Phenethylamine Derivatives, Compositions, and Methods of Use

Abstract

Hallucinogenic and entactogenic compounds, the use of such compounds in treating diseases associated with serotonin receptors or monoamine transporters, pharmaceutical compositions such as tablet compositions and kits containing the compounds, methods of delivering the compounds in a mist via inhalation, and methods of treating diseases or disorders associated with serotonin receptors or monoamine transporters such as inflammation, central nervous system (CNS) disorders, or psychological disorders with the compounds of the invention are disclosed.

Description

[Technical Field]

[0001] cross reference This application claims priority to U.S. Provisional Application No. 63 / 268,020, filed February 15, 2022, and U.S. Provisional Application No. 63 / 268,024, filed February 15, 2022, each of which is incorporated by reference in its entirety.

[0002] The present disclosure relates generally to chemical compounds, in some embodiments to serotonin 5-HT2 receptor agonists, in some embodiments to serotonin receptor modulators, and in some embodiments to monoamine transporter modulators, for use in treating diseases associated with the 5-HT2 receptor, and for use in treating diseases associated with monoamine transporters. [Background technology]

[0003] The "Background" discussion provided herein is for purposes of generally presenting the contents of the present disclosure. To the extent described in this Background section, the work of the currently named inventors, as well as aspects of the discussion that may not have been admitted as prior art at the time of filing, are not expressly or impliedly admitted as prior art against the present invention.

[0004] Serotonin 5-HT2 receptors (5-HT2Rs) contain 5-HT 2A , 5-HT 2B , and 5-HT 2CThere are three closely related subtypes of psychedelics, which are the primary targets of classical serotonergic hallucinogens such as lysergic acid diethylamide (LSD), psilocybin, and 2,5-dimethoxy-4-bromoamphetamine (DOB). Classical serotonergic hallucinogens and entactogens, which also modulate the activity of monoamine transporters, including the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), have been implicated in a number of central nervous system (CNS) disorders (Reiff, CM, Richman, EE, Nemeroff, CB, Carpenter, LL, Widge, AS, Rodriguez, CI, Kalin, NH, and McDonald, WM, 2020, Psychedelics and Psychedelic-Assisted Psychotherapy, Am J Psychiatry 177, 391-410), such as: (i) post-traumatic stress disorder (PTSD) (Jerome, L., Feduccia, AA, Wang, JB, Hamilton, S., Yazar-Klosinski, B., Emerson, A., Mithoefer, MC, and Doblin, R., 2020, Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials, Psychopharmacology (Berl) 237, 2485-2497), (ii) major depressive disorder (MDD), (iii) treatment-resistant depression (TRD) (Goldberg, SB, Pace, BT, Nicholas, 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, C.B., Taitano, EK, and Delgado, PL, 2006, Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder, J Clin Psychiatry 67, 1735-1740), (v) social anxiety disorder (ClinicalTrials.gov number NCT02008396), (vi) substance use disorders (including, but not limited to, alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder), (vii) anorexia nervosa, (viii) bulimia nervosa (ClinicalTrials.gov numbers NCT04454684 and NCT04052568), (ix) Alzheimer's disease (ClinicalTrials.gov number NCT04123314), (x) cluster headache and migraine. (Nichols, DE, 2016, Psychedelics, Pharmacol Rev 68, 264-355; Johnson, MW, Hendricks, PS, Barrett, FS, and Griffiths, RR, 2019, Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function, Pharmacol Ther 197, 83-102; Sewell, RA, Halpern, JH, and Pope, HG, Jr., 2006, Response of cluster headache to psilocybin and LSD, Neurology 66, 1920-1922, ClinicalTrials.gov number NCT04218539) It has been actively investigated by research and medical communities to alleviate cluster headache.

[0005] These agents are also being investigated to alleviate conditions of the autonomic nervous system (ANS), including pulmonary disorders (e.g., asthma and chronic obstructive pulmonary disorder (COPD)) and cardiovascular disorders (e.g., atherosclerosis), among others (Nichols, DE, Johnson, MW, and Nichols, CD, 2017, Psychedelics as Medicines: An Emerging New Paradigm, Clin Pharmacol Ther 101, 209-219; Flanagan, TW, Sebastian, MN, Battaglia, DM, Foster, TP, Cormier, SA, and Nichols, CD, 2019, 5-HT2 receptor activation alleviates airway inflammation and structural remodeling in a chronic mouse asthma model, Life Sci 236, 116-790; Flanagan, TW, Sebastian, MN, Battaglia, DM, Foster, TP, Maillet, EL, and Nichols, CD, 2019, Activation of 5-HT2 Receptors Reduces Inflammation in Vascular Tissue and Cholesterol Levels in High-Fat Diet-Fed Apolipoprotein E Knockout Mice,Sci Rep 9,13444, Sexton,JD,Nichols,CD,and Hendricks,PS,2019,Population Survey Data Informing the Therapeutic Potential of Classic and Novel Phenethylamine,Tryptamine,and Lysergamide Psychedelics, Front Psychiatry 10,896).

[0006] Several studies have progressed to Phase III trials, for example, the use of 3,4-methylenedioxymethamphetamine for the treatment of PTSD (Feduccia, A.A., Jerome, L., Yazar-Klosinski, B., Emerson, A., Mithoefer, M.C., and Doblin, R., 2019, Breakthrough for Trauma Treatment: Safety and Efficacy of MDMA-Assisted Psychotherapy Compared to Paroxetine and Sertraline, Front Psychiatry 10, 650), and a Phase 1 trial of 3,4,5-trimethoxyphenethylamine (mescaline) has begun (ClinicalTrials.gov number NCT04227756).

[0007] Mechanistically, the therapeutic effects of hallucinogenic phenethylamines / amphetamines are due to their ability to activate serotonin (5-HT) receptors, particularly 5-HT 2A It is thought to be mediated by interaction with receptors, including 5-HT1 receptors (e.g., 5-HT 1A , 5-HT 1B Other targets may also be involved, including 5-HT (Nichols, DE, 2016, Psychedelics, Pharmacol Rev 68, 264-355; Canal, CE, 2018, Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action, Handb Exp Pharmacol 252, 227-260). 2C Contributions from the serotonin 5-HT receptor may be involved in the reported anti-additive properties of classical hallucinogens (Canal, C.E., and Murnane, K.S., 2017). 2Creceptor and the non-addictive nature of classic hallucinogens, J Psychopharmacol 31, 127-143). The effects of entactogens, phenethylamines, including MDMA and MDA, are primarily mediated by their interaction with monoamine transporters, particularly the serotonin (SERT) and dopamine (DAT) transporters (Jayanthi, LD, and Ramamoorthy, S., 2005, Regulation of monoamine transporters: influence of psychostimulants and therapeutic antidepressants, AAPS J 7, E728-738).

[0008] The safety profile of hallucinogens and entactogens remains a significant issue for clinical use, and treatment protocols are challenged by the following factors: 1) a relatively slow onset of hallucinogenic therapeutic benefit; 2) long-acting effects, often requiring daily patient supervision; 3) numerous acute neuropsychiatric and gastrointestinal adverse effects, including anxiety, fear, tachycardia, hypertension, elevated body temperature, nausea, and vomiting, with many acute adverse effects resulting from high drug concentrations ("spikes") in the blood immediately after oral administration; 4) low brain bioavailability (e.g., observed with methacholine); 5) therapeutic effects requiring high oral doses (e.g., observed with methacaline and MDMA); and 6) toxicity, such as neurotoxicity and cardiac toxicity (Schenk, S., and Newcombe, D., 2018, Methylenedioxymethamphetamine (MDMA) in Psychiatry: Pros, Cons, and Suggestions, J Clin Psychopharmacol 38,632-638, Garcia-Romeu, A., Kersgaard, B., and Addy, PH, 2016, Clinical applications of hallucinogens: A review, Exp Clin Psychopharmacol 24,229-268, Morgan, L., 2020, MDMA-assisted psychotherapy for people diagnosed with treatment-resistant PTSD: what it is and what it isn't, Ann Gen Psychiatry 19,33, Schenk, S., and Newcombe, D., 2018, Methylenedioxymethamphetamine (MDMA) in Psychiatry: Pros, Cons, and Suggestions, J Clin Psychopharmacol 38, 632-638, Huang, X.-P., Setola, V., Yadav, PN, Allen, JA, Logan, SC, Hanson, BJ, Revankar, C., Robers, M., Doucette, C., and Roth, BL.,2009,Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine(2B)Receptor Agonists:Implications for Drug Safety Assessment,Molecular Pharmacology 76,710-722、Rothman,R.B.,and Baumann,M.H.,2009,Serotonergic drugs and valvular heart disease,Expert Opin Drug Saf 8,317-329、Parrott,A.C.,2014,The potential dangers of using MDMA for psychotherapy,J Psychoactive Drugs 46,37-43、Meyer,J.S.,2013,3,4-methylenedioxymethamphetamine (MDMA):current perspectives,Subst Abuse Rehabil 4,83-99、Baylen,C A.,and Rosenberg,H.,2006,A review of the acute subjective effects of MDMA / ecstasy,Addiction 101,933-947、Shulgin,A.,and Shulgin,Ann.,1991,Pihkal:a chemical love story,Transform Press,Berkeley,CA、Barrett,F.S.,Bradstreet,M.P.,Leoutsakos,J.S.,Johnson,M.W.,and Griffiths,R.R.,2016,The Challenging Experience Questionnaire:Characterization of challenging experiences with psilocybin mushrooms,J Psychopharmacol 30,1279-1295)。.

[0009] For drugs containing a methylenedioxy ring, such as 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), and 3,4-methylenedioxyphenethylamine (MDPEA), metabolic degradation, including O-demethylation (primarily mediated by the CYP2D6 enzyme), contributes to poor exposure. (Tucker, GT, Lennard, MS, Ellis, SW, Woods, HF, Cho, AK, Lin, LY, Hiratsuka, A., Schmitz, DA, and Chu, TYY, 1994, The demethylenation of methylenedioxymethamphetamine ("ecstasy") by debrisoquine hydroxylase (CYP2D6), Biochemical Pharmacology 47, 1151-1156; Schmid, Y., Vizeli, P., Hysek, CM, Prestin, K., Meyer, Zu Schwabedissen, HE, and Liechti, ME, 2016, CYP2D6 function moderates the pharmacokinetics and pharmacodynamics of 3,4-methylene-dioxymethamphetamine in a controlled study in healthy individuals, Pharmacogenet Genomics 26,397-401).For example, MDPEA is biologically inactive due to extensive first-pass metabolism, whereas the metabolism of drugs such as MDMA follows nonlinear pharmacokinetics, which results in a disproportionate increase in plasma MDMA concentrations with relatively small dose increases, contributing to increased toxicity (de la Torre, R., Farre, M., Roset, PN, Pizarro, N., Abanades, S., Segura, M., Segura, J., and Cami, J., 2004, Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition, Ther Drug Monit 26, 137-144; de la Torre, R., Farre, M., Ortuno, J., Mas, M., Brenneisen, R., Roset, PN, Segura, J., and Cami, J., 2000, Non-linear pharmacokinetics of MDMA ('ecstasy') in humans, British journal of clinical pharmacology 49,104-109, Farre, M., de la Torre, R., Mathuna, BO, Roset, PN, Peiro, AM, Torrens, M., Ortuno, J., Pujadas, M., and Cami, J., 2004, Repeated doses administration of MDMA in humans: pharmacological effects and pharmacokinetics, Psychopharmacology (Berl) 173, 364-375).Indeed, the metabolism of methylenedioxy-containing drugs leads to high exposure to toxic metabolites, such as 3,4-dihydroxymethamphetamine, in the case of MDMA, a cardiotoxic metabolite (Schindler, CW, Thorndike, EB, Blough, BE, Tella, SR, Goldberg, SR, and Baumann, MH, 2014, Effects of 3,4-methylenedioxymethamphetamine (MDMA) and its main metabolites on cardiovascular function in conscious rats, Br J Pharmacol 171, 83-91).

[0010] In the case of amphetamines such as MDMA, 2,4,5-trimethoxyphenylamphetamine (TMA-2), and 1-(2,5-dimethoxy-4-(methylthio)phenyl)propan-2-amine (DOT), the lipophilic α-side chain methyl group on the phenethylamine scaffold generally enhances pharmacokinetic and pharmacodynamic properties compared to phenethylamine. Thus, they generally have longer half-lives than phenethylamine. They also have higher intrinsic activity at their targets; for example, substituted amphetamine hallucinogens are full agonists at G protein-coupled receptors (GPCRs) versus their phenethylamine analogs, which are partial agonists. (Rickli, A., Luethi, D., Reinisch, J., Buchy, D., Hoener, MC, and Liechti, ME, 2015, Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs), Neuropharmacology 99, 546-553; Monte, AP, Marona-Lewicka, D., Parker, MA, Wainscott, DB, Nelson, DL, and Nichols, DE, 1996, Dihydrobenzofuran analogues of hallucinogens. 3. Models of 4-substituted (2,5-dimethoxyphenyl) alkylamine derivatives with rigidified methoxy groups,J Med Chem 39,2953-2961, Monte,AP,Waldman,SR,Marona-Lewicka,D.,Wainscott,DB,Nelson,DL,Sanders-Bush,E.,and Nichols,DE,1997,Dihydrobenzofuran analogues of hallucinogens.4.Mescaline derivatives,J Med Chem 40,2997-3008, Pottie,E., Cannaert, A., and Stove, CP, 2020, In vitro structure-activity relationship determination of 30 psychedelic new psychoactive substances by means of beta-arrestin 2 recruitment to the serotonin 2A receptor, Arch Toxicol; Rickli, A., Moning, OD, Hoener, MC, and Liechti, ME, 2016, Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens, Eur Neuropsychopharmacol 26, 1327-1337). Therefore, substituted amphetamines generally have a higher risk of side effects and toxicity compared with substituted phenethylamines. Furthermore, enantiomeric amphetamines can induce different effects, be metabolized at different rates, and are gender- and race-dependent, with differentiation between poor and rapid metabolizers resulting in even more unpredictable pharmacokinetic outcomes. For example, the (S)-enantiomer of MDMA has been shown to exhibit greater stimulant-like properties, while the (R)-enantiomer has been shown to exhibit greater 5-HT2-mediated hallucinogenic properties. The (S)-enantiomer of MDMA is also metabolized more rapidly than the (R)-enantiomer, resulting in two effects: 1) a lower AUC and plasma half-life of the (S)-enantiomer compared to the (R)-enantiomer, and 2) a more sustained bioavailability of the (S)-enantiomer of the active metabolite MDMA.

[0011] In the case of 3,4,5-substituted phenethylamines, such as mescaline, which is found in cacti such as peyote (Lophophora williamsii) and San Pedro (Echinopsis pachanoi), the hallucinogenic effects are also due to 5-HT 2C and 5-HT 1A5-HT with contribution from agonism at the receptor 2A(Nichols, DE, 2004, Hallucinogens, Pharmacol Ther 101, 131-181; Rickli, A., Luethi, D., Reinisch, J., Buchy, D., Hoener, MC, and Liechti, ME, 2015, Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs), Neuropharmacology 99, 546-553; Braden, MR, Parrish, JC, Naylor, JC, and Nichols, DE, 2006, Molecular interaction of serotonin 5-HT2A receptor residues Phe339(6.51) and Phe340(6.52) with superpotent N-benzyl phenethylamine agonists, Mol Pharmacol 70, 1956-1964). Like other members of this class, mesaccharin induces changes in perception, cognition, emotion, and mood that may underlie its reported neuropsychiatric and psychospiritual benefits (Johnson, MW, Hendricks, PS, Barrett, FS, and Griffiths, RR, 2019, Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function, Pharmacol Ther 197, 83-102).However, although mescaline is orally active, it has a slow onset of action only at high doses (e.g., about 300 mg) due to low brain bioavailability, and causes nausea (Shulgin, A., and Shulgin, Ann., 1991, Pihkal: a chemical love story, Transform Press, Berkeley, CA).

[0012] Clearly, the safe therapeutic window for hallucinogens and entactogens, such as those containing a methylenedioxy ring, amphetamines, and 3,4,5-substituted phenethylamines, is very narrow, and controlling drug exposure and maintaining drug concentrations within a safe and effective range has proven difficult. Summary of the Invention

[0013] In view of the foregoing, there is a need for novel hallucinogen and entactogen compounds with improved and predictable pharmacokinetic properties that are shorter in duration, bioavailable, less toxic, cause fewer side effects, and exhibit enhanced oral activity at lower doses. There is a further need for efficient, more convenient, and controllable compound formulations that do not result in neurologically toxic (e.g., psychotomimetic) plasma concentrations.

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

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

[0016] It is another object of the present disclosure to provide novel methods of treating a subject with a disease or disorder associated with the serotonin 5-HT2 receptor or monoamine transporter with compounds.

[0017] It is another object of the present disclosure to provide novel tablet compositions, such as single-layer orally administered tablet compositions, comprising the compound.

[0018] It is another object of the present disclosure to provide novel kits containing formulations of compounds for use in therapy.

[0019] It is yet another object of the present disclosure to provide novel methods of delivering compounds in aerosols, preferably mists, via inhalation, such as for the treatment of central nervous system (CNS) or psychological disorders.

[0020] It is yet another object of the present invention to provide novel uses of compounds for treating a subject having a disease or disorder associated with the serotonin 5-HT2 receptor or monoamine transporter, such as a central nervous system (CNS) disorder or a psychological disorder.

[0021] These and other objectives, which will become apparent during the detailed description below, are achieved by the inventors' discovery of novel compounds described herein (e.g., compounds of Formulas (I)-(V)), including those that maintain preferential binding to G protein-coupled receptors (GPCRs), e.g., 5-HT2 receptors, monoamine transporters, or 5-HT1 receptors, that are bioavailable (e.g., orally bioavailable), have improved exposure (i.e., preventing high drug concentration spikes observed acutely after administration), and have advantageous enzymatic degradation profiles that prevent bioactivation to toxic metabolites. As a result, the disclosed compounds have reduced propensity for side effects, toxicity, and interpatient variability, thereby improving the therapeutic window and enabling practical use in clinical settings. The novel compounds are based on specific molecular modifications—modifications identified only after significant research—that delay or avoid enzymatic degradation at specific sites and / or introduce metabolic soft spots at other sites.

[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, During the ceremony, X 1 and X 2 are independently hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl; Y 1 and Y 2 are independently hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl; R 2 and R 3 are independently hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, -OR a , -SR a and R 4 and R 5 are independently hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, -OR a , -SR a , or -SeR a or R 4 and R 5 are optionally joined together with the atoms to which they are attached to form a heterocycloalkyl or heteroaryl; R 6 and R 7 are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or alternatively, R 6 and R 7 together with the nitrogen atom to which they are attached, are optionally joined to form a substituted or unsubstituted heterocycloalkyl; Each R a are independently hydrogen, deuterium, substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3 to C6 10 is cycloalkyl, At least one of the conditions (i) to (iii) is satisfied, (i)X 1 , X 2 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 at least one of which contains deuterium; (ii)R 4 and R 5 are bonded together with the atoms to which they are bonded to form a heterocycloalkyl or heteroaryl containing deuterium or fluorine, and / or a benzo[d][1,3]oxathiol group; (iii)R 4 But, -OR a , -SR a , or -SeR a and R 4 R in a is C1-C6 alkyl substituted with one or more halogens; However, X 1 , X 2 , Y 1 , and Y 2 are each hydrogen or deuterium, R 2 and R 5 Both -OR a or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, provided that: (2)X 1 , X 2 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 The compound according to (1), wherein at least one of the groups contains deuterium. (3)R 4 and R 5are bonded together with the atoms bound thereto to form a heterocycloalkyl or heteroaryl containing deuterium or fluorine, and / or a benzo[d][1,3]oxathiol group. (4)R 4 But, -OR a , -SR a , or -SeR a and R a is a C1-C6 alkyl substituted with one or more halogens. (5) The compound according to any one of (1) to (4), which is an agonist of a serotonin 5-HT2 receptor. (6) The compound is a serotonin 5-HT 2A The compound according to any one of (1) to (5), which is an agonist of a receptor. (7) A compound according to any one of (1) to (3) or (5) to (6), having the structure of formula (II): [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, During the ceremony, X 1 and X 2 are independently hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl; Y 1 and Y 2 are independently hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl; R 2 and R 3 are independently hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, -OR a , or -SR a and R 6 and R 7are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or alternatively, R 6 and R 7 together with the nitrogen atom to which they are attached, are optionally joined to form a substituted or unsubstituted heterocycloalkyl; Each R a are independently hydrogen, deuterium, substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3 to C6 10 is cycloalkyl, A is O or S, Z 1 and Z 2 are independently hydrogen, deuterium, or fluorine; If A is O, then X 1 , X 2 ,Y 1 ,Y 2 ,R 2 ,R 3 ,R 6 ,R 7 ,Z 1 ,Z 2 At least one of the groups contains deuterium and / or Z 1 and Z 2 or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein at least one of: (8)R 2 But, -OR a The compound according to (7), (9)X 1 and X 2 is hydrogen. (10)X 1 and X 2 is deuterium. (11)X 1 is hydrogen or deuterium, and X 2is a substituted or unsubstituted C1 to C6 alkyl. (12) The compound according to any one of (7) to (11), wherein A is S. (13) The compound according to any one of (7) to (11), wherein A is O. (14)Z 1 and Z 2 is hydrogen. (15)Z 1 and Z 2 is deuterium. (16) [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] The compound according to any one of (7) to (15), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, selected from the group consisting of: (17) having the structure of formula (III), [ka] During the ceremony, X 1 and X 2 are independently hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl; Y 1 and Y 2 are independently hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl; R 4 is a substituted or unsubstituted C1-C6 alkyl, -OR a , -SR a , or -SeR a and R 6 and R 7are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or alternatively, R 6 and R 7 together with the nitrogen atom to which they are attached, are optionally joined to form a substituted or unsubstituted heterocycloalkyl; Each R a are independently hydrogen, deuterium, substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3 to C6 10 is cycloalkyl, X 1 , X 2 ,Y 1 ,Y 2 ,R 4 ,R 6 ,R 7 , R a At least one of the groups contains deuterium, and / or R 4 But, -OR a , -SR a , or -SeR a and R 4 R in a is C1-C6 alkyl substituted with one or more halogen atoms, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. (18)R 4 But, -SMe, -SCD 3, -SCF 3, -SEt,-SnPr, -SCH2CH2CF3,-SCH2CH2CF2H,-SCH2CH2CFH2,-Me,-CD3,-CF3,-OMe,-OCD3,-OCF3, The compound according to (17), which is -OCH2CH2CF3, -OCH2CH2CF2H, -OCH2CH2CFH2, or -Br. (19)Each R aare independently -Me, -CD3, or -CF3. (20)X 1 and X 2 is hydrogen. (21)X 1 and X 2 is deuterium. (twenty two) [ka] [ka] [ka] [ka] [ka] [ka] [ka] The compound according to any one of (17) to (21), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, selected from the group consisting of: (23) A pharmaceutical composition comprising the compound according to any one of (1) to (22) and a pharmaceutically acceptable excipient. (24) The pharmaceutical composition according to (23), wherein the compound is present in the pharmaceutical composition with a purity of at least 50% by weight, based on the total weight of the compound's isotopologues present in the pharmaceutical composition. (25) The pharmaceutical composition according to (23) or (24), wherein any position in the compound having deuterium has a minimum deuterium incorporation of at least 50 atomic % at the site of deuteration. (26) The pharmaceutical composition according to any one of (23) to (25), which is substantially free of other isotopologues of the compound. (27) The pharmaceutical composition according to any one of (23) to (26), which is formulated for oral administration. (28) The pharmaceutical composition according to any one of (23) to (27), which is formulated for administration via inhalation. (29) A method for treating a subject having a disease or disorder associated with a serotonin 5-HT2 receptor or a monoamine transporter, comprising: A method comprising administering a therapeutically effective amount of a compound according to any one of (1) to (22) to a subject. (30) The method according to (29), wherein the disease or disorder associated with a serotonin 5-HT2 receptor or a monoamine transporter is a neuropsychiatric disease or an inflammatory disease or disorder. (31) The method according to (29) or (30), wherein the disease or disorder associated with a serotonin 5-HT2 receptor or a monoamine transporter is a central nervous system (CNS) disorder. (32) The method of (31), wherein the central nervous system (CNS) disorder is selected from the group consisting of post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation 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 disease, post-mortem symptoms from SARS-CoV-2 infection (COVID-19), cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain, aphantasia, childhood-onset dysfluency disorder, severe neurocognitive disorder, mild neurocognitive disorder, sexual dysfunction, chronic fatigue syndrome, Lyme disease, and obesity. (33) The method according to (31) or (32), wherein the central nervous system (CNS) disorder is pain. (34) The method according to (31) or (32), wherein the central nervous system (CNS) disorder is sexual dysfunction. (35) The method according to (29) or (30), wherein the disease or disorder associated with a serotonin 5-HT2 receptor or a monoamine transporter is an autonomic nervous system (ANS) disorder. (36) The method according to (35), wherein the autonomic nervous system (ANS) disorder is a pulmonary disorder or a cardiovascular disorder. (37) The method according to any one of (29) to (36), wherein the compound is administered orally, sublingually, bucally, topically, via injection, or via inhalation. (38) A single-layer tablet composition for oral administration, comprising the compound according to (1) to (22) and a polymer. (39) The monolayer oral administration tablet composition according to (38), wherein the composition is adapted for maximum sustained release. (40) The monolayer oral administration tablet composition according to (38) or (39), wherein the tablet composition comprises a combination of (i) a water-insoluble neutrally charged nonionic matrix, (ii) a polymer carrying one or more negatively charged groups, and (iii) a compound. (41) The monolayer oral tablet composition according to (40), wherein the water-insoluble, neutrally charged nonionic matrix is ​​selected from a cellulose-based polymer alone or reinforced by mixing with a component selected from the group consisting of starch, wax, neutral gum, polymethacrylate, PVA, PVA / PVP blends, and mixtures thereof. (42) The monolayer oral administration tablet composition according to (41), wherein the cellulose-based polymer is hydroxypropyl methylcellulose (HPMC). (43) The monolayer tablet composition for oral administration according to any one of (40) to (42), wherein the polymer carrying one or more negatively charged groups is selected from the group consisting of polyacrylic acid, polylactic acid, polyglycolic acid, polymethacrylate carboxylate, cation exchange resins, clays, zeolites, hyaluronic acid, anionic gums, salts thereof, and mixtures thereof. (44) The monolayer oral tablet composition according to (43), wherein the anionic rubber is selected from the group consisting of natural materials and semi-synthetic materials. (45) The monolayer oral tablet composition according to (44), wherein the natural material is selected from the group consisting of alginic acid, pectin, xanthan gum, carrageenan, locust bean gum, gum arabic, gum karaya, guar gum, and gum tragacanth. (46) The monolayer oral tablet composition according to (44) or (45), wherein the semi-synthetic material is selected from the group consisting of carboxymethyl-chitin and cellulose gum. (47) The monolayer tablet composition for oral administration according to any one of (38) to (46), which contains a therapeutically effective amount of a compound for the treatment of pain. (48) The monolayer tablet composition for oral administration according to any one of (38) to (46), which contains a therapeutically effective amount of a compound for treating brain injury. (49) The monolayer tablet composition for oral administration according to any one of (38) to (46), which contains a therapeutically effective amount of a compound for treating depression. (50) The monolayer oral administration tablet composition according to any one of (38) to (46), which contains a therapeutically effective amount of a compound for use in treating a disease or disorder associated with a serotonin 5-HT2 receptor or a monoamine transporter. (51) The disease or disorder is post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or behavior, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders (including bipolar I disorder and bipolar II disorder), cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, substance use disorder (alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder), anorexia nervosa, bulimia nervosa, binge eating disorder, Alzheimer's disease, post-mortem symptoms from SARS-CoV-2 infection (COVID-19), cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset dysphagia, severe neurocognitive disorder, mild neurocognitive disorder, sexual dysfunction, chronic fatigue syndrome, Lyme disease, and obesity. (52) The monolayer orally administered tablet composition according to (50), wherein the disease or disorder is a condition of the autonomic nervous system (ANS). (53) The monolayer tablet composition for oral administration according to (52), wherein the disease or disorder is a pulmonary disorder. (54) The monolayer tablet composition for oral administration according to (52), wherein the disease or disorder is a cardiovascular disorder. (55) The monolayer tablet composition for oral administration according to any one of (50) to (54), wherein the composition achieves a combined concentration of the compound in plasma in the range of 10 to 500 ng / ml and maintains this concentration during the release period. (56) The monolayer tablet composition for oral administration according to any one of (38) to (55), wherein the polymer contains one or more negatively charged groups. (57) A tablet composition formulated for oral administration, comprising the compound according to (1) to (22) and a polymer. (58) The tablet composition according to (57), wherein the polymer contains one or more negatively charged groups. (59) The tablet composition according to (57) or (58), wherein the polymer contains one or more acid groups. (60) The tablet composition according to any one of (57) to (59), wherein the polymer comprises a water-insoluble, neutrally charged nonionic matrix. (61) The tablet composition according to (60), wherein the water-insoluble, neutrally charged nonionic matrix is ​​selected from a cellulose-based polymer alone or reinforced by mixing with a component selected from the group consisting of starch, wax, neutral gum, polymethacrylate, PVA, PVA / PVP blends, and mixtures thereof. (62) The tablet composition according to (61), wherein the cellulose-based polymer is hydroxypropyl methylcellulose (HPMC). (63) A kit for treating a subject, comprising: 1) the monolayer orally administered tablet composition according to any one of (38) to (56); and 2) instructions for use in treating pain. (64) The kit according to (63), wherein the polymer comprises one or more negatively charged groups. (65) A kit for treating a subject, comprising: 1) the monolayer orally administered tablet composition according to any one of (38) to (56); and 2) instructions for use in treating brain injury. (66) The kit according to (65), wherein the polymer comprises one or more negatively charged groups. (67) A kit for treating a subject, comprising: 1) the monolayer orally administered tablet composition according to any one of (38) to (56); and 2) instructions for use in treating depression. (68) The kit according to (67), wherein the polymer comprises one or more negatively charged groups. (69) A kit for treating a subject, comprising: 1) the monolayer orally administered tablet composition according to any one of (38) to (56); and 2) instructions for use in treating a disease or disorder associated with a serotonin 5-HT2 receptor or a monoamine transporter. (70) The kit according to (69), wherein the polymer comprises one or more negatively charged groups. (71) A method for delivering a hallucinogen to a patient in need thereof, comprising administering via inhalation a hallucinogen dissolved in the liquid phase of an aerosol (e.g., a mist), wherein the hallucinogen comprises a compound according to any one of (1) to (22). (72) The method according to (71), wherein the hallucinogen is delivered to the central nervous system of the patient. (73) The method according to (71) or (72), wherein the hallucinogen is delivered in air, oxygen, or a mixture of helium and oxygen. (74) The method according to any one of (71) to (73), wherein the hallucinogen is delivered in a mixture of helium and oxygen. (75) The method according to (74), wherein the mixture of helium and oxygen is heated to about 50°C to about 60°C. (76) The method according to (74) or (75), wherein helium is present in the mixture of helium and oxygen at about 50-90% and oxygen is present in the mixture of helium and oxygen at about 10-50%. (77) The method according to any one of (74) to (76), further comprising administering a pre-treatment inhalation therapy prior to administration of the mixture of helium and oxygen and the hallucinogen. (78) The method of (77), wherein the pretreatment comprises administering to the patient via inhalation a mixture of helium and oxygen heated to about 90°C to about 120°C. (79) The method of any one of (71) to (78), further comprising: (i) administering to the patient via inhalation a mixture of helium and oxygen heated to about 90°C to about 120°C; and (ii) administering to the patient via inhalation an aerosol (e.g., mist) comprising helium and oxygen heated to about 50°C to about 60°C and a hallucinogen. (80) The method according to (79), further comprising repeating steps (i) and (ii) one or more times. (81) A hallucinogen is delivered to the central nervous system of a patient with at least a 25% improvement in drug bioavailability compared to oral delivery, and max At least a 25% increase in T compared to oral delivery max The method according to any one of (71) to (80), wherein the method is accompanied by at least a 50% reduction in the amount of the hydroxybenzoates, or a combination thereof. (82) A method for treating a central nervous system (CNS) disorder or a psychological disorder, comprising administering via inhalation a hallucinogen dissolved in an aerosol (e.g., a mist), wherein the hallucinogen comprises a compound according to any one of (1) to (22). (83) The method according to (82), wherein the hallucinogen is delivered in air, oxygen, or a mixture of helium and oxygen. (84) The method of (83), wherein the hallucinogen is delivered in a mixture of helium and oxygen, and the mixture of helium and oxygen is heated to about 50°C to about 60°C prior to administering the hallucinogen to the patient. (85) CNS disorders include post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or behavior, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders (including bipolar I disorder and bipolar II disorder), cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, and substance use disorders (alcohol use disorder, opioid use disorder, amphetamine use disorder). The method according to any one of (82) to (84), wherein the condition is anorexia nervosa, bulimia nervosa, binge eating disorder, Alzheimer's disease, post-mortem symptoms from SARS-CoV-2 infection (COVID-19), cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset dysphagia, severe neurocognitive disorder, mild neurocognitive disorder, sexual dysfunction, chronic fatigue syndrome, Lyme disease, or obesity. (86) A method for treating a subject having a disease or disorder associated with a serotonin receptor or a monoamine transporter, comprising: A method comprising administering to a subject a therapeutically effective amount of a compound according to any one of (1) to (22) transdermally, subcutaneously, or intramuscularly via an automatic injection device. (87) A compound having the structure of formula (IV): [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, During the ceremony, X 1 is hydrogen or deuterium, X 2 is a substituted or unsubstituted C1-C6 alkyl; Y 1 and Y 2 are independently hydrogen or deuterium; R 3 is hydrogen or deuterium, R 4is hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, -OR b , -SR b , or -SeR b and R 6 and R 7 are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or alternatively, R 6 and R 7 together with the nitrogen atom to which they are attached, are optionally joined to form a substituted or unsubstituted heterocycloalkyl; Each R a are independently substituted or unsubstituted C1-C6 alkyl, Each R b is hydrogen, deuterium, substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3 to C 10 is cycloalkyl, However, X 1 , X 2 , Y 1 ,Y 2 ,R 3 ,R 4 ,R 6 ,R 7 , and R a At least one of the groups contains deuterium, and / or R 4 But, -OR b , -SR b , or -SeR b and R 4 R in b is C1-C6 alkyl substituted with one or more halogens, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. (88) [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, selected from the group consisting of: (89) A pharmaceutical composition comprising the compound according to (87) and a pharmaceutically acceptable excipient. (90) A method for treating a subject having a disease or disorder associated with a serotonin 5-HT2 receptor or a monoamine transporter, comprising: A method comprising administering a therapeutically effective amount of a compound according to (87) to a subject. (91) The method according to (90), wherein the disease or disorder associated with a serotonin 5-HT2 receptor or a monoamine transporter is a neuropsychiatric disease or an inflammatory disease or disorder. (92) The method according to (90), wherein the disease or disorder associated with a serotonin 5-HT2 receptor or a monoamine transporter is a central nervous system (CNS) disorder. (93) The method of (92), wherein the central nervous system (CNS) disorder is selected from the group consisting of post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation 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 disease, post-mortem symptoms from SARS-CoV-2 infection (COVID-19), cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain, aphantasia, childhood-onset dysfluency disorder, severe neurocognitive disorder, mild neurocognitive disorder, sexual dysfunction, chronic fatigue syndrome, Lyme disease, and obesity. (94) A compound having the structure of formula (V): [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, During the ceremony, X 1 and X 2 are independently hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl; Y 1 and Y 2 are independently hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl; R 4 and R 5 are independently hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, -OR a , -SRa , or -SeR a or R 4 and R 5 are optionally joined together with the atoms to which they are attached to form a heterocycloalkyl or heteroaryl; R 6 and R 7 are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or alternatively, R 6 and R 7 together with the nitrogen atom to which they are attached, are optionally joined to form a substituted or unsubstituted heterocycloalkyl; Each R a are independently hydrogen, deuterium, substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3 to C6 10 is cycloalkyl, Each R b is hydrogen, deuterium, substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3 to C 10 The compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: (95) [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] 94. The compound according to (94), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, selected from the group consisting of: (96) A pharmaceutical composition comprising the compound according to (94) or (95) and a pharmaceutically acceptable excipient. (97) A method for treating a subject having a disease or disorder associated with a serotonin 5-HT2 receptor or a monoamine transporter, comprising: A method comprising administering a therapeutically effective amount of a compound according to (94) or (95) to a subject. (98) The method according to (97), wherein the disease or disorder associated with a serotonin 5-HT2 receptor or a monoamine transporter is a neuropsychiatric disease or an inflammatory disease or disorder. (99) The method according to (97), wherein the disease or disorder associated with a serotonin 5-HT2 receptor or a monoamine transporter is a central nervous system (CNS) disorder. (100) The method of (99), wherein the central nervous system (CNS) disorder is selected from the group consisting of post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation 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 disease, post-mortem symptoms from SARS-CoV-2 infection (COVID-19), cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain, aphantasia, childhood-onset dysfluency disorder, severe neurocognitive disorder, mild neurocognitive disorder, sexual dysfunction, chronic fatigue syndrome, Lyme disease, and obesity. (101) Use of a compound according to any one of (1) to (22) for treating a subject having a disease or disorder, including a disease or disorder associated with a serotonin 5-HT2 receptor or a monoamine transporter. (102) Use of the compound according to (87) or (88) for treating a subject having a disease or disorder, including a disease or disorder associated with a serotonin 5-HT2 receptor or a monoamine transporter. (103) Use of the compound according to (94) or (95) for treating a subject having a disease or disorder, including a disease or disorder associated with a serotonin 5-HT2 receptor or a monoamine transporter. [Brief explanation of the drawings]

[0024] The foregoing paragraphs have been provided by way of general introduction and are not intended to limit the scope of the claims that follow. The described embodiments, together with further advantages, will be best understood by reference to the following detailed description when considered in conjunction with the accompanying drawings.

[0025] [Figure 1] 1 shows a synthetic route for making compound II-11. [Figure 2] 1 shows a synthetic route for making compound II-14. [Figure 3] 1 shows a synthetic route for making compound II-15. [Figure 4] 1 shows a synthetic route for making compound II-16. [Figure 5] 1 shows a synthetic route for making compound II-17. [Figure 6] 1 shows a synthetic route for making compound II-20. [Figure 7] 1 shows a synthetic route for making compound II-21. [Figure 8] 1 shows a synthetic route for making compound II-58. [Figure 9] Synthetic routes are provided for making compounds of formula (II) with unsubstituted amino (—NH) groups, e.g., compounds II-1, II-4, II-5, II-9, II-10, II-12, II-13, II-18, II-19, II-27, II-29, and II-44. [Figure 10] Synthetic routes are provided for making compounds of formula (II) using methylamino (-NHMe) or methyl-d3-amino groups (-NHCD3), such as compounds II-2, II-3, II-6, II-7, II-8, II-31, II-33, II-35, II-40, II-42, II-45, II-47, and II-48. [Figure 11] 1 shows a synthetic route for making compound III-1. [Figure 12] 1 shows a synthetic route for making compound III-2. [Figure 13] 1 shows a synthetic route for making compound III-3. [Figure 14] 1 shows a synthetic route for making compound III-4. [Figure 15] 1 shows a synthetic route for making compound III-5. [Figure 16] 1 shows a synthetic route for making compound III-7. [Figure 17] 1 shows a synthetic route for making compound IV-1. [Figure 18]1 shows a synthetic route for making compound IV-9 in both the (R) and (S) enantiomers. [Figure 19] 1 shows a synthetic route for making compound IV-36. [Figure 20] A general procedure for the resolution of phenylpropan-2-amine (e.g., amphetamine) enantiomers using fractional crystallization is presented. [Figure 21] 1 shows a synthetic route for making Reference Compound 1. [Figure 22] 1 shows a synthetic route for making Reference Compound 2. [Figure 23] Graph showing agonist-labeled 5-HT2A radioligand ([H]LSD) competitive binding using compound III-5. Data shown are the average results of four experiments combined (N=12 replicates per concentration for test compound, N=8 for 5-HT). The Kd of [H]LSD was set to 0.78 nM, and data was analyzed using a two-site fitted K model (GraphPad Prism 9). Data points for -10 samples represent the total specific binding (no compound present). [Figure 24] 1 is a graph showing agonist-labeled 5-HT2A radioligand ([H]LSD) competitive binding using compound IV-1. Data shown are the average results of two combined experiments (N=12 replicates per concentration for test compound, N=4 for 5-HT). The Kd of [H]LSD was set to 0.78 nM, and data was analyzed using a one-site fitted K model (GraphPad Prism 9). Data points for -10 samples represent the total specific binding (no compound present). 5-HT data fit better with a two-site model; however, for simplicity, the results of a one-site model are shown. [Figure 25]Figure 1 shows a graph showing agonist-labeled 5-HT2A radioligand ([H]LSD) competitive binding using the R and S enantiomers of compound IV-9. Data shown are the average results of five experiments combined (N = 15 replicates). The Kd of [H]LSD was set to 0.78 nM, and data was analyzed using a one-site fitted K model (GraphPad Prism 9). Data points for -10 samples represent the total specific binding (no compound present). The 5-HT data fit better with a two-site model; however, for simplicity, the results of a one-site model are shown. [Figure 26] Figure 1 shows a graph depicting agonist-labeled 5-HT2A radioligand ([H]LSD) competitive binding using the R and S enantiomers of Reference Compound 2. Data shown are the average results of four experiments combined (N = 12 replicates). The Kd of [H]LSD was set to 0.78 nM, and data were analyzed using a one-site fitted K model (GraphPad Prism 9). Data points for -10 samples represent the total specific binding (no compound present). The 5-HT data fit better with a two-site model; however, for simplicity, results from a one-site model are shown. DETAILED DESCRIPTION OF THE INVENTION

[0026] In the following detailed description of embodiments of the present disclosure, numerous specific details are set forth in order to provide a thorough understanding of embodiments of the present disclosure. However, it will be apparent to those skilled in the art that embodiments of the present disclosure may be practiced without these specific details. In other instances, well-known methods, procedures, components, and circuits have not been described in detail as not to unnecessarily obscure aspects of the embodiments of the present disclosure.

[0027] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0028] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3 carbon atoms. This term includes, by way of example, straight-chain and branched hydrocarbyl groups such as methyl (CH-), ethyl (CHCH-), n-propyl (CHCHCH-), isopropyl ((CH)CH-), n-butyl (CHCHCHCH-), isobutyl ((CH)CHCH-), sec-butyl ((CH)(CHCH)CH-), t-butyl ((CH)C-), n-pentyl (CHCHCHCHCHCH-), and neopentyl ((CH)CCH-).

[0029] The term "substituted alkyl" refers to an alkyl group, as defined herein, wherein one or more carbon atoms in the alkyl chain are optionally substituted with -O-, -N-, -S-, -S(O) n -(n is 0 to 2), -NR- (R is hydrogen or alkyl), and substituted with a heteroatom such as deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO 2- Heteroaryl and -NR ’ R ’’ , where R ’ and R ’‘may be the same or different and have 1 to 10 substituents selected from the group consisting of hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclic groups.

[0030] "Alkylene" is -O-, -NR 10 -, -NR 10 C(O)-, -C(O)NR 10 - refers to a divalent aliphatic hydrocarbyl group having 1 to 6 carbon atoms, including 1 to 3 carbon atoms, either straight or branched, optionally interrupted with one or more groups selected from, for example, methylene (-CH-), ethylene (-CHCH-), n-propylene (-CHCHCH-), iso-propylene (-CHCH(CH)-), (-C(CH)CHCH-), (-C(CH)CHC(O)-), (-C(CH)CHC(O)NH-), (-CH(CH)CH-), and the like.

[0031] "Substituted alkylene" refers to an alkylene group having 1 to 3 hydrogens replaced with a substituent, as described for carbon in the definition of "substituted" below.

[0032] The term "alkane" refers to alkyl and alkylene groups as defined herein.

[0033] The terms "alkylaminoalkyl," "alkylaminoalkenyl," and "alkylaminoalkynyl" refer to R ’ NHR ” - refers to the group R ’ is an alkyl group as defined herein, and R ” is an alkylene, alkenylene, or alkynylene group as defined herein.

[0034] The terms "alkaryl" or "aralkyl" refer to the groups -alkylene-aryl and -substituted alkylene-aryl, where alkylene, substituted alkylene, and aryl are defined herein.

[0035] "Alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like. The term "alkoxy" also refers to the groups alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.

[0036] The term "substituted alkoxy" refers to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O-, where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl, and substituted alkynyl are as defined herein.

[0037] The term "alkoxyamino" refers to the group --NH-alkoxy, where alkoxy is as defined herein.

[0038] The term "haloalkoxy" refers to an alkyl-O- group in which one or more hydrogen atoms on the alkyl group have been replaced with a halo group and includes, by way of example, groups such as trifluoromethoxy.

[0039] The term "haloalkyl" refers to an alkyl group substituted as described above, in which one or more hydrogen atoms on the alkyl group are replaced with a halo group. Examples of such groups include, but are not limited to, fluoroalkyl groups such as trifluoromethyl, difluoromethyl, trifluoroethyl, etc.

[0040] The term "alkylalkoxy" refers to the groups -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl, where alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0041] The term "alkylthioalkoxy" refers to the groups -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl, and substituted alkylene-S-substituted alkyl, where alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0042] "Alkenyl" refers to a straight or branched chain hydrocarbyl group having 2 to 6 carbon atoms, e.g., 2 to 4 carbon atoms, and having at least one site of double bond unsaturation, e.g., 1 to 2. The term includes, by way of example, bivinyl, allyl, and but-3-en-1-yl. The term includes cis and trans isomers or mixtures of these isomers.

[0043] The term "substituted alkenyl" refers to an alkenyl group, as defined herein, having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, 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.

[0044] "Alkynyl" refers to a straight-chain or branched monovalent hydrocarbyl group having from 2 to 6 carbon atoms, e.g., 2 to 3 carbon atoms, and having at least 1 site of triple bond unsaturation, e.g., 1 or 2. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CHC≡CH).

[0045] The term "substituted alkynyl" refers to an alkynyl group, as defined herein, having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, 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.

[0046] "Alkynyloxy" refers to the group -O-alkynyl, where alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like.

[0047] "Acyl" includes HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, 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)-, ... "C(O)-," "substituted heteroaryl-C(O)-," "heterocyclyl-C(O)-," and "substituted heterocyclyl-C(O)-" groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, acyl includes the "acetyl" group CHC(O).

[0048] "Acylamino" is -NR 20 C(O) alkyl group, -NR 20 C(O)-substituted alkyl group, -NR 20 C(O)cycloalkyl group, -NR 20 C(O)-substituted cycloalkyl groups, -NR 20 C(O) cycloalkenyl group, -NR 20 C(O)-substituted cycloalkenyl group, -NR 20 C(O) alkenyl group, -NR 20 C(O)-substituted alkenyl group, -NR 20 C(O) alkynyl group, -NR 20 C(O)-substituted alkynyl group, -NR 20 C(O) aryl group, -NR 20 C(O) substituted aryl group, -NR 20 C(O) heteroaryl group, -NR 20 C(O)-substituted heteroaryl groups, -NR 20 C(O) heterocyclic groups, and -NR 20 C(O)-substituted heterocyclic groups, R 20is hydrogen or alkyl, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0049] "Aminocarbonyl" or the term "aminoacyl" refers to -C(O)NR 21 R 22 R refers to the group 21 and R 22 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0050] "Aminocarbonylamino" is -NR 21 C(O)NR 22 R 23 R refers to the group 21 , R 22 , and R 23 is independently selected from hydrogen, alkyl, aryl, or cycloalkyl, and two R groups are joined to form a heterocyclyl group.

[0051] The term "alkoxycarbonylamino" refers to the group -NRC(O)OR, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl, where alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0052] The term "acyloxy" refers to the groups 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-, where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0053] "Aminosulfonyl" is -SO2NR 21 R 22 R refers to the group 21 and R 22 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0054] "Sulfonylamino" is -NR 21 SO2R 22 R refers to the group 21 and R 22is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 are optionally joined together with the atoms bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0055] "Aryl" or "ar" refers to a monovalent aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (e.g., as in a phenyl group) or a ring system having multiple fused rings, which may or may not be aromatic, provided that the point of attachment is through an aromatic ring atom (examples of such aromatic ring systems include naphthyl, anthryl, and indanyl). This term includes, by way of example, phenyl and naphthyl. Unless constrained by the definition of an aryl substituent, such aryl groups may be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, 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, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamido, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and trihalomethyl.

[0056] "Aryloxy" refers to the group --O-aryl, where aryl is as defined herein and includes, for example, phenoxy, naphthoxy, etc., and includes optionally substituted aryl groups, also as defined herein.

[0057] "Amino" refers to the group NH2.

[0058] The term "substituted amino" refers to the group -NRR, where if at least one R is not hydrogen, then each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl.

[0059] The term "azido" refers to the group -N3.

[0060] "Carboxyl", "carboxy" or "carboxylate" refers to -CO2H or a salt thereof.

[0061] "Carboxyl-ester" or "carboxy-ester", or the term "carboxyalkyl" or "carboxylalkyl" refers to a -C(O)O-alkyl group, a -C(O)O-substituted alkyl group, a -C(O)O-alkenyl group, a -C(O)O-substituted alkenyl group, a -C(O)O-alkynyl group, a -C(O)O-substituted alkynyl group, a -C(O)Oaryl group, a -C(O)O-substituted aryl group, a -C(O)O-cycloalkyl group, a -C(O)O-substituted cycloalkyl group, a -C(O)O-cycloalkenyl ...substituted cycloalkyl group, a -C(O)O-cycloalkenyl group, a -C(O)O-substituted cycloalkyl group, a -C(O)O-substituted cycloalkyl group, a -C(O)O-cycloalkenyl group, a -C(O)O-substituted cycloalkyl group, a -C(O)O-substituted cycloalkyl group, a -C(O) "C(O)O" refers to alkyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0062] "(Carboxyl-ester)oxy" or "carbonate" refers to an -OC(O)O-alkyl group, an -OC(O)O-substituted alkyl group, an -OC(O)O-alkenyl group, an -OC(O)O-substituted alkenyl group, an -OC(O)O-alkynyl group, an -OC(O)O-substituted alkynyl group, an -OC(O)O-aryl group, an -OC(O)O-substituted aryl group, an -OC(O)O-cycloalkyl group, an -OC(O)O-substituted cycloalkyl group, an -OC(O)O-cycloalkenyl group, an -OC(O)O-substituted cycloalkyl group, an -OC(O)O-substituted cycloalkenyl ... refers to a cycloalkenyl group, an -OC(O)O-heteroaryl group, an -OC(O)O-substituted heteroaryl group, an -OC(O)O-heterocyclic group, and an -OC(O)O-substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0063] "Cyano" or "nitrile" refers to the group --CN.

[0064] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings, including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like. Such cycloalkyl groups include, for example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl.

[0065] The term "substituted cycloalkyl" includes but is not limited to deuterium, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, 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, -SO 2- Alkyl, -SO 2- It refers to a cycloalkyl group having 1 to 5 substituents, or 1 to 3 substituents, selected from substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.

[0066] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond, eg, 1 to 2 double bonds.

[0067] The term "substituted cycloalkenyl" includes but is not limited to deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, 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, -SO 2- Alkyl, -SO2- It refers to a cycloalkenyl group having 1 to 5 substituents, or 1 to 3 substituents, selected from substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

[0068] "Cycloalkynyl" refers to a non-aromatic cycloalkyl group of 5 to 10 carbon atoms having single or multiple rings and at least one triple bond.

[0069] "Cycloalkoxy" refers to -O-cycloalkyl.

[0070] "Cycloalkenyloxy" refers to -O-cycloalkenyl.

[0071] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0072] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0073] "Heteroaryl" refers to an aromatic group of 1 to 15 carbon atoms, such as 1 to 10 carbon atoms, and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl, imidazolyl, or furyl) or multiple condensed rings within the ring system (e.g., in groups such as indolizinyl, quinolinyl, benzofuran, benzimidazolyl, or benzothienyl), provided that at least one ring within the ring system is aromatic and that at least one ring within the ring system is aromatic if the point of attachment is through an atom in the aromatic ring. In certain embodiments, the nitrogen and / or sulfur ring atoms of a heteroaryl group are optionally oxidized to provide N-oxide (N→O), sulfinyl, or sulfonyl moieties. This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless constrained by the definition of a heteroaryl substituent, such heteroaryl groups can include acyloxy, hydroxy, thiol, acyl, 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, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamido, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2- Alkyl, -SO 2- Substituted alkyl, -SO2-aryl and It may be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents selected from -SO2-heteroaryl and trihalomethyl.

[0074] The term "heteroaralkyl" refers to the group alkylene-heteroaryl, where alkylene and heteroaryl are defined herein. This term includes, by way of example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.

[0075] "Heteroaryloxy" refers to -O-heteroaryl.

[0076] "Heterocycle," "heterocyclic," "heterocycloalkyl," and "heterocyclyl" refer to saturated or unsaturated groups having a single ring or multiple fused rings, including fused bridges and spiro ring systems, and having 3 to 20 ring atoms, including 1 to 10 heteroatoms. These ring atoms are selected from the group consisting of nitrogen, sulfur, or oxygen; in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided the point of attachment is through a non-aromatic ring. In certain embodiments, the nitrogen and / or sulfur atoms of a heterocyclic group are optionally oxidized to form N-oxide, -S(O)-, or -SO2- moiety.

[0077] Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine. These include benzo[b]thiophene, ...

[0078] Unless constrained by the definition of a heterocyclic substituent, such heterocyclic groups can be substituted with deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted alkyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, 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, -SO 2- Alkyl, It may be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents selected from -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and fused heterocycle.

[0079] "Heterocyclyloxy" refers to the group --O-heterocyclyl.

[0080] The term "heterocyclylthio" refers to the group heterocyclic -S-.

[0081] The term "heterocyclene" refers to a diradical group formed from a heterocycle, as defined herein.

[0082] The term "hydroxyamino" refers to the group --NHOH.

[0083] "Nitro" refers to the NO2 group.

[0084] "Oxo" refers to the (=O) atom.

[0085] "Sulfonyl" refers to an SO2 alkyl group, an SO2-substituted alkyl group, or a SO 2- Alkenyl group, SO2-substituted alkenyl group, SO 2- Cycloalkyl groups, SO2-substituted cycloalkyl groups, SO 2- Cycloalkenyl groups, SO2-substituted cycloalkenyl groups, SO 2- Aryl groups, SO2-substituted aryl groups, SO 2- Heteroaryl groups, SO2-substituted heteroaryl groups, SO 2- Sulfonyl refers to heterocyclic and SO-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Sulfonyl includes, by way of example, methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-.

[0086] "Sulfonyloxy" refers to an -OSO2-alkyl group, an -OSO2-substituted alkyl group, an -OSO2-alkenyl group, an -OSO2-substituted alkenyl group, an -OSO2-cycloalkyl group, an -OSO2-substituted cycloalkyl group, -OSO2-cycloalkenyl group, -OSO2-substituted cycloalkenyl group, -OSO2-aryl group, -OSO2-substituted aryl group, refers to an -OSO2-heteroaryl group, an -OSO2-substituted heteroaryl group, an -OSO2-heterocyclic group, and an -OSO2-substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0087] The term "aminocarbonyloxy" refers to the group -OC(O)NRR, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic, where alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.

[0088] "Thiol" refers to the group --SH.

[0089] The term "thioxo" or "thioketo" refers to the atom (=S).

[0090] The term "alkylthio" or "thioalkoxy" refers to an -S-alkyl group, where alkyl is as defined herein. In certain embodiments, the sulfur may be oxidized to -S(O)-. Sulfoxides can exist as one or more stereoisomers.

[0091] The term "substituted thioalkoxy" refers to an --S-substituted alkyl group.

[0092] The term "thioaryloxy" refers to an aryl-S- group, where aryl is as defined herein, including an optionally substituted aryl group, as defined herein.

[0093] The term "thioheteroaryloxy" refers to the group --S-heteroaryl, where heteroaryl is as defined herein, including an optionally substituted aryl group, as defined herein.

[0094] The term "thioheterocyclooxy" refers to the group -S-heterocyclyl, where heterocyclyl is as defined herein, including optionally substituted heterocyclyl groups, as defined herein.

[0095] Further to the disclosure herein, when used to modify a particular group or radical, the term "substituted" can also mean that one or more hydrogen atoms of the particular group or radical are each, independently of one another, replaced with the same or different substituents as defined below.

[0096] In addition to the groups disclosed for each individual term herein, substituents (such as =O, =NR) to replace one or more hydrogens on a saturated carbon atom in the specified group or radical are also included. 70 , =N-OR 70 , =N2, or =S) is a deuterium, -R 60 , halo, =O, -OR 70 , -SR 70 , -NR 80 R 80 , trihalomethyl, -CN, -OCN, -SCN, -NO, -NO2, =N2, -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)O - M + ,-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)OM + ,-OC(O)OR 70 ,-OC(S)OR 70 ,-NR 70 C(O)R 70 ,-NR 70 C(S)R 70 ,-NR 70 CO2 - 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 )NR 80 R 80 and R 60 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; and each R 70 are independently hydrogen or R 60 and each R 80 are independent, R 70 or alternatively two R 80’together with the nitrogen atom to which they are attached form a 5-, 6-, or 7-membered heterocycloalkyl, which optionally contains 1 to 4 additional heteroatoms, which may be the same or different, selected from the group consisting of O, N, and S, wherein N may have —H or C1-C3 alkyl substitution; and each M + is a counter ion with a net single positive charge. + are independently, e.g., K + , Na + , Li + Alkaline ions such as + N(R 60 )4, or ammonium ions such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 (The subscript 0.5 means that one of the counterions of such divalent alkaline earth ions is the ionized form of the compounds of the present disclosure, and the other typical counterion, such as chloride, or a doubly ionized compound disclosed herein, can serve as the counterion of such divalent alkaline earth ion, or a doubly ionized compound disclosed herein can serve as the counterion of such divalent alkaline earth ion.) A specific example is -NR 80 R 80 is meant to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, N-methyl-piperazin-1-yl, and N-morpholinyl.

[0097] Further to the disclosure herein, substituents of hydrogen on unsaturated carbon atoms in "substituted" alkene, alkyne, aryl, and heteroaryl groups can be deuterium, -R, unless otherwise specified. 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 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2[[ID=3】7] - M + , -CO2R 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 [[ID=5】0]], -C(NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 , -NR - M + , -NR 70 , -NR 70 , -NR 70 , -NR 70 , -NR 70 , -NR 80 R 80 , -NR 70 , -NR 70 , -C(NR 70 , and -NR 70 , -C(NR 70 )NR 80 R 80 and R60 , R 70 , R 80 , and M + is as previously defined, except that in the case of a substituted alkene or alkyne, the substituent is -O - M + , -OR 70 , -SR 70 , or -S - M + isn't it.

[0098] In addition to the groups disclosed for each individual term herein, the substituents of hydrogen on a nitrogen atom in "substituted" heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R 60 , -OM + , -OR 70 , -SR 70 , -SM + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R 70 ,-S(O)2OM + ,-S(O)2OR 70 ,-OS(O)2R 70 ,-OS(O)2OM + ,-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 70C(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 70 C(NR 70 )NR 80 R 80 and R 60 , R 70 , R 80 , and M + is as previously defined.

[0099] Further to the disclosure herein, in some embodiments, a substituted group has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0100] It is understood that for all of the substituents defined above, polymers achieved by defining the substituent to have further substituents thereon (e.g., a substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, which is in turn substituted with a substituted aryl group, etc.) are not intended to be encompassed herein. In such cases, the maximum number of such substitutions is three. For example, the sequential substitution of substituted aryl groups specifically contemplated herein is limited to substituted aryl-(substituted aryl)-substituted aryl. However, for example, a substituent defined as a polyether may have more than three sequential substitutions, e.g., -O-(CHCHO) n It may contain -H, where n can be 1, 2, 3, or more.

[0101] Unless otherwise indicated, naming of substituents not expressly defined herein is accomplished by naming the terminal portion of the functional group followed by the adjacent functional group toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-OC(O)-.

[0102] For any group disclosed herein that contains one or more substituents, it is of course understood that such group does not include any substitutions or substitution patterns that are sterically infeasible and / or synthetically impractical. Furthermore, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0103] As used herein, the term "fat" refers to a compound having a long-chain (straight-chain) hydrophobic moiety composed of hydrogen and 4 to 26 carbon atoms, and can be fully saturated or partially unsaturated.

[0104] When a substituent or group is described as "containing deuterium" or "comprising deuterium," it is to be understood that the substituent or group itself can be deuterium, or the substituent or group can contain at least one deuterium substitution in its chemical structure. For example, if the substituent "-R" is defined as containing deuterium, it is to be understood that -R can be -D (-deuterium), or a group such as -CD consistent with the other requirements set forth for -R.

[0105] The phrases "pharmaceutically acceptable," "physiologically acceptable," and the like are used herein to refer to compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment, suitable for use in contact with human tissue without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. When referring to salts, the phrases "pharmaceutically acceptable salt," "physiologically acceptable salt," and the like mean salts that are acceptable for administration to a patient, such as a mammal (salts having counterions that have acceptable mammalian safety for a given administration regimen). As is well known in the art, such salts can be prepared from pharmaceutically acceptable inorganic or organic bases, such as sodium, potassium, calcium, magnesium, lithium, aluminum, zinc, and ammonium, as well as tetraalkylammonium salts (e.g., salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine, etc.), and, where the molecule contains a basic functional group, addition salts with inorganic acids, e.g., hydrochlorides, hydrobromides, sulfates, sulfamates, phosphates, etc. The salts may be derived from salts, nitrates, perchlorates, etc., as well as addition salts with organic acids, such as formates, tartrates, besylates, mesylates, acetates, maleates, malonates, oxalates, fumarates, benzoates, salicylates, succinates, oxalates, glycolates, hemixalates, hemifumarates, propionates, stearates, lactates, citrates, ascorbates, pamoates, hydroxymaleates, phenylacetates, glutamates, 2-acetoxybenzoates, tosylates, ethanedisulfonates, isethionates, etc. The term "salt thereof" refers to a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation. Where applicable, the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds not intended for administration to a patient. As an example, salts of the present compounds include those in which the compound is protonated with an inorganic or organic acid to form a cation and has the conjugate base of the inorganic or organic acid as the anionic component of the salt.

[0106] "Solvate" refers to a physical association of a compound or salt of the present disclosure with one or more solvent molecules, whether organic, inorganic, or a mixture of both. This physical association includes hydrogen bonding. In certain instances, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in a solvate can exist in an ordered and / or irregular arrangement. A solvate may contain either stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. Some examples of solvents include, but are not limited to, methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. When the solvent is water, the solvate formed is a hydrate (e.g., monohydrate, dihydrate, etc.). Thus, exemplary solvates include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, etc. Methods of solvation are generally known in the art.

[0107] "Stereoisomer" and "stereoisomers" refer to compounds that have the same atomic connectivity but different atomic arrangements in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. All forms of the compounds, including racemates and optically pure stereoisomers, are contemplated herein. Chemical formulas and compounds that have at least one asymmetric center but are drawn without reference to stereochemistry are intended to include both the racemate and the individual stereoisomers, such as R- and / or S-stereoisomers, each permutation of the diastereomers, so long as such diastereomers are geometrically feasible.

[0108] "Tautomer" refers to alternative forms of molecules that differ only in the electronic bonding of atoms and / or in the position of protons, such as enol-keto, imine-enamine, and neutral / zwitterionic tautomers, or tautomeric forms of heteroaryl groups containing the -N=C(H)-NH- ring atom configuration, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. Other tautomeric ring atom configurations are possible. For example, a compound containing an acid group and a base group in the same molecule that is shown in the neutral form may exist in zwitterionic form, as is the case with amino acid / ammonium carboxylate tautomers. A given chemical formula or name is intended to encompass all tautomeric forms thereof, if they exist.

[0109] "Prodrug" is meant to refer to a compound that can be converted into a biologically active compound described herein under physiological conditions or by solvation. Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. For example, prodrugs such as esters, phosphate esters, etc. may be inactive when administered to a subject, but are converted into active compounds in vivo, for example, by hydrolysis to a free carboxylic acid or a free hydroxyl group. Prodrug compounds often offer advantages such as solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties. The term "prodrug" is also meant to include any covalently bonded carrier that releases the active compound in vivo when such prodrug is administered to a mammalian subject. As used herein, prodrugs of active compounds can be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to form a free hydroxyl, amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Prodrugs include compounds in which a hydroxyl, amino, or mercapto group is bonded to any group that cleaves to form a free hydroxyl, free amino, or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, derivatives of amine functional groups in active compounds, such as esters (e.g., acetates, formates, benzoates, etc.), carbonates, carbamates, and dihydrogen phosphate derivatives of alcohols or amides (e.g., acetamides, formamides, benzamides, amides formed from amino acids, etc.), carbamates, etc.

[0110] The compounds of the present disclosure may, in some cases, exist in crystalline or amorphous solid forms, and these solid forms are therefore contemplated herein. A "crystalline" solid is a type of solid whose fundamental three-dimensional structure contains a highly regular pattern of atoms or molecules forming a crystal lattice with long-range order, and thus exhibits sharp, characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern. In some instances, a crystalline solid may exist in different crystalline forms known as "polymorphs," which have the same chemical composition but differ in packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs may have different solid-state physical properties that affect, for example, the solubility, dissolution rate, bioavailability, chemical and physical stability, flowability, and compressibility of the compound, as well as the safety and efficacy of pharmaceuticals based on the compound. In the process of preparing polymorphs, further refinement, with respect to physical or optical purity, may also be achieved. As used herein, the term "amorphous" refers to a solid material that has substantially no long-range order in its molecular positions; the molecules are arranged randomly, with no clearly defined arrangement, e.g., no molecular packing, and no long-range order. Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions, and do not have a distinct melting point. For example, an amorphous material is a solid material that does not have a substantially sharp characteristic crystalline peak in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of amorphous solids. Thus, an "amorphous" subject compound / material is one characterized as having substantially no crystallinity, e.g., less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, or 0%, i.e., at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% amorphous, as determined, for example, by XRPD.For example, in some embodiments, percent crystallinity may be determined by measuring the intensity of one or more peaks in an XRPD diffractogram compared to a reference peak, which may be an internal standard. Other characterization techniques, such as modulated differential scanning calorimetry (mDSC) analysis, Fourier transform infrared spectroscopy (FTIR), and other quantitative methods, including quantitative methods that provide the above percentages in terms of weight percent, may also be used to determine the percent amorphous or crystalline of the subject compounds / materials.

[0111] It will be understood that the compounds herein may exist in different salt, solvate, stereoisomer, tautomer, crystalline / amorphous (including polymorph) forms, and that the present disclosure is intended to include all permutations thereof, for example, solvates of pharmaceutically acceptable salts of stereoisomers of the subject compounds.

[0112] A "vapor" is a solid substance in the gas phase at a temperature below its critical temperature, meaning that the vapor can be condensed to a liquid by increasing its pressure without decreasing the temperature.

[0113] As used herein, an "aerosol" is a suspension of fine solid particles or liquid droplets in a gas phase (e.g., air, oxygen, helium, nitrous oxide, and other gases, and mixtures thereof). As used herein, a "mist" is a subset of aerosol, distinct from vapor, and is a dispersion of liquid droplets (liquid phase) suspended in a gas phase (e.g., air, oxygen, helium, and mixtures thereof). The liquid droplets of an aerosol or mist may contain a drug moiety dissolved in an aqueous liquid, an organic solvent, or a mixture thereof. The gas phase of an aerosol or mist may contain other gases, including air, oxygen, helium, or mixtures thereof. A mist does not contain solid particles. The aerosols and mists of the present disclosure can be generated by any suitable method and device, examples of which are described herein, for example, through the use of an inhaler or nebulizer.

[0114] As used herein, the term "inhalation session" describes the administration event in which a subject inhales a given dose of drug, regardless of the number of breaths required to inhale the given dose.For example, a subject prescribed to take 10 mg of drug twice a day will perform two inhalation sessions, each inhalation session providing 10 mg of drug.The duration and number of breaths of each inhalation session will depend on factors such as the inhalation device used, the amount of drug inhaled per breath, the drug concentration of the dosage form, and the breathing pattern of the subject.

[0115] As used herein, the term "release period" describes the time window during which any compound described herein is released from a dosage form (e.g., a matrix) to achieve a plasma concentration of the compound described herein. The start of the release period is defined from the time of administration to a subject, which is considered to be approximately equivalent to entry into the stomach and initial dissolution by gastric enzymes and acids.

[0116] As used herein, the term "maximum sustained release" describes the release window of certain formulations of the present disclosure that are formulated to increase the release period to a maximum value, which in the case of the enteral route is ultimately limited by the time the gastrointestinal tract naturally expels all of the drug with food.

[0117] The term "tamper-resistant" is recognized in the art to describe an aspect of a drug formulation that makes it more difficult to use the formulation to abuse the drug portion of the formulation, whether through extraction for intravenous use or crushing for free base use, thus reducing the risk of drug abuse.

[0118] As used herein, the term "steady state" describes a stable or steady state level of a molecule concentration, such as the concentration of any compound described herein.

[0119] As used herein, the term "composition" is equivalent to the term "formulation."

[0120] As used herein, the term "administration event" describes the administration of a given dose to a subject within a short time window, such as, for example, less than 10 minutes. An oral administration event may be in the form of, for example, the administration of one or more pills within the short time window.

[0121] As used herein, the term "treating" or "treatment" means treating or treating a disease or medical condition in a patient, e.g., a mammal (particularly a human), including ameliorating the disease or medical condition, such as, for example, eliminating or causing regression of the disease or medical condition in the patient, inhibiting the disease or medical condition, e.g., by slowing or arresting the onset of the disease or medical condition in the patient, or alleviating the symptoms of the disease or medical condition in the patient. In some embodiments, prophylactic treatment may prevent the occurrence of a disease or medical condition in a subject.

[0122] A "patient" or "subject," as used interchangeably herein, can be any mammal, including, for example, a human or non-human subject. The patient or subject can have the condition being treated or can be susceptible to the condition being treated.

[0123] As used herein, unless otherwise specified, the terms "prevent," "preventing," and "prevention" refer to the prevention of the onset, recurrence, or spread of a disease, disorder, or condition, or one or more symptoms thereof. The term encompasses the inhibition or reduction of symptoms of a particular disease, disorder, or condition. Subjects with a family history of a disease, disorder, or condition are particularly, in certain embodiments, candidates for a preventative regimen. Additionally, subjects with a history of recurrent symptoms are also potential candidates for prevention. In this regard, the term "prevention" may be used interchangeably with the term "prophylactic treatment."

[0124] As used herein, and unless otherwise specified, the terms "manage," "managing," and "management" refer to preventing or slowing the progression, spread, or worsening of a disease, disorder, or condition, or one or more symptoms thereof. Often, the beneficial effects a subject derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease, disorder, or condition. In this regard, the term "managing" encompasses treating a subject afflicted with a particular disease, disorder, or condition in an effort to prevent or minimize the recurrence of the disease, disorder, or condition, or one or more symptoms thereof.

[0125] A "therapeutically effective amount" refers to that amount of a compound sufficient to treat a particular disorder or disease, or one or more symptoms thereof, and / or prevent the disease or disorder from occurring.

[0126] As used herein, and unless otherwise specified, a "prophylactically effective amount" of an active agent is an amount sufficient to prevent a disease, disorder, or condition, or to prevent its recurrence. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic effect of another prophylactic agent.

[0127] The term "administration schedule" refers to a plan that chronologically shows the type, amount, duration, and procedure of drug treatment, including the dosage, administration method, administration order, and administration date of each drug. The designated administration date is determined before the start of drug administration. Administration is continued by repeating a series of administration schedules, each of which is considered a "course." A "continuous" administration schedule means that the drug is administered daily without interruption during the treatment course. If the administration schedule follows an "intermittent" administration schedule, the days of administration may be followed by "rest days" or non-administration days of the drug during the course. A "drug holiday" indicates that the drug is not administered according to a predetermined administration schedule. For example, after receiving several treatment courses, a subject may be prescribed a regulated drug holiday as part of the administration schedule, for example, before resuming active treatment.

[0128] The term "toxic spike" is used herein to describe a spike in the concentration of any compound described herein that results in sedative or psychotomimetic side effects (e.g., hallucinations, dizziness, and nausea), or any undesirable and / or unintended secondary effects resulting in a subjective experience qualitatively different from that of normal individuals administered the pharmaceutical. These experiences may include derealization, depersonalization, hallucinations, and / or sensory distortions in vision, hearing, smell, touch, proprioception, and / or other perceptual modifications, and / or other substantial subjective changes in cognition, memory, emotion, and consciousness. If unwanted, unintended, and / or severe, such side effects may affect not only the immediate impact but also treatment compliance. In particular, side effects may be more pronounced at blood concentration levels of about 250, 300, 400, or 500 ng / L or greater.

[0129] As used herein, and unless otherwise specified, a "neuropsychiatric disease or disorder" is a behavioral or psychological problem associated with a known neurological condition, typically defined as a constellation of coexisting symptoms. Examples of neuropsychiatric disorders include, but are not limited to, schizophrenia, cognitive impairment in schizophrenia, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder and mania, depression, or any combination thereof.

[0130] As used herein, "inflammatory condition" or "inflammatory disease" broadly refers to chronic or acute inflammatory diseases. Inflammatory conditions and diseases include, but are not limited to, post-mortem symptoms from SARS-CoV-2 infection (COVID-19), e.g., "long covid," rheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthritis), spondyloarthropathies (e.g., ankylosing spondylitis, reactive arthritis, Reiter's syndrome), crystal arthropathies (e.g., gout, pseudogout, calcium pyrophosphate deposition disease), multiple sclerosis, Lyme disease, polymyalgia rheumatica; connective tissue diseases (e.g., systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, Sjogren's syndrome); vasculitis (e.g., nodular vasculitis, ... inflammatory conditions, including those resulting from trauma or ischemia (e.g., polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome), sarcoidosis; vascular diseases, including atherosclerosis, and vascular occlusive diseases (e.g., atherosclerosis, ischemic heart disease, myocardial infarction, stroke, peripheral vascular disease), and vascular stent restenosis; and ophthalmic diseases, including uveitis, corneal disease, iritis, iridocyclitis, glaucoma, and cataracts.

[0131] All diseases and disorders listed herein may be defined as set forth in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) published by the American Psychiatric Association or the International Classification of Diseases (ICD) published by the World Health Organization.

[0132] As used herein, and unless otherwise specified, compounds that provide a "hallucinatory" effect may also include compounds that are "entactogenic," i.e., compounds that produce experiences of emotional togetherness, oneness, relatedness, emotional openness, i.e., empathy or sympathy, as particularly observed and reported for the experience of 3,4-methylenedioxymethamphetamine (MDMA).

[0133] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. As used throughout this description and the claims that follow, the meaning of "a," "an," and "the" includes plural references as well as singular references unless the context clearly indicates otherwise. The term "about" in connection with a numerical value means that the value varies above and below 5%. For example, a value of about 100 means 95 to 105 (or any value between 95 and 105).

[0134] compound The present inventors have identified novel phenethylamine-type compounds based on specific molecular modifications that exhibit preferential binding to G protein-coupled receptors (GPCRs), such as the 5-HT2 receptor, that are bioavailable (e.g., orally bioavailable), have improved exposure (i.e., preventing high drug concentration spikes observed soon after administration), and have favorable enzymatic degradation profiles that prevent bioactivation to toxic metabolites. As a result, the disclosed compounds have reduced propensity for side effects, toxicity, and interpatient variability, thereby improving the therapeutic window and enabling practical use in clinical settings. The novel phenethylamine-type compounds are based on specific molecular modifications that delay or avoid enzymatic degradation at specific sites and / or introduce metabolic soft spots at other sites—modifications identified only after significant research.

[0135] Formula (I) A compound according to formula (I), [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is disclosed herein; During the ceremony, X 1 and X 2 are independently hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl; Y 1 and Y2 are independently hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl; R 2 and R 3 are independently hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, -OR a , or -SR a and R 4 and R 5 are independently hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, -OR a , -SR a , or -SeR a or R 4 and R 5 together with the atoms to which they are attached, optionally joined to form a heterocycloalkyl or heteroaryl; R 6 and R 7 are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or alternatively, R 6 and R 7 together with the nitrogen atom to which they are attached, are optionally joined to form a substituted or unsubstituted heterocycloalkyl; Each R a are independently hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3-C 10 is cycloalkyl, At least one of the conditions (i) to (iii) is satisfied, (i)X 1 ,X 2 ,Y 1 ,Y 2 ,R 2 ,R 3 ,R 4 ,R 5 ,R 6 , R 7at least one of which contains deuterium; (ii)R 4 and R 5 are bonded together with the atoms to which they are bonded to form a heterocycloalkyl or heteroaryl containing deuterium or fluorine, and / or a benzo[d][1,3]oxathiol group; (iii)R 4 -OR a , -SR a , or -SeR a and R 4 R in a is C1-C6 alkyl substituted with one or more halogens; However, X 1 , X 2 , Y 1 , and Y 2 are each hydrogen or deuterium, R 2 and R 5 Both -OR a provided that it is not.

[0136] 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. In some embodiments, X 1 and X 2 are different. In some embodiments, X 1 is hydrogen or deuterium, and X 2 is a substituted or unsubstituted C 1~ In some embodiments, X is C alkyl. 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X 2is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, CD2H, CD3, CFH2, CF2H, -CF3, etc. In some embodiments, X 1 and X 2 One of the atoms is deuterium and the other is hydrogen.

[0137] Y 1 and Y 2 can 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. In some embodiments, Y 1 and Y 2 In some embodiments, Y 1 and Y 2 One of Y is deuterium and the other is hydrogen. 1 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, Y 2 is a substituted or unsubstituted C1-C6 alkyl.

[0138] In some embodiments, R 2 is deuterium. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 2 is a substituted C1-C6 alkyl. 2When R is substituted C1-C6, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 2 -OR a In some embodiments, R 2 -SR a is.

[0139] In some embodiments, R 3 is deuterium. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 3 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 3 is a substituted C1-C6 alkyl. 3 When R is substituted C1-C6, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 3 -OR a In some embodiments, R 3 -SR a is.

[0140] In some embodiments, R 4 is deuterium. In some embodiments, R 4 is hydrogen.

[0141] In some embodiments, R 4 is a halogen, for example, —Br, —F, —Cl, or —I.

[0142] In some embodiments, R 4 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 is a substituted C1-C6 alkyl. 4 However, when substituted C1-C6, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, cycloalkyl, etc. 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), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc.

[0143] In some embodiments, R 4 -OR a , S.R. a , or -SeR a and R 4 R in a is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3-C 10 In some embodiments, R 4 -OR a In some embodiments, R 4 -SR a In some embodiments, R 4 -SeRa In some embodiments, R 4 R in a is hydrogen. In some embodiments, R 4 R in a is deuterium. In some embodiments, R 4 R in a is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 4 R in a is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 R in a is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, polar substituents such as hydroxyl or polyether substituents, cycloalkyl, and the like. The C1-C6 alkyl group may contain one or more substituents. In some embodiments, R 4 R in a is a substituted C alkyl group, examples of which may include, but are not limited to, -CDH, -CDH, -CD, -CFH, -CFH, -CF, and -CHC≡N. In some embodiments, R 4 R in a is a substituted C alkyl group, examples of which may include, but are not limited to, -CDHCDH, -CDHCDH, -CDCD, -CHCFH, -CHCFH, -CHCF, and -CHCHC≡N. In some embodiments, R 4 R in a is not a substituted C2 alkyl group, such as a C2 fluoroalkyl group. 4 R in ais a substituted C alkyl group, examples of which may include, but are not limited to, -CH2CH2CF3, -CH2CH2CF2H, -CH2CH2CFH2, -CH2CF2CF2H, and -CH2CH2CH2C≡N. In some embodiments, R 4 R in a is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, etc. In some embodiments, R 4 R in a is a substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, R 4 R in a is unsubstituted alkynyl. In some embodiments, R 4 R in a is unsubstituted acetylenyl (—C≡CH). In some embodiments, R 4 R in a is unsubstituted propargyl (—CHC≡CH). In some embodiments, R 4 R in a is -CHCHC≡CH. In some embodiments, R 4 R in a is -CHCHCHC≡CH. In some embodiments, R 4 R in a is -CH2CH2CH2CH2C≡CH. In some embodiments, R 4 R in a is substituted alkynyl. In some embodiments, R 4 R in a is substituted propargyl (e.g., —CFC≡CH). In some embodiments, R 4 R in a is -CF2CH2C≡CH. In some embodiments, R 4 R in a is -CF2CH2CH2C≡CH. In some embodiments, R 4 R in ais -CF2CH2CH2CH2C≡CH. In some embodiments, R 4 R in a is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C-C 10 cycloalkyl, or substituted or unsubstituted C4-C8 cycloalkyl, or substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R 4 R in a is an unsubstituted cycloalkyl (e.g., unsubstituted C-C 10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 4 R in a is a substituted cycloalkyl (e.g., substituted C 10 Cycloalkyl groups are substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. Cycloalkyl groups may contain one or more substituents.

[0144] In some embodiments, R 4 -SMe, -SCD 3, -SCF 3, -SCF2H,-SCFH2,-SEt,-SnPr, -SCH2CF3,-SCH2CF2H,-SCH2CFH2,-SCH2CH2CF3,-SCH2CH2CF2H,-SCH2CH2CFH2, -SCH2CF2CF2H,-SCH2C≡CH,-SC≡CH,-SCF2C≡CH,-SCH2CH2CH2C≡CH, -SCF2CH2CH2C≡CH,-Me,CD3,CF3,-t-Bu,-C(CD3)3,OMe,OCD3,OCF3,-OCF2H, -OCFH2,OCH2CF3,-OCH2CF2H,-OCH2CFH2,OCH2CH2CF3,-OCH2CH2CF2H, -OCH2CH2CFH2,-OCH2CF2CF2H,-OCH2C≡CH,-OC≡CH,-CH2CH2CH2CH2C≡CH, -CF2CH2CH2CH2C≡CH,-Cl,-I,-Br,SeMe,-SeCD 3, -SeCF 3, -SeCF2H, -SeCFH2, -SeEt, -SenPr,-SeCH2CF3,-SeCH2CF2H,-SeCH2CFH2,-SeCH2CH2CF3,-SeCH2CH2CF2H, -SeCH2CH2CFH2,-SeCH2CF2CF2H,-SeCH2C≡CH,-SeC≡CH,-SeCF2C≡CH, -SeCH2CH2CH2C≡CH, or -SeCF2CH2CH2C≡CH.

[0145] In some embodiments, R 5 is deuterium. In some embodiments, R 5 is hydrogen.

[0146] In some embodiments, R 5 is a halogen, for example, —Br, —F, —Cl, or —I.

[0147] In some embodiments, R 5 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 5 is a substituted C1-C6 alkyl. 5In the case of a substituted C1-C6 group, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, cycloalkyl, etc. 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), the substituted C1 alkyl group may be -CDH2, It may be -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc.

[0148] In some embodiments, R 5 -OR a , S.R. a , or -SeR a and R 5 R in a is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3-C 10 In some embodiments, R 5 -OR a In some embodiments, R 5 -SR a In some embodiments, R 5 -SeR a In some embodiments, R 5 R in a is hydrogen. In some embodiments, R 5 R in a is deuterium. In some embodiments, R 5 R in a is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 5 R in a is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 5 R in ais a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, polar substituents such as hydroxyl, or polyether substituents. The C1-C6 alkyl group may contain one or more substituents. In some embodiments, R 5 R in a is a substituted C alkyl group, examples of which may include, but are not limited to, -CDH, -CDH, -CD, -CFH, -CFH, -CF, and -CHC≡N. In some embodiments, R 5 R in a is a substituted C alkyl group, examples of which may include, but are not limited to, -CDHCDH, -CDHCDH, -CDCD, -CHCFH, -CHCFH, -CHCF, and -CHCHC≡N. In some embodiments, R 5 R in a is not a substituted C2 alkyl group, such as a C2 fluoroalkyl group. 5 R in a is a substituted C alkyl group, examples of which may include, but are not limited to, -CH2CH2CF3, -CH2CH2CF2H, -CH2CH2CFH2, -CH2CF2CF2H, and -CH2CH2CH2C≡N. In some embodiments, R 5 R in a is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, etc. In some embodiments, R 5 R in a is a substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, R 5 R in a is unsubstituted alkynyl. In some embodiments, R 5 R in a is unsubstituted acetylenyl (—C≡CH). In some embodiments, R 5 R in ais unsubstituted propargyl (—CHC≡CH). In some embodiments, R 5 R in a is -CHCHC≡CH. In some embodiments, R 5 R in a is -CHCHCHC≡CH. In some embodiments, R 5 R in a is -CH2CH2CH2CH2C≡CH. In some embodiments, R 5 R in a is substituted alkynyl. In some embodiments, R 5 R in a is substituted propargyl (e.g., —CFC≡CH). In some embodiments, R 5 R in a is -CF2CH2C≡CH. In some embodiments, R 5 R in a is -CF2CH2CH2C≡CH. In some embodiments, R 5 R in a is -CF2CH2CH2CH2C≡CH. In some embodiments, R 5 R in a is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C-C 10 cycloalkyl, or substituted or unsubstituted C4-C8 cycloalkyl, or substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R 5 R in a is an unsubstituted cycloalkyl (e.g., unsubstituted C-C 10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 5 R in a is a substituted cycloalkyl (e.g., substituted C 10Cycloalkyl groups are substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. Cycloalkyl groups may contain one or more substituents.

[0149] In some embodiments, R 5 -SMe, -SCD 3, -SCF 3, -SCF2H,-SCFH2,-SEt,-SnPr,-SCH2CF3,-SCH2CF2H,-SCH2CFH2,-SCH2CH2CF3,-SCH2CH2CF2H,-SCH2CH2CFH2, -SCH2CF2CF2H,-SCH2C≡CH,-SC≡CH,-SCF2C≡CH,-SCH2CH2CH2C≡CH,-SCF2CH2CH2C≡CH,-Me,CD3,CF3,-t-Bu,-C( CD3)3,OMe,OCD3,OCF3,-OCF2H,-OCFH2,OCH2CF3,-OCH2CF2H,-OCH2CFH2,OCH2CH2CF3,-OCH2CH2CF2H,-OCH2CH 2CFH2,-OCH2CF2CF2H,-OCH2C≡CH,-OC≡CH,-CH2CH2CH2CH2C≡CH,-CF2CH2CH2CH2C≡CH,-Cl,-I,-Br,SeMe,-SeCD 3, -SeCF 3, -SeCF2H, -SeCFH2, -SeEt, -SenPr, -SeCH2CF3, -SeCH2CF2H, -SeCH2CFH2, -SeCH2CH2CF3, -SeCH2CH2CF2H, -SeCH2CH2CFH2, -SeCH2CF2CF2H, -SeCH2C≡CH, -SeC≡CH, -SeCF2C≡CH, -SeCH2CH2CH2C≡CH, or -SeCF2CH2CH2C≡CH.

[0150] In some embodiments, R4 and R 5 R, together with the atoms to which they are attached, form a heterocycloalkyl or heteroaryl, and particular mention is made of a benzo[d][1,3]oxathiol group or a benzo[d][1,3]dioxole group. 4 and R 5 In embodiments where are bonded together with the atoms attached thereto to form a benzo[d][1,3]oxathiol group or a benzo[d][1,3]dioxole group, either the oxathiol ring or the dioxole ring may be further substituted with substituents as defined herein, e.g., with deuterium substituents, with halogen (e.g., fluorine) substituents, and the like.

[0151] R 6 and R 7 can be the same or different. In some embodiments, R 6 and R 7 are the same. For example, in some embodiments, R 6 and R 7 In some embodiments, both R 6 and R 7 are different. For example, in some embodiments, R 6 is hydrogen and R 7 R is unsubstituted or substituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 6 and R 7 may independently be hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R 6 and R 7can independently be hydrogen, unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and hexyl), or C1-C6 alkyl substituted with one or more deuterium atoms (e.g., -CDH2, -CD2H, -CD3).

[0152] In some embodiments, R 6 and / or R 7 is an unsubstituted C1-C6 alkyl, for example, an unsubstituted C1 alkyl, an unsubstituted C2 alkyl, an unsubstituted C3 alkyl, an unsubstituted C4 alkyl, an unsubstituted C5 alkyl, or an unsubstituted C6 alkyl. 6 and / or R 7 is an unsubstituted straight chain C2-C6 alkyl. In some embodiments, R 6 and / or R 7 is an unsubstituted branched C3 to C 10 Examples of unsubstituted C1-C6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.

[0153] In some embodiments, R 6 and / or R 7 is a substituted C1-C6 alkyl, for example, a substituted C1 alkyl, a substituted C2 alkyl, a substituted C3 alkyl, a substituted C4 alkyl, a substituted C5 alkyl, or a substituted C6 alkyl. The alkyl group may include one or more substituents. The alkyl group may be substituted with any one or more substituents listed herein, examples of which may include, but are not limited to, polar substituents such as deuterium, halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. In some embodiments, R6 and / or R 7 is a C1-C6 alkyl substituted with one or more deuterium atoms, examples of which include, but are not limited to, -CDH2, -CD2H, -CD3, -CD2CD3, and -CD2CD2CD3. In some embodiments, R 6 and / or R 7 is a C1-C6 alkyl substituted with one or more fluorine atoms, i.e., a fluoroalkyl group. Examples of fluoroalkyl groups include -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CH2CF2CHF2, -CH2CF2CF3, -CH(CF3)2, and In some embodiments, R 6 and / or R 7 is a C1-C6 alkyl substituted with one or more deuterium atoms and one or more fluorine atoms, examples of which include, but are not limited to, -CD2CH2F, -CD2CHF2, -CD2CF3, -CD2CH2CH2F, -CD2CH2CHF2, -CD2CH2CF3, -CD2CD2CH2, -CD2CD2CHF2, -CD2CD2CF3, -CD2CH2CH2CH2F, -CD2CH2CH2CHF2, -CD2CH2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3.

[0154] In some embodiments, R 6 and / or R 7 is a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. The C1-C6 alkyl is, for example, a substituted or unsubstituted C3-C 10In some embodiments, the C1-C6 alkyl may be substituted with an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C6 alkyl). 10 In some embodiments, the C1-C6 alkyl is a substituted cycloalkyl (e.g., a substituted C3-C6 alkyl), examples of which include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 10 The cycloalkyl group may be substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one or more substituents. In some embodiments, R 6 and / or R 7 is a C1 alkyl substituted with a substituted or unsubstituted cycloalkyl, with particular mention being made of cyclopropylmethyl (-CH2C3H5).

[0155] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, and the like.

[0156] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted, for example, substituted or unsubstituted propargyl.

[0157] In some embodiments, R 6 and / or R 7is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C-C 10 cycloalkyl, or substituted or unsubstituted C4-C8 cycloalkyl, or substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R 6 and R 7 is an unsubstituted cycloalkyl (e.g., unsubstituted C-C 10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 6 and / or R 7 is a substituted cycloalkyl (e.g., substituted C 10 Cycloalkyl groups are substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. Cycloalkyl groups may contain one or more substituents.

[0158] In some embodiments, R 6 and / or R 7 is a substituted or unsubstituted heterocycloalkyl. In some embodiments, the unsubstituted or substituted heterocycloalkyl group can be a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, R 6 and / or R 7is an unsubstituted heterocycloalkyl such as those described herein, examples of which include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, and 1,3-dioxolane. In some embodiments, R 6 and / or R 7 is a substituted heterocycloalkyl. The substituents can be any of those listed herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), oxo, and hydroxyl. The heterocycloalkyl group can contain one or more substituents.

[0159] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted aryl. In some embodiments, R 6 and / or R 7 is unsubstituted aryl, examples of which include, but are not limited to, phenyl and naphthyl. In some embodiments, R 6 and / or R 7 is a substituted aryl. The substituents can be any of those listed herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The aryl group may contain one or more substituents.

[0160] In some embodiments, R 6 and / or R7 is substituted or unsubstituted heteroaryl. In some embodiments, R 6 and / or R 7 is unsubstituted heteroaryl, examples of which include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, thiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and pyrazolyl. 6 and / or R 7 is a substituted heteroaryl. The substituents can be any of those listed herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The heteroaryl group may contain one or more substituents.

[0161] In some embodiments, R 6 is hydrogen and R 7 is unsubstituted or substituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R 6 is hydrogen and R 7 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 6 is hydrogen and R 7is an unsubstituted C1-C6 alkyl, a C1-C6 alkyl substituted with one or more deuterium atoms, a C1-C6 alkyl substituted with one or more fluorine atoms, or a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. For example, in some embodiments, R 6 is hydrogen and R 7 is methyl, ethyl, propyl, -CD3, or cyclopropylmethyl (-CH2C3H5).

[0162] In some embodiments, R 6 and R 7 are joined together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl. In some embodiments, R 6 and R 7 are joined together with the nitrogen atom to which they are attached to form an unsubstituted heterocycloalkyl. An unsubstituted heterocycloalkyl group can be, for example, a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may optionally be fused to other rings. An unsubstituted heterocycloalkyl group must have at least one nitrogen ring atom (R 6 and R 7 R includes a nitrogen atom (an intervening nitrogen atom) and may optionally include at least one additional hetero ring atom, which may be one or more of nitrogen, sulfur, or oxygen, for a total of 1, 2, 3, or 4 hetero ring atoms (at least one of which is a nitrogen ring atom). 6 and R 7 together with the nitrogen atom to which they are attached include: [ka] These include, but are not limited to:

[0163] In some embodiments, R 6 and R 7are joined together with the nitrogen atom to which they are attached to form a substituted heterocycloalkyl. A substituted heterocycloalkyl group can be, for example, a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may optionally be fused to other rings. A substituted heterocycloalkyl group must have at least one nitrogen ring atom (R 6 and R 7 and optionally, additional heterocyclic atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 heterocyclic atoms (at least one of which is a nitrogen ring atom). Examples of substituted heterocycloalkyl groups include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, or thiomorpholine, each substituted with at least one substituent. The substituents may be any of those listed herein, which may include, but are not limited to, polar substituents such as deuterium, halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. R 6 and R 7 together with the nitrogen atom to which they are attached includes heterocycloalkyl groups substituted with one, two, three, four, or more substituents, which may be located on carbon or hetero ring atoms.

[0164] R 6 and R 7 together with the nitrogen atom to which they are attached include: [ka] These include, but are not limited to:

[0165] R 2 ~R 5 Each R if present in one or more of a are independently hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3-C 10 In some embodiments, each R a can independently be hydrogen, deuterium, unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl), or substituted C1-C6 alkyl, with preferred substituents including, but not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, and the like. In some embodiments, R a is a substituted or unsubstituted C1-C6 alkyl, preferably a C1-C3 alkyl, preferably a substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, -CH3, -CDH2, -CD2H, -CD3, -CFH2, -CF2H, and -CF3. In some embodiments, each R a is -CH3. In some embodiments, each R a is -CD3. In some embodiments, two or more R a In such a case, each R a can be the same or different. In some embodiments, each R a are the same. In some embodiments, each R a are different, for example, one R a is -CH3 and the other is -CD3.

[0166] In some embodiments, R 2 ~R 5 One or more Ra is hydrogen. In some embodiments, R 2 ~R 5 One or more R a is deuterium. In some embodiments, R 2 ~R 5 One or more R a is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 2 ~R 5 R in one or more of a is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 2 ~R 5 R in one or more of a is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, polar substituents such as hydroxyl or polyether substituents, cycloalkyl, and the like. The C1-C6 alkyl group may contain one or more substituents. In some embodiments, R 2 ~R 5 R in one or more of a is a substituted C alkyl group, examples of which include -CDH, -CDH, -CD, These may include, but are not limited to, -CFH, -CFH, -CF, and -CHC≡N. In some embodiments, R 2 ~R 5 R in one or more of a is a substituted C2 alkyl group, examples of which include -CDHCDH2, These may include, but are not limited to, -CDHCD2H, -CD2CD3, -CH2CFH2, -CH2CF2H, -CH2CF3, and -CH2CH2C≡N. In some embodiments, R 2 ~R 5 R in one or more of ais a substituted C alkyl group, examples of which may include, but are not limited to, -CH2CH2CF3, -CH2CH2CF2H, -CH2CH2CFH2, -CH2CF2CF2H, and -CH2CH2CH2C≡N. In some embodiments, R 2 ~R 5 R in one or more of a is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, etc. In some embodiments, R 2 ~R 5 R in one or more of a is a substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, R 2 ~R 5 R in one or more of a is unsubstituted alkynyl. In some embodiments, R 2 ~R 5 R in one or more of a is unsubstituted acetylenyl (—C≡CH). In some embodiments, R 2 ~R 5 R in one or more of a is unsubstituted propargyl (—CHC≡CH). In some embodiments, R 2 ~R 5 R in one or more of a is -CHCHC≡CH. In some embodiments, R 2 ~R 5 R in one or more of a teeth, In some embodiments, R 2 ~R 5 R in one or more of a teeth, In some embodiments, R 2 ~R 5 R in one or more of a is substituted alkynyl. In some embodiments, R 2 ~R5 R in one or more of a is substituted propargyl (e.g., —CFC≡CH). In some embodiments, R 2 ~R 5 R in one or more of a teeth, In some embodiments, R 2 ~R 5 One or more R a is -CF2CH2CH2C≡CH. In some embodiments, R 2 ~R 5 R in one or more of a is -CF2CH2CH2CH2C≡CH. In some embodiments, R 2 ~R 5 R in one or more of a is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C-C 10 cycloalkyl, or substituted or unsubstituted C4-C8 cycloalkyl, or substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R 2 ~R 5 R in one or more of a is an unsubstituted cycloalkyl (e.g., unsubstituted C-C 10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 2 ~R 5 R in one or more of a is a substituted cycloalkyl (e.g., substituted C 10Cycloalkyl groups are substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. Cycloalkyl groups may contain one or more substituents.

[0167] R a Consistent with the above discussion about R 2 ~R 3 Either one or both of the following may be independently selected from the group consisting of -OR a or -SR a R may be 4 ~R 5 Either one or both of the following may be independently selected from the group consisting of -OR a , -SR a , or -SeR a Examples include -SMe, -SCD 3, -SCF 3, -SCF2H,-SCFH2,-SEt,-SnPr,-SCH2CF3,-SCH2CF2H,-SCH2CFH2,-SCH2CH2CF3,-SCH2CH2C F2H,-SCH2CH2CFH2,-SCH2CF2CF2H,-SCH2C≡CH,-SC≡CH,-SCF2C≡CH,-SCH2CH2CH2C≡CH,-SC F2CH2CH2C≡CH,-OMe,-OCD3,-OCF3,-OCF2H,-OCFH2,-OCH2CF3,-OCH2CF2H,-OCH2CFH2,-O CH2CH2CF3,-OCH2CH2CF2H,-OCH2CH2CFH2,-OCH2CF2CF2H,-OCH2C≡CH,-OC≡CH,SeMe,-SeCD 3, -SeCF 3,Examples include, but are not limited to, -SeCF2H, -SeCFH2, -SeEt, -SenPr, -SeCH2CF3, -SeCH2CF2H, -SeCH2CFH2, -SeCH2CH2CF3, -SeCH2CH2CF2H, -SeCH2CH2CFH2, -SeCH2CF2CF2H, -SeCH2C≡CH, -SeC≡CH, -SeCF2C≡CH, -SeCH2CH2CH2C≡CH, or -SeCF2CH2CH2C≡CH.

[0168] As noted above, any of the above embodiments of the compound of formula (I) may be substituted or unsubstituted by any of the following conditions (i) to (iii): (i) X 1 , X 2 ,Y 1 ,Y 2 ,R 2 ,R 3 ,R 4 ,R 5 ,R 6 ,R 7 at least one of R contains deuterium; 4 and R 5 are bonded together with the atoms to which they are bonded to form a heterocycloalkyl or heteroaryl containing deuterium or fluorine, and / or a benzo[d][1,3]oxathiol group; (iii) R 4 -OR a , -SR a , or -SeR a and R 4 R in a is C1-C6 alkyl substituted with one or more halogens, provided that X 1 , X 2 , Y 1 , and Y 2 are each hydrogen or deuterium, R 2 and R 5 Both of each -OR a For clarity, a compound for which at least one of conditions (i) to (iii) is satisfied does not necessarily satisfy the remaining conditions. For example, a compound for which condition (i) is satisfied does not necessarily satisfy conditions (ii) or (iii).

[0169] In some embodiments, X 1 , X 2 ,Y 1 ,Y 2 ,R 2 ,R 3 ,R 4 ,R 5 ,R 6 ,R 7 At least one of R 4 and R 5 may be combined together with the atoms to which they are bonded to form a deuterium- or fluorine-containing heterocycloalkyl or heteroaryl, and / or benzo[d][1,3]oxathiol group, which may be optionally substituted, for example, with one or more deuterium and / or one or more halogens (e.g., fluorine). In some embodiments, R 4 -OR a , -SR a , or -SeR a and R 4 R in a is a C1-C6 alkyl substituted with one or more halogens (i.e., R 4 is an -O-C1-C6 alkyl group (wherein the alkyl group is substituted with one or more halogens), an -S-C1-C6 alkyl group (wherein the alkyl group is substituted with one or more halogens), or a -Se-C1-C6 alkyl group (wherein the alkyl group is substituted with one or more halogens).

[0170] Formula (II) In some embodiments, the compound has the structure of formula (II): [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; During the ceremony, X 1 and X 2 are independently hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl; Y1 and Y 2 are independently hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl; R 2 and R 3 are independently hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, -OR a , or -SR a and R 6 and R 7 are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or alternatively, R 6 and R 7 together with the nitrogen atom to which they are attached, are optionally joined to form a substituted or unsubstituted heterocycloalkyl; Each R a are independently hydrogen, deuterium, substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3 to C6 10 is cycloalkyl, A is O or S; Z 1 and Z 2 are independently hydrogen, deuterium, or fluorine; If A is O, then X 1 , X 2 ,Y 1 ,Y 2 ,R 2 ,R 3 ,R 6 ,R 7 ,Z 1 , Z 2 At least one of the groups contains deuterium and / or Z 1 and Z 2 At least one of the groups is fluorine.

[0171] X 1 and X 2may 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. In some embodiments, X 1 and X 2 are different. In some embodiments, X 1 is hydrogen or deuterium, and X 2 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, X 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, CD2H, CD3, CFH2, CF2H, -CF3, etc. In some embodiments, X 1 and X 2 One of the atoms is deuterium and the other is hydrogen.

[0172] Y 1 and Y 2 can 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. In some embodiments, Y 1 and Y 2 In some embodiments, Y 1 and Y 2 One of Y is deuterium and the other is hydrogen. 1is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, Y 2 is a substituted or unsubstituted C1-C6 alkyl.

[0173] In some embodiments, R 2 is deuterium. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 2 is a substituted C1-C6 alkyl. 2 When R is substituted C1-C6, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 2 -OR a In some embodiments, R 2 -SR a is.

[0174] In some embodiments, R 3 is deuterium. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 3is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 3 is a substituted C1-C6 alkyl. 3 When R is substituted C1-C6, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 3 -OR a In some embodiments, R 3 -SR a is.

[0175] R 6 and R 7 can be the same or different. In some embodiments, R 6 and R 7 are the same. For example, in some embodiments, R 6 and R 7 In some embodiments, both R 6 and R 7 are different. For example, in some embodiments, R 6 is hydrogen and R 7 R is unsubstituted or substituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 6 and R 7may independently be hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R 6 and R 7 can independently be hydrogen, unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and hexyl), or C1-C6 alkyl substituted with one or more deuterium atoms (e.g., -CDH2, -CD2H, -CD3).

[0176] In some embodiments, R 6 and / or R 7 is an unsubstituted C1-C6 alkyl, for example, an unsubstituted C1 alkyl, an unsubstituted C2 alkyl, an unsubstituted C3 alkyl, an unsubstituted C4 alkyl, an unsubstituted C5 alkyl, or an unsubstituted C6 alkyl. 6 and / or R 7 is an unsubstituted straight chain C2-C6 alkyl. In some embodiments, R 6 and / or R 7 is an unsubstituted branched C3 to C 10 Examples of unsubstituted C1-C6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.

[0177] In some embodiments, R 6 and / or R 7is a substituted C1-C6 alkyl, for example, a substituted C1 alkyl, a substituted C2 alkyl, a substituted C3 alkyl, a substituted C4 alkyl, a substituted C5 alkyl, or a substituted C6 alkyl. The alkyl group may include one or more substituents. The alkyl group may be substituted with any one or more substituents listed herein, examples of which may include, but are not limited to, polar substituents such as deuterium, halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. In some embodiments, R 6 and / or R 7 is a C1-C6 alkyl substituted with one or more deuterium atoms, examples of which include, but are not limited to, -CDH2, -CD2H, -CD3, -CD2CD3, and -CD2CD2CD3. In some embodiments, R 6 and / or R 7 is a C1-C6 alkyl substituted with one or more fluorine atoms, i.e., a fluoroalkyl group. Examples of fluoroalkyl groups include -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CH2CF2CHF2, -CH2CF2CF3, -CH(CF3)2, and In some embodiments, R 6 and / or R 7is a C1-C6 alkyl substituted with one or more deuterium atoms and one or more fluorine atoms, examples of which include, but are not limited to, -CD2CH2F, -CD2CHF2, -CD2CF3, -CD2CH2CH2F, -CD2CH2CHF2, -CD2CH2CF3, -CD2CD2CH2, -CD2CD2CHF2, -CD2CD2CF3, -CD2CH2CH2CH2F, -CD2CH2CH2CHF2, -CD2CH2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3.

[0178] In some embodiments, R 6 and / or R 7 is a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. The C1-C6 alkyl is, for example, a substituted or unsubstituted C3-C 10 In some embodiments, the C1-C6 alkyl may be substituted with an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C6 alkyl). 10 In some embodiments, the C1-C6 alkyl is a substituted cycloalkyl (e.g., a substituted C3-C6 alkyl), examples of which include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 10 The cycloalkyl group may be substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one or more substituents. In some embodiments, R6 and / or R 7 is a C1 alkyl substituted with a substituted or unsubstituted cycloalkyl, with particular mention being made of cyclopropylmethyl (-CH2C3H5).

[0179] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, and the like.

[0180] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted, for example, substituted or unsubstituted propargyl.

[0181] In some embodiments, R 6 and / or R 7 is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C-C 10 cycloalkyl, or substituted or unsubstituted C4-C8 cycloalkyl, or substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R 6 and R 7 is an unsubstituted cycloalkyl (e.g., unsubstituted C-C 10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 6 and / or R 7 is a substituted cycloalkyl (e.g., substituted C 10Cycloalkyl groups are substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. Cycloalkyl groups may contain one or more substituents.

[0182] In some embodiments, R 6 and / or R 7 is a substituted or unsubstituted heterocycloalkyl. In some embodiments, the unsubstituted or substituted heterocycloalkyl group can be a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, R 6 and / or R 7 is an unsubstituted heterocycloalkyl such as those described herein, examples of which include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, and 1,3-dioxolane. In some embodiments, R 6 and / or R 7 is a substituted heterocycloalkyl. The substituents can be any of those listed herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), oxo, and hydroxyl. The heterocycloalkyl group can contain one or more substituents.

[0183] In some embodiments, R 6 and / or R7 is substituted or unsubstituted aryl. In some embodiments, R 6 and / or R 7 is unsubstituted aryl, examples of which include, but are not limited to, phenyl and naphthyl. In some embodiments, R 6 and / or R 7 is a substituted aryl. The substituents can be any of those listed herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The aryl group may contain one or more substituents.

[0184] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted heteroaryl. In some embodiments, R 6 and / or R 7 is unsubstituted heteroaryl, examples of which include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, thiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and pyrazolyl. 6 and / or R 7is a substituted heteroaryl. The substituents can be any of those listed herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The heteroaryl group may contain one or more substituents.

[0185] In some embodiments, R 6 is hydrogen and R 7 is unsubstituted or substituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R 6 is hydrogen and R 7 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 6 is hydrogen and R 7 is an unsubstituted C1-C6 alkyl, a C1-C6 alkyl substituted with one or more deuterium atoms, a C1-C6 alkyl substituted with one or more fluorine atoms, or a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. For example, in some embodiments, R 6 is hydrogen and R 7 is methyl, ethyl, propyl, -CD3, or cyclopropylmethyl (-CH2C3H5).

[0186] In some embodiments, R 6 and R 7 are joined together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl. In some embodiments, R 6 and R 7are joined together with the nitrogen atom to which they are attached to form an unsubstituted heterocycloalkyl. An unsubstituted heterocycloalkyl group can be, for example, a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may optionally be fused to other rings. An unsubstituted heterocycloalkyl group must have at least one nitrogen ring atom (R 6 and R 7 R includes a nitrogen atom (an intervening nitrogen atom) and may optionally include at least one additional hetero ring atom, which may be one or more of nitrogen, sulfur, or oxygen, for a total of 1, 2, 3, or 4 hetero ring atoms (at least one of which is a nitrogen ring atom). 6 and R 7 together with the nitrogen atom to which they are attached include: [ka] These include, but are not limited to:

[0187] In some embodiments, R 6 and R 7 are joined together with the nitrogen atom to which they are attached to form a substituted heterocycloalkyl. A substituted heterocycloalkyl group can be, for example, a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may optionally be fused to other rings. A substituted heterocycloalkyl group must have at least one nitrogen ring atom (R 6 and R 7and optionally, additional heterocyclic atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 heterocyclic atoms (at least one of which is a nitrogen ring atom). Examples of substituted heterocycloalkyl groups include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, or thiomorpholine, each substituted with at least one substituent. The substituents may be any of those listed herein, which may include, but are not limited to, polar substituents such as deuterium, halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. R 6 and R 7 together with the nitrogen atom to which they are attached includes heterocycloalkyl groups substituted with one, two, three, four, or more substituents, which may be located on carbon or hetero ring atoms.

[0188] R 6 and R 7 together with the nitrogen atom to which they are attached include: [ka] These include, but are not limited to:

[0189] R 2 or R 3 When present in one or both ofa are independently hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3-C 10 In some embodiments, each R a can independently be hydrogen, deuterium, unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl), or substituted C1-C6 alkyl, with preferred substituents including, but not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, cycloalkyl, and the like. In some embodiments, R a is a substituted or unsubstituted C1-C6 alkyl, preferably a C1-C3 alkyl, preferably a substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, -CH3, -CDH2, -CD2H, -CD3, -CFH2, -CF2H, and -CF3. In some embodiments, each R a is -CH3. In some embodiments, each R a is -CD3. In some embodiments, two or more R a In such a case, each R a can be the same or different. In some embodiments, each R a are the same. In some embodiments, each R a are different, for example, one R a is -CH3 and the other is -CD3.

[0190] In some embodiments, R 2 ~R 3 R in one or more of a is hydrogen. In some embodiments, R 2 ~R 3 R in one or more of a is deuterium. In some embodiments, R 2 ~R 3 R in one or more ofa is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 2 ~R 3 R in one or more of a is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 2 ~R 3 R in one or more of a is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, polar substituents such as hydroxyl, or polyether substituents. The C1-C6 alkyl group may contain one or more substituents. In some embodiments, R 2 ~R 3 R in one or more of a is a substituted C alkyl group, examples of which include -CDH, -CDH, -CD, -CFH, These may include, but are not limited to, -CFH, -CF, and -CHC≡N. In some embodiments, R 2 ~R 3 R in one or more of a is a substituted C alkyl group, examples of which may include, but are not limited to, -CDHCDH, -CDHCDH, -CDCD, -CHCFH, -CHCFH, -CHCF, and -CHCHC≡N. In some embodiments, R 2 ~R 3 R in one or more of a is a substituted C alkyl group, examples of which may include, but are not limited to, -CH2CH2CF3, -CH2CH2CF2H, -CH2CH2CFH2, -CH2CF2CF2H, and -CH2CH2CH2C≡N. In some embodiments, R 2 ~R 3 R in one or more of ais substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, etc. In some embodiments, R 2 ~R 3 R in one or more of a is a substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, R 2 ~R 3 R in one or more of a is unsubstituted alkynyl. In some embodiments, R 2 ~R 3 R in one or more of a is unsubstituted acetylenyl (—C≡CH). In some embodiments, R 2 ~R 3 R in one or more of a is unsubstituted propargyl (—CHC≡CH). In some embodiments, R 2 ~R 3 R in one or more of a is -CHCHC≡CH. In some embodiments, R 2 ~R 3 R in one or more of a is -CHCHCHC≡CH. In some embodiments, R 2 ~R 3 One or more R a is -CH2CH2CH2CH2C≡CH. In some embodiments, R 2 ~R 3 R in one or more of a is substituted alkynyl. In some embodiments, R 2 ~R 3 R in one or more of a is substituted propargyl (e.g., —CFC≡CH). In some embodiments, R 2 ~R 3 R in one or more of a teeth, In some embodiments, R 2 ~R 3One or more R a is -CF2CH2CH2C≡CH. In some embodiments, R 2 ~R 3 R in one or more of a is -CF2CH2CH2CH2C≡CH. In some embodiments, R 2 ~R 3 R in one or more of a is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C-C 10 cycloalkyl, or substituted or unsubstituted C4-C8 cycloalkyl, or substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R 2 ~R 3 R in one or more of a is an unsubstituted cycloalkyl (e.g., unsubstituted C-C 10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 2 ~R 3 R in one or more of a is a substituted cycloalkyl (e.g., substituted C 10 Cycloalkyl groups are substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. Cycloalkyl groups may contain one or more substituents.

[0191] R a Consistent with the above discussion about R 2 and R 3 are, independently of each other, -OR a or -SR aExamples include -SMe, -SCD 3, -SCF 3, Examples include, but are not limited to, -SCF2H, -SCFH2, -SEt, -SnPr, -SCH2CF3, -SCH2CF2H, -SCH2CFH2, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -SCH2CF2CF2H, -SCH2C≡CH, -SC≡CH, -SCF2C≡CH, -SCH2CH2CH2C≡CH, -SCF2CH2CH2C≡CH, -OMe, -OCD3, -OCF3, -OCF2H, -OCFH2, OCH2CF3, -OCH2CF2H, -OCH2CFH2, OCH2CH2CF3, -OCH2CH2CF2H, -OCH2CH2CFH2, -OCH2CF2CF2H, -OCH2CF2CF2H, -OCH2C≡CH, -OC≡CH. In some embodiments, R 2 -OR a or -SR a However, on the other hand, R 3 is hydrogen. In some embodiments, R 3 -OR a or -SR a However, on the other hand, R 2 is hydrogen.

[0192] In some embodiments, A is O (oxygen). In some embodiments, A is S (sulfur).

[0193] Z 1 and Z 2 can be the same or different. In some embodiments, Z 1 and Z 2 are the same. In some embodiments, Z 1 and Z 2 is hydrogen. In some embodiments, Z 1 and Z 2 is deuterium. In some embodiments, Z 1 and Z 2 is fluorine. In some embodiments, Z 1 and Z 2 are different. In some embodiments, Z 1 and Z2 One of them is deuterium and the other is hydrogen.

[0194] As noted above, any of the above embodiments of compounds of formula (II) may also be used where A is O and X 1 , X 2 ,Y 1 ,Y 2 ,R 2 ,R 3 ,R 6 ,R 7 ,Z 1 ,Z 2 At least one of the groups contains deuterium, and / or Z 1 and Z 2 is fluorine.

[0195] In some embodiments, the compound, e.g., the compound of formula (II), [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0196] A list of compound numbers, IUPAC names, and substituents for the compounds identified above is provided in Table 1. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] Compounds of formula (II) can advantageously delay or avoid metabolic degradation that leads to the formation of toxic by-products, such as O-demethylation, allowing for bioavailable administration regimens with reduced toxicity and off-target activity. Compounds of formula (II) can also incorporate compounds with metabolically labile groups, such as benzo[d][1,3]oxathiol groups, for controlled, consistent exposure and shortened effects.

[0197] Formula (III) In some embodiments, the compound has the structure of formula (III): [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; During the ceremony, X 1 and X 2 are independently hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl; Y 1 and Y 2are independently hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl; R 4 is a substituted or unsubstituted C1-C6 alkyl, -OR a , -SR a , or -SeR a and R 6 and R 7 are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or alternatively, R 6 and R 7 together with the nitrogen atom to which they are attached, are optionally joined to form a substituted or unsubstituted heterocycloalkyl; Each R a are independently hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3-C 10 is cycloalkyl, X 1 , X 2 ,Y 1 ,Y 2 ,R 4 ,R 6 ,R 7 ,R a At least one of the groups contains deuterium, and / or R 4 -OR a , -SR a , or -SeR a and R 4 R in a is a C1-C6 alkyl substituted with one or more halogens.

[0198] 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 X2 is hydrogen. In some embodiments, X 1 and X 2 is deuterium. In some embodiments, X 1 and X 2 are different. In some embodiments, X 1 is hydrogen or deuterium, and X 2 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, X 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X 2 is a substituted C1-C6 alkyl. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group can be -CDH2, -CD2H, -CD3, -CFH2, In some embodiments, X may be -CFH, -CF, etc. 1 and X 2 One of the atoms is deuterium and the other is hydrogen.

[0199] Y 1 and Y 2 can 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. In some embodiments, Y 1 and Y 2 In some embodiments, Y 1 and Y 2 One of Y is deuterium and the other is hydrogen. 1 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, Y 2 is a substituted or unsubstituted C1-C6 alkyl.

[0200] In some embodiments, R 4 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 is a substituted C1-C6 alkyl. 4 In the case of a substituted C1-C6 group, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, cycloalkyl, etc. 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), the substituted C1 alkyl group may be -CDH2, It may be -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc.

[0201] In some embodiments, R 4 -OR a , S.R. a , or -SeR a and R 4 R in a is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3-C 10 In some embodiments, R 4 -OR a In some embodiments, R 4 -SR a In some embodiments, R 4 -SeR a In some embodiments, R 4 R in a is hydrogen. In some embodiments, R 4 R in a is deuterium. In some embodiments, R 4 R in ais a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 4 R in a is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 R in a is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, polar substituents such as hydroxyl or polyether substituents, cycloalkyl, and the like. The C1-C6 alkyl group may contain one or more substituents. In some embodiments, R 4 R in a is a substituted C alkyl group, examples of which may include, but are not limited to, -CDH, -CDH, -CD, -CFH, -CFH, -CF, and -CHC≡N. In some embodiments, R 4 R in a is a substituted C alkyl group, examples of which may include, but are not limited to, -CDHCDH, -CDHCDH, -CDCD, -CHCFH, -CHCFH, -CHCF, and -CHCHC≡N. In some embodiments, R 4 R in a is not a substituted C2 alkyl group, such as a C2 fluoroalkyl group. 4 R in a is a substituted C alkyl group, examples of which may include, but are not limited to, -CH2CH2CF3, -CH2CH2CF2H, -CH2CH2CFH2, -CH2CF2CF2H, and -CH2CH2CH2C≡N. In some embodiments, R 4 R in a is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, etc. In some embodiments, R 4 R in ais a substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, R 4 R in a is unsubstituted alkynyl. In some embodiments, R 4 R in a is unsubstituted acetylenyl (—C≡CH). In some embodiments, R 4 R in a is unsubstituted propargyl (—CHC≡CH). In some embodiments, R 4 R in a is -CHCHC≡CH. In some embodiments, R 4 R in a is -CHCHCHC≡CH. In some embodiments, R 4 R in a is -CH2CH2CH2CH2C≡CH. In some embodiments, R 4 R in a is substituted alkynyl. In some embodiments, R 4 R in a is substituted propargyl (e.g., —CFC≡CH). In some embodiments, R 4 R in a is -CF2CH2C≡CH. In some embodiments, R 4 R in a is -CF2CH2CH2C≡CH. In some embodiments, R 4 R in a is -CF2CH2CH2CH2C≡CH. In some embodiments, R 4 R in a is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C-C 10 cycloalkyl, or substituted or unsubstituted C4-C8 cycloalkyl, or substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R a and R 4 At least one of the following is an unsubstituted C3-C 10and cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R 4 R in a is a substituted cycloalkyl (e.g., substituted C 10 Cycloalkyl groups are substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. Cycloalkyl groups may contain one or more substituents.

[0202] In some embodiments, R 4 -SMe, -SCD 3, -SCF 3, -SCF2H,-SCFH2,-SEt,-SnPr,-SCH2CF3,-SCH2CF2H,-SCH2CFH2,-SCH2CH2CF3,-SCH2CH2CF2H,-S CH2CH2CFH2,-SCH2CF2CF2H,-SCH2C≡CH,-SC≡CH,-SCF2C≡CH,-SCH2CH2CH2C≡CH,-SCF2CH2CH2C≡C H,-Me,CD3,CF3,-t-Bu,-C(CD3)3,OMe,OCD3,OCF3,-OCF2H,-OCFH2,OCH2CF3,-OCH2CF2H,-OCH2C FH2,OCH2CH2CF3,-OCH2CH2CF2H,-OCH2CH2CFH2,-OCH2CF2CF2H,-OCH2C≡CH,-OC≡CH,SeMe,-SeCD 3, -SeCF 3,-SeCF2H,-SeCFH2,-SeEt,-SenPr,-SeCH2CF3,-SeCH2CF2H,-SeCH2CFH2,-SeCH2CH2CF3,-SeCH2CH2CF2H,-SeC H2CH2CFH2,-SeCH2CF2CF2H,-SeCH2C≡CH,-SeC≡CH,-SeCF2C≡CH,-SeCH2CH2CH2C≡CH,or-SeCF2CH2CH2C≡CH.In some embodiments,R 4 is-SMe,-SCD 3, -SCF 3, -SEt, -SnPr, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -Me, -CD3, -CF3, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, -OCH2CH2CFH2, or -Br.

[0203] R 6 and R 7 can be the same or different. In some embodiments, R 6 and R 7 are the same. For example, in some embodiments, R 6 and R 7 In some embodiments, both R 6 and R 7 are different. In some embodiments, R 6 is hydrogen and R 7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. 6 and R 7 may independently be hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R 6 and R 7can independently be hydrogen, unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and hexyl), or C1-C6 alkyl substituted with one or more deuterium atoms (e.g., -CDH2, -CD2H, -CD3).

[0204] In some embodiments, R 6 and / or R 7 is an unsubstituted C1-C6 alkyl, for example, an unsubstituted C1 alkyl, an unsubstituted C2 alkyl, an unsubstituted C3 alkyl, an unsubstituted C4 alkyl, an unsubstituted C5 alkyl, or an unsubstituted C6 alkyl. 6 and / or R 7 is an unsubstituted straight chain C2-C6 alkyl. In some embodiments, R 6 and / or R 7 is an unsubstituted branched C3 to C 10 Examples of unsubstituted C1-C6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.

[0205] In some embodiments, R 6 and / or R 7 is a substituted C1-C6 alkyl, for example, a substituted C1 alkyl, a substituted C2 alkyl, a substituted C3 alkyl, a substituted C4 alkyl, a substituted C5 alkyl, or a substituted C6 alkyl. The alkyl group may include one or more substituents. The alkyl group may be substituted with any one or more substituents listed herein, examples of which may include, but are not limited to, polar substituents such as deuterium, halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. In some embodiments, R6 and / or R 7 is a C1-C6 alkyl substituted with one or more deuterium atoms, examples of which include, but are not limited to, -CDH2, -CD2H, -CD3, -CD2CD3, and -CD2CD2CD3. In some embodiments, R 6 and / or R 7 is a C1-C6 alkyl substituted with one or more fluorine atoms, i.e., a fluoroalkyl group. Examples of fluoroalkyl groups include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CH2CF2CHF2, -CH2CF2CF3, -CH(CF3)2, and -CH(CH3)CF3. In some embodiments, R 6 and / or R 7 is a C1-C6 alkyl substituted with one or more deuterium atoms and one or more fluorine atoms, examples of which include, but are not limited to, -CD2CH2F, -CD2CHF2, -CD2CF3, -CD2CH2CH2F, -CD2CH2CHF2, -CD2CH2CF3, -CD2CD2CH2, -CD2CD2CHF2, -CD2CD2CF3, -CD2CH2CH2CH2F, -CD2CH2CH2CHF2, -CD2CH2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3.

[0206] In some embodiments, R 6 and / or R 7 is a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. The C1-C6 alkyl is, for example, a substituted or unsubstituted C3-C 10In some embodiments, the C1-C6 alkyl may be substituted with an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C6 alkyl). 10 In some embodiments, the C1-C6 alkyl is substituted with a substituted cycloalkyl (e.g., a substituted C3-C6 alkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 10 The cycloalkyl group may be substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one or more substituents. In some embodiments, R 6 and / or R 7 is a C1 alkyl substituted with a substituted or unsubstituted cycloalkyl, with particular mention being made of cyclopropylmethyl (-CH2C3H5).

[0207] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, and the like.

[0208] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted, for example, substituted or unsubstituted propargyl.

[0209] In some embodiments, R 6 and / or R 7is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C-C 10 cycloalkyl, or substituted or unsubstituted C4-C8 cycloalkyl, or substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R 6 and R 7 is an unsubstituted cycloalkyl (e.g., unsubstituted C-C 10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 6 and / or R 7 is a substituted cycloalkyl (e.g., substituted C 10 Cycloalkyl groups are substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. Cycloalkyl groups may contain one or more substituents.

[0210] In some embodiments, R 6 and / or R 7 is a substituted or unsubstituted heterocycloalkyl. In some embodiments, the unsubstituted or substituted heterocycloalkyl group can be a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, R 6 and / or R 7is an unsubstituted heterocycloalkyl such as those described herein, examples of which include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, and 1,3-dioxolane. In some embodiments, R 6 and / or R 7 is a substituted heterocycloalkyl. The substituents can be any of those listed herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), oxo, and hydroxyl. The heterocycloalkyl group can contain one or more substituents.

[0211] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted aryl. In some embodiments, R 6 and / or R 7 is unsubstituted aryl, examples of which include, but are not limited to, phenyl and naphthyl. In some embodiments, R 6 and / or R 7 is a substituted aryl. The substituents may be any of those listed herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The aryl group may contain one or more substituents.

[0212] In some embodiments, R 6 and / or R7 is substituted or unsubstituted heteroaryl. In some embodiments, R 6 and / or R 7 is unsubstituted heteroaryl, examples of which include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, thiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and pyrazolyl. 6 and / or R 7 is a substituted heteroaryl. The substituents can be any of those listed herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The heteroaryl group may contain one or more substituents.

[0213] In some embodiments, R 6 is hydrogen and R 7 is unsubstituted or substituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R 6 is hydrogen and R 7 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 6 is hydrogen and R 7is an unsubstituted C1-C6 alkyl, a C1-C6 alkyl substituted with one or more deuterium atoms, a C1-C6 alkyl substituted with one or more fluorine atoms, or a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. For example, in some embodiments, R 6 is hydrogen and R 7 is methyl, ethyl, propyl, -CD3, or cyclopropylmethyl (-CH2C3H5).

[0214] In some embodiments, R 6 and R 7 are joined together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl. In some embodiments, R 6 and R 7 are joined together with the nitrogen atom to which they are attached to form an unsubstituted heterocycloalkyl. An unsubstituted heterocycloalkyl group can be, for example, a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may optionally be fused to other rings. An unsubstituted heterocycloalkyl group must have at least one nitrogen ring atom (R 6 and R 7 R includes a nitrogen atom (an intervening nitrogen atom) and may optionally include at least one additional hetero ring atom, which may be one or more of nitrogen, sulfur, or oxygen, for a total of 1, 2, 3, or 4 hetero ring atoms (at least one of which is a nitrogen ring atom). 6 and R 7 together with the nitrogen atom to which they are attached include: [ka] These include, but are not limited to:

[0215] In some embodiments, R 6 and R 7are joined together with the nitrogen atom to which they are attached to form a substituted heterocycloalkyl. A substituted heterocycloalkyl group can be, for example, a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may optionally be fused to other rings. A substituted heterocycloalkyl group must have at least one nitrogen ring atom (R 6 and R 7 and optionally, additional heterocyclic atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 heterocyclic atoms (at least one of which is a nitrogen ring atom). Examples of substituted heterocycloalkyl groups include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, or thiomorpholine, each substituted with at least one substituent. The substituents may be any of those listed herein, which may include, but are not limited to, polar substituents such as deuterium, halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. R 6 and R 7 together with the nitrogen atom to which they are attached includes heterocycloalkyl groups substituted with one, two, three, four, or more substituents, which may be located on carbon or hetero ring atoms.

[0216] R 6 and R 7 together with the nitrogen atom to which they are attached include: [ka] These include, but are not limited to:

[0217] Each R a are independently hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3-C 10 In some embodiments, each R a can independently be hydrogen, deuterium, unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl), or substituted C1-C6 alkyl, with preferred substituents including, but not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, cycloalkyl, and the like. In some embodiments, R a is a substituted or unsubstituted C1-C6 alkyl, preferably a C1-C3 alkyl, preferably a substituted or unsubstituted C1 alkyl, examples of which include -CH3, -CDH2, -CD2H, Examples include, but are not limited to, -CD, -CFH, -CFH, and -CF. a is any other R a In some embodiments, each R a are the same. In some embodiments, each R a is -CH3. In some embodiments, each R a is -CD3. In some embodiments, each R a In some embodiments, R is located at the meta position of the phenyl group. a are the same, while R 4 Any R that exists in a can be the same as or different from those at the meta position of the phenyl group. aare independently -Me, -CD3, -CF3, -Et, -nPr, -CH2CH2CF3, -CH2CH2CF2H, or -CH2CH2CFH2.

[0218] In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is hydrogen. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is deuterium. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 and R at one or more of the meta positions of the phenyl group a is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, cycloalkyl, and the like. The C1-C6 alkyl group may contain one or more substituents. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is a substituted C alkyl group, examples of which may include, but are not limited to, -CDH, -CDH, -CD, -CFH, -CFH, -CF, and -CHC≡N. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group ais a substituted C alkyl group, examples of which may include, but are not limited to, -CDHCDH, -CDHCDH, -CDCD, -CHCFH, -CHCFH, -CHCF, and -CHCHC≡N. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is a substituted C alkyl group, examples of which may include, but are not limited to, -CH2CH2CF3, -CH2CH2CF2H, -CH2CH2CFH2, -CH2CF2CF2H, and -CH2CH2CH2C≡N. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, etc. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is a substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is unsubstituted alkynyl. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is unsubstituted acetylenyl (—C≡CH). In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is unsubstituted propargyl (—CHC≡CH). In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is -CHCHC≡CH. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is -CHCHCHC≡CH. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group ais -CH2CH2CH2CH2C≡CH. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is substituted alkynyl. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is substituted propargyl (e.g., —CFC≡CH). In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is -CF2CH2C≡CH. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is -CF2CH2CH2C≡CH. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is -CF2CH2CH2CH2C≡CH. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C-C 10 cycloalkyl, or substituted or unsubstituted C4-C8 cycloalkyl, or substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is an unsubstituted cycloalkyl (e.g., unsubstituted C-C 10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 4 and R at one or more of the meta positions of the phenyl group a is a substituted cycloalkyl (e.g., substituted C 10Cycloalkyl groups are substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. Cycloalkyl groups may contain one or more substituents.

[0219] As noted above, any of the above embodiments of compounds of formula (III) may also include X 1 , X 2 ,Y 1 ,Y 2 ,R 4 ,R 6 ,R 7 ,R a At least one of the groups contains deuterium, and / or R 4 But, -OR a , -SR a , or -SeR a and R 4 R in a is a C1-C6 alkyl substituted with one or more halogens (i.e., R 4 is an —O—C1-C6 alkyl group (wherein the alkyl group is substituted with one or more halogens), an —S—C1-C6 alkyl group (wherein the alkyl group is substituted with one or more halogens), or a —Se—C1-C6 alkyl group (wherein the alkyl group is substituted with one or more halogens).

[0220] In some embodiments, the compound, e.g., the compound of formula (III), [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0221] A list of compound numbers, IUPAC names, and substituents for the compounds identified above is provided in Table 2. [Table 11] [Table 12] [Table 13] [Table 14] [Table 15]

[0222] The compound of formula (III) may have advantageous brain bioavailability and thus exhibit enhanced oral activity even at lower doses.As a result, the compound of formula (III) may be suitable for microdosing to achieve sustained therapeutic benefit with reduced toxicity.

[0223] Formula (IV) In some embodiments, the compound has the structure of formula (IV): [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, During the ceremony, X 1 is hydrogen or deuterium, X 2 is a substituted or unsubstituted C1-C6 alkyl, Y 1 and Y 2 are independently hydrogen or deuterium; R 3 is hydrogen or deuterium, R 4 is hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, -OR b , -SR b , or -SeR b and R 6 and R 7 are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or alternatively, R 6 and R 7 together with the nitrogen atom to which they are attached, are optionally joined to form a substituted or unsubstituted heterocycloalkyl; Each R a are independently substituted or unsubstituted C1-C6 alkyl, Each R b is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3-C 10 is cycloalkyl, However, X 1 , X 2 ,Y 1 ,Y 2 ,R 3 ,R 4 ,R 6 ,R 7 , and R a At least one of the groups contains deuterium, and / or R 4 But, -OR b , -SR b , or -SeR b and R 4 R in b is C1-C6 alkyl substituted with one or more halogens.

[0224] In some embodiments, X 1 is hydrogen. In some embodiments, X 1 is deuterium.

[0225] In some embodiments, X 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, CD2H, CD3, CFH2, CF2H, -CF3, etc.

[0226] Y 1 and Y 2 can be the same or different. In some embodiments, Y 1 and Y 2 are the same. In some embodiments, Y 1and Y 2 is hydrogen. In some embodiments, Y 1 and Y 2 is deuterium. In some embodiments, Y 1 and Y 2 One of the atoms is deuterium and the other is hydrogen.

[0227] In some embodiments, R 3 is deuterium. In some embodiments, R 3 is hydrogen.

[0228] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is deuterium.

[0229] In some embodiments, R 4 is a halogen, for example, —Br, —F, —Cl, or —I.

[0230] In some embodiments, R 4 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 is a substituted C1-C6 alkyl. 4 In the case of a substituted C1-C6 group, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, alkoxy, or polyether substituents, cycloalkyl, etc. 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), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc.

[0231] In some embodiments, R 4 is a substituted or unsubstituted C3-C 10In some embodiments, R 4 is unsubstituted C3~C 10 and cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R 4 is substituted C3~C 10 Cycloalkyl. Preferred substituents may include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, alkoxy, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents.

[0232] In some embodiments, R 4 -OR b , S.R. b , or -SeR b and R b is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3-C 10 In some embodiments, R 4 -OR b and R b is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C 10 Cycloalkyl, preferably substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C 10 Cycloalkyl, for example, substituted C1-C6 alkyl groups as defined and exemplified herein, unsubstituted C1-C6 alkyl groups, substituted C3-C6 alkyl groups, 10 Cycloalkyl group or unsubstituted C3-C 10 In some embodiments, R 4 -SR b and R b is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C 10Cycloalkyl, preferably substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C 10 Cycloalkyl, for example, substituted C1-C6 alkyl groups as defined and exemplified herein, unsubstituted C1-C6 alkyl groups, substituted C3-C6 alkyl groups, 10 Cycloalkyl group or unsubstituted C3-C 10 In some embodiments, R 4 -SeR b and R b is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C 10 Cycloalkyl, preferably substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C 10 Cycloalkyl, for example, substituted C1-C6 alkyl groups as defined and exemplified herein, unsubstituted C1-C6 alkyl groups, substituted C3-C6 alkyl groups, 10 Cycloalkyl group or unsubstituted C3-C 10 It is a cycloalkyl group.

[0233] In some embodiments, R b is hydrogen. In some embodiments, R b is deuterium. In some embodiments, R b is a substituted or unsubstituted C1-C6 cycloalkyl. In some embodiments, R b is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. b is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, cycloalkyl, and the like. The C1-C6 alkyl group may contain one or more substituents. In some embodiments, R bis a substituted C alkyl group, examples of which may include, but are not limited to, -CDH, -CDH, -CD, -CFH, -CFH, -CF, and -CHC≡N. In some embodiments, R b is a substituted C alkyl group, examples of which may include, but are not limited to, -CDHCDH, -CDHCDH, -CDCD, -CHCFH, -CHCFH, -CHCF, and -CHCHC≡N. In some embodiments, R b is not a substituted C2 alkyl group, such as a C2 fluoroalkyl group. b is a substituted C alkyl group, examples of which may include, but are not limited to, -CH2CH2CF3, -CH2CH2CF2H, -CH2CH2CFH2, -CH2CF2CF2H, and -CH2CH2CH2C≡N. In some embodiments, R b is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, etc. In some embodiments, R b is a substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, R b is unsubstituted alkynyl. In some embodiments, R b is unsubstituted acetylenyl (—C≡CH). In some embodiments, R b is unsubstituted propargyl (—CHC≡CH). In some embodiments, R b is -CHCHC≡CH. In some embodiments, R b teeth, In some embodiments, R b is -CH2CH2CH2CH2C≡CH. In some embodiments, R b is substituted alkynyl. In some embodiments, R b is substituted propargyl (e.g., —CFC≡CH). In some embodiments, R b is -CF2CH2C≡CH. In some embodiments, Rb is -CF2CH2CH2C≡CH. In some embodiments, R b is -CF2CH2CH2CH2C≡CH. In some embodiments, R b is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C-C 10 cycloalkyl, or substituted or unsubstituted C4-C8 cycloalkyl, or substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R b is an unsubstituted cycloalkyl (e.g., unsubstituted C-C 10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R b is a substituted cycloalkyl (e.g., substituted C 10 Cycloalkyl groups are substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. Cycloalkyl groups may contain one or more substituents.

[0234] In some embodiments, R 4 -SMe, -SCD 3, -SCF 3,-SCF2H,-SCFH2,-SEt,-SnPr,-SCH2CF3,-SCH2CF2H,-SCH2CFH2,-SCH2CH2CF3,-SCH2CH2CF2H,-SCH2CH2CFH2,-SC H2CF2CF2H,-SCH2C≡CH,-SC≡CH,-SCF2C≡CH,-SCH2CH2CH2C≡CH,-SCF2CH2CH2C≡CH, -Me, -CD3, -CF3, -t-Bu, -C(CD3) 3, -Cyclopentyl, -OMe, OCD3,OCF3,-OCF2H,-OCFH2,OCH2CF3,-OCH2CF2H,-OCH2CFH2,OCH2CH2CF3,-OCH2CH2CF2H,-OCH 2CH2CFH2,-OCH2CF2CF2H,-OCH2C≡CH,-OC≡CH,-CH2CH2CH2CH2C≡CH,-CF2CH2CH2CH2C≡CH,-Cl,-I,-Br,SeMe,-SeCD 3, -SeCF 3, -SeCF2H, -SeCFH2, -SeEt, -SenPr, -SeCH2CF3, -SeCH2CF2H, -SeCH2CFH2, -SeCH2CH2CF3, -SeCH2CH2CF2H, -SeCH2CH2CFH2, -SeCH2CF2CF2H, -SeCH2C≡CH, -SeC≡CH, -SeCF2C≡CH, -SeCH2CH2CH2C≡CH, or -SeCF2CH2CH2C≡CH. In some embodiments, R 4 -SMe, -SCD 3, -SCF 3, In some embodiments, R is selected from the group consisting of: -SCFH, SCHCHCF, -SCHCHCFH, -SCHCHCFH, -SEt, -Sn-Pr, -Me, -CD, -CF, -t-Bu, -C(CD), -cyclopentyl, -OMe, -OCD, -OCF, -OCHCHCF, -OCHCHCFH, -OCHCHCFH, -Cl, -I, or -Br. 4 is selected from the group consisting of -SMe, -Me, -OCD, -CF, -t-Bu, or -cyclopentyl. 4is selected from the group consisting of -SCF, -SCFH,SCHCHCF, -SCHCHCFH, -SCHCHCFH, -OCHCHCF, -OCHCHCFH, and -OCHCHCFH. 4 is -SCF3, -SCF2H, SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -OCH2CH2CF3, -OCH2CH2CF2H, or -OCH2CH2CFH2, other substituents (i.e., X 1 , X 2 ,Y 1 ,Y 2 ,R 3 ,R 6 ,R 7 , and R a ) may or may not contain deuterium. In a preferred embodiment, R 4 is -SCF3.

[0235] R 6 and R 7 can be the same or different. In some embodiments, R 6 and R 7 are the same. For example, in some embodiments, R 6 and R 7 In some embodiments, both R 6 and R 7 are different. In some embodiments, R 6 is hydrogen and R 7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. 6 and R 7may independently be hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R 6 and R 7 can independently be hydrogen, unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and hexyl), or C1-C6 alkyl substituted with one or more deuterium atoms (e.g., -CDH2, -CD2H, -CD3). In some embodiments, R 6 and R 7 is hydrogen.

[0236] In some embodiments, R 6 and / or R 7 is an unsubstituted C1-C6 alkyl, for example, an unsubstituted C1 alkyl, an unsubstituted C2 alkyl, an unsubstituted C3 alkyl, an unsubstituted C4 alkyl, an unsubstituted C5 alkyl, or an unsubstituted C6 alkyl. 6 and / or R 7 is an unsubstituted straight chain C2-C6 alkyl. In some embodiments, R 6 and / or R 7 is an unsubstituted branched C3 to C 10 Examples of unsubstituted C1-C6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.

[0237] In some embodiments, R 6 and / or R 7is a substituted C1-C6 alkyl, for example, a substituted C1 alkyl, a substituted C2 alkyl, a substituted C3 alkyl, a substituted C4 alkyl, a substituted C5 alkyl, or a substituted C6 alkyl. The alkyl group may include one or more substituents. The alkyl group may be substituted with any one or more substituents listed herein, examples of which may include, but are not limited to, polar substituents such as deuterium, halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. In some embodiments, R 6 and / or R 7 is a C1-C6 alkyl substituted with one or more deuterium atoms, examples of which include, but are not limited to, -CDH2, -CD2H, -CD3, -CD2CD3, and -CD2CD2CD3. In some embodiments, R 6 and / or R 7 is a C1-C6 alkyl substituted with one or more fluorine atoms, i.e., a fluoroalkyl group. Examples of fluoroalkyl groups include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CH2CF2CHF2, -CH2CF2CF3, -CH(CF3)2, and -CH(CH3)CF3. In some embodiments, R 6 and / or R 7is a C1-C6 alkyl substituted with one or more deuterium atoms and one or more fluorine atoms, examples of which include, but are not limited to, -CD2CH2F, -CD2CHF2, -CD2CF3, -CD2CH2CH2F, -CD2CH2CHF2, -CD2CH2CF3, -CD2CD2CH2, -CD2CD2CHF2, -CD2CD2CF3, -CD2CH2CH2CH2F, -CD2CH2CH2CHF2, -CD2CH2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3.

[0238] In some embodiments, R 6 and / or R 7 is a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. The C1-C6 alkyl is, for example, a substituted or unsubstituted C3-C 10 In some embodiments, the C1-C6 alkyl may be substituted with an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C6 alkyl). 10 In some embodiments, the C1-C6 alkyl is substituted with a substituted cycloalkyl (e.g., a substituted C3-C6 alkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 10 The cycloalkyl group may be substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one or more substituents. In some embodiments, R6 and / or R 7 is a C1 alkyl substituted with a substituted or unsubstituted cycloalkyl, with particular mention being made of cyclopropylmethyl (-CH2C3H5).

[0239] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, and the like.

[0240] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted, for example, substituted or unsubstituted propargyl.

[0241] In some embodiments, R 6 and / or R 7 is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C-C 10 cycloalkyl, or substituted or unsubstituted C4-C8 cycloalkyl, or substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R 6 and R 7 is an unsubstituted cycloalkyl (e.g., unsubstituted C-C 10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 6 and / or R 7 is a substituted cycloalkyl (e.g., substituted C 10Cycloalkyl groups are substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. Cycloalkyl groups may contain one or more substituents.

[0242] In some embodiments, R 6 and / or R 7 is a substituted or unsubstituted heterocycloalkyl. In some embodiments, the unsubstituted or substituted heterocycloalkyl group can be a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, R 6 and / or R 7 is an unsubstituted heterocycloalkyl such as those described herein, examples of which include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, and 1,3-dioxolane. In some embodiments, R 6 and / or R 7 is a substituted heterocycloalkyl. The substituents can be any of those listed herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), oxo, and hydroxyl. The heterocycloalkyl group can contain one or more substituents.

[0243] In some embodiments, R 6 and / or R7 is substituted or unsubstituted aryl. In some embodiments, R 6 and / or R 7 is unsubstituted aryl, examples of which include, but are not limited to, phenyl and naphthyl. In some embodiments, R 6 and / or R 7 is a substituted aryl. The substituents may be any of those listed herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The aryl group may contain one or more substituents.

[0244] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted heteroaryl. In some embodiments, R 6 and / or R 7 is unsubstituted heteroaryl, examples of which include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, thiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and pyrazolyl. 6 and / or R 7is a substituted heteroaryl. The substituents can be any of those listed herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The heteroaryl group can contain one or more substituents.

[0245] In some embodiments, R 6 is hydrogen and R 7 is unsubstituted or substituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R 6 is hydrogen and R 7 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 6 is hydrogen and R 7 is an unsubstituted C1-C6 alkyl, a C1-C6 alkyl substituted with one or more deuterium atoms, a C1-C6 alkyl substituted with one or more fluorine atoms, or a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. For example, in some embodiments, R 6 is hydrogen and R 7 is methyl, ethyl, propyl, -CD3, or cyclopropylmethyl (-CH2C3H5).

[0246] In some embodiments, R 6 and R 7 are joined together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl. In some embodiments, R 6 and R 7are joined together with the nitrogen atom to which they are attached to form an unsubstituted heterocycloalkyl. An unsubstituted heterocycloalkyl group can be, for example, a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may optionally be fused to other rings. An unsubstituted heterocycloalkyl group must have at least one nitrogen ring atom (R 6 and R 7 R includes a nitrogen atom (an intervening nitrogen atom) and may optionally include at least one additional hetero ring atom, which may be one or more of nitrogen, sulfur, or oxygen, for a total of 1, 2, 3, or 4 hetero ring atoms (at least one of which is a nitrogen ring atom). 6 and R 7 together with the nitrogen atom to which they are attached include: [ka] These include, but are not limited to:

[0247] In some embodiments, R 6 and R 7 are joined together with the nitrogen atom to which they are attached to form a substituted heterocycloalkyl. A substituted heterocycloalkyl group can be, for example, a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may optionally be fused to other rings. A substituted heterocycloalkyl group must have at least one nitrogen ring atom (R 6 and R 7and optionally, additional heterocyclic atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 heterocyclic atoms (at least one of which is a nitrogen ring atom). Examples of substituted heterocycloalkyl groups include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, or thiomorpholine, each substituted with at least one substituent. The substituents may be any of those listed herein, which may include, but are not limited to, polar substituents such as deuterium, halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. R 6 and R 7 together with the nitrogen atom to which they are attached includes heterocycloalkyl groups substituted with one, two, three, four, or more substituents, which may be located on carbon or hetero ring atoms.

[0248] R 6 and R 7 together with the nitrogen atom to which they are attached include: [ka] These include, but are not limited to:

[0249] Each R a can be the same or different. In some embodiments, each Ra are the same. a are independently substituted or unsubstituted C1-C6 alkyl, preferably substituted or unsubstituted C1-C3 alkyl, preferably substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, -CH3, -CDH2, -CD2H, -CD3, -CFH2, -CF2H, and -CF3. In some embodiments, each R a is -CH3. In some embodiments, each R a is -CD3. In some embodiments, each R a are different, for example, one R a is -CH3 and the other is -CD3.

[0250] In some embodiments, X 1 is hydrogen or deuterium, and X 2 is methyl, and Y 1 and Y 2 are each hydrogen or each deuterium, and R 3 is hydrogen, and each R a is -CH3 or -CD3, and R 4 is SMe,-SCD 3, -SCF 3, -SCF2H,-SCFH2,-SEt,-SnPr,-SCH2CF3,-SCH2CF2H,-SCH2CFH2,-SCH2CH2CF3,-SCH2CH2CF2H,-SCH2CH2CFH2,-SC H2CF2CF2H,-SCH2C≡CH,-SC≡CH,-SCF2C≡CH,-SCH2CH2CH2C≡CH,-SCF2CH2CH2C≡CH,-Me,CD3, -CF3, -t-Bu, -C(CD3)3 , -Cyclopentyl, -OMe, OCD3,OCF3,-OCF2H,-OCFH2,OCH2CF3,-OCH2CF2H,-OCH2CFH2,OCH2CH2CF3,-OCH2CH2CF2H,-OCH 2CH2CFH2,-OCH2CF2CF2H,-OCH2C≡CH,-OC≡CH,-CH2CH2CH2CH2C≡CH,-CF2CH2CH2CH2C≡CH,-Cl,-I,-Br,SeMe,-SeCD 3, -SeCF 3,-SeCF2H, -SeCFH2, -SeEt, -SenPr, -SeCH2CF3, -SeCH2CF2H, -SeCH2CFH2, -SeCH2CH2CF3, -SeCH2CH2CF2H, -SeCH2CH2CFH2, -SeCH2CF2CF2H, -SeCH2C≡CH, -SeC≡CH, -SeCF2C≡CH, -SeCH2CH2CH2C≡CH, or -SeCF2CH2CH2C≡CH, preferably -SMe, -SCD 3, -SCF 3, -SCF2H, SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -SEt, -Sn-Pr, -Me, -CD3, -CF3, -t-Bu, -C(CD3)3, -cyclopentyl, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, -OCH2CH2CFH2, -Cl, -I, or -Br; R 6 and R 7 is hydrogen.

[0251] As noted above, any of the above embodiments of compounds of formula (IV) may also include X 1 , X 2 ,Y 1 ,Y 2 ,R 3 ,R 4 ,R 6 ,R 7 , and R a At least one of R contains deuterium, and / or 4 But, -OR b , -SR b , or -SeR b and R 4 R in b is C1-C6 alkyl substituted with one or more halogens.

[0252] In some embodiments, X 1 , X 2 ,Y 1 ,Y 2 ,R 3 ,R 4 ,R 6 ,R 7 , and R aAt least one of R 4 -OR b , -SR b , or -SR b and R 4 R in b is a C1-C6 alkyl substituted with one or more halogens (i.e., R 4 is an -O-C1-C6 alkyl group (wherein the alkyl group is substituted with one or more halogens), an -S-C1-C6 alkyl group (wherein the alkyl group is substituted with one or more halogens), or a -Se-C1-C6 alkyl group (wherein the alkyl group is substituted with one or more halogens).

[0253] In some embodiments, the compound, e.g., the compound of formula (IV), [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0254] A list of compound numbers, IUPAC names, and substituents for the compounds identified above is provided in Table 3. [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22]

[0255] Compounds of formula (IV) may have enhanced pharmacokinetic properties with less drug spikes and less accumulation of toxic metabolites, thereby reducing early-onset adverse effects (e.g., anxiety and nausea) and allowing for lower dosing regimens that reduce neurotoxicity and cardiovascular adverse events (including tachycardia, hypertension, and valvular heart disease) associated with chronic administration. Furthermore, compounds disclosed herein (e.g., compounds of formula (IV)) may normalize the different biological effects and metabolic rates between enantiomeric partners to achieve more predictable pharmacokinetic outcomes and reduced interpatient variability.

[0256] Formula (V) In some embodiments, the compound has the structure of formula (V): [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, During the ceremony, X 1 and X 2 are independently hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl; Y 1 and Y 2 are independently hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl; R 4 and R 5 are independently hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, -OR a , -SR a , or -SeR a or R 4 and R 5 together with the atoms to which they are attached, optionally joined to form a heterocycloalkyl or heteroaryl; R 6 and R 7are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or alternatively, R 6 and R 7 together with the nitrogen atom to which they are attached, are optionally joined to form a substituted or unsubstituted heterocycloalkyl; Each R a are independently hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3-C 10 is cycloalkyl, Each R b is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3-C 10 It is cycloalkyl.

[0257] 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. In some embodiments, X 1 and X 2 are different. In some embodiments, X 1 is hydrogen or deuterium, and X 2 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, X 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X 2is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, CD2H, CD3, CFH2, CF2H, -CF3, etc. In some embodiments, X 1 and X 2 One of the atoms is deuterium and the other is hydrogen.

[0258] Y 1 and Y 2 can 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. In some embodiments, Y 1 and Y 2 In some embodiments, Y 1 and Y 2 One of Y is deuterium and the other is hydrogen. 1 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, Y 2 is a substituted or unsubstituted C1-C6 alkyl.

[0259] In some embodiments, R 4 is deuterium. In some embodiments, R 4 is hydrogen.

[0260] In some embodiments, R 4 is a halogen, for example, —Br, —F, —Cl, or —I.

[0261] In some embodiments, R 4is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 is a substituted C1-C6 alkyl. 4 In the case of a substituted C1-C6 group, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, cycloalkyl, etc. 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), the substituted C1 alkyl group may be -CDH2, It may be -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc.

[0262] In some embodiments, R 4 -OR a , S.R. a , or -SeR a and R 4 R in a is hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3-C 10 In some embodiments, R 4 -OR a In some embodiments, R 4 -SR a In some embodiments, R 4 -SeR a In some embodiments, R 4 R in a is hydrogen. In some embodiments, R 4 R in a is deuterium. In some embodiments, R 4 R in a is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 4 R ina is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 R in a is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, polar substituents such as hydroxyl or polyether substituents, cycloalkyl, and the like. The C1-C6 alkyl group may contain one or more substituents. In some embodiments, R 4 R in a is a substituted C alkyl group, examples of which may include, but are not limited to, -CDH, -CDH, -CD, -CFH, -CFH, -CF, and -CHC≡N. In some embodiments, R 4 R in a is a substituted C alkyl group, examples of which may include, but are not limited to, -CDHCDH, -CDHCDH, -CDCD, -CHCFH, -CHCFH, -CHCF, and -CHCHC≡N. In some embodiments, R 4 R in a is not a substituted C2 alkyl group, such as a C2 fluoroalkyl group. 4 R in a is a substituted C alkyl group, examples of which may include, but are not limited to, -CH2CH2CF3, -CH2CH2CF2H, -CH2CH2CFH2, -CH2CF2CF2H, and -CH2CH2CH2C≡N. In some embodiments, R 4 R in a is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, etc. In some embodiments, R 4 R in ais a substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, R 4 R in a is unsubstituted alkynyl. In some embodiments, R 4 R in a is unsubstituted acetylenyl (—C≡CH). In some embodiments, R 4 R in a is unsubstituted propargyl (—CHC≡CH). In some embodiments, R 4 R in a is -CHCHC≡CH. In some embodiments, R 4 R in a is -CHCHCHC≡CH. In some embodiments, R 4 R in a is -CH2CH2CH2CH2C≡CH. In some embodiments, R 4 R in a is substituted alkynyl. In some embodiments, R 4 R in a is substituted propargyl (e.g., —CFC≡CH). In some embodiments, R 4 R in a is -CF2CH2C≡CH. In some embodiments, R 4 R in a is -CF2CH2CH2C≡CH. In some embodiments, R 4 R in a is -CF2CH2CH2CH2C≡CH. In some embodiments, R 4 R in a is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C-C 10 cycloalkyl, or substituted or unsubstituted C4-C8 cycloalkyl, or substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R a and R 4 At least one of the following is an unsubstituted C3-C 10and cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R 4 R in a is a substituted cycloalkyl (e.g., substituted C 10 Cycloalkyl groups are substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. Cycloalkyl groups may contain one or more substituents.

[0263] In some embodiments, R 4 -SMe, -SCD 3, -SCF 3, -SCF2H,-SCFH2,-SEt,-SnPr,-SCH2CF3,-SCH2CF2H,-SCH2CFH2,-SCH2CH2CF3,-SCH2CH2CF2H,-SCH2CH2CFH2, -SCH2CF2CF2H,-SCH2C≡CH,-SC≡CH,-SCF2C≡CH,-SCH2CH2CH2C≡CH,-SCF2CH2CH2C≡CH,-Me,CD3,CF3,-t-Bu,-C( CD3)3,OMe,OCD3,OCF3,-OCF2H,-OCFH2,OCH2CF3,-OCH2CF2H,-OCH2CFH2,OCH2CH2CF3,-OCH2CH2CF2H,-OCH2CH 2CFH2,-OCH2CF2CF2H,-OCH2C≡CH,-OC≡CH,-CH2CH2CH2CH2C≡CH,-CF2CH2CH2CH2C≡CH,-Cl,-I,-Br,SeMe,-SeCD 3, -SeCF 3,-SeCF2H, -SeCFH2, -SeEt, -SenPr, -SeCH2CF3, -SeCH2CF2H, -SeCH2CFH2, -SeCH2CH2CF3, -SeCH2CH2CF2H, -SeCH2CH2CFH2, -SeCH2CF2CF2H, -SeCH2C≡CH, -SeC≡CH, -SeCF2C≡CH, -SeCH2CH2CH2C≡CH, or -SeCF2CH2CH2C≡CH.

[0264] In some embodiments, R 5 is deuterium. In some embodiments, R 5 is hydrogen.

[0265] In some embodiments, R 5 is a halogen, for example, —Br, —F, —Cl, or —I.

[0266] In some embodiments, R 5 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 5 is a substituted C1-C6 alkyl. 5 However, when substituted C1-C6, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, cycloalkyl, etc. 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), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc.

[0267] In some embodiments, R 5 -OR a , S.R. a , or -SeR a and R 5 R in ais hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3-C 10 In some embodiments, R 5 -OR a In some embodiments, R 5 -SR a In some embodiments, R 5 -SeR a In some embodiments, R 5 R in a is hydrogen. In some embodiments, R 5 R in a is deuterium. In some embodiments, R 5 R in a is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 5 R in a is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 5 R in a is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, polar substituents such as hydroxyl, or polyether substituents. The C1-C6 alkyl group may contain one or more substituents. In some embodiments, R 5 R in a is a substituted C alkyl group, examples of which may include, but are not limited to, -CDH, -CDH, -CD, -CFH, -CFH, -CF, and -CHC≡N. In some embodiments, R 5 R in ais a substituted C alkyl group, examples of which may include, but are not limited to, -CDHCDH, -CDHCDH, -CDCD, -CHCFH, -CHCFH, -CHCF, and -CHCHC≡N. In some embodiments, R 5 R in a is not a substituted C2 alkyl group, such as a C2 fluoroalkyl group. 5 R in a is a substituted C alkyl group, examples of which may include, but are not limited to, -CH2CH2CF3, -CH2CH2CF2H, -CH2CH2CFH2, -CH2CF2CF2H, and -CH2CH2CH2C≡N. In some embodiments, R 5 R in a is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, etc. In some embodiments, R 5 R in a is a substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, R 5 R in a is unsubstituted alkynyl. In some embodiments, R 5 R in a is unsubstituted acetylenyl (—C≡CH). In some embodiments, R 5 R in a is unsubstituted propargyl (—CHC≡CH). In some embodiments, R 5 R in a is -CHCHC≡CH. In some embodiments, R 5 R in a is -CHCHCHC≡CH. In some embodiments, R 5 R in a is -CH2CH2CH2CH2C≡CH. In some embodiments, R 5 R in a is substituted alkynyl. In some embodiments, R 5 R in ais substituted propargyl (e.g., —CFC≡CH). In some embodiments, R 5 R in a is -CF2CH2C≡CH. In some embodiments, R 5 R in a is -CF2CH2CH2C≡CH. In some embodiments, R 5 R in a is -CF2CH2CH2CH2C≡CH. In some embodiments, R 5 R in a is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C-C 10 cycloalkyl, or substituted or unsubstituted C4-C8 cycloalkyl, or substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R 5 R in a is an unsubstituted cycloalkyl (e.g., unsubstituted C-C 10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 5 R in a is a substituted cycloalkyl (e.g., substituted C 10 Cycloalkyl groups are substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. Cycloalkyl groups may contain one or more substituents.

[0268] In some embodiments, R 5 -SMe, -SCD 3, -SCF 3,-SCF2H,-SCFH2,-SEt,-SnPr,-SCH2CF3,-SCH2CF2H,-SCH2CFH2,-SCH2CH2CF3,-SCH2CH2CF2H,-SCH2CH2CFH2, -SCH2CF2CF2H,-SCH2C≡CH,-SC≡CH,-SCF2C≡CH,-SCH2CH2CH2C≡CH,-SCF2CH2CH2C≡CH,-Me,CD3,CF3,-t-Bu,-C( CD3)3,OMe,OCD3,OCF3,-OCF2H,-OCFH2,OCH2CF3,-OCH2CF2H,-OCH2CFH2,OCH2CH2CF3,-OCH2CH2CF2H,-OCH2CH 2CFH2,-OCH2CF2CF2H,-OCH2C≡CH,-OC≡CH,-CH2CH2CH2CH2C≡CH,-CF2CH2CH2CH2C≡CH,-Cl,-I,-Br,SeMe,-SeCD 3, -SeCF 3, -SeCF2H, -SeCFH2, -SeEt, -SenPr, -SeCH2CF3, -SeCH2CF2H, -SeCH2CFH2, -SeCH2CH2CF3, -SeCH2CH2CF2H, -SeCH2CH2CFH2, -SeCH2CF2CF2H, -SeCH2C≡CH, -SeC≡CH, -SeCF2C≡CH, -SeCH2CH2CH2C≡CH, or -SeCF2CH2CH2C≡CH.

[0269] In some embodiments, R 4 and R 5 R is bonded together with the atoms to which it is attached to form a heterocycloalkyl or heteroaryl, and specifically refers to a benzo[d][1,3]oxathiol group or a benzo[d][1,3]dioxole group. 4 and R 5 In embodiments where are bonded together with the atoms attached thereto to form a benzo[d][1,3]oxathiol group or a benzo[d][1,3]dioxole group, either the oxathiol ring or the dioxole ring may be further substituted with substituents as defined herein, e.g., with deuterium substituents, with halogen (e.g., fluorine) substituents, and the like.

[0270] R 6 and R7 can be the same or different. In some embodiments, R 6 and R 7 are the same. For example, in some embodiments, R 6 and R 7 In some embodiments, both R 6 and R 7 are different. In some embodiments, R 6 is hydrogen and R 7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. 6 and R 7 may independently be hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R 6 and R 7 can independently be hydrogen, unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and hexyl), or C1-C6 alkyl substituted with one or more deuterium atoms (e.g., -CDH2, -CD2H, -CD3).

[0271] In some embodiments, R 6 and / or R 7 is an unsubstituted C1-C6 alkyl, for example, an unsubstituted C1 alkyl, an unsubstituted C2 alkyl, an unsubstituted C3 alkyl, an unsubstituted C4 alkyl, an unsubstituted C5 alkyl, or an unsubstituted C6 alkyl. 6 and / or R 7 is an unsubstituted straight chain C2-C6 alkyl. In some embodiments, R 6 and / or R 7 is an unsubstituted branched C3 to C 10Examples of unsubstituted C1-C6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.

[0272] In some embodiments, R 6 and / or R 7 is a substituted C1-C6 alkyl, for example, a substituted C1 alkyl, a substituted C2 alkyl, a substituted C3 alkyl, a substituted C4 alkyl, a substituted C5 alkyl, or a substituted C6 alkyl. The alkyl group may include one or more substituents. The alkyl group may be substituted with any one or more substituents listed herein, examples of which may include, but are not limited to, polar substituents such as deuterium, halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. In some embodiments, R 6 and / or R 7 is a C1-C6 alkyl substituted with one or more deuterium atoms, examples of which include, but are not limited to, -CDH2, -CD2H, -CD3, -CD2CD3, and -CD2CD2CD3. In some embodiments, R 6 and / or R 7is a C1-C6 alkyl substituted with one or more fluorine atoms, i.e., a fluoroalkyl group. Examples of fluoroalkyl groups include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CH2CF2CHF2, -CH2CF2CF3, -CH(CF3)2, and -CH(CH3)CF3. In some embodiments, R 6 and / or R 7 is a C1-C6 alkyl substituted with one or more deuterium atoms and one or more fluorine atoms, examples of which include, but are not limited to, -CD2CH2F, -CD2CHF2, -CD2CF3, -CD2CH2CH2F, -CD2CH2CHF2, -CD2CH2CF3, -CD2CD2CH2, -CD2CD2CHF2, -CD2CD2CF3, -CD2CH2CH2CH2F, -CD2CH2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3.

[0273] In some embodiments, R 6 and / or R 7 is a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. The C1-C6 alkyl is, for example, a substituted or unsubstituted C3-C 10 In some embodiments, the C1-C6 alkyl may be substituted with an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C6 alkyl). 10In some embodiments, the C1-C6 alkyl is substituted with a substituted cycloalkyl (e.g., a substituted C3-C6 alkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 10 The cycloalkyl group may be substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one or more substituents. In some embodiments, R 6 and / or R 7 is a C1 alkyl substituted with a substituted or unsubstituted cycloalkyl, with particular mention being made of cyclopropylmethyl (-CH2C3H5).

[0274] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, and the like.

[0275] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted, for example, substituted or unsubstituted propargyl.

[0276] In some embodiments, R 6 and / or R 7 is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C-C 10 cycloalkyl, or substituted or unsubstituted C4-C8 cycloalkyl, or substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R 6 and R 7is an unsubstituted cycloalkyl (e.g., unsubstituted C-C 10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 6 and / or R 7 is a substituted cycloalkyl (e.g., substituted C 10 Cycloalkyl groups are substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. Cycloalkyl groups may contain one or more substituents.

[0277] In some embodiments, R 6 and / or R 7 is a substituted or unsubstituted heterocycloalkyl. In some embodiments, the unsubstituted or substituted heterocycloalkyl group can be a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, R 6 and / or R 7 is an unsubstituted heterocycloalkyl such as those described herein, examples of which include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, and 1,3-dioxolane. In some embodiments, R 6 and / or R 7is a substituted heterocycloalkyl. The substituents can be any of those listed herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), oxo, and hydroxyl. The heterocycloalkyl group can contain one or more substituents.

[0278] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted aryl. In some embodiments, R 6 and / or R 7 is unsubstituted aryl, examples of which include, but are not limited to, phenyl and naphthyl. In some embodiments, R 6 and / or R 7 is a substituted aryl. The substituents may be any of those listed herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The aryl group may contain one or more substituents.

[0279] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted heteroaryl. In some embodiments, R 6 and / or R 7is unsubstituted heteroaryl, examples of which include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, thiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and pyrazolyl. 6 and / or R 7 is a substituted heteroaryl. The substituents can be any of those listed herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The heteroaryl group can contain one or more substituents.

[0280] In some embodiments, R 6 is hydrogen and R 7 is unsubstituted or substituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R 6 is hydrogen and R 7 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 6 is hydrogen and R 7 is an unsubstituted C1-C6 alkyl, a C1-C6 alkyl substituted with one or more deuterium atoms, a C1-C6 alkyl substituted with one or more fluorine atoms, or a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. For example, in some embodiments, R 6 is hydrogen and R 7is methyl, ethyl, propyl, -CD3, or cyclopropylmethyl (-CH2C3H5).

[0281] In some embodiments, R 6 and R 7 are joined together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl. In some embodiments, R 6 and R 7 are joined together with the nitrogen atom to which they are attached to form an unsubstituted heterocycloalkyl. An unsubstituted heterocycloalkyl group can be, for example, a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may optionally be fused to other rings. An unsubstituted heterocycloalkyl group must have at least one nitrogen ring atom (R 6 and R 7 R includes a nitrogen atom (an intervening nitrogen atom) and may optionally include at least one additional hetero ring atom, which may be one or more of nitrogen, sulfur, or oxygen, for a total of 1, 2, 3, or 4 hetero ring atoms (at least one of which is a nitrogen ring atom). 6 and R 7 together with the nitrogen atom to which they are attached include: [ka] These include, but are not limited to:

[0282] In some embodiments, R 6 and R 7 are joined together with the nitrogen atom to which they are attached to form a substituted heterocycloalkyl. A substituted heterocycloalkyl group can be, for example, a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may optionally be fused to other rings. A substituted heterocycloalkyl group must have at least one nitrogen ring atom (R 6 and R 7and optionally, additional heterocyclic atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 heterocyclic atoms (at least one of which is a nitrogen ring atom). Examples of substituted heterocycloalkyl groups include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, or thiomorpholine, each substituted with at least one substituent. The substituents may be any of those listed herein, which may include, but are not limited to, polar substituents such as deuterium, halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. R 6 and R 7 together with the nitrogen atom to which they are attached includes heterocycloalkyl groups substituted with one, two, three, four, or more substituents, which may be located on carbon or hetero ring atoms.

[0283] R 6 and R 7 together with the nitrogen atom to which they are attached include: [ka] These include, but are not limited to:

[0284] R 4 and R 5 When present in one or both ofa are independently hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C3-C 10 In some embodiments, each R a can independently be hydrogen, deuterium, unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl), or substituted C1-C6 alkyl, with preferred substituents including, but not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, and the like. In some embodiments, R a is a substituted or unsubstituted C1-C6 alkyl, preferably a C1-C3 alkyl, preferably a substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, -CH3, -CDH2, -CD2H, -CD3, -CFH2, -CF2H, and -CF3. In some embodiments, each R a is -CH3. In some embodiments, each R a is -CD3. In some embodiments, R a is R 4 and R 5 In such cases, each R a can be the same or different. In some embodiments, each R a are the same. In some embodiments, each R a are different, for example, one R a is -CH3 and the other is -CD3.

[0285] In some embodiments, R 4 and R 5 R in one or both of a is hydrogen. In some embodiments, R 4 and R 5 R in one or both of a is deuterium. In some embodiments, R 4 and R5 R in one or both of a is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 4 and R 5 R in one or both of a is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 and R 5 R in one or both of a is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, cycloalkyl, and the like. The C1-C6 alkyl group may contain one or more substituents. In some embodiments, R 4 and R 5 R in one or both of a is a substituted C alkyl group, examples of which may include, but are not limited to, -CDH, -CDH, -CD, -CFH, -CFH, -CF, and -CHC≡N. In some embodiments, R 4 and R 5 R in one or both of a is a substituted C alkyl group, examples of which may include, but are not limited to, -CDHCDH, -CDHCDH, -CDCD, -CHCFH, -CHCFH, -CHCF, and -CHCHC≡N. In some embodiments, R 4 and R 5 R in one or both of a is a substituted C alkyl group, examples of which may include, but are not limited to, -CH2CH2CF3, -CH2CH2CF2H, -CH2CH2CFH2, -CH2CF2CF2H, and -CH2CH2CH2C≡N. In some embodiments, R 4 and R 5 R in one or both of ais substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, etc. In some embodiments, R 4 and R 5 R in one or both of a is a substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, R 4 and R 5 R in one or both of a is unsubstituted alkynyl. In some embodiments, R 4 and R 5 R in one or both of a is unsubstituted acetylenyl (—C≡CH). In some embodiments, R 4 and R 5 R in one or both of a is unsubstituted propargyl (—CHC≡CH). In some embodiments, R 4 and R 5 R in one or both of a is -CHCHC≡CH. In some embodiments, R 4 and R 5 R in one or both of a teeth, In some embodiments, R 4 and R 5 R in one or both of a teeth, In some embodiments, R 4 and R 5 R in one or both of a is substituted alkynyl. In some embodiments, R 4 and R 5 R in one or both of a is substituted propargyl (e.g., —CFC≡CH). In some embodiments, R 4 and R 5 R in one or both of a teeth, In some embodiments, R 4 and R 5 R in one or both of a is -CF2CH2CH2C≡CH. In some embodiments, R 4 and R 5 R in one or both of a is -CF2CH2CH2CH2C≡CH. In some embodiments, R 4 and R 5 R in one or both of a is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C-C 10 cycloalkyl, or substituted or unsubstituted C4-C8 cycloalkyl, or substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R 4 and R 5 R in one or both of a is an unsubstituted cycloalkyl (e.g., unsubstituted C-C 10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 4 and R 5 R in one or both of a is a substituted cycloalkyl (e.g., substituted C 10 The cycloalkyl group is a cycloalkyl group. The cycloalkyl group can be substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group can contain one or more substituents. R a Consistent with the above discussion about R 4 ~R 5 Either one or both of the following may be independently selected from the group consisting of -ORa , -SR a , or -SeR a Examples include -SMe, -SCD 3, -SCF 3, -SCF2H,-SCFH2,-SEt,-Sn-Pr, -SCH2CF3, -SCH2CF2H,-SCH2CFH2,-SCH2CH2CF3,-SCH2CH2 CF2H,-SCH2CH2CFH2,-SCH2CF2CF2H,-SCH2C≡CH,-SC≡CH,-SCF2C≡CH,-SCH2CH2CH2C≡CH,-S CF2CH2CH2C≡CH,-OMe,-OCD3,-OCF3,-OCF2H,-OCFH2,-OCH2CF3,-OCH2CF2H,-OCH2CFH2,-O CH2CH2CF3,-OCH2CH2CF2H,-OCH2CH2CFH2,-OCH2CF2CF2H,-OCH2C≡CH,-OC≡CH,SeMe,-SeCD 3, -SeCF 3, Examples include, but are not limited to, -SeCF2H, -SeCFH2, -SeEt, -SenPr, -SeCH2CF3, -SeCH2CF2H, -SeCH2CFH2, -SeCH2CH2CF3, -SeCH2CH2CF2H, -SeCH2CH2CFH2, -SeCH2CF2CF2H, -SeCH2C≡CH, -SeC≡CH, -SeCF2C≡CH, -SeCH2CH2CH2C≡CH, or -SeCF2CH2CH2C≡CH.

[0286] In some embodiments, R b is hydrogen. In some embodiments, R b is deuterium. In some embodiments, R b is a substituted or unsubstituted C1-C6 cycloalkyl. In some embodiments, R b is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. bis a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, cycloalkyl, and the like. The C1-C6 alkyl group may contain one or more substituents. In some embodiments, R b is a substituted C alkyl group, examples of which may include, but are not limited to, -CDH, -CDH, -CD, -CFH, -CFH, -CF, and -CHC≡N. In some embodiments, R b is a substituted C alkyl group, examples of which may include, but are not limited to, -CDHCDH, -CDHCDH, -CDCD, -CHCFH, -CHCFH, -CHCF, and -CHCHC≡N. In some embodiments, R b is not a substituted C2 alkyl group, such as a C2 fluoroalkyl group. b is a substituted C alkyl group, examples of which include -CH2CH2CF3, -CH2CH2CF2H, -CH2CH2CFH2, These may include, but are not limited to, -CHCFCFH, and -CHCHCHC≡N. In some embodiments, R b is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, etc. In some embodiments, R b is a substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, R b is unsubstituted alkynyl. In some embodiments, R b is unsubstituted acetylenyl (—C≡CH). In some embodiments, R b is unsubstituted propargyl (—CHC≡CH). In some embodiments, R b is -CHCHC≡CH. In some embodiments, R b teeth, In some embodiments, R bis -CH2CH2CH2CH2C≡CH. In some embodiments, R b is substituted alkynyl. In some embodiments, R b is substituted propargyl (e.g., —CFC≡CH). In some embodiments, R b is -CF2CH2C≡CH. In some embodiments, R b is -CF2CH2CH2C≡CH. In some embodiments, R b is -CF2CH2CH2CH2C≡CH. In some embodiments, R b is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C-C 10 cycloalkyl, or substituted or unsubstituted C4-C8 cycloalkyl, or substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R b is an unsubstituted cycloalkyl (e.g., unsubstituted C-C 10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R b is a substituted cycloalkyl (e.g., substituted C 10 Cycloalkyl groups are substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. Cycloalkyl groups may contain one or more substituents.

[0287] In some embodiments, X 1 ,X 2 ,Y 1 ,Y 2 ,R 4 ,R 5 ,R7 , R a , and R b At least one of R 4 -OR a , -SR a , or -SR a and R 4 R in a is an unsubstituted C1-C6 alkyl (i.e., R 4 is an —O—C1-C6 alkyl group, an —S—C1-C6 alkyl group, or an —Se—C1-C6 alkyl group). In some embodiments, R 4 -OR a , -SR a , or -SR a and R 4 R in a is a C1-C6 alkyl substituted with one or more halogens (i.e., R 4 is an —O—C1-C6 alkyl group (wherein the alkyl group is substituted with one or more halogens), an —S—C1-C6 alkyl group (wherein the alkyl group is substituted with one or more halogens), or a —Se—C1-C6 alkyl group (wherein the alkyl group is substituted with one or more halogens). In some embodiments, R 5 -OR a , -SR a , or -SR a and R 5 R in a is an unsubstituted C1-C6 alkyl (i.e., R 4 is an —O—C1-C6 alkyl group, an —S—C1-C6 alkyl group, or an —Se—C1-C6 alkyl group). In some embodiments, R 5 -OR a , -SR a , or -SR a and R 5 R in a is a C1-C6 alkyl substituted with one or more halogens (i.e., R 4is an —O—C1-C6 alkyl group (wherein the alkyl group is substituted with one or more halogens), an —S—C1-C6 alkyl group (wherein the alkyl group is substituted with one or more halogens), or a —Se—C1-C6 alkyl group (wherein the alkyl group is substituted with one or more halogens). In some embodiments, R b is deuterium. In some embodiments, R b is C1-C6 alkyl substituted with one or more deuterium atoms. In some embodiments, R b is a C1-C6 alkyl substituted with one or more halogens (for example, -CF3 or -CF2H).

[0288] In some embodiments, the compound, e.g., the compound of formula (V), [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0289] Compounds of Formulas (I)-(V) may contain asymmetric centers. In such cases, Formulas (I)-(V) and compounds therein are depicted without regard to stereochemistry, but the compounds may exist as different stereoisomers. Accordingly, the present disclosure encompasses all possible stereoisomers, including not only racemates but also individual enantiomers (enantiomerically pure compounds) and non-racemic mixtures thereof. When compounds are desired as single enantiomers, they may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods, all of which are known in the art. Resolution of the final product, intermediate, or starting material may be carried out by any suitable method in the art.

[0290] In some embodiments, the compounds described herein, e.g., compounds of Formulas (I)-(V), are racemic. In some embodiments, the compounds described herein, e.g., compounds of Formulas (I)-(V), are enantiomerically pure. In some embodiments, the compounds described herein, e.g., compounds of Formulas (I)-(V), are non-asymmetric (achiral).

[0291] In some embodiments, the compound is an agonist of the serotonin 5-HT2 receptor. 2A In some embodiments, the compound may be an agonist of a receptor. In some embodiments, the compound is a modulator of a monoamine transporter. In some embodiments, the compound is a modulator of a serotonin transporter (SERT). In some embodiments, the compound is a modulator of a norepinephrine transporter (NET). In some embodiments, the compound is a modulator of a dopamine transporter (DAT). In some embodiments, administration of the compound induces a hallucinogenic effect. In some embodiments, administration of the compound does not induce a hallucinogenic effect (e.g., at doses that would classically produce hallucinogenic effects). In some embodiments, administration of the compound induces an entactogenic effect.

[0292] Also disclosed herein are pharmaceutically acceptable salts of the compounds of the present disclosure, e.g., compounds of Formulas (I)-(V). The acid used to form the pharmaceutically acceptable salt of a compound of Formulas (I)-(V) may be a mono-, di-, tri-, tetra-, or may contain more acid groups. The acid group may be, for example, a carboxylic acid, sulfonic acid, phosphonic acid, or other acidic moiety containing at least one replaceable hydrogen atom.Examples of acids that may be used in the preparation of pharmaceutically acceptable (acid addition) salts disclosed herein include acetic acid, 2,2-dichloroacetic acid, phenylacetic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthyl 2-sulfonic acid, benzophenone-1,2-dione ... toluene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.), benzoic acids (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, etc.), boric acid, (+)-camphoric acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, formic acid, fumaric acid, galactaric acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glutamic acid, Licholic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (-)-D-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, (+)-D-malic acid, hydroxymaleic acid, malonic acid, (±)-DL-mandelic acid, isethionic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, succinic acid, sulfuric acid, sulfamic acid, tannic acid, tartaric acid (e.g., DL-tartaric acid, (+)-L-tartaric acid, (-)-D-tartaric acid), thiocyanic acid, propionic acid, valeric acid, and fatty acids (including fatty mono- and di-acids, e.g., adipic (hexanedio) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, caprylic (octanoic) acid, palmitic (hexadecenoic) acid, sebacic acid, undecylenic acid, caproic acid, etc.). In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (I)-(V) is a fatty acid salt.The fatty acids used to prepare the fatty acid salts of the compounds of Formulas (I)-(V) may be fatty mono- or di-acids and may contain a fatty hydrocarbon portion consisting of hydrogen and 4, 6, 8, 10, 12, 14, 16, and up to 26, up to 24, up to 22, up to 20, or up to 18 carbon atoms, and may be fully saturated or partially unsaturated. In some embodiments, the pharmaceutically acceptable salt of a compound of Formulas (I)-(V) is an adipate, laurate, linoleate, myristate, caprate, stearate, oleate, caprylate, palmitate, sebacate, undecylenate, or caproate salt of a compound of Formulas (I)-(V).

[0293] Methods for preparing pharmaceutically acceptable salt forms of pharmaceutical compounds are known to those skilled in the art. In some embodiments, the method comprises: (a) suspending a compound of Formula (I)-(V) in a solvent or mixture of solvents; (b) contacting an acid with a compound of Formula (I)-(V) to provide a mixture; (c) optionally heating the mixture; (d) optionally cooling the mixture; (e) isolating the salt.

[0294] A variety of solvents can be used in the disclosed methods, including one or more protic solvents, one or more aprotic solvents, or mixtures thereof. In some embodiments, the solvent used in the method of preparing the salt is a protic solvent. In some embodiments, the solvent used in the method of preparing the salt is selected from the group consisting of methanol, ethanol, propanol, isopropanol (IPA), butanol, 2-butanol, acetone, butanone, dioxane (1,4-dioxane), water, tetrahydrofuran (THF), acetonitrile (MeCN), an ether solvent (e.g., t-butyl methyl ether (TBME)), hexane, heptane, octane, and combinations thereof. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is tetrahydrofuran.

[0295] Acids suitable for use in preparing pharmaceutically acceptable acid addition salts can include those previously described. The acid can be an inorganic acid, such as hydrochloric acid, or an organic acid, preferably an organic acid. In some embodiments, the acid is an organic acid selected from the group consisting of ascorbic acid, citric acid, fumaric acid, maleic acid, malonic acid, (-)-L-malic acid, (+)-L-tartaric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, benzoic acid, salicylic acid, succinic acid, oxalic acid, D-glucuronic acid, glutarate, and acetic acid. In some embodiments, the acid is an organic acid selected from the group consisting of benzenesulfonic acid, (+)-L-tartaric acid, fumaric acid, acetic acid, citric acid, malonic acid, succinic acid, oxalic acid, benzoic acid, and salicylic acid. In some embodiments, the acid is a fatty acid, such as adipic (hexanedio) acid, lauric (dodecano) acid, linoleic acid, myristic (tetradecano) acid, capric (decano) acid, stearic (octadecano) acid, oleic acid, caprylic (octano) acid, palmitic (hexadeceno) acid, sebacic acid, undecylenic acid, caproic acid, and the like, with particular mention being made of adipic (hexanedio) acid, lauric (dodecano) acid, linoleic acid, myristic (tetradecano) acid, capric (decano) acid, stearic (octadecano) acid, oleic acid, and caprylic (octano) acid.

[0296] In some embodiments, a stoichiometric (or superstoichiometric) amount of acid is contacted with a compound of Formulae (I)-(V). In some embodiments, a substoichiometric (e.g., 0.5 molar equivalent) amount of acid is contacted with a compound of Formulae (I)-(V). For example, when the acid contains at least two acidic protons (e.g., two or more carboxylic acid groups) and the target salt is a hemi-acid salt, using a substoichiometric amount of acid may be desirable.

[0297] In some embodiments, the mixture is heated, for example, to reflux, before cooling.

[0298] In some embodiments, the mixture is cooled, causing the salt to precipitate from solution. In some embodiments, the salt precipitates from solution in a crystalline form. In some embodiments, the salt precipitates from solution in an amorphous form.

[0299] Isolation of the salt can be accomplished by a variety of well-known isolation techniques, such as filtration, decantation, etc. In some embodiments, the isolation step comprises filtering the mixture.

[0300] After isolation, additional crystallization and / or recrystallization steps may also be optionally performed, if desired, to, for example, increase purity, crystallinity, etc.

[0301] In some embodiments, the compounds of the present disclosure, e.g., compounds of Formulas (I)-(V), or pharmaceutically acceptable salts, stereoisomers, or prodrugs thereof, are in the form of a solvate. Examples of solvate forms include, but are not limited to, hydrates, methanolate salts, ethanolate salts, isopropanolate salts, etc., with hydrates and ethanolate salts being preferred. Solvates can be formed from stoichiometric or non-stoichiometric amounts of solvent molecules. Solvates of the compounds of the present disclosure may be in the form of an isolatable solvate. In one non-limiting example, as a hydrate, the compound may be a monohydrate, a dihydrate, etc. Solvates of the compounds of the present disclosure also include solution-phase forms. Thus, in some embodiments, the present disclosure provides solution-phase compositions of the compounds of the present disclosure, or any pharmaceutically acceptable salt thereof, in a solvated form, preferably a fully solvated form.

[0302] In some embodiments, compounds of the present disclosure, e.g., compounds of Formulas (I)-(V), or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, are provided in crystalline form, e.g., as determined by XRPD. Accordingly, pharmaceutical compositions may be prepared from compounds of Formulas (I)-(V) in crystalline form, including one or more polymorphic forms, and used in the treatments described herein. Crystalline forms may be advantageous in terms of stability and may provide well-defined physical properties that are desirable for pharmaceutical preparation and administration.

[0303] In some embodiments, compounds of the present disclosure, e.g., compounds of Formulas (I)-(V), or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, are provided in amorphous form, e.g., as determined by XRPD. Accordingly, pharmaceutical compositions may be prepared from compounds of Formulas (I)-(V), or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, in one or more amorphous forms and used in the treatments described herein. Amorphous forms typically have higher aqueous solubility and dissolution rates compared to their crystalline counterparts, and therefore may be suitable for fast-acting dosage forms adapted to rapidly release the active agent, such as orodispersible dosage forms (ODx), immediate-release (IR) dosage forms, and the like.

[0304] The compounds of the present disclosure, such as compounds of Formulas (I)-(V), or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, can generally be prepared according to or analogous to the synthetic routes exemplified herein. Other synthetic routes can also be used in accordance with techniques and procedures known to those skilled in the art.

[0305] Therapeutic Uses and Methods Also disclosed herein are methods of treating a subject having a disease or disorder, the methods comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formulas (I)-(V), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof). In some embodiments, the disease or disorder is associated with the serotonin 5-HT2 receptor. In some embodiments, the disease or disorder is associated with a monoamine transporter.

[0306] The dosage and frequency (single or multiple doses) of the compounds administered herein can vary depending on a variety of factors, including, but not limited to, the compound being administered; the disease / condition being treated; the route of administration; the subject's body size, age, sex, health, weight, body mass index, and diet; the nature and extent of the symptoms of the disease being treated; the presence of other diseases or other health problems; the type of concomitant therapy; and complications from any disease or treatment regimen. Other treatment regimens or agents can be used in conjunction with the methods and compounds disclosed herein.

[0307] Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration found to be effective in animals. A dose in humans can be adjusted by monitoring the response to treatment and adjusting the dose upward (titrating) or downward (tapering).

[0308] Dosage can vary depending on the requirements of the subject and the compound used.In the context of the pharmaceutical compositions provided herein, the dosage administered to a subject should be sufficient to bring about a beneficial therapeutic response in the subject over time.The size of the dosage will also be determined by the existence, nature and extent of adverse side effects.Generally, treatment is initiated with a smaller dosage that is less than the optimal dosage of the compound.The dosage is then increased by small increments until the optimal effect under the circumstances is reached.

[0309] Dosage amount and interval can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated, thereby providing a treatment regimen commensurate with the severity of the individual's disease state.

[0310] Routes of administration can include oral routes (e.g., enteral / gastric delivery, buccal administration, e.g., buccal, lingual, and sublingual routes), parenteral routes (e.g., intravenous, intradermal, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration), topical routes (e.g., conjunctival, intracorneal, intraocular, ocular, auricular, transdermal, nasal (e.g., intranasal), vaginal, urethral, ​​respiratory, and rectal administration), inhalation, or others sufficient to affect a beneficial therapeutic response.

[0311] Administration may follow a continuous or intermittent dosing schedule. The dosing schedule may vary depending on the active ingredient employed, the condition being treated, the route of administration, etc. For example, administration of a compound of Formula (I)-(V), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, may be administered once daily (QD) or in divided doses throughout the day, such as twice daily (BID), three times daily (TID), four times daily (QID), or more. In some embodiments, administration may be performed every night (QHS). In some embodiments, administration is performed as needed (PRN). Administration may also be performed on a weekly basis, such as once weekly, twice weekly, three times weekly, four times weekly, every other week, every two weeks, or less frequently. The dosing schedule may specify a set number of treatments per course of treatment, for example, a compound of Formulas (I)-(V), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, may be administered 1, 2, 3, 4, 5, 6, 7, or 8 times per course of treatment. Other dosing schedules may be deemed appropriate using sound medical judgment.

[0312] Administration can be continuous (administration 7 days per week) or intermittent, depending, for example, on the pharmacokinetics and clearance / accumulation of the drug in a particular subject. If intermittent, the schedule can be, for example, 4 days of administration and 3 days of rest (rest days) per week, or any other intermittent administration schedule deemed appropriate based on sound medical judgment. For example, intermittent administration can involve the administration of a single dose within a treatment course. Continuous or intermittent administration continues for a particular treatment course, typically at least a 28-day cycle (1 month), which can be repeated with or without a rest period. Longer or shorter courses, such as 14 days, 18 days, 21 days, 24 days, 35 days, 42 days, 48 ​​days, or more, or any range therebetween, can also be used. The course can be repeated without or with a rest period, depending on the subject. Other schedules are possible depending on the presence or absence of adverse events, response to treatment, patient convenience, etc.

[0313] Utilizing the teachings provided herein, one can design an effective prophylactic or therapeutic treatment regimen that does not cause substantial toxicity and is fully effective in treating the clinical symptoms exhibited by a particular patient. This plan should include careful selection of an active compound by considering factors such as the potency of the compound, relative bioavailability, the patient's weight, the presence and severity of adverse side effects, the preferred mode of administration, and the toxicity profile of the selected agent.

[0314] A therapeutically effective amount of a compound of the present disclosure can vary depending on the various factors described above, but typically, a compound of Formulas (I)-(V) is administered in an amount of about 0.00001 mg to about 10 mg per kilogram of subject body weight, or any range therebetween, for example, about 0.00001 mg / kg, about 0.00005 mg / kg, about 0.0001 mg / kg, about 0.0005 mg / kg, about 0.001 mg / kg, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, It is provided in an amount of about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, or about 10.0 mg / kg of the compound of formula (I) to (V) (based on active form).

[0315] Compounds of the present disclosure (e.g., compounds of Formulae (I)-(V), or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof) can be administered at hallucinogenic doses. Hallucinogenic doses, oral or otherwise, can, in some embodiments, range from about 0.3 mg / kg, about 0.35 mg / kg, about 0.4 mg / kg, about 0.45 mg / kg, about 0.5 mg / kg, and up to 5 mg / kg, about 4 mg / kg, about 3 mg / kg, about 2 mg / kg, about 1 mg / kg, about 0.95 mg / kg, about 0.9 mg / kg, about 0.85 mg / kg, about 0.8 mg / kg, about 0.75 mg / kg, about 0.7 mg / kg, about 0.65 mg / kg, about 0.6 mg / kg, about 0.55 mg / kg of a compound of Formulae (I)-(V) (active form basis). As noted above, higher doses may be administered in some embodiments. The hallucinogenic doses may be administered orally or by other means once, potentially with repeated administration at intervals of at least one week. In some cases, no more than five doses are administered in any one treatment course. The course may be repeated as needed, with or without a rest period. Such acute treatment regimens may involve psychotherapy before, during, and / or after administration of the hallucinogenic doses. These treatments are appropriate for the various mental health disorders disclosed herein, including, but not limited to, major depressive disorder (MDD), treatment-resistant depression (TRD), anxiety disorders, and substance use disorders (e.g., alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, smoking, and cocaine use disorder).

[0316] Compounds of the present disclosure (e.g., compounds of Formulas (I)-(V), or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof) can be administered at non-hallucinogenic (yet potentially serotonergic) concentrations, have low toxicity, and achieve long-term therapeutic benefit, and therefore may be suitable for microdosing. Non-hallucinogenic doses, by oral or other means, in some embodiments, are about 0.00001 mg / kg, about 0.00005 mg / kg, about 0.0001 mg / kg, about 0.0005 mg / kg, about 0.001 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, and up to about 0.3 mg / kg. The dose range for the compound of Formulas (I)-(V) (active dose) may be about 0.25 mg / kg, about 0.2 mg / kg, about 0.15 mg / kg, about 0.1 mg / kg, about 0.083 mg / kg, about 0.08 mg / kg, about 0.075 mg / kg, about 0.07 mg / kg, about 0.06 mg / kg, about 0.05 mg / kg, about 0.04 mg / kg, about 0.03 mg / kg, or about 0.02 mg / kg. Typically, a non-hallucinogenic dose is administered orally up to daily for a course of treatment (e.g., one month). However, there is no limit to the number of administrations of a non-hallucinogenic dose, and administration may be less frequent or more frequent if deemed appropriate. The course may be repeated as needed, with or without a rest period.

[0317] Non-hallucinogenic doses may also be achieved by transdermal delivery, subcutaneous administration, etc., via modified, controlled, slow-release, or sustained-release dosage forms, including, but not limited to, depot dosage forms, implants, patches, and pumps that can be remotely controlled as needed, where the dose achieves blood levels similar to low oral doses, but will nevertheless not produce hallucinations.

[0318] Non-hallucinogenic doses can be used, for example, for the chronic treatment or maintenance of various diseases or disorders disclosed herein, including, but not limited to, depression (e.g., MDD), inflammation, pain, and neuroinflammation.

[0319] A compound of the present disclosure (e.g., a compound of Formula (I)-(V), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof) may be used in a maintenance regimen. As used herein, a "maintenance regimen" generally refers to administration of a compound of the present disclosure (e.g., a compound of Formula (I)-(V), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof) after achievement of a target dose, e.g., after completion of an escalation regimen, and / or after a favorable clinical response, e.g., improvement of the patient's condition, to either the same or a different drug. In some embodiments, the patient is administered a first drug for the treatment regimen and a second drug for the maintenance regimen, wherein the first and second drugs are different. For example, a patient may be administered a treatment regimen with a first drug that is not a compound of the present disclosure (the first drug being, for example, a serotonergic hallucinogen such as LSD, psilocybin, MDMA, dimethyltryptamine, or a drug that does not cause hallucinations), followed by a maintenance regimen with a compound of the present disclosure (as a second drug). In another example, a compound of the present disclosure is used in the treatment regimen (first drug) that is different from the drug (second drug) used in the maintenance regimen. In some embodiments, the patient is administered the same compound of the present disclosure for both the treatment regimen and the maintenance regimen. In either case, a maintenance dose of a compound of the present disclosure may be used to "maintain" the therapeutic response and / or prevent relapse. When the same compound of the present disclosure is used in both the original treatment regimen and the maintenance regimen, the maintenance dose of the compound may be sub-therapeutic. In some embodiments, the maintenance dose is a dose that causes hallucinations. In some embodiments, the maintenance dose is a dose that does not cause hallucinations. Generally, administration is performed daily or intermittently for a maintenance regimen, although the maintenance regimen can also be performed continuously, for example, over a period of days, weeks, months, or years. Additionally, maintenance doses can be administered chronically or over an extended period of time to a patient. The subject treated herein may have a disease or disorder associated with the serotonin 5-HT2 receptor. The subject treated herein may have a disease or disorder associated with a monoamine transporter.

[0320] In some embodiments, the disease or disorder is a neuropsychiatric disease or disorder or an inflammatory disease or disorder, hi some embodiments, the neuropsychiatric disease or disorder is not schizophrenia or cognitive impairment in schizophrenia.

[0321] In some embodiments, the disease or disorder is major depressive disorder (MDD), treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), bipolar disorder and related disorders (including but not limited to bipolar I disorder, bipolar II disorder, cyclothymic disorder), obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, substance use disorders (including but not limited to alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, smoking, and cocaine use disorder), eating disorders (including but not limited to anorexia nervosa, bulimia nervosa, binge eating disorder, etc.), Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, minor rheumatoid arthritis, and rheumatoid arthritis. These disorders include, but are not limited to, childhood-onset fluency disorder, severe neurocognitive disorder, mild neurocognitive disorder, suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), chronic fatigue syndrome, Lyme disease, gambling disorder, paraphilic disorders (including, but not limited to, pedophilic disorder, exhibitionism disorder, voyeuristic disorder, fetishistic disorder, sexual masochism or sadism disorder, cross-dressing disorder, etc.), sexual dysfunction (e.g., decreased libido, hypoactive sexual desire disorder (HSDD), etc.), peripheral neuropathy, obesity, and central nervous system (CNS) disorders, including, but not limited to, post-mortem symptoms from SARS-CoV-2 infection (COVID-19), e.g., "long covid."

[0322] In some embodiments, the methods provided herein are used to treat a subject with a depressive disorder. As used herein, the term "depressive disorder" or "depression" refers to a group of disorders characterized by a persistent low mood over a period of time that can affect a person's thoughts, behavior, emotions, and sense of well-being. In some embodiments, a depressive disorder disrupts a person's physical and mental function. In some embodiments, a depressive disorder causes physical symptoms such as weight loss, aches or pains, headaches, cramps, or indigestion. In some embodiments, a depressive disorder causes mental symptoms such as persistent sadness, hopelessness and irritability, guilt, lethargy or helplessness, loss of interest or pleasure in hobbies and activities, difficulty concentrating, difficulty remembering, or difficulty making decisions. In some embodiments, the depressive disorder is major depressive disorder (MDD), atypical depression, bipolar disorder, catatonic depression, depressive disorder due to physical illness, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, or treatment-resistant depression (TRD).

[0323] In some embodiments, the disease or disorder is major depressive disorder (MDD). As used herein, the term "major depressive disorder" refers to a condition characterized by periods of depressed mood present in most situations. Major depressive disorder is often accompanied by low self-esteem, loss of interest in usually enjoyable activities, low energy, and pain without a clear cause. In some instances, the definition of major depression is characterized by depressive symptoms lasting at least two weeks. In some instances, individuals experience periods of depression several years apart. In some instances, individuals experience depressive symptoms nearly constantly. Major depressive disorder can adversely affect an individual's personal, work, or school life, as well as sleep, eating habits, and general health. Approximately 2-7% of adults with major depressive disorder commit suicide, and up to 60% of adults who commit suicide had major depressive disorder or another related mood disorder. Dysthymia is a subtype of major depressive disorder that consists of the same cognitive and physical problems as major depressive disorder, but with less severe but longer-lasting symptoms. Examples of symptoms of major depressive disorder include, but are not limited to, feelings of sadness, fear, emptiness, or hopelessness, angry outbursts, minor irritability or frustration, loss of interest or pleasure in most or all usual activities, sleep disturbances including insomnia or hypersomnia, fatigue or lack of energy, loss of appetite, weight loss or gain, anxiety, agitation, or restlessness, diminished ability to think, speak, or move, feelings of lethargy or guilt, fixation on past failures or self-blame, disturbed thinking, concentration, decision-making, and memory, frequent thoughts of death, suicidal thoughts, suicide attempts, or suicide, and unexplained physical problems such as back pain or headaches.

[0324] As used herein, the term "atypical depression" refers to a condition in which an individual exhibits a long-term pattern of signs of mood reactivity (i.e., mood brightening in response to actual or potential positive events), significant weight gain, increased appetite, hypersomnia, feeling heavy and sluggish in the arms or legs, and / or sensitivity to interpersonal rejection that results in significant social or occupational impairment. Exemplary symptoms of atypical depression include, but are not limited to, daily feelings of sadness or melancholy, loss of pleasure in previously enjoyable activities, significant changes (gain or loss) in weight or appetite, near-daily insomnia or hypersomnia, noticeable physical restlessness or exhaustion, daily fatigue or low energy, near-daily feelings of hopelessness, helplessness or excessive guilt, near-daily problems concentrating or making decisions, recurring thoughts of death or suicide, suicide attempts, or attempted suicide.

[0325] As used herein, the term "bipolar disorder" refers to a condition in which an individual experiences unusual changes in mood, energy, activity level, and ability to perform daily tasks. Individuals with bipolar disorder experience periods of unusual agitation, changes in sleep patterns and activity levels, and abnormal behavior. These distinct periods are called "mood episodes." Mood episodes are significantly different from the person's typical mood and behavior. Examples of symptoms of mania and excessive behavior include, but are not limited to, unusually cheerful, volatile, or irritable behavior; increased activity, energy, or irritability; exaggerated feelings of happiness and confidence; decreased need for sleep; unusual talkativeness, racing thoughts, distractibility, and poor decision-making, such as continually spending money, taking sexual risks, or making foolish investments. Examples of depressive episodes or symptoms of low mood include, but are not limited to, feelings of melancholy, such as sadness, emptiness, hopelessness, or fear; a marked loss of interest in or a sense of unenjoyment in all or nearly all activities; marked weight loss or weight gain, or decreased or increased appetite; insomnia or hypersomnia (excessive sleep or excessive sleepiness); restless or sluggish behavior; fatigue or low energy; feelings of helplessness or excessive or inappropriate guilt; impaired thinking or concentration; or indecisiveness; and thoughts of suicide or attempted suicide. Bipolar disorders include bipolar I disorder, bipolar II disorder, and cyclothymic disorder. Bipolar I disorder is defined by a manic episode lasting at least 7 days or by severe manic symptoms requiring hospitalization. Subjects with bipolar I disorder may also experience depressive episodes, typically lasting at least 2 weeks. Depressive episodes with mixed characteristics, i.e., simultaneous depressive and manic symptoms, are also possible. Bipolar II disorder is characterized by a pattern of depressive and hypomanic episodes, but without the severe manic episodes typical of bipolar I disorder. Cyclothymic disorder (also called cyclothymia) is characterized by periods of hypomanic symptoms (...

Claims

1. having the structure of formula (II): 【Chemistry 1】 During the ceremony, X １ and X ２ are independently hydrogen, deuterium, or substituted or unsubstituted C １ ~C ６ is alkyl, Y １ and Y ２ are independently hydrogen, deuterium, or substituted or unsubstituted C １ ~C ６ is alkyl, R ２ and R ３ are independently hydrogen, deuterium, halogen, substituted or unsubstituted C １ ~C ６ Alkyl, -OR ａ , or -SR ａ and R ６ is hydrogen, substituted or unsubstituted C １ ~C ６ alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or alternatively, R ６ and R ７ together with the nitrogen atom to which they are attached, are optionally joined to form a substituted or unsubstituted heterocycloalkyl; R 7 is substituted C 1 -C 6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or alternatively, R 6 and R 7 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl; Each R ａ are independently hydrogen, deuterium, substituted or unsubstituted C １ ~C ６ Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C ３ ~C １０ is cycloalkyl, A is O or S; Z １ and Z ２ are independently hydrogen, deuterium, or fluorine; When A is O, Z １ and Z ２ at least one of which is fluorine; A compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

2. 2. The compound of claim 1, wherein A is S. 【Request Item 3】 【Chemistry 2】 10. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

4. having the structure of formula (III): 【Transformation 3】 During the ceremony, X １ and X ２ are independently hydrogen, deuterium, or substituted or unsubstituted C １ ~C ６ is alkyl, Y １ and Y ２ are independently hydrogen, deuterium, or substituted or unsubstituted C １ ~C ６ is alkyl, R ４ But -SeR ａ and R ６ and R ７ are independently hydrogen, substituted or unsubstituted C １ ~C ６ alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or alternatively, R ６ and R ７ together with the nitrogen atom to which they are attached, are optionally joined to form a substituted or unsubstituted heterocycloalkyl; Each R ａ are independently hydrogen, deuterium, substituted or unsubstituted C １ ~C ６ Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C ３ ~C １０ is cycloalkyl, R ４ R in ａ is C substituted with one or more halogens １ ~C ６ or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: 【Request Item 5】 【Chemistry 4】 5. The compound of claim 4, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

6. A compound having the structure of formula (IV): 【Transformation 5】 or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, During the ceremony, X 1 is hydrogen or deuterium; X 2 is a substituted or unsubstituted C 1 -C 6 alkyl; Y 1 and Y 2 are independently hydrogen or deuterium; R 3 is hydrogen or deuterium; R 4 is hydrogen, deuterium, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, —OR b , —SR b , or —SeR b ; R 6 and R 7 are independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or alternatively, R 6 and R 7 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl; each R a is independently substituted or unsubstituted C 1 -C 6 alkyl; each R b is hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C 3 -C 10 cycloalkyl; A compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, provided that at least one of X 1 , X 2 , Y 1 , Y 2 , R 3 , R 4 , R 6 , R 7 , and R a contains deuterium, and / or R 4 is -OR b , -SR b , or -SeR b , and R b in R 4 is C 1 -C 6 alkyl substituted with one or more halogens. 【Request Item 7】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 7. The compound of claim 6, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

8. A compound having the structure of formula (V): [Chemistry 18] or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, During the ceremony, X 1 and X 2 are independently hydrogen, deuterium, or substituted or unsubstituted C 1 -C 6 alkyl; Y 1 and Y 2 are independently hydrogen, deuterium, or substituted or unsubstituted C 1 -C 6 alkyl; R 4 and R 5 are independently hydrogen, deuterium, halogen, substituted or unsubstituted C 1 -C 6 alkyl, —OR a , —SR a , or —SeR a , or R 4 and R 5 together with the atoms to which they are attached are optionally joined to form a heterocycloalkyl or heteroaryl; R 6 and R 7 are independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or alternatively, R 6 and R 7 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl; each R a is independently hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C 3 -C 10 cycloalkyl; A compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein each R b is hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C 3 -C 10 cycloalkyl. 【Request Item 9】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 9. The compound of claim 8, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

10. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable excipient.

11. 11. The pharmaceutical composition of claim 10, wherein any position in said compound having deuterium has a minimum deuterium incorporation of at least 50 atomic percent at the site of deuteration.

12. 11. The pharmaceutical composition of claim 10, formulated for oral administration.

13. 11. The pharmaceutical composition of claim 10, formulated for administration via inhalation.

14. Serotonin 5-HT ２ A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 for use in the treatment of a disease or disorder associated with a receptor or monoamine transporter.

15. Serotonin 5-HT ２ The disease or disorder associated with a receptor or monoamine transporter is (i) a neuropsychiatric or inflammatory disease or disorder; (ii) central nervous system (CNS) disorders; (iii) a central nervous system (CNS) disorder selected from the group consisting of post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation 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 disease, post-mortem symptoms from SARS-CoV-2 infection (COVID-19), cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain, aphantasia, childhood-onset dysfluency disorder, severe neurocognitive disorder, mild neurocognitive disorder, sexual dysfunction, chronic fatigue syndrome, Lyme disease, and obesity. (iv) pain; (v) sexual dysfunction; (vi) an autonomic nervous system (ANS) disorder; or (vii) pulmonary or cardiovascular disorders The pharmaceutical composition of claim 14, wherein

16. A monolayer orally administered tablet composition comprising a compound according to any one of claims 1 to 9 and a polymer.

17. A tablet composition formulated for oral administration, comprising a compound according to any one of claims 1 to 9 and a polymer.

18. 1) the pharmaceutical composition according to claim 10, and 2) serotonin 5-HT ２ A kit for treating a subject, comprising instructions for use in treating a disease or disorder associated with a receptor or monoamine transporter.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 for use in the treatment of a disease or disorder associated with a serotonin receptor or a monoamine transporter via transdermal, subcutaneous, or intramuscular administration using an automatic injection device.

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