharmaceutically acceptable salt thereof), It is possible to achieve the same effect as the comparative oral tablets not described in the above.

[0383] In some embodiments of the present disclosure, the oral administration event that provides an appropriate single unit dose is a single It may contain one tablet or multiple tablets.

[0384] Additionally, some active ingredients are added to protect the tablet from the acidic environment of the stomach and to maintain long-term release. Various types of enteric coatings may be used in embodiments.

[0385] In some embodiments of the present disclosure, the single layer tablet or caplet is coated with a protective layer of the inactive pharmaceutical ingredient. by coating the matrix with a layer to form a modified release formulation, e.g. The drug is released steadily, avoiding concentration bursts at premature release points.

[0386] Some embodiments of the present disclosure include compounds described herein (e.g., compounds of formula (I)-(IV) or a pharmaceutically acceptable salt thereof as a controlled release formulation. The present invention provides a pharmaceutical preparation that, at a plasma concentration of the compound, produces sedation or psychotic effects. The ability to obtain therapeutically effective concentrations of any of these oral modified-release formulations without a significant spike in toxicity. The formulation may be in the form of a tablet, caplet, or granule. A compound described herein (e.g., a compound of formula The compound (I) to (IV) or a pharmaceutically acceptable salt thereof. In these formulations, the compounds described herein (e.g., compounds of Formulas (I)-(IV)) or a pharmaceutically acceptable salt thereof (e.g., other tablet formulations described herein). The single core layer containing the drug delivery pores (as defined by the formulation) may or may not have drug delivery pores. Without wishing to be bound by theory, these systems Because it uses water osmolality for quality-controlled delivery, delivery rate is independent of gastrointestinal conditions. In combination with the novel and inventive aspects of the present disclosure, Osmotic asymmetric-membrane tec phology) or AMT (e.g., insoluble For single-layer tablets, caplets, or granules coated with an asymmetric microporous membrane techniques) to produce formulations useful in the treatment methods and kits described herein. That's fine.

[0387] In some embodiments of the present disclosure, any of the compounds described herein may be prepared by, for example, hydrochloric acid. It may be formulated as a pharmaceutically acceptable salt such as a salt, aspartate, succinate, etc. whereby the counter ion is a compound described herein (e.g., a compound of Formula (I) to Formula (I) IV) compounds) does not significantly affect the formulations described herein, or does not materially affect the achievement of the desired therapeutic effect of any of the compounds. i.e., tablets, caplets, capsules, gel capsules, capsules (caps) or The therapeutically effective amount (based on the indication) is similarly stably released from an oral pharmaceutical composition such as granules. and any of the compounds described herein (e.g., compounds of formula (I) to formula (IV)). or its pharmaceutically acceptable salts, which, in the concentration thereof, produce sedative or psychotomimetic toxic spies. Examples of salts within this range include, but are not limited to, hydrochloric acid, hydrobromic acid, and the like. Salts with dilute acids such as hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and e.g. For example, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid sulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, maleic acid, citric acid, succinic acid salts with organic acids such as citric acid, tartaric acid, and other minerals and carboxylic acids known to those skilled in the art Additional examples include salts with, for example, sodium, potassium, calcium, Salts with inorganic cations such as magnesium, lithium, aluminum, zinc, etc.; and e.g. Ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methyl Examples of salts include salts formed with pharmaceutically acceptable amines such as tirglucamine and procaine. In certain embodiments, the pharmaceutically acceptable salt is a hydrochloride salt.

[0388] Common tablet formulations

[0389] The formulations of the present disclosure may be in the form of, for example, tablets, capsules, caplets, gel capsules, and capsules. Orally administered pharmaceutical compositions, such as cell (cap) compositions, which are coated Uncoated or coated tablets, caplets and capsules (film-coated) Oral Use Oral pharmaceutical compositions for the treatment of ulcers may contain additives such as diluents, disintegrants, binders, lubricants, powder flow improvers, humectants, etc. pharmaceutically acceptable inactive excipients such as lubricants, sweeteners, flavoring agents, coloring agents, and preservatives; Mixed compounds, for example, compounds described herein (e.g., compounds of formulas (I) to (IV)) Furthermore, the oral pharmaceutical compositions of the present disclosure may contain, for example, Oral administration, obtained by dry granulation with single or multiple compression of powders or granules In some embodiments, the oral pharmaceutical composition is prepared using a wet granulation technique. In some embodiments, the oral pharmaceutical composition may be obtained using molding, heating / anilining, or the like. The polymer may be obtained by molding, or by extrusion techniques.

[0390] In some embodiments, the oral tablet is a solid right cylinder, the ends of which may be flat or convex. In some embodiments, the surface is convex. Lines or break-marks (scorings), symbols, or or other marks.

[0391] In some embodiments, the break marks allow the tablet to be precisely subdivided to provide sub-tablet doses. In some embodiments of the present disclosure, the tablet composition may contain, for example, a diluent, Binders, disintegrants, glidants, lubricants, modifying the behavior of the dosage form and active ingredients in the gastrointestinal tract substances, colouring substances and flavouring substances approved by the appropriate national or local authorities When such excipients are used, they may be present in the active ingredient. have been shown not to adversely affect the stability, dissolution rate, bioavailability, safety or efficacy of the There must be no incompatibilities between any of the components of the dosage form.

[0392] Coated tablets may be coated with, for example, natural or synthetic resins, polymers, rubbers, fillers, Sugars, plasticizers, polyols, waxes, colorings approved by the appropriate national or local authorities A tablet coated with one or more layers of a mixture of substances, such as a food additive, a food additive, and a flavoring substance. Such coating materials may be used to coat active ingredients, such as compounds described herein (e.g., compounds of the formula (I) to (IV)) or a pharmaceutically acceptable salt thereof Tablets are susceptible to e.g. burst release from the matrix, release of the active ingredient from air, moisture or light. For a variety of reasons, including protection, masking unpleasant tastes and odors, or improving appearance The material used for coating may be applied as a solution or suspension. It may be applied.

[0393] In some embodiments, the manufacturing process for oral pharmaceutical compositions, e.g., tablets, includes manufacturing controls and In some embodiments, the oral pharmaceutical composition meets Good Manufacturing Practice (GMP) requirements. In the manufacture of the present invention, one or more measures selected from the following are taken: mixing with an excipient to ensure homogeneity; Ensure that the oral pharmaceutical composition is carried out in a manner that ensures the Adequate mechanical strength to prevent collapse or breakage during subsequent processing such as tubing and distribution ensure the retention of active ingredients; minimize degradation of active ingredients; minimize risk of microbial contamination to minimize the risk of cross-contamination. For tablets with scratches (crack marks or marked tablets) that are intended to be subdivided In manufacturing, the following measures are taken: Refills are made as appropriate to ensure patients receive the intended dose. Ensure the validity of the split marks with respect to the uniformity of mass or content of the divided portions.

[0394] Generally, a suitable dose is about 0.05 mg / kg of body weight of the recipient per day. The range is from 0.01 to about 10 mg per kilogram of body weight per day, preferably about The range is 0.1 to about 5 mg, preferably about 0 mg per kilogram of body weight per day. The range is from about 0.5 to about 3 mg per kilogram of body weight per day, preferably from about 1 to about 3 mg per kilogram of body weight per day. Additional details regarding formulation and administration techniques can be found in the scientific literature and It is described in detail in the patent literature, e.g., Remington's Pharmaceuticals utical Sciences,Maack Publishing Co,East See the latest edition of Remington's on Pa. ("Remington's"). Once formulated in a suitable carrier, it is placed in an appropriate container and labeled for treatment of the indicated condition. Any of the compounds described herein (e.g., compounds of formulas (I) to (IV)) may be For administration of a formulation containing either of these compounds, or a pharmaceutically acceptable salt thereof, such labeling shall be The instructions include, for example, instructions regarding the amount, frequency, method of administration, treatment regimen, and indication.

[0395] kit Some embodiments of the present disclosure include compounds described herein (e.g., compounds of Formulas (I) to (IV) ) or a pharmaceutically acceptable salt thereof. The present invention provides a kit comprising a compound described herein (e.g., The present invention relates to a compound of formula (I) to (IV) or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for oral administration such as a pill in any one of the formulations described herein. Compositions and treatments for diseases, injuries or conditions, such as pain, as described herein; instructions for use in prevention or control.

[0396] In some embodiments of the present disclosure, the pain treated is cancer pain, e.g., refractory cancer pain. In some embodiments of the present disclosure, the pain being treated is post-operative pain. In some embodiments, the pain being treated is orthopedic pain. In some embodiments of the present disclosure, the pain being treated is back pain. In some embodiments of the present disclosure, the pain to be treated is neuropathic pain. In some embodiments of the present disclosure, the pain being treated is chronic pain. In some embodiments, the pain being treated is chronic pain in opioid-tolerant patients. do.

[0397] In some embodiments, the disease or disorder is a disease associated with the serotonin 5-HT2 receptor. Or a disability.

[0398] In some embodiments, the disease or disorder is selected from the group consisting of disorders of the central nervous system (CNS). Selected, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment resistance Transsexual depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or behavior Bipolar disorder, including non-suicidal self-injury disorder (NSSID), bipolar disorder type I, and bipolar disorder type II and related disorders, cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD) ), social anxiety disorder, alcohol use disorder, opioid use disorder, amphetamine use disorder substance use disorders, including nicotine use disorder, and cocaine use disorder; anorexia nervosa; Bulimia, binge eating disorder, Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder ADHD, pain and neuropathic pain, aphantasia, childhood onset dysphagia, cognitive impairment These include dementia, mild dementia, sexual dysfunction, chronic fatigue syndrome, Lyme disease, and obesity. In some embodiments, the disease or disorder comprises a condition of the autonomic nervous system (ANS).

[0399] In some embodiments, the disease or disorder includes asthma and chronic obstructive pulmonary disorder (COPD). Including lung disorders.

[0400] In some embodiments, the disease or disorder is a cardiovascular disorder, including atherosclerosis. Includes.

[0401] Some embodiments of the present disclosure include compounds described herein (e.g., compounds of Formulas (I) to (IV) ) or a pharmaceutically acceptable salt thereof. The present invention provides a kit comprising a compound described herein (e.g., The present invention relates to a compound of formula (I) to (IV) or a pharmaceutically acceptable salt thereof. a pharmaceutical composition, such as a tablet pharmaceutical composition for oral administration as a pill, in any one of the formulations disclosed; and instructions for use in the treatment of traumatic brain injury.

[0402] Some embodiments of the present disclosure include compounds described herein (e.g., compounds of Formulas (I) to (IV) ) or a pharmaceutically acceptable salt thereof. The present invention provides a kit comprising a compound described herein (e.g., The present invention relates to a compound of formula (I) to (IV) or a pharmaceutically acceptable salt thereof. a pharmaceutical composition, such as a tablet pharmaceutical composition for oral administration as a pill, in any one of the formulations disclosed; and instructions for use in the treatment of depression.

[0403] Some embodiments of the present disclosure include compounds described herein (e.g., compounds of Formulas (I) to (IV) ) or a pharmaceutically acceptable salt thereof. The present invention provides a kit comprising a compound described herein (e.g., The present invention relates to a compound of formula (I) to (IV) or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions, such as tablet pharmaceutical compositions for oral administration, such as pills, of the disclosed formulations, and migraine, For example, instructions for use in treating migraine with aura.

[0404] Some embodiments of the present disclosure include compounds described herein (e.g., compounds of Formulas (I) to (IV) ) or a pharmaceutically acceptable salt thereof. The present invention provides a kit comprising a compound described herein (e.g., The present invention relates to a compound of formula (I) to (IV) or a pharmaceutically acceptable salt thereof. The disclosed pharmaceutical compositions, such as tablet pharmaceutical compositions for oral administration like pills, and the treatment of intractable asthma and instructions for use in medical treatment.

[0405] Some embodiments of the present disclosure include compounds described herein (e.g., compounds of Formulas (I) to (IV) ) or a pharmaceutically acceptable salt thereof. The present invention provides a kit comprising a compound described herein (e.g., The present invention relates to a compound of formula (I) to (IV) or a pharmaceutically acceptable salt thereof. a pharmaceutical composition, such as a tablet pharmaceutical composition for oral administration as a pill, in any one of the formulations disclosed; and instructions for use in the treatment of stroke.

[0406] Some embodiments of the present disclosure include compounds described herein (e.g., compounds of Formulas (I) to (IV) ) or a pharmaceutically acceptable salt thereof. The present invention provides a kit comprising a compound described herein (e.g., The present invention relates to a compound of formula (I) to (IV) or a pharmaceutically acceptable salt thereof. a pharmaceutical composition, such as a tablet pharmaceutical composition for oral administration as a pill, in any one of the formulations disclosed; and instructions for use in the treatment of alcoholism.

[0407] In some embodiments, the instructions form an integral component of the packaging for the tablet composition. do.

[0408] In embodiments, the present disclosure provides a method for treating a patient for whom, for example, phenethylamine therapy is indicated, contemplated, or recommended. Subjects diagnosed with, suffering from, or susceptible to a disease, disorder, or condition that may be treated. The present invention features an oral modified release pharmaceutical composition for oral administration to a subject for therapeutic purposes. In this case, the subject is in need of treatment with the oral modified release pharmaceutical composition. The oral controlled-release pharmaceutical composition is (a) To treat, prevent, and / or manage a disease, disorder, or condition in a subject a compound described herein (e.g., a compound of Formulas (I)-(IV)) in an amount effective to or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient; Thereby, when the controlled-release pharmaceutical composition is orally administered to the subject, the controlled-release Since the stable release of the drug from the pharmaceutical composition is maintained, No neurotoxic spikes occur in the subject's plasma during the drug release period. .

[0409] Compliance with drug approval standards In some embodiments, the formulations of the present disclosure comply with certain industry-recognized drug approval standards. In particular, the formulations disclosed herein are compliant with the Federal Food, Drug, and Cosmetic Act. Compliant and acceptable under homogeneity, homogeneity in content analysis, and / or dissolution / disintegration analysis All such analyses are based on the standards established by the relevant drug approval standards. is.

[0410] In some embodiments, certain procedures are performed throughout manufacturing by implementing appropriate in-process controls. These are designed to ensure the effectiveness of each stage of manufacturing. In-process controls during tablet manufacturing include the moisture content of the final lubricant mixture, granule size, and , the flow rate of the final mixture, and, where relevant, the uniformity of the mass of the tablet cores before coating. In-process controls during tablet manufacturing include the uniformity of the dimensions (thickness, diameter), mass, and other parameters of the final dosage form. consistency, hardness and / or crushing force, friability, disintegration rate, or dissolution rate (e.g., modified-release Suitable methods that can be used to demonstrate some of these properties include: Suitable testing methods are known in the art.

[0411] In some embodiments, the packaging protects the pharmaceutical composition, including the tablet, from light, moisture, and damage during transport. It is probably adequate or required to provide protection from scratches.

[0412] In additional embodiments, the commercially available formulations (e.g., kits) are manufactured with controlled manufacturing and quality control. Comply with labeling requirements established under Good Manufacturing Practice (GMP). Such labeling shall include: Below is included. (1) Name of the drug; (2) Name of active ingredient; International Nonproprietary Name (INN) should be used whenever possible. ; (3) the amount of active ingredient in each tablet and the number of tablets in the container; (4) the manufacturer-assigned batch number (lot number); (5) Expiration date and, if applicable, date of manufacture; (6) Any special storage conditions or handling precautions that may be required; (7) Any directions for use, warnings, and precautions that may be required; (8) The name and address of the manufacturer or person responsible for marketing the product; (9) For tablets with a scratch mark, the instructions for use shall include a description of the dosage provided for less than one tablet. If subdivision is included, the label must include: Do not consume immediately. Storage conditions and duration of use for any unused or unused subdivisions.

[0413] In some embodiments, a pharmaceutical composition, such as a tablet, can be packaged without losing its integrity. Able to withstand handling, including packaging and transportation.

[0414] In some embodiments, the present disclosure provides a method for treating sedative disorders, e.g., rheumatoid arthritis, at any plasma concentration of the compound. Oral administration without neurological or psychotic toxicity spikes To ensure a steady release of any of the compounds in therapeutically effective concentrations from the tablet, any of the compounds described in the document (e.g., compounds of formula (I) to (IV)) or pharmaceutical compositions thereof In some embodiments, the method provides a method for formulating a physiologically acceptable salt of a compound of formula (I) or (II). (i) a water-insoluble, neutrally charged non-ionic matrix; (ii) a polymeric polymer bearing one or more negatively charged groups; and (iii) a compound described herein (e.g., a compound represented by Formulas (I) to (IV) ) or a pharmaceutically acceptable salt thereof, In some embodiments, the method comprises the steps of: (i) forming a tablet composition for oral administration of a layer; For example, polyethylene oxide having a MW of about 2,000 to about 7,000 KDa, including HPMC. (ii) a compound described herein (e.g., a compound represented by Formula (I)-(I V) or a pharmaceutically acceptable salt thereof, for example In some embodiments, the method comprises the steps of: Polyethylene oxide (PEO), including PMC, and a compound described herein (e.g., a compound of the formula (I) to (IV) or a pharmaceutically acceptable salt thereof. The tablet composition further comprises polyethylene glycol (PEG), e.g. PEG 8K, polymers carrying one or more negatively charged groups, e.g., polyacrylic acid. and / or may be subjected to further heating / annealing conditions, e.g. extrusion. In some embodiments, the formulations of the present disclosure may be administered in combination with other active therapeutic agents, such as those that reduce pain. In some embodiments, the products of the present disclosure may be administered in combination with an opioid to treat the condition. The drug serves the purpose of being an opioid-sparing drug, i.e., it provides the necessary Reduces the amount of opioid needed.

[0415] In some embodiments, the formulations of the present disclosure are not administered in combination with other active therapeutic agents.

[0416] In some embodiments, the formulations of the present disclosure may be administered in combination with another phenethylamine formulation or derivative thereof, For example, it may be administered in combination with a fast-release formulation of phenethylamine or its derivatives. stomach.

[0417] In some embodiments, the present disclosure provides a method for treating sedation or Therapeutically effective concentrations of the compound from an oral tablet without psychotomimetic toxicity spikes To ensure stable release of any compound described herein (e.g., a compound of Formula (I) to (IV)) or a pharmaceutically acceptable salt thereof. The method provides for the administration of a compound described herein (e.g., For example, the preparation of any of the compounds of formula (I) to (IV) or a pharmaceutically acceptable salt thereof. These formulations include a compound described herein (e.g., a compound represented by Formulas (I) to (IV) The single core layer containing either the compound of formula (I) or a pharmaceutically acceptable salt thereof is In some embodiments, the device is surrounded by a semi-permeable membrane with or without delivery holes. The present invention relates to novel and inventive pharmaceutical compositions (e.g., compounds described herein (e.g., compounds of Formula (I)) ) to a compound of formula (IV)) and an osmotic asymmetric membrane technology (osmot IC asymmetric-membrane technology) or AMT (e.g., coating with insoluble, asymmetric, microporous membranes produced by controlled phase separation) The present invention relates to a method for producing a tablet comprising the steps of: Formulations useful in the methods and kits may also be made.

[0418] Inhalation administration Also disclosed herein is a method for administering hallucinogens by mist inhalation. Most hallucinogens, including those in the salt form, have good water solubility, making them suitable for mist inhalation. This is the route of administration.

[0419] Hallucinogens that can be used for mist inhalation administration include compounds described herein (e.g., , compounds of formulas (I) to (IV)), or pharmaceutically acceptable salts thereof.

[0420] Hallucinogens (compounds described herein, e.g., compounds of Formulas (I)-(IV), or The dosage of the hallucinogen (including pharmaceutically acceptable salts thereof) may vary. An "effective amount" or "therapeutically effective amount" can refer to a composition containing an amount of a compound that is effective to treat a condition, disorder, or condition. A drug is an amount of a drug sufficient to treat or ameliorate a disease or condition. The actual amount may depend, inter alia, on the condition being treated. The dose and frequency (single dose) of the hallucinogen administered may be varied. The dose (or multiple doses) can vary depending on various factors, including the route of administration. The recipient's size, age, sex, health status, weight, body mass index, and diet and treatment were the nature and severity of the illness, the presence of other illnesses or other health-related problems, These include the type of therapy used, as well as complications resulting from any disease or treatment regimen. Other therapeutic regimens or agents may be used in combination with the methods and compounds disclosed herein. It can be used.

[0421] Therapeutically effective amounts for use in humans can be determined from animal models. The doses used may be formulated to achieve concentrations found to be effective in animals. Dosage in humans can be adjusted upward or downward based on monitoring the human's response to treatment. This can be adjusted by adjusting the

[0422] Dosages may vary depending on the requirements of the subject and the hallucinogen used. In the context of hallucinogens, the dose administered to a subject is sufficient to produce beneficial therapeutic effects in the subject over a long period of time. The amount must be sufficient to induce a therapeutic response. Treatment is initiated with a small dose, and the starting dose is determined by the presence, nature, and extent of the is less than the optimal dose of the hallucinogen. The dosage may be increased in small increments.

[0423] The dosage and interval of administration should be such that they provide a level of the administered compound that is effective for the clinical indication being treated. This allows for individualized treatment tailored to the severity of an individual's disease state. A treatment regimen is provided.

[0424] It is less toxic and yet still very effective in treating the clinical symptoms presented by the patient. An effective prophylactic or therapeutic regimen can be designed. This regimen may include, for example: the potency of the compound, its relative bioavailability, the patient's weight, the presence and severity of adverse side effects, By considering factors such as the method of administration and the toxicity profile of the selected hallucinogen, This may include selecting a hallucinogen.

[0425] Hallucinogens range from about 1 μg to about 10.0 mg or more per inhalation session. (or any range between about 1 μg and about 10.0 mg), for example, about 1 μg, 2 μg, 5 μg, μg, 6μg, 10μg, 13μg, 15μg, 20μg, 30μg, 40μg, 50μg g, 60μg, 70μg, 80μg, 90μg, 100μg, 110μg, 120μg, 130μg, 140μg, 150μg, 160μg, 170μg, 180μg, 190μg g, 200μg, 210μg, 220μg, 230μg, 240μg, 250μg, 26 0μg, 270μg, 280μg, 290μg, 300μg, 400μg, 500μg, 1.0mg, 2.0mg, 3.0mg, 4.0mg, 5.0mg, 6.0mg, 7.0m It may be administered at doses of 8.0 mg, 9.0 mg, 10.0 mg or more. In embodiments, the subject receives about 1, 2, 3, 4, 5 or more inhalation sessions per day. In some embodiments, subjects may receive a steroid dose every other day, twice a week, or three times a week. In some embodiments, the patient may receive about 1, 2, 3, 4, 5, or more inhalation sessions. In this case, the subject is asked to take the test every other month, twice a month, three times a month, or four times a month, approximately 1, 2, 3, 4, Five or more inhalation sessions may be taken.

[0426] Pharmaceutical compositions containing hallucinogens may be prepared and administered in a variety of dosage formulations. Preparations of include solutions and emulsions, e.g., water, water / propylene glycol solutions. , or an organic solvent.

[0427] Aqueous solutions suitable for inhalation use are prepared by dissolving the active hallucinogen or its derivatives in water. Suitable stabilizers and thickeners may be added. Malchon describes a method of dissolving a liquid hallucinogen or its derivatives in a viscous substance, such as natural or synthetic rubber. gums, resins, methylcellulose, sodium carboxymethylcellulose, and other suspensions Alternatively, the composition may be prepared by dispersing the composition in water together with an agent.

[0428] Some hallucinogens may have limited solubility in water and therefore may require the use of surfactants or Other suitable co-solvents may be required. Such co-solvents include: Polysorbates 20, 60, and 80; Pluronic F-68, F-84, and and P-103; cyclodextrin; and polyoxyl 35 castor oil. Co-solvents are typically employed at levels of about 0.01% to about 2% by weight. Reduce physical separation of emulsion components in formulations to reduce variability during administration. and / or otherwise improve the formulation by increasing the viscosity of the solution beyond that of a simple aqueous solution. In some cases, a higher viscosity is desired. Such viscosity enhancers include, for example, polyvinyl alcohols. Alcohol, Polyvinylpyrrolidone, Methylcellulose, Hydroxypropylmethylcellulose cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl Cellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and Such solvents are typically present in amounts of from about 0.01% by weight to about 2% by weight. It is employed at a weight percent level.

[0429] When in salt form, the hallucinogen or derivative thereof may be dissolved in an organic solvent. , e.g., acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2- Dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetone Amides, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol , ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol , methyl butyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, Lysine, sulfolane, tetralin, toluene, 1,1,2-trichloroethylene, or The organic solvent may be, for example, an ester solvent, a ketone solvent, or an alcohol. The solvents may belong to functional group categories such as solvents, amide solvents, ether solvents, hydrocarbon solvents, etc. , each of which can be used.

[0430] mist In some embodiments, a method is provided for delivering hallucinogens by mist inhalation. may be delivered using air, oxygen, and / or a mixture of oxygen and helium. Air, oxygen, and / or a mixture of oxygen and helium delivered at room temperature or heated In some embodiments, the mist containing the hallucinogen or derivative thereof may be heated. It is delivered via inhalation using a helium-oxygen (HELIOX) mixture. The viscosity of is so low that helium-oxygen mixtures produce gas flows characterized by laminar flow. One of the major obstacles to dose delivery via inhalation is respiratory tract deposition of the drug. Laminar airflow reduces this and allows air to reach the deep lung regions, a highly desirable property. The author administers a dissolved free base or salt formulation of a hallucinogen or its derivative as a mist to the patient's lungs. Hallucinogens or derivatives can be inhaled into the alveolar region of the lungs. The drug may be delivered to the patient's fluid lining and absorbed systemically into the patient's blood circulation. These formulations advantageously enter the bloodstream efficiently upon inhalation into the alveolar region of the lung. can be delivered.

[0431] Device suitable for delivery of heated or unheated air, oxygen, or helium-oxygen mixtures. For example, the continuous mode nebulizer Flo-Mist (Phillips) and Hope (B&B Medical Technologies), and e.g. For example, Medipure™ Heliox-LCQ System (PraxAir ) and accessories such as regulators, e.g. Precision Control In some embodiments, the control box is a tethered unit, such as a tethered unit, such as a tethered unit, or ... The complete delivery setup is described, for example, in Russian Patent No. RU199823U1. It may also be a device that

[0432] As used herein, the term "Heliox" refers to helium gas (He). In some embodiments, the Heliox mixture is In a mixture of helium and oxygen, helium is added at about 50%, 60%, 70%, 80%, or 9%. 0%, and in a mixture of helium and oxygen, oxygen may be present at about 50%, 40%, 30%, It may contain 0% or 10% of helium. Oxygen in ratios of 50:50, 60:40, 70:30, 80:20, 90:10, or In some embodiments, the heliox may be present in a laminar flow. May lower airway resistance through increased and decreased resistance to turbulent flow.

[0433] Heating the Heliox mixture reduces the permeability of physical barriers important for drug absorption. By heating the mucosal surface, peripheral It improves blood circulation, relaxes interstitial junctions, and increases permeability through other mechanisms. Helium has a thermal conductivity that is approximately 10 times higher than that of oxygen or nitrogen. This promotes more efficient heat transfer. The anhydrous Heliox mixture can reach temperatures as high as 110°C. Even if heated to a temperature of 100°C, it can be safely used as a pre-treatment step. Water heliox mixtures can heat the mucosal surfaces of the lungs and airways more efficiently .

[0434] Various types of personal inhalers are known in the art. Generally, personal inhalers contain a solid The inhaler is characterized by heating the drug or compound. It operates by direct heating to the smoldering point. Vaporization of solids or solid concentrates occurs by convection over the conductor. Convective heating of solid concentrates occurs when a heating element is brought into contact with water or another liquid and then The hot steam then directly heats the solid or solid concentrate to its thin smoke point, Conduction heating is used to release vapors that are inhaled by the user. It involves direct contact between the solid and the heating element, which allows the solid to reach its light smoke point and release vapors. Inhalers are more beneficial than smoking in terms of lung damage, but vapors Vaporized drugs / active agents may be significantly degraded by the heat of vaporization.

[0435] Steam is a solid substance in the gas phase below its critical temperature, which means that steam This means that it can be liquefied to a liquid by increasing the pressure without decreasing the temperature. .

[0436] As used herein, mist refers to a gas phase (e.g., air, oxygen) that is different from steam. A mist is a dispersion of droplets (liquid phase) suspended in a gas (air, gasoline, helium, and mixtures thereof). The droplets may contain a hallucinogen or a derivative thereof dissolved in an aqueous liquid or an organic solvent. The liquid phase of the mist droplets can contain thousands or millions of molecules. The gas phase can contain air, oxygen, helium, and mixtures thereof. does not contain solid particles. Mists may be sprayed in any manner, including, for example, by use of an inhaler or nebulizer. It can be prepared by any suitable method.

[0437] In some embodiments, the hallucinogen is delivered via a nebulizer. The drug is mixed with a heated helium-oxygen mixture to form a mist of water droplets containing the stimulant. For example, a hallucinogen preparation may be placed in a liquid medium and delivered to a device such as a nebulizer. In some embodiments, the nebulizer may be a device that can be used to create a mist, e.g. For example, compressed air compressor nebulizers, ultrasonic nebulizers, vibrating mesh or Horn-type nebulizer or microprocessor-controlled breath-activated nebulizer In some embodiments, the nebulizer device may be, for example, a device as described in Russian Patent No. RU1 It may also be a device as described in US Pat. No. 99823U1.

[0438] A nebulizer produces a fine mist of a solution or suspension of a drug, such as a hallucinogen, and delivers it to the lungs. A nebulizer is a device that delivers a liquid to the patient. To deliver the drug by nebulization, the drug is atomized. may be dispersed in a liquid medium such as water, ethanol, or propylene glycol. Furthermore, the hallucinogen or its derivatives may be incorporated into, for example, liposomes, polymers, emulsions, etc. , delivered in vehicles such as micelles, nanoparticles, or polyethyleneimine (PEI). The liquid drug for the nebulizer may be, for example, an aqueous solution or a viscous solution. After forced dispersion (for example, by gas jet, ultrasonic or mesh vibration), The dissolved hallucinogen is contained within the droplets, which are then inhaled. The mist is dispersed into the air or Even droplets containing the drug in another desired mixture (e.g., a mixture of helium and oxygen) good.

[0439] Jet nebulizer (compressed air nebulizer or compressor nebulizer) In some embodiments, jet sprayers (also known as jet sprayers) use compressed gas to create the mist. The nebulizer is a microprocessor-controlled breath-activated nebulizer. Also called breath-activated nebulizers, breath-activated nebulizers produce a continuous mist that the patient The mist is produced only when inhaled, rather than when inhaled. It is created by passing a stream of air through a venturi inside a bowl or cup. A venturi accelerates the flow of a fluid by forcing it into a conical tube. At that limit, the fluid increases its velocity, thereby decreasing its pressure. When the fluid leaves the compression point, the pressure increase is equal to atmospheric pressure. or return to pipe level pressure. This creates a low pressure zone, which This pulls droplets from the drug solution in the nebulizer bowl through the supply tube and then creates a mist. A stream of droplets is generated and flows into the mouthpiece. As the air flow increases, the particle size increases. The droplets and solvent saturate the released gas, reducing the amount of gas released. The wet nebulizer cools the drug solution inside the nebulizer, increasing the solute concentration in the residual volume. The baffles in the nebulizer bowl or cup can become clogged with larger particles. Hold them and place them back into the solution in the nebulizer bowl or cup to nebulize again. When the subject inhales, air is mixed through the nebulizer bowl. By using a small particle size distribution, the mist output during inhalation can be increased. Although dust formation may occur, reducing the particle size may also increase the spray time.

[0440] A commonly used unit of measure for droplet size is the mass median diameter (MMD), It is defined as the mean droplet diameter by mass. Its units are mass mean aerodynamic diameter, The MMD droplet size of a jet nebulizer is: Approximately 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0 , 8.0, 9.0, 10.0 μm or more (or any range between approximately 1.0 and 10.0 μm) The range may be smaller than that of an ultrasonic nebulizer.

[0441] Ultrasonic nebulizers convert alternating current into high-frequency (approximately 1 to 3 MHz) acoustic energy. The mist is generated using the vibration of a piezoelectric crystal, which dissolves the solution into droplets on the surface. The resulting mist is drawn from or through the device by the patient's inhalation. The particles are then pushed out by an airflow generated by a small compressor. The nebulizers may include large volume ultrasonic nebulizers and small volume ultrasonic nebulizers. The noise tends to be larger with ultrasonic nebulizers than with jet nebulizers. The MMD droplet sizes of the ultrasonic nebulizer are approximately 2.0, 2.5, 3.0, 3.5, and 4.0. , 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 10. 0 μm or more (or any range of about 2.0 to 10.0 μm). The riser is a high density droplet size of approximately 100, 150, 200, 250, 300 μm / L or more. It can generate mist.

[0442] Mesh nebulizer devices use the vibration of a piezoelectric crystal to indirectly generate mist. Mesh nebulizers include, for example, active mesh nebulizers and passive mesh nebulizers. Dynamic mesh nebulizers are examples of active mesh nebulizers. Active mesh nebulizers use a piezoelectric element. However, the piezoelectric element contracts and expands with the application of electrical current to open precise holes that are in contact with the chemical solution. The mist is generated by vibrating a mesh that has thousands of holes in it, using the vibration of a piezoelectric crystal. An open thin metal plate can be vibrated. One side of the plate is in contact with the liquid to be atomized. When the liquid is touched, vibrations are transmitted through the holes, forming a mist of tiny droplets. The Schnebulizer uses a horn-shaped vibrator to passively vibrate a tapered, perforated plate. An example of an active mesh nebulizer is the Aerone b (registered trademark) (Aerogen, Galway, Ireland) and eFlow ( (registered trademark) (PARI GmbH, Starnberg, Germany), while Microa ir NE-U22® (Omron, Bannockburn, IL) is a passive Mesh nebulizers are precise and customizable. By changing the pore size of the mesh, the device allows for the use of drug solutions of various viscosities. The output speed can be adjusted to various values. The size of the holes in the mesh (which can be customized to the application) Therefore, the droplet size can be determined very accurately. , electroplating, and laser cutting to remove liquid particles in the respirable range. Nebulizer meshes can be manufactured to grow inside the body. The meshes are made of metal alloys or Metals used to manufacture the mesh include platinum, palladium, and The droplet size is approximately twice the mesh hole size. Therefore, the mesh holes are approximately 0.1, 0.5, 1.0, 1.5, and 2. 0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 μm or more (or approximately 0.1 to 5. The mist generated by a mesh nebulizer can be Varies based on the geometry of the mesh, the material the mesh is made from, and the method by which the mesh was generated. In other words, different meshes can suspend different sizes of liquid particles in the gas. Generally, the MMD droplet size for mesh nebulizers is approximately 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5. , 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 Alternatively, the thickness may be 7.0 μm or more (any value between about 1.0 and 7.0 μm).

[0443] Furthermore, the droplet size is programmable, especially by modifying the geometry of the nebulizer. Additionally, a specific desired droplet size can be provided. The volume of the liquid to be atomized and the velocity of the droplets can be controlled independently. can also be precisely controlled by adjusting the frequency and amplitude of the mesh vibration. Additionally, you can customize the number of holes in the mesh and their layout on the mesh. Mesh nebulizers can be either electrically or battery powered. It is possible.

[0444] (for any atomization method described herein), The mist output rate per 1 mL of mist cloud is, for example, 0.1, 0.2, 0.3 , 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 mL / min or more (or approximately 0.1 to 0 Any type of nebulizer may be used. The residual volumes in the reservoir were approximately 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0. 6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1. 6, 1.7, 1.8, 1.9, 2.0 mL or more (or any value between approximately 0.01 and 2.0 mL) The ability to precisely control the droplet size allows the droplet size to be adjusted to the drug concentration. This has the advantage that it can be directly correlated to the release kinetics (KDR). This can be achieved by precise control of droplet size. Using approximately 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5. 0, 6.0, 7.0, 8.0, 9.0, 10.0 μm or more (or approximately 0.5 to 10.0 μm) It can be delivered by a mist with MMD droplet sizes in any range of m.

[0445] In some embodiments, the hallucinogen is administered via continuous positive airway pressure (CPAP) or other pressure support. It can be delivered via a breathing apparatus. Pressure-assisted breathing apparatus can be delivered via a mouthpiece or nose cap. Continuous columnar compression at a fixed, specified pressure against the face and nose of the patient wearing the Pushes out air or other gases. When a patient's glottis opens to inhale, pressure is applied across the airway. As the patient exhales, the contracting lungs and chest wall release The pressure pushes air against the successive pressures until the two pressures are equal. This allows the air pressure inside the airway to equalize with the air pressure outside the machine, and the "sprint" helps open the airway. Improved oxygenation and airway management. Pressure-assisted breathing devices inject mist particles into the airflow in the breathing circuit. means for introducing mist particles into the breathing circuit when the patient exhales The device may be coupled with a means for interrupting the introduction. For example, see U.S. Patent No. 7,267,121. Please refer to.

[0446] In some embodiments, the mist is delivered by a device such as a metered dose inhaler (MDI). The MDI generates a mist of organic solvent droplets containing hallucinogens, In some embodiments, the mixture is optionally combined with a heated helium-oxygen mixture. The hallucinogen or its derivatives may be delivered via a metered dose inhaler, MDI. The chair is a canister containing hallucinogens or their derivatives and a propellant. a metering valve that dispenses the medication from the canister; an aspiration valve that receives the canister and forms an opening for oral inhalation; The actuator body and the opening of the actuator body receive the drug from the canister. The actuator body and the actuator stem may be arranged to guide the drug to the area. By moving the medication canister relative to the actuator stem, the metering valve In some embodiments, the hallucinogen or derivative thereof is released into the pressurized volume of the MDI. Dissolved in a liquid propellant mixture (which may contain small amounts of volatile organic solvents) stored in a container A "metered dose" is a dose pre-packaged in a single dose inhaler, or In the case of a multi-dose inhaler, the dose is automatically measured from the reservoir in preparation for inhalation. The MDI device may be supported by a spacer. The MDI spacer is The MDI spacer is a spacer placed between the MDI and the user's mouth. This allows the droplets in the atomized dose to settle slightly and mix with air or other gases. This ensures efficient delivery of a metered dose to the user's lungs when inhaled. is designed to deliver a metered dose of drug to the lungs because the dose is moving very quickly. Despite this, the atomized spray droplets from the MDI are inhaled into the user's lungs. Instead, it hits the back of the user's throat and sticks to it. The MDI device helps prevent users from inhaling the metered dose directly from the MDI. The device offers the advantage of periodic administration, which is not restricted in the manufacture of medicines. It can be controlled.

[0447] Delivery of hallucinogens and helium-oxygen mixtures The methods disclosed herein provide for the systemic delivery of low doses of hallucinogens or derivatives thereof In particular, hallucinogens or derivatives thereof can be delivered to the CNS of a patient. High doses can be toxic or harmful, and can be optimized for the metabolic and therapeutic needs of each individual patient. It is associated with undesirable side effects that may be avoided by using lower doses. Described herein are methods for treating various central nervous system (CNS) diseases and other conditions. The method comprises the steps of: providing an agent and a gas such as air, oxygen, helium, or a mixture of helium and oxygen ( That is, through the inhalation of a mist containing gases such as heliox mixtures. In some embodiments, the method comprises delivering a hallucinogen or derivative thereof to a patient. Oxygen, helium, or a mixture of helium and oxygen may be heated. Oxygen-helium with reducer and mask connected by an air connection tube The method may further include using a device containing a balloon containing the mixture, The vise has an additional heating element that can heat the gas up to 120°C, and vibrates Equipped with a porous plate or mesh to ensure the passage of droplets less than 5 microns in size. Includes a nebulizer, a disinfection unit, and a disinfection unit.

[0448] In some embodiments, the hallucinogen or derivative thereof is administered to, for example, the alveoli, alveolar ducts, and / or The drug is delivered to the lower respiratory tract, including the bronchioles and other lung compartments. From there, the drug enters the bloodstream and is released into the central nervous system. In some embodiments of the present disclosure, the mist can be inhaled and transferred to the bloodstream. By delivering hallucinogens to patients in need, patients can avoid passing through the liver and achieve CN. Hallucinogens can be delivered to S. by administering them via inhalation, as a gaseous form of the drug. or drugs dispersed in liquids or mists bypass first-pass metabolism to produce hallucinogens or This allows the derivatives to be rapidly delivered to the bloodstream. This is known as the "first-pass effect" or "pre-systemic metabolism." First-pass metabolism, also known as "first-pass metabolism," occurs when a drug enters the liver and undergoes extensive biotransformation. This states:

[0449] In some embodiments, the method provides a treatment step in which the hallucinogen is administered at a concentration of about 5 0℃, 51℃, 52℃, 53℃, 54℃, 55℃, 56℃, 57℃, 58℃, 59℃, 6 A mixture of helium and oxygen heated above 0°C (or any temperature range between 50°C and 60°C) By administering atomized hallucinogens or their derivatives via inhalation, In some embodiments, the hallucinogen mist or vapor can be administered to a patient in need thereof. 0.1 microns to about 10 microns (e.g., about 10, 5, 4, 3, 2, 1, 0.1 or In some embodiments, the hallucinogen or The derivative can be atomized through a nebulizer, which can be used to atomize the dissolved The inhalant is produced as a mist containing the hallucinogen. In some embodiments, the atomized hallucinogen is In some embodiments, the patient inhales, causing the patient delivery line to be pulled down. The atomized hallucinogens are delivered to the patient via a patient delivery system using a carrier gas for inhalation. The carrier gas can be air, oxygen, a mixture of oxygen and helium, heated air, or It may be hot oxygen or a mixture of heated helium and oxygen.

[0450] In some embodiments, the treatment step may be preceded by a pretreatment step. The pretreatment step may include first administering a pretreatment inhalation therapy prior to administration of the hallucinogen or its derivative mist. In some embodiments, the pre-treatment inhalation step may include administering (i) via inhalation and approximately 90℃, 91℃, 92℃, 93℃, 94℃, 95℃, 96℃, 97℃, 98℃, 99℃, 100℃, 101℃, 102℃, 103℃, 104℃, 105℃, 106℃, 1 07℃, 108℃, 109℃, 110℃, 111℃, 112℃, 113℃, 114℃, 1 15℃, 116℃, 117℃, 118℃, 119℃, 120℃ or above (or 90℃ to 12 administering air, oxygen, or a mixture of helium and oxygen heated to a temperature (any range between 0°C and 100°C); (ii) No hallucinogens should be administered, followed by (iii) air, oxygen, a mixture of oxygen and helium, or heated air. administering a therapeutic course of inhaled helium, heated oxygen, or a mixture of heated helium and oxygen; Heated air, heated oxygen, or a mixture of heated helium and oxygen. is combined with atomized hallucinogens or their derivatives and heated to approximately 50°C, 51°C, 52°C, 53℃, 54℃, 55℃, 56℃, 57℃, 58℃, 59℃, 60℃ or higher (or about 50 The temperature may be any temperature within the range of 0.5 to 60°C.

[0451] In some embodiments of the present disclosure, the pre-treatment step (i) and the treatment step (ii) are performed using a combination of 0, 1, This may be repeated 2, 3, 4, 5, or more times. Steps (i) and (ii) may be repeated 0, 1, 2, 3, 4, 5 or more times, followed by a treatment step, which may be repeated 0, 1, 2, 3, 4, 5 or more times. In some embodiments of the present disclosure, the treatment step may be performed without a pretreatment step. It may be repeated 1, 2, 3, 4, 5 or more times.

[0452] Treatment may be administered once a week, twice a week, once a day, twice a day, or three times a day, with or without pretreatment. Each treatment may be administered over a period of about 1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 4 minutes, or more. It may be 5 minutes, 60 minutes or more.

[0453] The drug delivery procedure involves inhaling a hot, drug-free heliox mixture for priming. This effectively preheats the mucosal bed, which is then re-transported by the low-temperature heated heliox. and inhaling the atomized hallucinogen, wherein the atomized hallucinogen is inhaled using an inhalation device. It may contain a hot heliox mixture that does not contain liming agents. This is determined by the lower thermal resistance to the wet intake gas stream compared to the inlet gas stream. Thus, this procedure may be performed in multiple iterative cycles, in which case the target PK and The drug exposure was determined by the drug concentration, temperature, flow rate of the helium-oxygen mixture, composition of the mixture, and cycle time. The number and duration of the loops, time, and combinations of the above are all controlled by the loops.

[0454] The delivery methods described herein may be used to treat certain diseases and disorders. Treatment and management of a condition, disorder, disease, or one of the conditions, disorders, or diseases This refers to a method of reducing or eliminating the above symptoms, or a combination thereof. Treatment includes partial or complete halting of the progression of a condition, disorder, or disease, or the progression of a condition, disorder, or disease. Treatment may include partial or complete reversal of the underlying condition, disease or disorder. Therapeutic benefits, such as eradication or amelioration of one or more associated physiological or psychological symptoms can provide benefits and even if the patient is still affected by the condition. Improvement is observed in patients.

[0455] Thus, as used herein, the term "antibody" refers to a compound used to treat a central nervous system (CNS) disorder or a psychological disorder. A method of treating a patient is provided, the method comprising administering, via inhalation, a heated mixture of helium and heated oxygen and The treatment involves administering a nebulized hallucinogen to alleviate one or more symptoms of the disorder. It is possible.

[0456] In some embodiments, the hallucinogen is administered for the treatment of a CNS disease or other disorder. In some embodiments, the hallucinogen may be used to treat major depression, melancholic depression, atypical depression, or may be administered to treat depression, including dysthymia. Hallucinogens are used to treat anxiety disorders, obsessive-compulsive disorders, addictions (drug addiction, tobacco addiction, opioid addiction), Alcoholism, depression and anxiety (even if chronic or life-threatening) psychological disorders, including obsessive-compulsive behaviors or related symptoms (e.g., related to a diagnosis of a terminal illness) It may be administered therapeutically.

[0457] In some embodiments, the disease or disorder is selected from the group consisting of disorders of the central nervous system (CNS). Selected, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment resistance Transsexual depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or behavior Bipolar disorder, including non-suicidal self-injury disorder (NSSID), bipolar disorder type I, and bipolar disorder type II and related disorders, cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD) ), social anxiety disorder, alcohol use disorder, opioid use disorder, amphetamine use disorder substance use disorders, including nicotine use disorder, and cocaine use disorder; anorexia nervosa; Bulimia, binge eating disorder, Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder ADHD, pain and neuropathic pain, aphantasia, childhood onset dysphagia, cognitive impairment These include dementia, mild dementia, sexual dysfunction, chronic fatigue syndrome, Lyme disease, and obesity. In some embodiments, the disease or disorder may involve a condition of the autonomic nervous system (ANS). In some embodiments, the disease or disorder is a pulmonary disorder (e.g., asthma and chronic obstructive pulmonary disorder ( In some embodiments, the disease or disorder may include a cardiovascular disorder (e.g., COPD). These may include conditions such as atherosclerosis.

[0458] via a nebulizer (e.g., using a heated helium-oxygen mixture) (including psychedelic drugs), the method of delivering hallucinogens to the CNS (systemic drug delivery) has several advantages compared to oral delivery. This may result in beneficial improvements in PK parameters. In particular, hallucinogens are able to cross the blood-brain barrier and enter the brain. Compared to oral delivery, the optionally heated heliox mixture can be delivered Delivering hallucinogens to the CNS via a nebulizer with a compound is more effective than oral delivery. In some embodiments, the bioavailability can be increased by at least 25%. As described herein, the method of delivering hallucinogens to the CNS via a nebulizer includes: Bioavailability of approximately 10%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 80%, 85%, 90%, 95%, 99%, 99.9% or higher The CNS can be increased via a nebulizer as described herein. The method of delivering hallucinogens is T compared to oral delivery. max Reduce by at least 50% In some embodiments, the administration can be via a nebulizer as described herein. The method of delivering hallucinogens to the CNS is max About 30%, 40%, 50%, 55%, 60%, 65%, 70%, 80%, 85%, 90%, 95%, 99%, 99.9%, and can be further reduced. In some embodiments, Delivering hallucinogens to the CNS via a nebulizer has been shown to be more effective than oral delivery. max can be increased by at least 25%. The method of delivering hallucinogens to the CNS via a nebulizer is max About 10 %, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 80 %, 85%, 90%, 95%, 99%, 99.9% or more. Additionally, hallucinogens can be delivered to the CNS via a nebulizer as described herein. This approach allows for dose escalation and further exposure control in clinical protocols. Exposure control allows for adjustment of a patient's exposure history, resulting in improved overall treatment outcomes. This can be done.

[0459] In some embodiments, a system for administering a hallucinogen (or a salt thereof) is provided, comprising: The system comprises a container containing a solution of a hallucinogen (or a derivative or salt thereof) compound formulation. and any part physically connected to or enclosed with the container, with a size of about 0.1 microns to about 10 microns. (e.g., about 10, 5, 4, 3, 2, 1, 0.1 microns or less) It includes a nebulizer adapted to generate a mist of liquid.

[0460] Topical or Transdermal Dosage Forms and Administration A compound of the present disclosure (e.g., a compound of Formula (I) to (IV) or a pharmaceutically acceptable salt thereof) Dosage forms for topical or transdermal administration of benzodiazepines (potassium salts) include powders, sprays, ointments, pastes, and the like. Active Compounds The formulation may be prepared under sterile conditions using pharmaceutically acceptable excipients, and any preservatives, buffers, etc. that may be required. It may be mixed with a buffer, absorption enhancer, or propellant.

[0461] Ointments, pastes, creams, and gels may be used in addition to the active compounds of the present disclosure to treat, for example, animal Natural and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and It may also contain excipients such as zinc oxide, or mixtures thereof.

[0462] Powders and sprays can also contain insoluble materials such as lactose, talc, silicic acid, Aluminum hydroxide, calcium silicate, and polyamide powder, or any of these substances Sprays may also contain excipients such as mixtures of chlorofluorocarbons. and volatile unsubstituted hydrocarbons such as butane and propane. It may have.

[0463] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present disclosure to the body. That is, the compounds of the present disclosure may be administered via a transdermal patch at a constant concentration, This allows the compound to be administered gradually over a long period of time, eliminating the associated drug spikes. and toxicity is avoided.

[0464] The transdermal patch dosage forms herein contain varying amounts of active agent depending on the disease / condition being treated. The amount of active ingredient in a unit dose preparation may be, for example, 5 mg to 25 mg, or 10mg to 20mg, or 12mg to 18mg, or 13mg to 16mg, or The dosage may be varied or adjusted to 14 mg to 15 mg, or may be adjusted depending on the specific application and effectiveness. May be varied or adjusted as deemed appropriate using reasonable medical judgment according to the potency of the active ingredient. Transdermal patches formulated with the disclosed compounds may provide long-term relief with reduced toxicity. In some embodiments, the compounds of the present disclosure may be suitable for microdosing to achieve therapeutic benefit. The substance is serotonergic over an extended period, e.g., 24 hours or more, but not psychoactive. It may also be administered via a transdermal patch in lower concentrations.

[0465] In addition to the compounds of the present disclosure and any optional pharmaceutically acceptable excipients, Skin patches, as known to those skilled in the art, comprise a pressure-sensitive adhesive layer, a backing, and a release liner. The device may include one or more of the following:

[0466] Transdermal patch dosage forms are prepared by dissolving or dispersing the compound in a suitable medium. In some embodiments, the compounds of the present disclosure can be used in conjunction with polymers that form pressure-sensitive adhesive layers. Such transdermal patches may be prepared by dissolving or dispersing the drug directly in the polymer matrix. These are called drug-in-adhesive (DIA) patches. In the A patch, the active compound is distributed uniformly throughout the pressure-sensitive adhesive polymer matrix. In some embodiments, the compounds of the present disclosure comprise, in addition to the active compound: It may be provided in a layer containing a polymer matrix that is separate from the pressure-sensitive adhesive layer. In either case, the compounds of the present disclosure may be administered in combination with other agents, such as carriers and penetration / absorption enhancers. They may optionally be formulated with suitable excipients to increase the flux of the compound across the skin.

[0467] Examples of carrier substances include, but are not limited to, oleic acid, undecanoic acid, valeric acid, hydroxypropyl methylcellulose ... butanoic acid, pelargonic acid, capric acid, lauric acid, and eicosapentaenoic acid C8-C 22 Fatty acids; for example, octanol, nonanol, oleyl alcohol, decyl Alcohols and C8-C, such as lauryl alcohol 22 Fatty alcohols; e.g. oleic acid Ethyl myristate, isopropyl myristate, butyl stearate, and methyl laurate C8-C 22 Lower alkyl esters of fatty acids; for example, diisopropyl adipate C6-C 22 Di(lower) alkyl esters of; for example, glyceryl monolaurate C8-C 22 Monoglycerides of fatty acids; tetrahydrofurfuryl alcohol poly Ethylene glycol ether; polyethylene glycol, propylene glycol; 2-( 2-Ethoxyethoxy)ethanol;Diethylene glycol monomethyl ether;Polyethylene Alkyl aryl ethers of polyethylene oxide; Polyethylene oxide monomethyl ether ;Polyethylene oxide dimethyl ether;Glycerol;Ethyl acetate;Ethyl acetoacetate esters; N-alkylpyrrolidones; cyclodextrins, e.g., α-cyclodextrin , β-cyclodextrin, γ-cyclodextrin, or e.g., 2-hydroxypropanediol derivatives such as pyr-β-cyclodextrin; as well as terpenes / terpenoids, e.g. , limonene, linalool, myrcene, pinene, e.g., α-pinene, caryophyllene, cinnamyl toral, eucolyptol, and the like, including mixtures thereof; Examples include:

[0468] Examples of penetration agents / absorption enhancers include, but are not limited to, dodecylmethylsulfoxy octyl methyl sulfoxide, nonyl methyl sulfoxide, decyl methyl sulfoxide undecyl methyl sulfoxide, 2-hydroxydecyl methyl sulfoxide, 2-hydroxydecyl methyl sulfoxide 2-Hydroxy-undecylmethyl sulfoxide, 2-hydroxydodecylmethyl sulfoxide surfactants-lecithin organogels (PLO), e.g., poloxamer; an aqueous phase containing one or more of: mer, CARBOPOL, and PEMULEN; Isopropyl ammonium phosphate and one of PPG-2 myristyl ether propionate and mixtures thereof. Examples include:

[0469] The pressure sensitive adhesive layer may be made of, but is not limited to, polyacrylic acid (including alkyl acrylates). vinyl acetate), polyvinyl acetate, natural and synthetic rubbers (e.g., polyisobutylene) , ethylene vinyl acetate copolymer, polysiloxane, polyurethane, plasticized polyester Ether block amide copolymer, plasticized styrene-butadiene rubber block copolymer The transdermal patch of the present disclosure may be formed from polymers including, but not limited to, fluoropolymers ... The pressure sensitive adhesive layer used in the switch is an acrylic polymer pressure sensitive adhesive, preferably an acrylic polymer pressure sensitive adhesive. The acrylic copolymer pressure sensitive adhesive may be formed from: one or more alkyl (meth)acrylates (e.g., 2-ethylhexyl acrylate); Aryl (meth)acrylate; Aryl alkyl (meth)acrylate; and (meth) ) acrylate, for example, a hydroxyalkyl (meth)acrylate (e.g., hydroxy Diethyl acrylate, 2-hydroxypropyl acrylate, 3-hydroxypropyl Acrylates, 4-hydroxybutyl acrylate, 2-hydroxyethyl methacrylate methacrylate, 2-hydroxypropyl methacrylate, 3-hydroxypropyl methacrylate, and 4-hydroxybutyl methacrylate), (meth)acrylates (e.g., acrylate carboxylic acids containing alkoxy(meth)acrylates (e.g., methoxy(meth)acrylates) ethyl acrylate) and optionally one or more copolymerizable monomers (e.g. It is obtained by copolymerizing it with ethylenediaminetetraacetic acid (ethylenediaminetetraacetic acid), vinylpyrrolidone, vinyl acetate, etc. Specific examples of acrylic pressure-sensitive adhesives include, but are not limited to, DURO-TAK Products (Henkel), such as DURO-TAK 87-900A, DURO-TA K 87-9301, DURO-TAK 87-4098, DURO-TAK 87-2 074, DURO-TAK 87-235A, DURO-TAK 87-2510, DU RO-TAK 87-2287, DURO-TAK 87-4287, and DURO- TAK 87-2516 is an example.

[0470] Examples of backings used in the transdermal patch of the present disclosure include films, nonwoven fabrics, and Japanese paper. , soft backing such as woven cotton, knitted fabric, woven fabric, and laminated composite of nonwoven fabric and film Such backings are in close contact with the skin and are responsive to skin movements. Soft material that can be snuggled up, and the patch prevents skin rashes and irritation after prolonged use. It is preferable that the backing be made of a material that can suppress discomfort and other discomforts. Examples of materials include, but are not limited to, polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polystyrene Cotton, nylon, acetate rayon, rayon, rayon / polyethylene terephthalate Polyacrylonitrile, Polyvinyl alcohol, Acrylic polyurethane, Ethylene Stell polyurethane, ether polyurethane, styrene-isoprene-styrene copolymer -, styrene-butadiene-styrene copolymer, styrene-ethylene-propylene ethylene copolymer, styrene butadiene rubber, ethylene-vinyl acetate copolymer, or cellophane. Preferred backings do not adsorb or release the active agent. It inhibits the adsorption and release of active agents, improves the percutaneous absorption of active agents, and reduces skin rashes. To prevent or reduce other discomfort, the backing may be made of one or more layers of the above materials. It is preferable that the backing contains a material containing a polyimide and has water vapor permeability. However, 3M COTRAN products, e.g., 3M COTRAN Ethylene Vinyl Acetate Tate Film 9702, 3M COTRAN Ethylene Vinyl Acetate Film 9716, 3M COTRAN polyethylene film 9720, 3M COTRAN Ethylene vinyl acetate film 9728 is an example.

[0471] The release liners used in the transdermal patches of the present disclosure may include, but are not limited to, single-sided or double-sided release liners. The surface is a polyester film treated with a release coating, High quality paper with polyethylene lamination and glass treated with a release coating Release coatings include fluoropolymers, silicones, and fluorosilicones. The release liner may be a release coating, such as a cellulose acylate, a cellulose acylate copolymer, or any other release coating known to those skilled in the art. The transdermal patch may have a textured surface to facilitate easy removal of the transdermal patch from the package. Examples of release liners include, but are not limited to, SCOTCHPAK products from 3M, e.g. 3M SCOTCHPAK 9744, 3M SCOTCHPAK 9755, 3M S COTCHPAK 9709, and 3M SCOTCHPAK 1022 .

[0472] The methods disclosed herein using transdermal patch dosage forms preferably provide a therapeutic effect, e.g., for up to 72 hours. or up to 60 hours, or up to 48 hours, or up to 36 hours, e.g., 2 to 72 hours, or for a longer period such as 4-24 hours, or 10-18 hours, or 12-14 hours In particular, the compounds of the present disclosure provide low dose and stable systemic delivery of drugs. be able to be delivered steadily and consistently, avoiding harmful or unwanted side effects In some embodiments, the compounds of the present disclosure are serotonergic but not psychoactive. It is administered transdermally at concentrations lower than the active ingredient concentration.

[0473] Thus, as used herein, the compounds of the present disclosure (e.g., compounds of formulas (I) to (IV)) or a pharmaceutically acceptable salt thereof) via a transdermal patch, e.g. , central nervous system (CNS) disorders, psychological disorders, or autonomic nervous system (ANS) disorders Methods for treating diseases or disorders associated with the 5-HT2 receptor are provided. The compounds of the present disclosure are then released from the matrix of the transdermal patch (e.g., from a pressure-sensitive adhesive layer). The compound is capable of penetrating the skin of a subject and diffusing into the bloodstream of the subject.

[0474] In some embodiments, the compound is administered for the treatment of a CNS disease or other disorder. In some embodiments, the compounds may be used to treat major depression, melancholic depression, atypical depression, In some embodiments, the compound may be administered to treat depression, including dysthymia, or dysthymia. Hallucinogens are used to treat anxiety disorders, obsessive-compulsive disorders, and addictions (drug addiction, tobacco addiction, opioid addiction). , alcoholism, depression and anxiety (even chronic or life-threatening illnesses) Psychological disorders, including those related to a diagnosis of a terminal illness, obsessive-compulsive behavior, or related symptoms It may be administered to treat

[0475] In some embodiments, the disease or disorder is selected from the group consisting of disorders of the central nervous system (CNS). Selected, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment resistance Transsexual depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or behavior Bipolar disorder, including non-suicidal self-injury disorder (NSSID), bipolar disorder type I, and bipolar disorder type II and related disorders, cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD) ), social anxiety disorder, alcohol use disorder, opioid use disorder, amphetamine use disorder substance use disorders, including nicotine use disorder, and cocaine use disorder; anorexia nervosa; Bulimia, binge eating disorder, Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder ADHD, pain and neuropathic pain, aphantasia, childhood onset dysphagia, cognitive impairment These include dementia, mild dementia, sexual dysfunction, chronic fatigue syndrome, Lyme disease, and obesity. In some embodiments, the disease or disorder may involve a condition of the autonomic nervous system (ANS). In some embodiments, the disease or disorder is a pulmonary disorder (e.g., asthma and chronic obstructive pulmonary disorder ( In some embodiments, the disease or disorder may include a cardiovascular disorder (e.g., COPD). These may include conditions such as atherosclerosis. [Example]

[0476] I. Synthetic Route The compounds of the present disclosure and the reference compounds can generally be prepared according to the following synthetic procedures, as shown in Figures 1-15. It can be prepared accordingly or analogously by the following synthetic procedures.

[0477] Example 1 2-(2,5-bis(methoxy-d3)-4-(methylthio)phenyl)ethane-1-a Synthesis of amine (II-1). 2-(2,5-bis(methoxy-d3)-4-(methylthio)phenyl)ethane-1- The synthesis of amine (II-1) was carried out according to Figure 1. Phenolic starting material II-1 a was deprotonated using a solution of potassium carbonate in DMF, and the presence of deuterated methyl iodide Below, the bis(methoxy-d3)benzaldehyde intermediate (II-1b, 85%) Bis(methoxy-d3)benzaldehyde (II-1b) was dissolved in a solution of bromine in glacial acetic acid. The benzaldehyde intermediate (II-1c, 37%) was obtained by bromine treatment using HCl. Sodium borohydride was used to reduce the alcohol (II-1d, 92%). Displacement of the aryl group gave the benzyl bromide intermediate (II-1e, 94%), followed by carboxyl cyanide. Substitution with bromobenzyl cyanide gave benzyl cyanide (II-1f, 32%). Pd2(dba)3 / xanthane phosphatase between animide II-1f and sodium methanethiolate A catalytic cross-coupling reaction gave intermediate II-1g (44%). After reduction with lithium aluminum to increase the acidity, II-1 (75% The structure of the product was 1 Confirmed by H NMR. Overall yield 2.9%.

[0478] Example 2 2-(2,5-bis(methoxy-d3)-4-methylphenyl)ethan-1-amine (I Synthesis of I-2). 2-(2,5-bis(methoxy-d3)-4-methylphenyl)ethan-1-amine ( II-2) is synthesized by Shulgin (Shulgin, A., and Shulgi n,Ann.(1991) Pihkal:a chemical love stor y, Transform Press, Berkeley, CA) and later Maresh (Maresh,JJ,Ralko,AA,Speltz,T. E., Burke, J.L., Murphy, C.M., Gaskell, Z., Gir. el, J. K., Terranova, E., Richtscheidt, C., and Krzeszowiec, M. (2014) Chemoselective Zin c / HCl Reduction of Halogenated beta-Nitr ostyrenes:Synthesis of Halogenated Dopam Modified by (Synlett 25, 2891-2894) This is performed according to Figure 2 using the modified general procedure described above. Bis-alkylation of hydroxy-4-methylbenzaldehyde II-2a gives intermediate I I-2b is then obtained by nitroaldol condensation with nitromethane under buffered acidic conditions. This leads to the formation of β-nitrostyrene II-2c. The final product (II-2) was obtained by bis-reduction of the nitro group and alkene with zinc powder. The product is obtained as the Cl salt. The structure of the product is 1 Confirmed by H NMR.

[0479] Example 3 2-(4-(tert-butyl)-2,5-bis(methoxy-d3)phenyl)ethane- Synthesis of 1-amine (II-3). 2-(4-(tert-butyl)-2,5-bis(methoxy-d3)phenyl)ethane The synthesis of 1-amine (II-3) was carried out according to Figure 3. Starting materials using CD3I Bis-alkylation of (II-3a) gave intermediate II-3b (78%). Selective formylation with OCl3 and N-methylformanilide afforded benzalkonium chloride. The resulting benzaldehyde intermediate II-3c (63%) was added to the resulting benzaldehyde II-3c in a moderate amount. Nitroaldol condensation with nitromethane under acidic conditions yields β-nitrostyrene II-3d (72%) was formed. The final product (II-3, 32%) was treated with HCl. The product is obtained as a salt. The structure of the product is: 1 Confirmed by 1 H NMR.

[0480] Example 4 2-(4-cyclopentyl-2,5-bis(methoxy-d3)phenyl)ethane-1-a Synthesis of amine (II-4) 2-(4-cyclopentyl-2,5-bis(methoxy-d3)phenyl)ethane-1- The synthesis of amine (II-4) was carried out according to Figure 4. Iodobenzaldehyde starting material Pd(OAc)2 / Sphos-catalyzed interplay between II-4a and boronic ester II-4b Cross-coupling gave intermediate II-4c (78%), which was then reacted with buffered acid Nitroaldol condensation with nitromethane under alkaline conditions gave β-nitrostyrene II -4d was then formed by multi-site hydrogenation using Pd / C to give -4d as the HCl salt. The final product (II-4, 52%) was obtained. The structure of the product is: 1 Confirmed by H NMR It was.

[0481] Example 5 2-(4-bromo-2,5-bis(methoxy-d3)phenyl)ethane-1,1,2,2 Synthesis of -d4-1-amine (II-14). 2-(4-bromo-2,5-bis(methoxy-d3)phenyl)ethane-1,1,2, The synthesis of 2-d4-1-amine (II-14) was carried out by Shulgin (Shulgin, A ., and Shulgin, Ann. (1991) Pihkal: a chemical al love story,Transform Press,Berkeley,C A) and later reported by Maresh (Maresh, JJ, Ralko, A. A., Speltz, T. E., Burke, J. L., Murphy, C. M., Ga. skell, Z., Girel, J. K., Terranova, E., Richtsc. heidt, C., and Krzeszowiec, M. (2014) Chemos elective Zinc / HCl Reduction of Halogenat ed beta-Nitrostyrenes:Synthesis of Halog Enated Dopamine Analogues,Synlett 25,289 1-2894) according to Figure 5 using the modified general procedure. Bis-alkylation of 2,5-dihydroxybenzonitrile (II-14a) with I Intermediate II-14b is formed by the reaction of 1,2-dichloro-2,3-dichloro-1,4-dichloro-2,4 ...2,4-dichloro-1,4-dichloro- e,SE,and Lee,HS,1992,Selective Conve. rsion of Aromatic Nitriles to Aldehydes by Lithium Tris(Dihexylamino)Aluminum Hy (Org Prep Proced Int 24, 331-334) Using the developed method, lithium tris(dihexylamino)aluminum deuteride Deuteration was performed by reduction using deuterium hydride (Li(hex---2N)3AlD). β-Nitrostyrene II-14d was prepared by the reaction of β-nitrostyrene with buffered acid It is formed using nitroaldol condensation with nitromethane under conditions followed by deuterium oxide. The alkene was reduced by treatment with sodium borohydride and silicon dioxide to give the intermediate Interbody II-14e (Sinhababu, AK, and Borchardt, R. T. (1983) Silica Gel-Assisted Reduction o f Nitrostyrenes to 2-Aryl-1-Nitroalkanes with Sodium-Borohydride,Tetrahedron Let ters 24,227-230), followed by Yamada (Yamada,T. ,Kuwata,M.,Takakura,R.,Monguchi,Y.,Sajik i, H., and Sawama, Y. (2018) Organocatalytic Nitroaldol Reaction Associated with Deu terium-Labeling,Adv Synth Catal 360,637- α-position deuterium exchange using basic resin WA30 and heavy water, developed by 641) The intermediate II-14f is formed by the reaction of zinc powder in methanol-containing hydrochloric acid. Reduction of the nitro group gives intermediate II-14g, which is then selectively brominated to give the final product. The product (II-14) is obtained. The structure of the product is: 1 Confirmed by H NMR.

[0482] Example 6 2-(2,5-dimethoxy-4-(methyl-d3)phenyl)ethan-1-amine (II Synthesis of I-1) 2-(2,5-dimethoxy-4-(methyl-d3)phenyl)ethan-1-amine (I II-1) was synthesized by Shulgin (Shulgin, A., and Shulgi n,Ann.(1991) Pihkal:a chemical love stor y, Transform Press, Berkeley, CA) and later Maresh (Maresh,JJ,Ralko,AA,Speltz,T. E., Burke, J.L., Murphy, C.M., Gaskell, Z., Gir. el, J. K., Terranova, E., Richtscheidt, C., and Krzeszowiec, M. (2014) Chemoselective Zin c / HCl Reduction of Halogenated beta-Nitr ostyrenes:Synthesis of Halogenated Dopam Modified by (Synlett 25, 2891-2894) Lithium aluminum deuteration is carried out according to Figure 6 using the modified general procedure. The compound (LAD) was used to reduce methyl 2,5-dimethoxybenzoate (III-1a) to give This affords the benzyl alcohol intermediate III-1b, which is subsequently reacted with PBr3 to afford Further reaction with LAD affords the intermediate III-1c. Isoform III-1d was obtained, which was purified using N-methylformanilide and POCl3. The resulting benzaldehyde III-1e is selectively formylated under buffered acidic conditions. Nitroaldol condensation with methane yields β-nitrostyrene III-1f. Subsequently, bis-reduction of the nitro group and alkene using zinc powder in methanol-containing hydrochloric acid is carried out. The final product (III-1) is obtained as the HCl salt. The product structure is: 1 HNM Confirmed by R.

[0483] Example 7 2-(2,5-dimethoxy-4-(2-(methyl-d3)propan-2-yl-1,1, Synthesis of 1,3,3,3-d6)phenyl)ethan-1-amine (III-2) 2-(2,5-dimethoxy-4-(2-(methyl-d3)propan-2-yl-1,1 Synthesis of 1,3,3,3-d6)phenyl)ethan-1-amine (III-2) is shown in Figure 7 The Friedel-Crafts alkylation of the starting material (III-2a) was carried out according to the method described above. butyl bromide-d9 and aluminum chloride to give intermediate III-2b This was then lithiated with n-butyllithium and quenched with DMF. Benzaldehyde III-2c was converted to a nitroalcohol using nitromethane under buffered acidic conditions. The β-nitrostyrene III-2d was formed by cycloaddition of β-nitrostyrene III-2d. , followed by bis-reduction of the nitro group and alkene using ethanolic hydrochloric acid to give the final product ( III-2) is obtained as the HCl salt. The structure of the product is: 1 Confirmed by H NMR .

[0484] Example 8 2-(2,5-dimethoxy-4-(methylthio)phenyl)ethane-1,1-d2-1- Synthesis of amine (IV-1) 2-(2,5-dimethoxy-4-(methylthio)phenyl)ethane-1,1-d2-1 The synthesis of amine (IV-1) was carried out according to Figure 8. Reduction of the proton IV-1a gave the benzyl alcohol (IV-1b, 95%). This was then converted to benzyl bromide (IV-1c, 96%) using PBr3. Substitution with potassium cyanide gave benzyl cyanide (IV-1d, 14%). Pd2(dba)3 / xanphos-catalyzed cross-linking using sodium methanethiolate Coupling gave intermediate IV-1e (44%), which was then reacted with aluminum chloride. The final product (IV-1) was obtained by reduction with lithium aluminum deuteride in the presence of ammonium. , 27%). The structure of the product is 1 Confirmed by 1 H NMR.

[0485] Example 9 2-(2,5-dimethoxy-4-(propylthio)phenyl)ethane-1,1-d2-1 -Synthesis of amine (IV-2). 2-(2,5-dimethoxy-4-(propylthio)phenyl)ethane-1,1-d2- The synthesis of 1-amine (IV-2) was carried out by Shulgin (Shulgin, A., and Shulgin, Ann. (1991) Pihkal: a chemical love Reported by story, Transform Press, Berkeley, CA Later, Maresh (Maresh, JJ, Ralko, AA, Spelt z, TE, Burke, JL, Murphy, CM, Gaskell, Z. , Girel, J.K., Terranova, E., Richtscheidt, C. , and Krzeszowiec, M. (2014) Chemoselective Zinc / HCl Reduction of Halogenated beta-N itrostyrenes:Synthesis of Halogenated Do (Pamine Analogues, Synlett 25, 2891-2894) This is carried out according to Figure 9 using the modified general procedure. Dimethoxybenzaldehyde (IV-2a) is the TH compound of potassium tert-butoxide. Using F solution, the thiol is first alkylated by deprotonating it, and then The resulting benzaldehyde IV-2b was added with n-propyl bromide under buffered acidic conditions. Nitroaldol condensation with nitromethane was carried out under the conditions c is formed. Subsequent treatment with sodium borohydride and silicon dioxide , selective reduction of the alkene to form intermediate IV-2d, followed by Yamada (Ya mada, T., Kuwata, M., Takakura, R., Monguchi, Y. .,Sajiki, H., and Sawama, Y. (2018) Organoca talytic Nitroaldol Reaction Associated w ith Deuterium-Labeling,Adv Synth Catal 3 60,637-641) developed a method for the α-position synthesis of α-hydroxybenzoates using the basic resin WA30 and heavy water. Deuterium exchange occurs to form intermediate IV-2e. Reduction of the nitro group using HCl affords the final product (IV-2) as the HCl salt. The structure is 1 Confirmed by H NMR.

[0486] Example 10 2-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)ethane-1,1-d Synthesis of 2-1-amine (IV-3). 2-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)ethane-1,1- The synthesis of d2-1-amine (IV-3) was carried out according to Figure 10. Starting material IV-3a The introduction of iodine into the thiophene was carried out using AgNO3 and I2, giving the iodoarene intermediate (IV-3 b, 81%), which was then reacted with FSOCF2C in the presence of a catalytic amount of CuI at 75 °C. Catalytic trifluoromethylation with OOMe in DMF afforded intermediate IV-3c( 66%). Reduction with sodium borohydride gave benzyl alcohol (IV -3d, 97%), which was then treated with PBr3 to give benzyl bromide (IV-3e, 62%). This was then converted to benzyl cyanide (IV-3) by displacement with potassium cyanide. f, 13%), which was then reacted with deuterated lithium aluminum chloride in the presence of aluminum chloride. After reduction with ammonium chloride to increase the acidity, the final product (IV-3, 60%) was converted to the HCl salt. The structure of the product is 1 Confirmed by 1 H NMR.

[0487] Example 11 2-(4-bromo-2,5-dimethoxyphenyl)ethane-1,1-d2-1-amine ( Synthesis of IV-5). 2-(4-bromo-2,5-dimethoxyphenyl)ethane-1,1-d2-1-amine The synthesis of (IV-5) was reported by Shulgin (Shulgin, A., and Shulgi n, Ann. (1991) Pihkal: a chemical love story ,Transform Press, Berkeley, CA) and later published by M aresh (Maresh,JJ,Ralko,AA,Speltz,TE ., Burke, J. L., Murphy, C. M., Gaskell, Z., Gire. l, J. K., Terranova, E., Richtscheidt, C., and Krzeszowiec, M. (2014) Chemoselective Zinc / HCl Reduction of Halogenated beta-Nitros tyrenes:Synthesis of Halogenated Dopamin (e Analogues, Synlett 25, 2891-2894) This is carried out according to Figure 11 using a modified general procedure. The compound (IV-5a) was subjected to nitroaldol condensation using nitromethane under buffered acidic conditions. This is followed by the formation of β-nitrostyrene IV-5b. Treatment with silicon dioxide selectively reduces the alkene to form intermediate IV-5c. This was followed by Yamada (Yamada, T., Kuwata, M., Takaku ra, R., Monguchi, Y., Sajiki, H., and Sawama, Y. (2018) Organocatalytic Nitroaldol React ion Associated with Deuterium-Labeling,A dv Synth Catal 360,637-641) Deuterium exchange at the α-position using WA30 and heavy water forms intermediate IV-5d. Reduction of the nitro group with zinc powder in ethanol-containing hydrochloric acid gave intermediate IV-5e. Then, selective bromination gives the final product (IV-5). The product structure is: 1 H Confirmed by NMR.

[0488] Example 12 2-(4-bromo-2,5-dimethoxyphenyl)ethane-1,1,2,2-d4-1- Synthesis of amine (IV-12). 2-(4-bromo-2,5-dimethoxyphenyl)ethane-1,1,2,2-d4-1 The synthesis of amine (IV-12) was carried out by Shulgin (Shulgin, A., and Shulgin, Ann. (1991) Pihkal: a chemical lov (The Story, Transform Press, Berkeley, CA) Maresh, JJ, Ralko, AA, Spe ltz,TE,Burke,JL,Murphy,CM,Gaskell, Z., Girel, J.K., Terranova, E., Richtscheidt, C., and Krzeszowiec, M. (2014) Chemoselecti ve Zinc / HCl Reduction of Halogenated bet a-Nitrostyrenes:Synthesis of Halogenated Dopamine Analogues,Synlett 25,2891-2894 ) is carried out according to Figure 12 using the modified general procedure. Starting material IV- 12a is Cha (Cha,JS,Lee,SE,and Lee,HS ,1992,Selective Conversion of Aromatic N itriles to Aldehydes by Lithium Tris(Dih exylamino)Aluminum Hydride,Org Prep Proc Deuterated benzoates were prepared using the method developed by aldehyde IV-12b and tris(dihexylamino)aluminum deuteride ( It is deuterated by reduction with Li(hex---2N)3AlD). The ethylene IV-12c was obtained by nitroaldol condensation with nitromethane under buffered acidic conditions. Subsequent treatment with sodium borodeuteride and silicon dioxide The alkene was reduced by the reaction to give intermediate IV-12d (Sinhababu, AK, a nd Borchardt, RT (1983) Silica Gel-Assist ed Reduction of Nitrostyrenes to 2-Aryl- 1-Nitroalkanes with Sodium-Borohydride,T etrahedron Letters 24, 227-230), followed by Yam ada(Yamada,T.,Kuwata,M.,Takakura,R.,Mong uchi, Y., Sajiki, H., and Sawama, Y. (2018)Org anocatalytic Nitroaldol Reaction Associa ted with Deuterium-Labeling,Adv Synth Ca tal 360,637-641) developed a basic resin WA30 and heavy water. Deuterium exchange at the α-position of the compound used results in the formation of intermediate IV-12e. Reduction of the nitro group with zinc dust in acid provides intermediate IV-12f. Selective bromination gives the final product (IV-12), whose structure is: 1 H NMR So it is confirmed.

[0489] Example 13 2-(2,5-dimethoxy-4-((trifluoromethyl)thio)phenyl)ethane-1 -Synthesis of amine (I-1) 2-(2,5-dimethoxy-4-((trifluoromethyl)thio)phenyl)ethane- The synthesis of 1-amine (I-1) was carried out according to Figure 13. Iodobenzaldehyde starting material Pd / XPhos-catalyzed cross-coupling between the starting material I-1a and AgSCF3 was carried out using iodine. In the presence of phenyltriethylammonium chloride, (1,5-cyclooctadiene)bis(trimethylammonium chloride) (trimethylsilylmethyl)palladium(II) catalyst to give intermediate (I-1b, The nitroaldol condensation was then carried out under buffered acidic conditions using nitromethane. This was followed by the formation of β-nitrostyrene (I-1c, 48%). Bis-reduction of the nitro group and alkene with zinc powder in hydrochloric acid gave the final product (I-1 , 33%) as the HCl salt. The structure of the product is 1 Confirmed by 1 H NMR.

[0490] Examples 14 to 25 Examples 14 to 25 are based on the results of Shulgin (Shulgin, A., and Shulgi n,Ann.(1991) Pihkal:a chemical love stor y, Transform Press, Berkeley, CA) and later Maresh (Maresh,JJ,Ralko,AA,Speltz,T. E., Burke, J.L., Murphy, C.M., Gaskell, Z., Gir. el, J. K., Terranova, E., Richtscheidt, C., and Krzeszowiec, M. (2014) Chemoselective Zin c / HCl Reduction of Halogenated beta-Nitr ostyrenes:Synthesis of Halogenated Dopam Modified by (Synlett 25, 2891-2894) Prepared according to schematic Figure 14 using the modified general procedure described above. Suitable starting materials (A) This is achieved by first deprotonating the thiol using potassium tert-butoxide. and subsequently alkylated with the appropriate fluoroalkyl halide (R b Z) is attached The resulting intermediate B is then added to the nitroalcohol-containing compound using nitromethane under buffered acidic conditions. This is followed by a zinc fine condensation reaction in methanolic hydrochloric acid to form β-nitrostyrene C. The nitro group and alkene were bis-reduced using the powder to obtain the final product (D) as the HCl salt. do.

[0491] Example 14: 2-(2,5-dimethoxy-4-((3,3,3-trifluoropropyl)thio)phen (I-2)nylethan-1-amine. The product structure is: 1 Confirmed by H NMR .

[0492] Example 15: 2-(4-((3,3-difluoropropyl)thio)-2,5-dimethoxyphenyl) Ethan-1-amine (I-3). The product structure is: 1 Confirmed by H NMR.

[0493] Example 16: 2-(4-((3-fluoropropyl)thio)-2,5-dimethoxyphenyl)ethane -1-amine (I-4). The product structure is: 1 Confirmed by H NMR.

[0494] Example 17: 2-(2,5-dimethoxy-4-(3,3,3-trifluoropropoxy)phenyl) Ethan-1-amine (I-5). The product structure is: 1 Confirmed by H NMR.

[0495] Example 18: 2-(4-(3,3-difluoropropoxy)-2,5-dimethoxyphenyl)ethane -1-amine (I-6). The product structure is: 1 Confirmed by H NMR.

[0496] Example 19: 2-(4-(3-fluoropropoxy)-2,5-dimethoxyphenyl)ethane-1-a Min (I-7). The product structure is 1 Confirmed by H NMR.

[0497] Example 20: 2-(2,5-bis(methoxy-d3)-4-((3,3,3-trifluoropropyl )thio)phenyl)ethan-1-amine (II-16). The product structure is: 1 H NMR So it is confirmed.

[0498] Example 21: 2-(4-((3,3-difluoropropyl)thio)-2,5-bis(methoxy-d3) )phenyl)ethan-1-amine (II-17). The product structure is: 1 by H NMR It is confirmed.

[0499] Example 22: 2-(4-((3-fluoropropyl)thio)-2,5-bis(methoxy-d3)phenyl (II-18) The structure of the product is: 1 Confirmed by H NMR can be.

[0500] Example 23: 2-(2,5-bis(methoxy-d3)-4-(3,3,3-trifluoropropoxy) )phenyl)ethan-1-amine (II-19). The product structure is: 1 by H NMR It is confirmed.

[0501] Example 24: 2-(4-(3,3-difluoropropoxy)-2,5-bis(methoxy-d3)phenyl (II-20) The structure of the product is: 1 Confirmed by H NMR can be.

[0502] Example 25: 2-(4-(3-fluoropropoxy)-2,5-bis(methoxy-d3)phenyl)ethoxy Tan-1-amine (II-21). The product structure is: 1 Confirmed by H NMR.

[0503] Reference compound 1 2-(2,5-dimethoxy-4-methylphenyl)ethan-1-amine (Reference Compound 1) Synthesis of (2C-D). 2-(2,5-dimethoxy-4-methylphenyl)ethan-1-amine (Reference Compound 1 The synthesis of 2,5-dimethoxy-4-methylbenzaldehyde is carried out according to Figure 15. Nitroaldol condensation of the β- Nitrostyrene (F) is formed. This is followed by the reaction of zinc powder in methanol-containing hydrochloric acid. Bis-reduction of the nitro group with the alkene gave the final product (reference compound 1) as the HCl salt. The product structure is as follows: 1 Confirmed by H NMR.

[0504] Reference compound 2 2-(4-bromo-2,5-dimethoxyphenyl)ethan-1-amine (Reference Compound 2) (2C-B) is commercially available and was purchased from Cayman Chemical Co. Ta.

[0505] II. formulation Preparation of ion exchange resin complexes The free base of the compound was purified by elution with a strong cation exchange resin (sodium form, Amberlite IRP69, Rohm & Haas, Sodium Polystyrene Sulfonate, Pharmaceutical Grade The maximum loading of the resin is 75-150 microns. , known to be about 5 meqv / g. In a typical procedure, the free base ( 10 mmol) is dissolved in 20 ml of ethanol. The resin (washed with 3 x 50 ml of ethanol) was added at room temperature using a magnetic stirrer and stirred for 2 h. Continue stirring. Then filter the resin and wash with ethanol (2 x 20 ml). Compound release from the body was measured at pH 1 (0.1M HCl) and 7.4 (0.1M phosphate buffer). buffer) and tested using a basket lysis apparatus.

[0506] Ion-exchange resin complex with compound (II-14): Ion-exchange resin complex with compound (II-14) The exchange resin complexes were prepared and the release profiles were investigated according to the procedure described above. At neutral pH, release is a fast process with more than 90% of the drug dissolved within 30 minutes. Release is significantly slower, with approximately 50% of the drug released in 1 hour and 80% released in 2 hours. Drug concentrations were measured using an Agilux 1100 setup and UV detection. It was decided by C.

[0507] Preparation of enteric-coated ion-exchange resin complex beads Seal Coating The compound-ion exchange resin composite beads are coated with Wurster coating module (bottom on a Niro-Aeromatic STREA 1 fluidized bed unit equipped with a Opadry 03K in a water-alcohol solvent system (88:12, isopropanol:water) 19229 coating (Colorcon, New Jersey, USA, 6% solids) The composition is seal coated at 2% by weight.

[0508] Enteric coating The resulting beads were then coated with Opadry Enteric 94O white coating ( Coating is performed using a coating agent (Colorcon, New Jersey, USA). The coating dispersion was prepared as a 10% solution in a water-alcohol solvent system (88:12, isopropanol:water). Placebo tablets were reconstituted with solids and applied to either a 5% or 12% weight gain. The enteric coating is carried out without a prior seal coating step. Samples are taken at 5, 6, 7, 8, 10, and 12% weight gain.

[0509] Drug Release Test Drug release at low pH was determined using Type I Apparatus 1 (basket) at 100 rpm. In the first stage, the dissolution medium is 1000 ml of 0.1N HCl at 37°C (±0.5°C). HCl, and the bead load is 2 g. After 1 hour of operation in this medium, the aliquots were collected. The resulting solution contains less than 1% total drug as determined by HPLC. The integrity of the applied enteric coating is confirmed. Drug release at neutral pH is 100 rp m, determined using the Type I apparatus 1 (basket). In the second stage, the dissolution medium is 1000 mL of 0.1 M phosphate buffer, pH 7.4, 37°C (±0.5°C), The media aliquots were taken at 15, 30, 60, 90, and 1 The samples were collected at 20 min and the drug content was determined using an Agilux 1100 setup and UV detection. The drug release is determined by HPLC using the following: drug release is approximately 50% at 1 hour and 80% at 2 hours. %, with a time-release profile similar to that of uncoated resin beads. there were.

[0510] Manufacturing of orally disintegrating tablets Orally disintegrating tablets contain microbiomes of drug-ion exchange resin complexes with sustained release properties. The formulation is designed by incorporating the sugars into a matrix of fast-disintegrating oral components. The purpose of the drug is to make administration of the drug easier, by helping to disperse the active substance in the oral cavity, The patient is then allowed to swallow without water.

[0511] The compound is formulated in composition PI-ODT-1, which is an orally disintegrating release tablet form. The composition contains Pharmaburst 500 (S), a sugar-based, fast-disintegrating matrix. Prepared by dry granulation using Pharmab (PI, PA, USA). Urst 500 contains 20g of enteric-coated compound-ion exchange resin complex biscuits. The mixture is mixed with the sugar and sieved through a 40 mesh sieve to break down any clumps. Then, the mixture was mixed in a 400 ml tube blender for 15 minutes at 200 rev / min. After mixing, add magnesium stearate (200 mg) and mix for a further 3 minutes. 250 mg convex tablets containing approximately 20 mg of active compound are manufactured in a TDP tablet press and Compressed using 9mm dye. Applying a compressive force of 8kN, it is 10-15kN. Tablets with hardness in the range of P are produced. Tablet disintegration time is determined to be 60-75 seconds. Dissolution was performed using 1x PBS buffer, pH 6.8, at 100 rpm, 37 ℃, in a Type II dissolution apparatus (paddle) (Distek Premiere 5100 dissolution system, Distek Inc., North Brunswick, USA) At predetermined intervals, 1 ml samples are withdrawn (without replacement), filtered, and analyzed. The amount of compound removed was determined by HPLC using an Agilent 1100 setup. (Nagy, J., and Veress, T., 2016, HPLC Ana lysis of Hallucinogenic Mushroom Alkaloi ds (Psilocin and Psilocybin) Applying Hy drophilic interaction chromatography (HI LIC), J Forensic Res 7, 356). The solution is used to calculate the amount of drug released.

[0512] Fatty acid salts of compounds The free base of the compound (10 mmol) was dissolved in 30 ml of acetone, and 10 mmol of Add acetic acid and mix for 5 minutes. Refrigerate the mixture overnight to make a 1:1 A white crystalline precipitate of salt is formed, the composition of which is confirmed by elemental analysis.

[0513] Preparation of transdermal skin patches and in vitro permeation testing Compound I-1 was formulated into a drug-in-adhesive (DIA) patch to provide long-term This allows for the stable delivery of sub-psychoactive doses over a period of time. The DIA patch was optimized for once-daily application (24-hour drug release). , a pressure sensitive acrylic adhesive, a backing film, and a release liner. In the preparation, 1.5 g of compound I-1 and 6.0 g of DURO-TAK 87-900A (acrylate copolymer pressure-sensitive adhesive; Henkel) was dissolved in 30 ml of methanol. The solution was stirred at room temperature for 30 minutes and then subjected to a micrometer-adjustable film applicator. A silicone-coated release liner (SCOTCHPAK; 3M, USA) was used. The mixture was spread on a palladium foil (Centopal) to obtain a wet film with a thickness of 300 microns. minutes, and then in a 75°C oven for 30 minutes to remove any residual solvent. The patch was then laminated with a backing film (COTRAN; 3M, St. Paul, USA). The mixture was then cut into appropriate sizes, wrapped in aluminum foil, and stored at room temperature. The final dry thickness of the couscous was 90 mm.

[0514] In vitro immersion of drug patches on human cadaver skin (Biopredic, USA) Penetration was assessed using a Franz diffusion cell. A circular transdermal patch was placed with the adhesive side facing the stratum corneum. The receptor cells were placed on the skin with the receptor cells facing outwards. For all in vitro tests, the diffusion cell area was 1.77 cm 2 The diffusion cell was maintained at 32°C, and the solution in the receptor cell was rotated continuously at 600 rpm. At the designated time points (2, 4, 6, 8, 10, 12, and 24 hours), 0.5 ml of the solution in the receptor cell was withdrawn and replaced with the same volume of fresh receptor medium. The concentration of FX in the samples was determined by LC-MS / MS analysis. Black g / h / cm 2 A range of flow rates was achieved, which is comparable to therapeutic exposure in human subjects. It should be interpreted.

[0515] III. test Pharmacological testing of 5-HT serotonin receptors The binding affinity (K i ) and functional efficacy (EC 50 ) is measured. Deuteration has little effect on affinity and functionality at key receptor targets Receptor affinity assay: As previously reported (Canal, CE .,Cordova-Sintjago,T.,Liu,Y.,Kim,MS,Mo rgan, D., and Booth, RG, 2013, Molecular ph. armacology and ligand docking studies re veil a single amino acid difference betw een mouse and human serotonin 5-HT2A rec eptors that impacts behavioral translati on of novel 4-phenyl-2-dimethylaminotetr alin ligands,J Pharmacol Exp Ther 347,70 5-716;Armstrong, JL, Casey, AB, Saraf, T. S., Mukherjee, M., Booth, R.G., and Canal, C.E. .,2020,(S)-5-(2'-Fluorophenyl)-N,N-dimet hyl-1,2,3,4-tetrahydronaphthalen-2-amine ,a Serotonin Receptor Modulator,Possesse s Anticonvulsant, Prosocial, and Anxiolyti c-like Properties in an Fmr1 Knockout Mo use Model of Fragile X Syndrome and Auti sm Spectrum Disorder,ACS Pharmacol Trans l Sci 3,509-523), 5-HT 1A , 5-HT 2(A,B,C) Receiving The affinity of the receptor is determined by radioligand competitive binding. Harvesting membranes from CHO-K1 or HEK293 cells expressing tonergic receptors , K. d concentration of radioligand and a test compound that competes for the receptor binding site. After equilibration, the reaction is carried out by the ligand-receptor-membrane complex. The cells were then terminated by collecting the coalescent (Microbeta, PerkinElmer). A scintillation counter (Microbeta2, PerkinElmer) was used. The radioactivity is measured by fitting the data to a nonlinear curve and i The value is Cheng-Pr It is calculated according to the usoff equation.

[0516] Receptor Functional Assay: 5-HT 1A Receptor-mediated Gi stimulation (cyclic adenosine monophosphate ( Decreased levels of cAMP) and 5-HT 2(A、B、C) Receptor-mediated Gq stimulation (I Phosphoinositide hydrolysis, which leads to the production of inositol phosphate 1 (IP1), is a standard This is a signal transduction pathway that has been reported previously (Canal, C.E., Cordov a-Sintjago, T., Liu, Y., Kim, M.S., Morgan, D., and Booth, RG, 2013, Molecular pharmacolo gy and ligand docking studies reveal as ingle amino acid difference between mousse e and human serotonin 5-HT2A receptors t hat impacts behavioral translation of no vel 4-phenyl-2-dimethylaminotetralin lig ands,J Pharmacol Exp Ther 347,705-716;Ca nal, C.E., Morgan, D., Felsing, D., Kondabolu, K., Rowland, NE, Robertson, KL, Sakhuja, R .,and Booth,RG,2014,A Novel Aminotetra lin-Type Serotonin (5-HT) (2C) Receptor- Specific Agonist and 5-HT2A Competitive Antagonist / 5-HT2B Inverse Agonist with P Reclinical Efficacy for Psychoses,J Phar m Exp Ther 349,533), e.g., fluorescence resonance energy Transfer (FRET) technology (e.g., LANCE Ultra cAMP TR-FRET (PerkinElmer) and IP-One HTRF (Cisbio) kits) Homogeneous time-resolved fluorescence (HTRF)-capable microarrays were prepared using commercially available kits employing Plate reader (e.g., Mithras LB 940, Berthold) Briefly, CHO-K1 expressing serotonergic receptors was used. Cells or HEK293 cells are incubated with test compounds in stimulation buffer. After equilibration, the donor and acceptor fluorescent conjugates in lysis buffer were used for reaction. The reaction is terminated and FRET is measured. The data are fitted with a nonlinear curve and compared with a positive control (e.g., , serotonin) compared to potency (e.g., EC 50 ) and efficacy (e.g., E MAX ) Calculate.

[0517] In vitro hepatic metabolism and kinetic effects of deuterium isotopes. Compounds (10 μl of a 2 μM solution) were added to 100 mg of rat liver microsomes, NADPH The regenerating system (1 mM NADP, 1 unit / ml isocitrate dehydrogenase, 5 mM iodopropanol) citric acid, 5 mM magnesium chloride), and 25 mM phosphate buffer (pH 7.4 At various time points (0-60 min), The reaction is terminated by adding 300 μl of acetonitrile. The precipitated salts and proteins were spun out in a centrifuge and the remaining solution was stirred for 3 The eluate was diluted with 100 μl of water and analyzed by LC / MS (ABS Sciex 4000 QTRAP L Inject into an Agilent 1200 system interfaced with a C / MS / MS mass spectrometer Metabolic stability can be estimated by assessing the rate of disappearance of the major parent peak.

[0518] Comparison of reference compound 2 (2C-B) with compound II-14 Following the above protocol, compound II-14 was 5 times more potent than reference compound 2 (2C-B). It was found to have a 0% longer half-life.

[0519] PK studies in rats and mice The pharmacokinetics of deuterated phenethylamines is studied in rats. The experiment as set dosing was performed with a surgically inserted internal jugular vein catheter. star female rats (Charles River, Andover, MA) Two groups of five (200-250g) rats were fasted for 12 hours and then given 5mg / kg deuterium hydroxide. Deuterated analogs and 5 mg / kg of related non-deuterated analogs were administered to each group via catheter. or by oral gavage. At 8 and 24 hours, plasma samples were analyzed for parent molecules using LC / MS spectroscopy. To determine the blood-to-plasma ratio (BPR), two separate analyses were performed on five animals. Each group was euthanized at 15 and 30 minutes, respectively, and brain and plasma samples were collected. The concentration of parent drug in the solution is determined by LC / MS spectroscopy.

[0520] Head-twitch response (HTR) As previously reported (Canal, C.E., and Morgan, D., 20 12,Head-twitch response in rodents induc ed by the hallucinogen 2,5-dimethoxy-4-i odoamphetamine:a comprehensive history,a re-evaluation of mechanisms,and its utility lity as a model,Drug Test Anal 4,556-576 ;Saraf,TS,Felsing,DE,Armstrong,JL, Booth,RG,and Canal,CE,2021,Evaluatio n of lorcaserin as an anticonvulsant in juvenile Fmr1 knockout mice,Epilepsy Res 175,106677), HTR assays were performed in adult male C57Bl / 6J mice. The mice were collected from the Jackson Laboratory (Burberry, Maine). Mice were obtained from the University of California, Berkeley (UC Berkeley). Mice were housed in standard laboratory cages and provided with food and water ad libitum. The animals were allowed to acclimate to the animal facility for at least one week before testing in the treatment room. On the day of administration, the mice were allowed to acclimate to the treatment room in their home cages for at least 60 minutes before administration of the test compound. Mice were injected subcutaneously and then immediately placed in a transparent polycarbonate box (46 × 10 mm). The HTR was performed by two trained individuals who were blinded to the treatment. Counts were performed by an observer using a handheld tally machine for 15 consecutive minutes.

[0521] Compounds I-1 and II-10 induced HTR, statistically different from vehicle. It was found that there was a difference in DOI between the positive control and the control (Fig. 16) Furthermore, deuteration of the 2,5-methoxy group increases the HTR reaction. This is probably due to the improved metabolic stability of the deuterated compounds. The data show that the non-deuterated analog (compound I-1) and the deuterated analog (compound I-2) I-10) both serotonin and 5-HT 2A Engaging and activating receptors in vivo It is confirmed that:

[0522] Competitive binding of radioligand Competitive binding of radioligands was performed as previously reported (Saraf, TS, Fe lsing,DE,Armstrong,JL,Booth,RG,and Canal,CE,2021,Evaluation of lorcaseri n as an anticonvulsant in juvenile Fmr1 knockout mice, Epilepsy Res 175, 106677), This was performed with minor modifications. Human serotonin 5-HT 2A Receptor cDNA encoding The plasmids were obtained from the cDNA Resource Center. Human embryonic kidney cells (HEK2 93, ATCC CRL-1573) containing 10% fetal bovine serum and no antibiotics. In a 100 mm dish containing Dulbecco's modified Eagle's medium, Cells were grown in a hood at approximately 85% confluency in TransIT-2020. 5–15 μg using a reagent (Mirus Bio, Madison, WI) After approximately 48 hours, cell membranes were collected by centrifugation. Serotonin (5-HT) hydrochloride was used as a positive control for all experiments, and nonspecific Mianserin hydrochloride (10 μM) was used to define specific binding. 2A Acceptance Each cell membrane homogenate expressing the ATP was incubated in a buffer solution with or without the test compound. In this state, 3 [H]ketanserin (PerkinElmer, Waltham, MA) 1.6 nM (human 5-HT 2A K at the receptor d ) in a 96-well plate After equilibration, each sample was placed under vacuum onto a filter pre-soaked in buffer. Rapid filtration through a fiberglass filter and lysing in ice-cold buffer using a cell harvester. The filters were immersed in scintillation fluid and counted every minute using a photodetector. Number detected. IC 50 Values ​​were computed using nonlinear, least-squares regression analysis Then, the Cheng-Prusoff equation (GraphPad Prism 9 .0, San Diego, California) using K i converted to a value.

[0523] Both compounds I-1 and II-10 inhibit serotonin 5-HT 2A Receptor apparent jaw The deuterated and non-deuterated compounds were found to be resistant to cleavage (Figure 17). There was no significant difference in affinity, suggesting that deuteration does not alter pharmacodynamics. This suggests that...

[0524] All patents, patent applications, and other scientific literature mentioned anywhere in this specification or technical literature, which is incorporated herein by reference in its entirety. The described embodiments are specifically disclosed or specifically disclosed herein. Therefore, even if any of the elements or limitations are not present, the invention may be practiced. For example, in each example herein, the terms "comprising," "consisting essentially of," and "consisting of" are used interchangeably. Either term "consisting of" may be used interchangeably with either of the other two terms while retaining its ordinary meaning. The terms and expressions employed are intended to be words of description and not of limitation. to exclude any equivalent of the properties shown and described, or portions thereof. There is no intention in the use of such terms and expressions, but various modifications are possible within the scope of the claims. It is recognized that the methods and compositions of the present invention are therefore Although specifically disclosed by their intended characteristics, modifications and variations of the concepts disclosed herein are also contemplated. The forms may be reclassified by those skilled in the art, and such modifications and variations are within the scope of the specification and are considered to be within the scope of the compositions and methods defined by the appended claims. It will be understood that.

[0525] Any term, element, phrase, group of terms, phrase, Each group or group of elements may be specifically excluded from the claims.

[0526] For example, ranges such as temperature ranges, time ranges, composition ranges, or concentration ranges may be provided herein. Where a range is provided, all intermediate and subranges and all individual ranges within the range provided are included. Any range or subrange contained in the description herein is intended to be included in this disclosure. It is understood that any subrange or individual value of a range is excluded from the scope of the present specification. Any element or step included in the description herein may be incorporated into a claimed composition or method. It will be understood that the

[0527] Additionally, properties or aspects of the compositions and methods may be classified into Markush groups or other alternative groups. Where described, one of skill in the art will recognize that the compositions and methods may be used to identify any of the Markush or other groups. It will be recognized that the invention may be described in terms of any individual component or subgroup of components. cormorant. Accordingly, the foregoing is merely illustrative of the principles of the methods and compositions. Although not expressly described or shown herein, the present invention embodies the principles of this disclosure and It will be understood that various arrangements may be devised which fall within the spirit and scope of the present invention. All examples and conditional language recited in the specification are intended to be illustrative and not restrictive of the scope of the present disclosure and the present invention. It is intended to assist the reader in understanding the concepts that they have contributed to advancing the field. and shall not be construed as being limited to such specifically listed examples and conditions. Furthermore, the spirit, aspects, and embodiments of the present disclosure and specific implementations thereof All statements herein that recite examples encompass both structural and functional equivalents thereof. Additionally, such equivalents include both currently known equivalents and equivalents developed in the future. and so on, i.e., developed to perform the same function regardless of structure. It is intended that all elements be included. Accordingly, the scope of the present disclosure extends beyond the scope of the present disclosure. It is not intended that the present disclosure be limited to the exemplary embodiments shown and described. The scope and spirit are embodied by the following:

Claims

1. A compound having the structure of Formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof. hand, During the ceremony, X １ and X ２ are independently hydrogen or deuterium, Y １ and Y ２ are independently hydrogen or deuterium, R ３ is hydrogen or deuterium, R ４ is a halogen, a substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C ３ -C １０ cycloalkyl, —OR ｂ , or -SR ｂ and Each R ａ are independently substituted or unsubstituted C １ -C ６ is alkyl, and R ｂ is hydrogen, deuterium, substituted or unsubstituted C １ -C ６ Alkyl, or substituted or is unsubstituted C ３ -C １０ is cycloalkyl, However, X １ , X ２ , Y １ , Y ２ , R ３ , R ４ , and R ａ At least one of , containing deuterium, and / or R ４ is -SCF ３ , -SCH ２ CH ２ CF ３ , -SC H ２ CH ２ CF ２ H、-SCH ２ CH ２ CFH ２ ,-OCH ２ CH ２ CF ３ ,-OCH ２ CH ２ CF ２ H, and —OCH ２ CH ２ CFH ２ A compound selected from the group consisting of:

2. Y １ and Y ２ The compound of claim 1 , wherein is hydrogen.

3. R ３ The compound of claim 1 , wherein is hydrogen.

4. X １ and X ２ The compound of claim 1 , wherein is hydrogen.

5. X １ and X ２ The compound of claim 1 , wherein is deuterium.

6. Each R ａ Ga-CH ３ or -CD ３ 2. The compound of claim 1, wherein:

7. R ４ が、-SMe、-SCD ３、 -SCF ３、 -SCH ２ CH ２ CF ３ 、-SCH ２ C H ２ CF ２ H、-SCH ２ CH ２ CFH ２ 、-SEt、-Sn-Pr、-Me、-CD ３ , -CF ３ , -t-Bu, -C(CD ３ ) ３ , -cyclopentyl, -OMe, -OCD ３ 、-OCF ３ ,-OCH ２ CH ２ CF ３ ,-OCH ２ CH ２ CF ２ H、-OCH ２ CH ２ CFH ２ , -Cl, -I, or -Br.

8. The compound of claim 1 having the structure of formula (II): 【Chemistry 2】 or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof. hand, During the ceremony, X １ and X ２ are independently hydrogen or deuterium, Y １ and Y ２ are independently hydrogen or deuterium, R ４ is a halogen, a substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C ３ -C １０ cycloalkyl, —OR ｂ , or -SR ｂ and R ｂ is hydrogen, deuterium, substituted or unsubstituted C １ -C ６ Alkyl, or substituted or is unsubstituted C ３ -C １０ The compound of claim 1 which is cycloalkyl.

9. X １ and X ２ The compound of claim 8 , wherein is hydrogen.

10. R ４ が、-SMe、-SCD ３、 -SCF ３、 -SCH ２ CH ２ CF ３ 、-SCH ２ C H ２ CF ２ H、-SCH ２ CH ２ CFH ２ 、-SEt、-Sn-Pr、-Me、-CD ３ , -CF ３ , -t-Bu, -C(CD ３ ) ３ , -cyclopentyl, -OMe, -OCD ３ 、-OCF ３ ,-OCH ２ CH ２ CF ３ ,-OCH ２ CH ２ CF ２ H、-OCH ２ CH ２ CFH ２ 9. The compound of claim 8, wherein the aryl group is -Cl, -I, or -Br.

11. R ４ But -SMe, -Me, -OCD ３ , -CF ３ , -t-Bu or -cyclopentyl 9. The compound of claim 8, wherein

12. The compound of claim 1 having the structure of formula (III): 【Transformation 3】 or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof. hand, During the ceremony, X １ and X ２ are independently hydrogen or deuterium, Y １ and Y ２ are independently hydrogen or deuterium, R ４ is C substituted with one or more deuterium atoms １ -C ６ Alkyl, substituted with one or more deuterium atoms C to be ３ -C １０ cycloalkyl, —OR ｂ , or -SR ｂ and Each R ａ are independently substituted or unsubstituted C １ -C ６ is alkyl, and R ｂ is C substituted with one or more deuterium atoms １ -C ６ Alkyl, or one or more deuterium C substituted with ３ -C １０ The compound of claim 1 which is cycloalkyl.

13. X １ and X ２ is hydrogen, and each R ａ But -CH ３ The compound according to claim 12, thing.

14. R ４ is -SCD ３ , -CD ３ , -C(CD ３ ) ３ or -OCD ３ Claim 1 2. The compound according to claim 2.

15. The compound of claim 1 having the structure of formula (IV): 【Chemistry 4】 or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof. hand, During the ceremony, Y １ and Y ２ are independently hydrogen or deuterium, R ４ is a halogen, a substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C ３ -C １０ cycloalkyl, —OR ｂ , or -SR ｂ and Each R ａ are independently substituted or unsubstituted C １ -C ６ is alkyl, and R ｂ is hydrogen, deuterium, substituted or unsubstituted C １ -C ６ Alkyl, or substituted or is unsubstituted C ３ -C １０ The compound of claim 1 which is cycloalkyl. 【Request Item 16】 【Chemistry 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The compound of claim 1 ,

17. The compound is a serotonin 5-HT ２ The compound of claim 1 which is an agonist of the receptor. Compound.

18. The compound is a serotonin 5-HT ２Ａ 10. The compound of claim 1, which is an agonist of the receptor. compound.

19. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

20. The compound is present in the pharmaceutical composition based on the total amount of isotopologues of the compound.

20. The pharmaceutical composition of claim 19, wherein the medicament is present in the pharmaceutical composition in a purity of at least 50% by weight. Pharmaceutical composition.

21. Any position of the compound having deuterium is at least 50% of the deuteration site.

20. The pharmaceutical composition of claim 19, having a minimum deuterium incorporation in atomic percent.

22. 20. The pharmaceutical composition of claim 19, substantially free of other isotopologues of said compound. 。

23. 20. The pharmaceutical composition of claim 19 formulated for oral administration.

24. 20. The pharmaceutical composition of claim 19, formulated for administration via inhalation.

25. Serotonin 5-HT ２ In a method of treating a subject having a disease or disorder associated with a receptor There was, A method comprising administering to the subject a therapeutically effective amount of the compound of claim 1.

26. Serotonin 5-HT ２ The disease or disorder associated with the receptor may also be a neuropsychiatric disorder.

26. The method of claim 25, wherein the disease or disorder is an inflammatory disease or disorder.

27. Serotonin 5-HT ２ The disease or disorder associated with the receptor is a central nervous system (CNS) 26. The method of claim 25, wherein the disorder is

28. The central nervous system (CNS) disorder is post-traumatic stress disorder (PTSD), major depression, Sexual Disorder (MDD), Treatment-Resistant Depression (TRD), Suicidal Thoughts, Suicidal Behavior, Suicidal Ideation or Major depressive disorder with suicidal behavior, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders Concurrent disorder, cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorders, substance use disorders, anorexia nervosa, bulimia nervosa, binge eating disorder, Alzheimer's disease, Cluster headaches and migraines, Attention Deficit Hyperactivity Disorder (ADHD), Pain, Aphantasia, Children Early-onset fluency, dementia, mild dementia, sexual dysfunction, chronic fatigue syndrome, Lyme disease, and obesity.

29. 28. The method of claim 27, wherein the central nervous system (CNS) disorder is pain.

30. 28. The method of claim 27, wherein the central nervous system (CNS) disorder is sexual dysfunction.

31. Serotonin 5-HT ２ The disease or disorder associated with a receptor is a neurotransmitter that is involved in the autonomic nervous system (ANS).

26. The method of claim 25, wherein the disorder is

32. 32. The method of claim 31, wherein the disorder of the autonomic nervous system (ANS) is a pulmonary disorder or a cardiovascular disorder. The method described.

33. The compound may be administered orally, sublingually, buccally, topically, by injection, or by inhalation.

26. The method of claim 25, wherein the administration is by oral administration.

34. A monolayer tablet composition for oral administration comprising the compound of claim 1 and a polymer.

35. 35. The monolayer oral tablet composition of claim 34, wherein the composition is adapted for maximum sustained release. Finished product.

36. The tablet composition comprises: (i) a water-insoluble, neutrally charged non-ionic matrix; (ii) one or more and (iii) the compound, 35. The monolayer oral tablet composition of claim 34.

37. The water-insoluble, neutrally charged non-ionic matrix may be starch, wax, or a mixture thereof. , neutral rubber, polymethacrylate, PVA, PVA / PVP blends, and blends thereof Cellulose-based compounds reinforced by mixing with a component selected from the group consisting of 37. The monolayer oral tablet composition of claim 36, wherein the polymer is selected from the group consisting of:

38. The cellulose-based polymer is hydroxypropyl methylcellulose (HPMC).

38. The monolayer tablet composition for oral administration according to claim 37,

39. The polymer carrying one or more negatively charged groups is selected from the group consisting of polyacrylic acid, polylactic acid, polyglycolic acid, and the like. Cholic acid, polymethacrylate carboxylate, cation exchange resin, clay, zeolite, hygroscopic anionic gums, salts thereof, and mixtures thereof; 37. The monolayer tablet composition for oral administration according to claim 36,

40. 10. The method of claim 9, wherein the anionic rubber is selected from the group consisting of natural and semi-synthetic materials.

39. A monolayer tablet composition for oral administration according to claim 39.

41. The natural substances include alginic acid, pectin, xanthan gum, carrageenan, locust Composed of bean gum, gum arabic, gum karaya, guar gum, and gum tragacanth 41. The monolayer oral tablet composition of claim 40, selected from the group:

42. The semi-synthetic material is selected from the group consisting of carboxymethyl-chitin and cellulose gum.

41. The monolayer tablet composition for oral administration according to claim 40, wherein

43. 35. The monolayer oral dosage form of claim 34, comprising a therapeutically effective amount of said compound for the treatment of pain. Oral tablet composition.

44. 35. The monolayer oral composition of claim 34, comprising a therapeutically effective amount of said compound for the treatment of traumatic brain injury. Tablet composition for administration.

45. 35. The monolayer oral composition of claim 34, comprising a therapeutically effective amount of said compound for the treatment of depression. Tablet composition for administration.

46. Serotonin 5-HT ２ For use in the treatment of a disease or disorder associated with the receptor 35. The monolayer oral tablet composition of claim 34, comprising a therapeutically effective amount of said compound.

47. The disease or disorder is selected from the group consisting of post-traumatic stress disorder (PTSD), major depressive disorder (MD), D) Treatment-Resistant Depression (TRD), suicidal ideation, suicidal behavior, or suicidal thoughts or behaviors Major depressive disorder, non-suicidal self-injury disorder (NSSID), bipolar disorder type I, bipolar disorder type II Bipolar disorder and related disorders, including psychiatric disorders, cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized depression, Generalized Anxiety Disorder (GAD), Social Anxiety Disorder, Alcohol Use Disorder, Opioid Use Disorder, Amphoebe substance use disorders, including steroid use disorder, nicotine use disorder, and cocaine use disorder; neurological disorders Anorexia nervosa, bulimia nervosa, binge eating disorder, Alzheimer's disease, cluster headaches and migraines, Attention-deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood onset Fluency, dementia, mild dementia, sexual dysfunction, chronic fatigue syndrome, Lyme disease, and obesity 47. The monolayer of claim 46, wherein the central nervous system (CNS) disorder is selected from the group consisting of: A tablet composition for oral administration.

48. 47. The monolayer of claim 46, wherein the disease or disorder is a condition of the autonomic nervous system (ANS). A tablet composition for oral administration.

49. 47. The monolayer tablet composition for oral administration according to claim 46, wherein the disease or disorder is a pulmonary disorder. 。

50. 47. The monolayer tablet for oral administration according to claim 46, wherein the disease or disorder is a cardiovascular disorder. composition.

51. the composition achieves a plasma integrated concentration of the compound in the range of 10 to 500 ng / ml; 47. The monolayer tablet composition for oral administration of claim 46, wherein this concentration is maintained throughout the release period.

52. 35. The monolayer tablet for oral administration according to claim 34, wherein the polymer comprises one or more negatively charged groups. composition.

53. A tablet composition formulated for oral administration comprising the compound of claim 1 and a polymer. thing.

54. 54. The tablet composition of claim 53, wherein the polymer comprises one or more negatively charged groups.

55. 54. The tablet composition of claim 53, wherein the polymer comprises one or more acid groups.

56. 54. The method of claim 53, wherein the polymer comprises a water-insoluble, neutrally charged, non-ionic matrix. Tablet composition.

57. The water-insoluble, neutrally charged non-ionic matrix may be starch, wax, or a mixture thereof. , neutral rubber, polymethacrylate, PVA, PVA / PVP blends, and blends thereof Cellulose-based compounds reinforced by mixing with a component selected from the group consisting of 57. The tablet composition of claim 56, wherein the polymer is selected from the group consisting of:

58. The cellulose-based polymer is hydroxypropyl methylcellulose (HPMC).

58. The tablet composition of claim 57.

59. 1) the monolayer tablet composition for oral administration according to claim 34, and 2) its use in the treatment of pain. A kit for treating a subject, including instructions for the treatment of the subject.

60. 60. The kit of claim 59, wherein the polymer comprises one or more negatively charged groups.

61. 1) the monolayer tablet composition for oral administration according to claim 34, and 2) its use in treating brain trauma. A kit for treating a subject, comprising instructions for use.

62. 62. The kit of claim 61, wherein the polymer comprises one or more negatively charged groups.

63. 1) the monolayer tablet composition for oral administration according to claim 34, and 2) its use in the treatment of depression. A kit for treating a subject, comprising instructions for use.

64. 64. The kit of claim 63, wherein the polymer comprises one or more negatively charged groups.

65. 1) the monolayer tablet composition for oral administration according to claim 34, and 2) serotonin 5-HT ２ and instructions for use in treating a disease or disorder associated with the receptor. Kit for treatment of

66. 66. The kit of claim 65, wherein the polymer comprises one or more negatively charged groups.

67. This involves administering hallucinogens dissolved in the liquid phase of the mist via inhalation to patients in need thereof.

10. A method of delivering a hallucinogen to a subject, wherein the hallucinogen comprises a compound of claim 1. Law.

68. 68. The method of claim 67, wherein the hallucinogen is delivered to the patient's central nervous system.

69. 10. The method of claim 1, wherein the hallucinogen is delivered with air, oxygen, or a mixture of helium and oxygen.

67. The method according to claim 67.

70. 70. The method of claim 69, wherein the hallucinogen is delivered with a mixture of helium and oxygen.

71. 71. The method of claim 70, wherein the mixture of helium and oxygen is heated to about 50° C. to about 60° C. How to do it.

72. The helium is present in the helium and oxygen mixture at about 50-90% and the oxygen 71. The method of claim 70, wherein the oxygen is present in the mixture of helium and oxygen at about 10-50%. How to do it.

73. administering a pre-treatment inhalation therapy prior to administration of the helium and oxygen mixture and the hallucinogen; 71. The method of claim 70, further comprising:

74. The pre-treatment comprises administering to the patient by inhalation helium heated to about 90°C to about 120°C.

74. The method of claim 73, comprising administering a mixture of oxygen.

75. (i) administering to the patient by inhalation a mixture of helium and oxygen heated to approximately 90°C to 120°C; and (ii) administering to said patient by inhalation a solution heated to about 50°C to 60°C. and administering a mist containing the hallucinogen and helium and oxygen.

67. The method according to claim 67.

76. 76. The method of claim 75, further comprising repeating steps (i) and (ii) at least once. The method described.

77. The hallucinogen has at least a 25% improvement in drug bioavailability compared to oral delivery, At least 25% C compared to delivery ｍａｘ an increase of at least 50% compared to oral delivery % of T ｍａｘ or a combination thereof, 68. The method of claim 67,

78. Central nervous system (CN)-related effects include administering hallucinogens dissolved in a mist by inhalation.

5. A method for treating a hallucinogen-containing disorder of the present invention, comprising administering to a subject a hallucinogen-containing disorder of the present invention, the method ... The method of claim 1, wherein the compound is

79. 10. The method of claim 1, wherein the hallucinogen is delivered with air, oxygen, or a mixture of helium and oxygen.

78. The method according to claim 78.

80. The hallucinogen is delivered with the helium and oxygen mixture, and the hallucinogen is delivered to the patient.

8. Claim 7, wherein the mixture of helium and oxygen is heated to about 50°C to about 60°C prior to administration of the agent.

9. The method according to claim 9.

81. The CNS disorder is post-traumatic stress disorder (PTSD), major depressive disorder (MDD), ), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, or suicidal ideation or behavior Major depressive disorder, non-suicidal self-injury disorder (NSSID), bipolar disorder type I, bipolar disorder type II Bipolar disorder and related disorders, including cyclothymic disorder, obsessive-compulsive disorder (OCD), and generalized anxiety Generalized Anxiety Disorder (GAD), Social Anxiety Disorder, Alcohol Use Disorder, Opioid Use Disorder, Amphetamine substance use disorders, including amine use disorder, nicotine use disorder, and cocaine use disorder; neurological disorders Anorexia, Bulimia Nervosa, Binge Eating Disorder, Alzheimer's Disease, Cluster and Migraine Headaches, Attention ADHD, pain and neuropathic pain, aphantasia, childhood-onset hyperactivity disorder Symptoms include: psoriasis, dementia, mild dementia, sexual dysfunction, chronic fatigue syndrome, Lyme disease, or obesity.

79. The method of claim 78,

82. A transdermal patch comprising a compound of claim 1.

83. 83. The method of claim 82, further comprising a pressure sensitive adhesive layer, a backing, and a release liner. Transdermal patch.

84. 84. The transdermal adhesive of claim 83, wherein the compound is uniformly distributed throughout the pressure-sensitive adhesive layer. patch.

85. 83. The transdermal patch of claim 82, comprising 5 mg to 25 mg of the compound.

86. Serotonin 5-HT ２ In a method of treating a subject having a disease or disorder associated with a receptor There was, 83. A therapeutically effective amount of the compound is administered to the subject via the transdermal patch of claim 82. A method comprising:

87. Serotonin 5-HT ２ The disease or disorder associated with the receptor may also be a neuropsychiatric disorder.

87. The method of claim 86, wherein the disease or disorder is an inflammatory disease or disorder.

88. Serotonin 5-HT ２ The disease or disorder associated with the receptor is a central nervous system (CNS) 87. The method of claim 86, wherein the disorder is

89. The central nervous system (CNS) disorder is post-traumatic stress disorder (PTSD), major depression, Sexual Disorder (MDD), Treatment-Resistant Depression (TRD), Suicidal Thoughts, Suicidal Behavior, Suicidal Ideation or Major depressive disorder with suicidal behavior, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders Concurrent disorder, cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorders, substance use disorders, anorexia nervosa, bulimia nervosa, binge eating disorder, Alzheimer's disease, Cluster headaches and migraines, Attention Deficit Hyperactivity Disorder (ADHD), Pain, Aphantasia, Children Early-onset fluency, dementia, mild dementia, sexual dysfunction, chronic fatigue syndrome, Lyme disease, and obesity.

90. Serotonin 5-HT ２ The disease or disorder associated with a receptor is a neurotransmitter that is involved in the autonomic nervous system (ANS).

87. The method of claim 86, wherein the disorder is

91. 91. The method of claim 90, wherein the disorder of the autonomic nervous system (ANS) is a pulmonary disorder or a cardiovascular disorder. The method described.

92. wherein 5 mg to 25 mg of the compound is administered to the subject over a period of 4 to 72 hours.

87. The method of claim 86.

93. The compound is administered at a concentration that is serotonergic but less than psychoactive.

87. The method of claim 86.

94. Serotonin 5-HT ２ In a method of treating a subject having a disease or disorder associated with a receptor There was, 10. The subject is administered a therapeutically effective amount of the compound of claim 1 transdermally via an automatic injection device. administering intravenously, subcutaneously, or intramuscularly.

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