Therapeutic phenethylamine compositions and methods of use

Abstract

Disclosed are phenethylamine compounds, uses of such compounds in treating diseases associated with the serotonin 5-HT2 receptor, 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 the serotonin 5-HT2 receptor, such as central nervous system (CNS) disorders or psychological disorders, inflammation, with the disclosed compounds.

Description

[Technical field]

[0001] cross reference This application claims priority to U.S. Provisional Application No. 63 / 268,019, filed February 15, 2022, U.S. Provisional Application No. 63 / 268,022, filed February 15, 2022, and U.S. Provisional Application No. 63 / 386,375, filed December 7, 2022, each of which is incorporated by reference in its entirety herein.

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

[0003] The "Background" description provided herein is for the purpose 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 description 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-HT 2 Receptor (5-HT 2 Rs) contains 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 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), and (iv) obsessive-compulsive disorder (OCD) (Moreno, FA, Wiegand, CB, 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 No. 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 Nos. NCT04454684 and NCT04052568), (ix) Alzheimer's disease (ClinicalTrials.gov No. 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) has been actively investigated by research and medical societies to alleviate the condition.

[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, 116790; 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, of the use of 3,4-methylenedioxymethamphetamine for the treatment of PTSD (Feduccia, AA, Jerome, L., Yazar-Klosinski, B., Emerson, A., Mithoefer, MC, 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 the hallucinogenic phenethylamines appear to be mediated by serotonin (5-HT) receptors, particularly 5-HT 2A It is thought to be mediated by interaction with 5-HT receptors. 1A Other targets, including 5-HT receptors, may also be involved (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). 2CContributions from receptors may be involved in the reported anti-additive properties of classical hallucinogens (Canal, CE, and Murnane, KS, 2017, The serotonin 5-HT2C receptor and the non-addictive nature of classical hallucinogens, J Psychopharmacol 31, 127-143). The effects of the entactogen phenethylamine are primarily mediated by interactions 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 challenge for clinical use (Hasler, F., Grimberg, U., Benz, MA, Huber, T., and Vollenweider, FX, 2004, Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study, Psychopharmacology (Berl) 172, 145-156; Carbonaro, TM, Bradstreet, MP, Barrett, FS, MacLean, KA, Jesse, R., Johnson, MW, and Griffiths, RR, 2016, Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences, J Psychopharmacol 30, 1268-1278; 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).

[0009] Apparently, the safe therapeutic window for this drug class is long-term increased serotonin release and 5-HT 2Bstimulation (Huang, X.-P., Setola, V., Yadav, PN, Allen, JA, Rogan, 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, RB, and Baumann, MH, 2009, Serotonergic drugs and valvular heart disease, Expert Opin Drug Saf 8, 317-329), depressive sequelae related to depletion of central serotonin levels (Parrott, AC, 2014, The potential dangers of using MDMA for psychotherapy, J Psychoactive Drugs 46,37-43), as well as numerous other acute adverse effects, including anxiety, fear, tachycardia, hypertension, hyperthermia, nausea, and vomiting (many of which are attributable to high drug concentrations ("spikes") in the blood immediately following oral administration) (Meyer, JS, 2013, 3,4-methylenedioxymethamphetamine (MDMA): current perspectives, Subst Abuse Rehabil 4,83-99; Baylen, CA, 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, FS, Bradstreet, MP, Leoutsakos, JS,Johnson,MW,and Griffiths,RR,2016,The Challenging Experience Questionnaire: Characterization of challenging experiences with psilocybin mushrooms,J Psychopharmacol 30,1279-1295) are very narrow due to the cardiovascular complications associated with psychedelics. Many hallucinogens and entactogens are also long acting, and therefore require daily supervision, given their narrow therapeutic window, which is a major obstacle to their clinical use.

[0010] One class of hallucinogenic phenethylamines is the 2C-X family of phenethylamines (phenethylamines containing 2,4,5 substitution, which have methoxy groups at the 2- and 5-positions of the phenyl group). Members of this class, such as 2,5-dimethoxy-4-bromophenethylamine (2C-B), can be used to treat sexual dysfunction (Shulgin, A., and Shulgin, Ann., 1991, Pihkal: a chemical love story, Transform Press, Berkeley, CA) and neuropsychiatric disorders, and to induce changes in perception, cognition, emotion, and mood that may underlie their reported neuropsychiatric therapeutic 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).

[0011] However, more extensive clinical trials and finding practical treatment protocols for 2C-X compounds have been challenged by the following factors: 1) poor oral bioavailability; 2) low brain penetration; 3) delayed effects from oral administration; 4) therapeutic effects requiring high doses; 5) acute psychiatric adverse events (AEs) such as fear, anxiety, and paranoia, cardiovascular events including tachycardia and hypertension, and gastrointestinal effects including nausea; and 6) toxicity.These properties are believed to be due to their rapid first-pass metabolism via deamination / oxidation by monoamine oxidase (MAO), MAO-A and MAO-B, and O-dealkylation by cytochrome P450 enzymes such as CYP2D6, and also their relatively hydrophilic nature (e.g., 2,4,5-trimethoxphenethylamine (2C-O) has a logP value of 0.98; ChemDraw), which limits their distribution to the brain (Suzuki, O., Katsumata, Y., and Oya, M., 1981, Oxidation of beta-phenylethylamine by both types of monoamine oxidase: examination of enzymes in brain and liver mitochondria of eight species, J Neurochem 36, 1298-1301; 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).For example, 2,4,5-trimethoxyphenethylamine (2C-O) is inactive after oral administration (Shulgin, A.T., 1978, Psychotomimetic Drugs: Structure-activity relationships. Chapter 6, In Handbook of psychopharmacology, V.11-Stimulants, pp 243-333, Plenum Press, New York).

[0012] The limitations of current 2C-X compounds and their formulations, as well as other hallucinogens and entactogens phenethylamines, are clear and it has proven difficult to control drug exposure and maintain drug concentrations within safe and effective ranges. Summary of the Invention

[0013] In view of the foregoing, there is a need for novel phenethylamine compounds, e.g., of the 2C-X variety, that are bioavailable, brain penetrant, have rapid onset, are short acting, have improved pharmacokinetic properties, and exhibit enhanced activity while minimizing psychiatric adverse events and toxicity. There is a further need for efficient, more convenient, and controllable phenethylamine formulations that do not result in neurologically toxic (e.g., psychotomimetic toxic) plasma concentrations.

[0014] It is therefore one 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] Diseases or disorders, such as serotonin 5-HT 2 It is another object of the present disclosure to provide novel methods of treating subjects having associated receptors 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 the compounds for use in therapy.

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

[0020] Serotonin 5-HT, central nervous system (CNS) or psychological disorders 2 It is yet another object of the present invention to provide novel uses of the compounds for treating a subject having a receptor-related disease or disorder.

[0021] These and other objects, which will become apparent during the course of the following detailed description, are directed to the treatment of G protein-coupled receptors (GPCRs), such as 5-HT 2 This is achieved by the inventors' discovery of novel 2C-X type phenethylamine compounds (e.g., compounds of formulas (I)-(VII)), including those with site-specific modifications (e.g., deuteration / fluorination) that maintain preferential binding to receptors, have improved exposure (e.g., preventing high drug concentration (spikes) observed acutely after administration), improved bioavailability, brain penetrance, and favorable enzymatic degradation profiles to prevent / reduce the formation of toxic metabolites.

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

[0023] (1) A compound having the structure of formula (I), [ka] or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, During the ceremony, X 1 and X2 are independently hydrogen or deuterium; Y 1 and Y 2 are independently hydrogen or deuterium; R 3 is hydrogen or deuterium, R 4 is halogen, substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 3 ~C 10 Cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR b , or -SR b 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 substituted or unsubstituted C 1 ~C 6 is alkyl, 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 is cycloalkyl, However, X 1 , X 2 ,Y 1 ,Y 2 ,R 3 ,R 4 ,R 6 , R 7 , and R aAt least one of the groups contains deuterium and / or R 4 But -SCF 3 , -SCF 2 H, -SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H,-OCF 3 ,-OCF 2 H, -OCFH 2 ,-OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H, -Cyclopentyl (-C 5 H 9 ), and -A(CF 2 ) m (CH 2 ) n Q; A is selected from the group consisting of S, O, CH 2 , or CF 2 wherein m is 0 to 3, n is 0 to 6, and Q is -C≡CH or -C≡N, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. (2) Y 1 and Y 2 is hydrogen. (3)R 3 is hydrogen. (4) X 1 and X 2is hydrogen. (5)X 1 and X 2 is deuterium. (6)Each R a But -CH 3 or -CD 3 The compound according to any one of (1) to (5), (7)R 4 But, -SMe, -SCD 3, -SCF 3, -SCF 2 H, -SCFH 2, SCH 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H,-SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -SEt, -Sn-Pr, -Me, -CD 3 , -CF 3 ,-t-Bu,-C(CD 3 ) 3 , -Cyclopentyl, -OMe, -OCD 3 ,-OCF 3 ,-OCF 2 H,-OCFH 2 ,-OCH 2 CH 2 CF 3 , -OCH 2 CH 2 CF 2 H,-OCH2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 The compound according to any one of (1) to (6), wherein C≡CH, -Cl, -I, or -Br is selected from the group consisting of: (8) having the structure of formula (II), [ka] or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, During the ceremony, X 1 and X 2 are independently hydrogen or deuterium; Y 1 and Y 2 are independently hydrogen or deuterium; R 4 is halogen, substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 3 ~C 10 Cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR b , or -SR b and 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 The compound according to (1), or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein R is cycloalkyl. (9)X 1 and X 2 is hydrogen. (10)R 4 But, -SMe, -SCD 3, -SCF 3, -SCF 2 H, -SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H,-SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -SEt, -Sn-Pr, -Me, -CD 3 , -CF 3 , -t-Bu, -C(CD 3 ) 3 , -Cyclopentyl, -OMe, -OCD 3 ,-OCF 3 ,-OCF 2 H,-OCFH 2 ,-OCH 2 CH 2 CF 3 , -OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 The compound according to (8) or (9), wherein C≡CH, -Cl, -I, or -Br. (11)R 4 But, -SMe, -SCF 3 , -SCF 2 H, -Me, -OCD 3 , -CF 3 , -t-Bu, or -cyclopentyl. (12) Having the structure of formula (II), [ka] or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, During the ceremony, X 1 and X 2 are independently hydrogen or deuterium; Y 1 and Y 2 are independently hydrogen or deuterium; R 4 C with one or more deuterium substitutions 1 ~C 6 Alkyl, C substituted with one or more deuterium 3 ~C 10 Cycloalkyl, -OR b , or -SR b and Each R a are independently substituted or unsubstituted C 1 ~C 6 is alkyl, R b C with one or more deuterium substitutions 1 ~C 6 Alkyl or C substituted with one or more deuterium 3 ~C 10The compound according to (1), or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein R is cycloalkyl. (13)X 1 and X 2 is hydrogen, and each R a But -CH 3 The compound according to (12), (14)R 4 But -SCD 3 , -CD 3 , -C(CD 3 ) 3 , or -OCD 3 The compound according to (12) or (13), (15) Having the structure of formula (IV), [ka] or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, During the ceremony, Y 1 and Y 2 are independently hydrogen or deuterium; R 4 is halogen, substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 3 ~C 10 Cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR b , or -SR b and Each R a are independently substituted or unsubstituted C 1 ~C 6 is alkyl, 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 10The compound according to (1), or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein R is cycloalkyl. (16) Having the structure of formula (V), [ka] or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, During the ceremony, X 1 and X 2 are independently hydrogen or deuterium; Y 1 and Y 2 are independently hydrogen or deuterium; R 4 is halogen, substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 3 ~C 10 Cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR b , or -SR b 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; R 7 is 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 substituted or unsubstituted C 1 ~C 6 is alkyl, 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 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 -SCF 3 , -SCF 2 H, -SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H,-OCF 3 ,-OCF 2 H, -OCFH 2 ,-OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H, -Cyclopentyl (-C 5 H9 ), and -A(CF 2 ) m (CH 2 ) n Q; A is selected from the group consisting of S, O, CH 2 , or CF 2 wherein m is 0 to 3, n is 0 to 6, and Q is -C≡CH or -C≡N, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, of the compound according to (1). (17)R 6 is hydrogen and R 7 But non-substituted C 1 ~C 6 Alkyl, C substituted with one or more deuterium atoms 1 ~C 6 Alkyl, C substituted with one or more fluorine atoms 1 ~C 6 C substituted with alkyl, or substituted or unsubstituted cycloalkyl 1 ~C 6 The compound according to (16), wherein the aryl group is alkyl. (18) [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0024] The preceding paragraphs have been provided by way of general introduction and are not intended to limit the scope of the following claims. 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, in which:

[0025] [Figure 1] 1 shows a synthetic route for making compound II-1. [Diagram 2] 1 shows a synthetic route for making compound II-2. [Diagram 3] 1 shows a synthetic route for making compound II-3. [Figure 4]1 shows a synthetic route for making compound II-4. [Diagram 5] 1 shows a synthetic route for making compound II-14. [Figure 6] 1 shows a synthetic route for making compound III-1. [Figure 7] 1 shows a synthetic route for making compound III-2. [Figure 8] 1 shows a synthetic route for making compound IV-1. [Figure 9] 1 shows a synthetic route for making compound IV-2. [Figure 10] 1 shows a synthetic route for making compound IV-3. [Figure 11] 1 shows a synthetic route for making compound IV-5. [Figure 12] 1 shows a synthetic route for making compound IV-12. [Figure 13] 1 shows a synthetic route for making compound I-1. [Figure 14] 1 shows a synthetic route for making compound I-2. [Figure 15] 1 shows a synthetic route for making compound I-3. [Figure 16] 1 shows a synthetic route for making compound I-4. [Figure 17] 1 shows a synthetic route for making compound I-5. [Figure 18] 1 shows a synthetic route for making compound I-6. [Figure 19] 1 shows a synthetic route for making compound I-7. [Figure 20] FIG. 1 shows synthetic routes for making compounds of formula (I) having a fluoropropoxy or fluorothiopropoxy substituent as R4, such as compounds II-16, II-17, II-18, II-19, II-20, and II-21. [Figure 21] 1 shows a synthetic route for making compound I-8. [Figure 22] 1 shows a synthetic route for making compound I-10. [Figure 23] 1 shows a synthetic route for making compound I-11. [Figure 24] 1 shows a synthetic route for making compound I-13. [Diagram 25] 1 shows a synthetic route for making compound II-10. [Figure 26] 1 shows a synthetic route for making compound II-23. [Figure 27] 1 shows a synthetic route for making compound V-1. [Figure 28] 1 shows a synthetic route for making compound VI-1. [Figure 29] 1 shows a synthetic route for making compound IV-33. [Diagram 30] 1 shows a synthetic route for making Reference Compound 1. [Diagram 31] Graph showing agonist-labeled 5-HT2A radioligand ([3H]ketanserin) competitive binding using compounds II-1 and IV-1. At least three independent experiments were performed with compounds tested in duplicate, and the data shown are the average results from all experiments. The Kd of [3H]ketanserin was set to 1.57 nM, and the data was analyzed using a one-site fitted Ki model (GraphPad Prism 9). The data points for -10 samples are the total specific binding (no compound present), and -4 was interpolated to complete the binding curve to 0 specific binding. [Diagram 32] Graph showing agonist-labeled 5-HT2A radioligand ([3H]ketanserin) competitive binding using compounds II-23 and IV-3. At least three independent experiments were performed with compounds tested in duplicate, and data shown are the average results from all experiments. The Kd of [3H]ketanserin was set to 1.57 nM, and data was analyzed using a one-site fitted Ki model (GraphPad Prism 9). Data points for -10 samples are the total specific binding (no compound present), and -4 was interpolated to complete the binding curve to 0 specific binding. [Diagram 33]Figure 1 shows agonist-labeled 5-HT2A radioligand ([3H]ketanserin) competitive binding using compounds I-1 and II-10 and 5-HT as a positive control. Data shown are average results of 2-6 experiments combined (N=6-12 replicates per concentration). The Kd of [3H]ketanserin was set to 1.57 nM and data was analyzed using a 2-site fitted Ki model (GraphPad Prism 9). Data points for -10 samples are total specific binding (no compound present) and -4 was interpolated to complete the binding curve to 0 specific binding. [Diagram 34] Figure 1 shows agonist-labeled 5-HT2A radioligand ([3H]LSD) competitive binding using compounds I-13 and II-4. Three independent experiments with compounds tested in duplicate (5-HT, control) or triplicate (I-13, II-4) were performed and data shown are the average results of all experiments combined (N=6-12 replicates per concentration). The Kd of [3H]LSD was set to 0.78 nM and data was analyzed using a one-site fitted Ki model (GraphPad Prism 9). Data points for -10 samples are total specific binding (no compound present) and -4 was interpolated to complete the binding curve to 0 specific binding. [Diagram 35] Graph showing agonist-labeled 5-HT2A radioligand ([3H]LSD) competitive binding using compounds VI-1, II-3, and III-2. Up to 11 independent experiments with 5-HT tested in duplicate and compounds II-3, III-2, VI-1 in triplicate were performed and data shown are the average results of all experiments combined (N=up to 33 replicates). The Kd of [3H]LSD was set to 0.78 nM and data was analyzed using a one-site fitted Ki model (GraphPad Prism 9). Data points for -10 samples are total specific binding (no compound present) and -4 was interpolated to complete the binding curve to 0 specific binding. [Diagram 36]Graph showing agonist-labeled 5-HT2A radioligand ([3H]LSD) competitive binding using compounds I-4 and I-7. Four independent experiments were performed with 5-HT tested in duplicate (N=8 replicates) and compounds I-4 and I-7 (N=12) in triplicate, and the data shown are the average results of all experiments combined. The Kd of [3H]LSD was set to 0.78 nM, and the data was analyzed using a one-site fitted Ki model (GraphPad Prism 9). The data points for the -10 samples are the total specific binding (no compound present), and -4 was interpolated to complete the binding curve to 0 specific binding. [Figure 37] Graph showing agonist-labeled 5-HT2A radioligand ([3H]LSD) competitive binding using compound I-3. Four independent experiments were performed with 5-HT tested in duplicate (N=8 replicates) and compound I-3 in triplicate (N=12), and the data shown is the average result of all experiments combined. The Kd of [3H]LSD was set to 0.78 nM, and the data was analyzed using a one-site fitted Ki model (GraphPad Prism 9). The data points of -10 samples are the total specific binding (no compound present), and -4 was interpolated to complete the binding curve to 0 specific binding. [Figure 38] Graph showing agonist-labeled 5-HT2A radioligand ([3H]LSD) competitive binding using compound I-2. Four independent experiments were performed with 5-HT tested in duplicate (N=8 replicates) and compound I-2 in triplicate (N=12), and the data shown is the average result of all experiments combined. The Kd of [3H]LSD was set to 0.78 nM, and the data was analyzed using a one-site fitted Ki model (GraphPad Prism 9). The data points of the -10 samples are the total specific binding (no compound present), and -4 was interpolated to complete the binding curve to 0 specific binding. [Figure 39]Graph showing agonist-labeled 5-HT2A radioligand ([3H]LSD) competitive binding using compounds I-5 and I-6. Seven independent experiments were performed with 5-HT tested in duplicate (N=14 replicates) and compounds I-5 and I-6 in triplicate (N=21), and the data shown are the average results of all experiments combined. The Kd of [3H]LSD was set to 0.78 nM, and the data was analyzed using a one-site fitted Ki model (GraphPad Prism 9). The data points of the -10 samples are the total specific binding (no compound present), and -4 was interpolated to complete the binding curve to 0 specific binding. [Diagram 40] Graph showing agonist-labeled 5-HT2A radioligand ([3H]LSD) competitive binding using compound I-8. Three independent experiments were performed with 5-HT tested in duplicate (N=6 replicates) and compound I-8 in triplicate (N=9), and the data shown is the average result of all experiments combined. The Kd of [3H]LSD was set to 0.78nM, and the data was analyzed using a one-site fitted Ki model (GraphPad Prism 9), with the data points of -10 samples being the total specific binding (no compound present), and -4 was interpolated to complete the binding curve to 0 specific binding. [Diagram 41] Graph showing agonist-labeled 5-HT2A radioligand ([3H]LSD) competitive binding using compound V-1. Two independent experiments were performed with 5-HT tested in duplicate (N=4 replicates) and compound V-1 in triplicate (N=6), and the data shown is the average result of all experiments combined. The Kd of [3H]LSD was set to 0.78 nM, and the data was analyzed using a one-site fitted Ki model (GraphPad Prism 9). The data points of the -10 samples are the total specific binding (no compound present), and -4 was interpolated to complete the binding curve to 0 specific binding. [Diagram 42]Graph showing the dose response of 5-HT2A functional assay as a percentage of control agonist response (5-HT).Compound I-1 was tested in duplicate at the concentrations shown, and EC50 and Emax values ​​were determined by nonlinear regression analysis of the concentration-response curves generated with average replicate values ​​using Hill equation curve fitting. [Diagram 43] Graph showing the dose response of 5-HT2A functional assay as a percentage of control agonist response (5-HT).Compounds I-3, I-8, and VI-1 were tested in duplicate at the concentrations shown, and EC50 and Emax values ​​were determined by nonlinear regression analysis of the concentration-response curves generated with average replicate values ​​using Hill equation curve fitting. [Diagram 44] Graph showing the dose response of 5-HT2A functional assay as a percentage of control agonist response (5-HT).Compound I-10 was tested in duplicate at the concentrations shown, and EC50 and Emax values ​​were determined by nonlinear regression analysis of the concentration-response curves generated with average replicate values ​​using Hill equation curve fitting. [Diagram 45] Graph showing the dose response of 5-HT2A functional assay as a percentage of control agonist response (5-HT).Compound V-1 was tested in duplicate at the concentrations shown, and EC50 and Emax values ​​were determined by nonlinear regression analysis of the concentration-response curves generated with average replicate values ​​using Hill equation curve fitting. [Figure 46] Graph showing the dose response of 5-HT2A functional assay (TRUPATH) as a percentage of control agonist response (5-HT).Compound V-1 was tested in 11 replicates at the concentrations shown, and EC50 and Emax values ​​were determined by nonlinear regression analysis of the concentration response curves generated with the average replicate values ​​using Hill equation curve fitting. [Figure 47] Graph showing the dose response of 5-HT2B functional assay as a percentage of control agonist response (5-HT).Compound I-1 was tested in duplicate at the concentrations shown, and EC50 and Emax values ​​were determined by nonlinear regression analysis of the concentration-response curves generated with average replicate values ​​using Hill equation curve fitting. [Figure 48]Graph showing the dose response of 5-HT2B functional assay as a percentage of control agonist response (5-HT).Compounds I-3, I-8, and VI-1 were tested in duplicate at the concentrations shown, and EC50 and Emax values ​​were determined by nonlinear regression analysis of the concentration-response curves generated with average replicate values ​​using Hill equation curve fitting. [Figure 49] Graph showing the dose response of 5-HT2B functional assay as a percentage of control agonist response (5-HT).Compound I-10 was tested in duplicate at the concentrations shown, and EC50 and Emax values ​​were determined by nonlinear regression analysis of the concentration-response curves generated with average replicate values ​​using Hill equation curve fitting. [Figure 50] Graph showing the dose response of 5-HT2B functional assay as a percentage of control agonist response (5-HT).Compound V-1 was tested in duplicate at the concentrations shown, and EC50 and Emax values ​​were determined by nonlinear regression analysis of the concentration-response curves generated with average replicate values ​​using Hill equation curve fitting. [Figure 51] Graph showing the dose response of 5-HT2C functional assay (TRUPATH) as a percentage of control agonist response (5-HT).Compound V-1 was tested in 9 replicates at the concentrations shown, and EC50 and Emax values ​​were determined by nonlinear regression analysis of the concentration response curves generated with the average replicate values ​​using Hill equation curve fitting. [Figure 52] 1 is a graph showing head-shaking responses in adult, male C57BL / 6J mice after subcutaneous administration of 0.1, 0.3, 1, and 3 mg / kg of compound I-1 and observed at the indicated time points. DOI was used as a positive control and vehicle was used as a negative control. [Figure 53A]FIG. 53B is a graph showing that oral administration of I-1 (1-10 mg / kg, PO) induced HTR in C57BL / 6 mice. I-1 at doses of 1, 3, and 10 mg / kg PO produced a dose-dependent increase in HTR similar to I-1 at 3 mg / kg SC (n=10 per group) and DOI at 1 mg / kg IP (n=4). HTR was compared to saline vehicle (n=4) over the course of 1-30 min (FIG. 53A) and 120-150 min (FIG. 53B) post-administration, showing that a significant number of head shakes were present in all test compound groups at 1-30 min and 120-150 min. *p<0.05, **p<0.01 vs. vehicle. [Figure 53B] Same as above. [Figure 54A] Graphs showing mean I-1 concentration ±SD over time in mouse plasma and brain samples in C57BL / 6J mice (n=3) dosed orally (FIG. 54A) or subcutaneously (FIG. 54B) at 3 mg / kg, with plasma and brain samples collected at the indicated time points. [Figure 54B] Same as above. [Figure 55A] Graphs showing mean concentrations ±SD of I-1 in rat plasma and brain samples over time on a linear scale after intravenous administration of 1 mg / kg (FIG. 55A) and oral administration of 5 mg / kg (FIG. 55B) to male Wistar rats (n=3). [Figure 55B] Same as above. [Figure 56A] Graphs showing the mean concentration ±SD of I-1 in rat plasma, brain, and CSF samples over time on a linear scale (FIG. 56A) and a logarithmic scale (FIG. 56B) after intravenous administration (1 mg / kg, subcutaneous) to male Sprague-Dawley rats (n=4 per time point). [Figure 56B] Same as above. [Figure 57A]57A-57J are graphs showing transcriptional changes in the frontal cortex of male C57BL / 6J mice in the acute phase (2 hours) following treatment with treatment groups A, B, C, and D for the following brain markers of neuroplasticity: bdnf (FIG. 57A), psd-95 (FIG. 57B), homer1 (FIG. 57C), Egr2 (FIG. 57D), cFos (FIG. 57E), mTOR (FIG. 57F), Creb1 (FIG. 57G), Syn1 (FIG. 57H), Nptn (FIG. 57I), and Igf1 (FIG. 57J). Statistical analysis by one-way ANOVA followed by multiple comparisons versus vehicle group for log-transformed data, reverse-transformed data presented, *=p<0.05, **=p<0.01, ****=p<0.001. [Figure 57B] Same as above. [Figure 57C] Same as above. [Fig. 57D] Same as above. [Figure 57E] Same as above. [Fig. 57F] Same as above. [Fig. 57G] Same as above. [Fig. 57H] Same as above. [Fig. 57I] Same as above. [Fig. 57J] Same as above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] In the following detailed description of the embodiments of the present disclosure, numerous specific details are set forth in order to provide a thorough understanding of the embodiments of the present disclosure. However, it will be apparent to those skilled in the art that the 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 so 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, for example, 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3, or 1 to 2 carbon atoms. This term includes, by way of example, methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-Butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), t-Butyl (t-Bu) ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -), and neopentyl ((CH 3 ) 3 CCH 2 -), and other linear and branched hydrocarbyl groups.

[0029] The term "substituted alkyl" refers to an alkyl group, as defined herein, wherein one or more carbon atoms in the alkyl chain may optionally be substituted with -O-, -N-, -S-, -S(O) n- (n is 0 to 2), -NR- (R is hydrogen or alkyl), and other heteroatoms are substituted, and deuterium, alkoxy, substituted alkoxy, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted 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, -SO 2 -Alkyl, -SO 2 -Aryl, -SO 2 -heteroaryl and -NR ’ R ’’ wherein R ’ and R ” may be the same or different and are selected from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclic.

[0030] "Alkylene" is -O-, -NR 10 -, -NR 10 C(O)-, -C(O)NR 10 -, and the like. This term refers to divalent aliphatic hydrocarbyl groups having 1 to 6 carbon atoms, including 1 to 3 carbon atoms, either straight or branched, optionally interrupted by one or more groups selected from methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), n-propylene (-CH 2 CH 2 CH 2 -), iso-propylene (-CH 2CH(CH 3 )-), (C(CH 3 ) 2 CH 2 CH 2 ),(C(CH 3 ) 2 CH 2 C(O)), (C(CH 3 ) 2 CH 2 C(O)NH), (-CH(CH 3 )CH 2 -) and others.

[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; 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, and n-pentoxy. The term "alkoxy" also refers to the groups alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are defined herein.

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

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

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

[0043] The term "substituted alkenyl" includes any of the following: 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 -substituted alkyl, -SO 2 -aryl and -SO 2 -heteroaryl refers to an alkenyl group, as defined herein, having 1 to 5 substituents, or 1 to 3 substituents selected from:

[0044] "Alkynyl" refers to a linear or branched monovalent hydrocarbyl group having 2 to 10 carbon atoms, e.g., 2 to 3 carbon atoms, 3 to 6 carbon atoms, and having at least 1, e.g., 1 to 2 sites of triple bond unsaturation. Examples of such alkynyl groups include acetylenyl (-C≡CH), and propargyl (-CH 2 C≡CH).

[0045] The term "substituted alkynyl" 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, 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 -substituted alkyl, -SO 2 -aryl and -SO 2 -heteroaryl refers to an alkynyl group, as defined herein, having 1 to 5 substituents, or 1 to 3 substituents selected from:

[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" means an HC(O)- group, an alkyl-C(O)- group, a substituted alkyl-C(O)- group, an alkenyl-C(O)- group, a substituted alkenyl-C(O)- group, an alkynyl-C(O)- group, a substituted alkynyl-C(O)- group, a cycloalkyl-C(O)- group, a substituted cycloalkyl-C(O)- group, a cycloalkenyl-C(O)- group, a substituted cycloalkenyl-C(O)- group, an aryl-C(O)- group, a substituted aryl-C(O)- group, a heteroaryl-C(O)- group, a (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 is an "acetyl" group, CH 3 Contains C(O).

[0048] "Acylamino" is -NR 20 C(O) alkyl group, -NR 20 C(O)-substituted alkyl groups, -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 groups, -NR 20 C(O) heteroaryl group, -NR 20 C(O)-substituted heteroaryl groups, -NR 20 C(O) heterocyclic groups, and -NR 20C(O)-substituted heterocyclic group, R 20 is hydrogen or alkyl, 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.

[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 to which they are attached 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 -SO 2 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 to which they are attached 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 SO 2 R 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 atom to which they are bound 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 can be any of the following: 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, -SO 2 -Alkyl, -SO 2 -substituted alkyl, -SO 2-Aryl, -SO 2 - optionally substituted with 1 to 5 substituents, or 1 to 3 substituents selected from heteroaryl and trihalomethyl.

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

[0057] "Amino" is NH 2 Refers to the base.

[0058] The term "substituted amino" refers to the group -NRR, where if at least one R is not hydrogen, 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 "azide" refers to -N 3 Refers to the base.

[0060] "Carboxyl", "carboxy" or "carboxylate" means -CO 2 H 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, -C(O)O-cycloalkyl groups, -C(O)O-substituted cycloalkyl groups, -C(O)O-cycloalkenyl groups, -C(O)O-substituted cycloalkenyl groups, -C(O)O-heteroaryl groups, -C(O)O-substituted heteroaryl groups, -C(O)O-heterocyclic groups, and -C(O)O refers to a 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.

[0062] "(Carboxyl ester)oxy" or "carbonate" refers to an -OC(O)O-alkyl group, -OC(O)O-substituted alkyl group, -OC(O)O-alkenyl group, -OC(O)O-substituted alkenyl group, -OC(O)O-alkynyl group, -OC(O)O-substituted alkynyl group, -OC(O)O-aryl group, -OC(O)O-substituted aryl group, -OC(O)O-cycloalkyl group, -OC(O)O-substituted cycloalkyl group, -OC(O)O-cycloalkenyl group, -OC(O)O-substituted cycloalkenyl group, -OC(O)O-heteroaryl group, -OC(O)O-substituted heteroaryl group, refers to the groups -OC(O)O-heterocyclic and -OC(O)O-substituted heterocyclic, 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, cyclohexyl, 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 any of the following: 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 -substituted alkyl, -SO 2 -aryl and -SO 2 -heteroaryl, or a cycloalkyl group having 1 to 5 substituents selected from 1 to 3 substituents.

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

[0067] The term "substituted cycloalkenyl" includes any of the following: 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, -SO 2- Substituted alkyl, -SO 2 -Aryl and -SO 2 -heteroaryl, or a cycloalkenyl group having 1 to 5 substituents selected from 1 to 3 substituents.

[0068] "Cycloalkynyl" refers to a non-aromatic cycloalkyl group of from 5 to 10 carbon atoms having single or multiple rings and having 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 1-15 carbon atoms, such as 1-10 carbon atoms, and 1-10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl, imidazolyl, or furyl) or multiple condensed rings in the ring system (e.g., in groups such as indolizinyl, quinolinyl, benzofuran, benzimidazolyl, or benzothienyl), where at least one ring in the ring system is aromatic, and at least one ring in the ring system is aromatic if the point of attachment is through an aromatic ring atom. In some embodiments, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide the N-oxide (N→O), sulfinyl, or sulfonyl moieties. The 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 be any of the following: 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, -SO 2 -Aryl and -SO 2 -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, and in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through a non-aromatic ring. In some embodiments, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to N-oxide, -S(O)-, or -SO 2 -Provide portions.

[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. , phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also called thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, tetrahydrofuranyl, benzo[d][1,3]oxathiol, and benzo[d][1,3]dioxole.

[0078] Unless constrained by the definition of a heterocyclic substituent, such heterocyclic groups can be any of the following: 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, -SO 2- Substituted alkyl, -SO 2 -Aryl, -SO 2- It may be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents selected from heteroaryl and fused heterocycle.

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

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

[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" is NO 2 Refers to the base.

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

[0085] "Sulfonyl" is SO 2 Alkyl group, SO 2 -substituted alkyl group, SO 2- Alkenyl group, SO 2 -substituted alkenyl group, SO 2- Cycloalkyl groups, SO 2 Substituted cycloalkyl groups, SO 2- Cycloalkenyl group, SO 2 -substituted cycloalkenyl group, SO 2- Aryl group, SO 2 -substituted aryl group, SO 2- Heteroaryl groups, SO 2 -substituted heteroaryl group, SO 2- Heterocyclic groups, and SO 2-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, by way of example, includes methyl-SO 2 -, Phenyl-SO 2 - and 4-methylphenyl-SO 2 -Includes.

[0086] "Sulfonyloxy" is -OSO 2 -Alkyl group, -OSO 2 -substituted alkyl group, -OSO 2 -Alkenyl group, -OSO 2 -substituted alkenyl group, -OSO 2 -cycloalkyl group, -OSO 2 -substituted cycloalkyl group, -OSO 2 -cycloalkenyl group, -OSO 2 -substituted cycloalkenyl group, -OSO 2 -aryl group, -OSO 2 -substituted aryl group, -OSO 2 heteroaryl group, -OSO 2 -substituted heteroaryl group, -OSO 2 -heterocyclic group, and -OSO 2 -refers to a 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] "Alkylthio" or the term "thioalkoxy" refers to an -S-alkyl group, where alkyl is as defined herein. In some embodiments, the sulfur may be oxidized to -S(O)-. Sulfoxides can exist as one or more stereoisomers.

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

[0092] The term "thioaryloxy" refers to an aryl-S- group, where the aryl group 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 to replace one or more hydrogens on a saturated carbon atom in the specified group or radical (such as =O, =NR, or =NR2) are also included to replace any two hydrogens on a single carbon. 70, =N-OR 70 , =N 2 , or ═S) is, unless otherwise specified, deuterium, -R 60 , halo, =O, OR 70 ,SR 70 ,NR 80 R 80 ,trihalomethyl,CN,OCN,SCN,NO,NO 2 ,=N 2 ,N 3 ,SO 2 R 70 ,SO 2 O - M + ,-SO 2 OR 70 , -OSO 2 R 70 ,-OSO 2 O - M + ,-OSO 2 OR 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 , -NR70 C(O)R 70 ,-NR 70 C(S)R 70 ,-NR 70 CO 2 - M + ,-NR 70 CO 2 R 70 ,-NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 ,-NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 and R 60 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; 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 the same or different additional 1 to 4 heteroatoms selected from the group consisting of O, N, and S, of which N is -H or C 1 ~C 3 may have alkyl substitution, and each M + is a counter ion with a net single positive charge. + are independent, e.g., K + , Na + , Li + Alkaline ions such as + N(R 60 ) 4 Ammonium ions such as [Ca 2+ ] 0.5 , [Mg 2+ ]0.5 , or [Ba 2+ ] 0.5 and the like (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 two ionized compound disclosed herein, can serve as the counterion of such divalent alkaline earth ion, or a two ionized compound disclosed herein can serve as the counterion of such divalent alkaline earth ion). A specific example is -NR 80 R 80 is -NH 2 , -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl and N-morpholinyl.

[0097] Further to the disclosure herein, the substitutents for 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,CF 3 ,CN,OCN,SCN,NO,NO 2 ,N 3 ,SO 2 R 70 ,-SO 3 - M + ,-SO 3 R 70 ,-OSO 2 R 70 ,-OSO 3 - M + ,-OSO 3 R 70 ,-PO 3 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 , -CO 2 - M + , -CO 2 R 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 , -OCO 2 - M + , -OCO 2 R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO 2 - M + , -NR 70 CO 2 R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 、 and -NR 70 C(NR 70 )NR 80 R 80 wherein R 60 , 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 the hydrogen on the nitrogen atom in "substituted" heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R 60 , O.M. + ,OR 70 ,SR 70 ,S.M. + ,-NR 80 R 80 , trihalomethyl, -CF 3 , -CN,-NO,-NO 2 ,-S(O) 2 R 70 ,-S(O) 2 O.M. + ,-S(O) 2 OR 70 ,-OS(O) 2 R 70 ,-OS(O) 2 O.M. + ,-OS(O) 2 OR 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)R70 ,-OC(O)OR 70 ,-OC(S)OR 70 ,-NR 70 C(O)R 70 ,-NR 70 C(S)R 70 ,-NR 70 C(O)OR 70 ,-NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 ,-NR 70 C(NR 70 )R 70 , and -NR 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 certain embodiments, a substituted group has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0100] Unless otherwise specified, it is understood that for all substituents defined above, polymers achieved by defining the substituents to have further substitutions thereon (e.g., 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 substitutions of substituted aryl groups specifically contemplated herein are 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-(CH 2 CH 2 O) nIt 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 of the groups disclosed herein that contain one or more substituents, it is of course understood that such groups do not include any substitutions or substitution patterns that are sterically impractical 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 compounds that have 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 "deuterium-containing" or "containing deuterium," it is to be understood that the substituent or group itself may be deuterium, or the substituent or group may contain at least one deuterium substitution in its chemical structure. For example, if the substituent "-R" is defined as containing deuterium, then -R can be -D (-deuterium), or -CD consistent with the other requirements set forth for -R. 3 It should be understood that the radical may be a group such as:

[0105] The phrases "pharmacologically 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 "pharmacologically acceptable salt," "physiologically acceptable salt," and the like, mean salts that are acceptable for administration to a patient, such as a mammal (salts having a counterion that has acceptable mammalian safety for a given administration regimen). As is well known in the art, such salts can be prepared from pharma- ceutically acceptable inorganic or organic bases, such as, for example, sodium, potassium, calcium, magnesium, lithium, aluminum, zinc, and ammonium, as well as tetraalkylammonium salts (e.g., salts formed with pharma- ceutically 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., hydrochloride, hydrobromide, sulfate, sulfamate, phosphate, 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 pharma- ceutically acceptable salt, although this is not required for salts of intermediate compounds that are 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 as the anionic component of the salt a conjugate base of the inorganic or organic acid.

[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 be present in an ordered and / or non-ordered 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, dimethylsulfoxide, 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 compounds are contemplated herein, including racemates and optically pure stereoisomers. Chemical formulas and compounds that have at least one asymmetric center but are drawn without reference to stereochemistry are intended to include both racemates and separate 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 the atoms and / or in the position of the 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 arrangement, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. Other tautomeric ring atom arrangements 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 in 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 indicate a compound that can be converted under physiological conditions or by solvation into a biologically active compound as described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharma- ceutically acceptable. For example, prodrugs such as esters, phosphate esters, etc., may be inactive when administered to a subject, but are converted in vivo into active compounds, for example, by hydrolysis into free carboxylic acid or free hydroxyl groups. Prodrug compounds often offer the advantage of 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., "Pro-drugs 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 fully incorporated herein by reference. The term "prodrug" is also meant to include any covalently bonded carrier that releases an active compound in vivo when such a 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 to the parent active compound in such a way that the modification is cleaved, either by routine manipulation or in vivo. Prodrugs include compounds in which a hydroxy, amino, or mercapto group is bonded to any group that is cleaved to form a free hydroxyl, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject.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, etc.), carbamates, etc.

[0110] The compounds of the present disclosure may in some cases exist in crystalline or amorphous solid forms, and thus these solid forms are contemplated herein. A "crystalline" solid is a type of solid whose basic three-dimensional structure contains a highly regular pattern of atoms or molecules that form 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", that have the same chemical composition but differ in packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs may have various solid 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 a polymorph, further purification may also be achieved in terms of physical or optical purity. As used herein, the term "amorphous" refers to a solid material that does not have substantial long-range order in the position of its molecules, and the molecules are arranged randomly, such that there is effectively no well-defined arrangement, e.g., no molecular packing, and no long-range order. Amorphous solids are generally isotropic, i.e., they 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., it 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 that is 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, the 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 the present disclosure is intended to include all permutations thereof, e.g., solvates of pharma- ceutically acceptable salts of stereoisomers of the subject compounds.

[0112] A "vapor" is a solid substance in the gas phase below its critical temperature, meaning that a vapor can be condensed into 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 an aerosol that is distinct from a vapor and is a dispersion of liquid droplets (liquid phase) suspended in a gas phase (e.g., air, oxygen, helium, and mixtures thereof). The 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 length of time 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 concentration of the drug in 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 a particular formulation of the present disclosure that has been formulated to increase the duration of release to a maximum value, which in the case of the enteral route is ultimately limited by the time the digestive 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 abuse of the drug.

[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" refers to treating or care of a disease or medical condition in a patient, e.g., a mammal (particularly a human), including ameliorating a disease or medical condition, e.g., causing elimination or regression of the disease or medical condition in the patient, inhibiting a 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, may be any mammal, including, for example, a human or non-human subject. The patient or subject may have the condition to be treated or may be susceptible to the condition to be 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 terms encompass 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 candidates for a preventive regimen in some embodiments. 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. In many cases, the beneficial effects that 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 suffering from a particular disease, disorder, or condition in an attempt 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 occurrence of the disease or disorder.

[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 showing the type, amount, duration, procedure, etc. of drugs in drug treatment in a chronological order, including the dosage, administration method, administration order, administration date, etc. of each drug. The date designated for administration is determined before the start of drug administration. Administration is continued by repeating a series of administration schedules as a "course." A "continuous" administration schedule means daily administration 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 at a given administration schedule. For example, after undergoing several courses of treatment, 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 produces neurological side effects of sedation or psychotomimetic effects (e.g., hallucinations, dizziness, and nausea), or any undesirable and / or unintended secondary effects that result in a subjective experience that is qualitatively different from the near normal caused by administering the pharmaceutical to an individual. 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 undesirable, unintended, and / or severe, such side effects may affect not only the immediate effects, but also treatment compliance. In particular, side effects may be more pronounced at blood concentration levels of about 250, 300, 400, 500 ng / L or higher.

[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", "inflammatory disease" refers to rheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthritis), spondyloarthropathy (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); blood diseases (e.g., arthritis, osteoarthritis, osteoporosis ... vascular diseases including atherosclerosis, ischemic heart disease, myocardial infarction, stroke, peripheral vascular disease, and vascular stent restenosis; 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, 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 in addition to the singular, 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).

[0133] compound The present inventors have discovered a novel compound that inhibits G protein-coupled receptors (GPCRs), such as 5-HT, that is bioavailable (e.g., orally bioavailable), distributes to the brain, has improved exposure (i.e., prevention of high drug spikes observed soon after administration), and has a favorable enzymatic degradation profile and clearance. 2 Novel phenethylamine compounds of the 2C-X type have been identified, including those that exhibit preferential binding to the receptor. As a result, the disclosed compounds may have reduced side effects and / or toxicity, reduced interpatient variability, rapid onset, and may be relatively short acting, thereby allowing practical use in clinical practice. In addition to the oral route of administration, these novel compounds may also have properties such as desirable lipophilicity that allow their administration via inhalation or transdermal routes, for example in the form of a transdermal patch. The novel 2C-X compounds are based on specific molecular modifications (e.g., involving deuteration and / or fluorination) that retard or avoid enzymatic degradation at certain sites, and in many cases introduce / maintain metabolic soft spots at other sites, modifications that were identified only after significant research.

[0134] Formula (I) [ka] or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is disclosed herein, During the ceremony, X 1 and X 2 are independently hydrogen or deuterium; Y 1 and Y 2 are independently hydrogen or deuterium; R 3 is hydrogen or deuterium, R 4 is halogen, substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 3 ~C 10Cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR b , or -SR b 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 substituted or unsubstituted C 1 ~C 6 is alkyl, 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 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 -SCF 3 , -SCF 2 H, -SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH2 ,-SCH 2 CF 2 CF 2 H,-OCF 3 ,-OCF 2 H, -OCFH 2 ,-OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H, and -Cyclopentyl (-C 5 H 9 ), and -A(CF 2 ) m (CH 2 ) n Q, A is selected from the group consisting of S, O, CH 2 , or CF 2 with the proviso that m is 0 to 3, n is 0 to 6, and Q is -C≡CH or -C≡N.

[0135] 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.

[0136] 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 1and Y 2 is deuterium.

[0137] In some embodiments, R 3 is deuterium. In some embodiments, R 3 is hydrogen.

[0138] In some embodiments, R 4 is a halogen, for example, -Br, -F, -Cl, or -I.

[0139] In some embodiments, R 4 is a substituted or unsubstituted C 1 ~C 6 In some embodiments, R 4 is unsubstituted C 1 ~C 6 and 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. Preferred unsubstituted alkyl groups are methyl and t-butyl. In some embodiments, R 4 is a substitution C 1 ~C 6 Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, hydroxyl, or polar substituents such as polyether substituents. 1 ~C 6 The alkyl group may include one or more substituents. In some embodiments, R 4 is a substitution C 1 Alkyl groups (i.e., substituted methyl groups), examples of which include -CDH 2 , -CD 2 H, -C.D. 3 , -CFH 2 , -CF 2 H, -CF 3 , and -CH 2 In some embodiments, R 4 is a substitution C 2alkyl groups, examples of which include -CDHCDH 2 , -CDHCD 2 H, -C.D. 2 CD 3 , -CH 2 CFH 2 , -CH 2 CF 2 H, -CH 2 CF 3 , and -CH 2 CH 2 In some embodiments, R 4 is C 2 Substituted C such as fluoroalkyl group 2 For example, in some embodiments, R 4 teeth, -CH 2 CFH 2 , -CH 2 CF 2 H or -CH 2 CF 3 In some embodiments, R 4 is a substitution C 3 is an alkyl group, examples of which include -CH 2 CH 2 CF 3 , -CH 2 CH 2 CF 2 H, -CH 2 CH 2 CFH 2 , -CH 2 CF 2 CF 2 H, and -CH 2 CH 2 CH 2 In some embodiments, R 4 teeth, -CH 2 CH 2 CFH 2 isn't it.

[0140] In some embodiments, R 4 is a substituted or unsubstituted C 3 ~C10 In some embodiments, R 4 is unsubstituted C 3 ~C 10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R 4 is a substitution C 3 ~C 10 Cycloalkyl. Cycloalkyl groups can be substituted with any one or more of the 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 can include one or more substituents.

[0141] In some embodiments, R 4 is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, and the like.

[0142] In some embodiments, R 4 is substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, and the like. In some embodiments, R 4 is unsubstituted alkynyl. In some embodiments, R 4 is unsubstituted acetylenyl (-C≡CH). In some embodiments, R 4 is unsubstituted propargyl (-CH 2 In some embodiments, R 4 teeth, -CH 2 CH 2 C≡CH. In some embodiments, R 4 -CH 2 CH 2 CH2 C≡CH. In some embodiments, R 4 teeth, -CH 2 CH 2 CH 2 CH 2 C≡CH. In some embodiments, R 4 is substituted alkynyl. In some embodiments, R 4 is a substituted propargyl (e.g., -CF 2 In some embodiments, R 4 teeth, -CF 2 CH 2 C≡CH. In some embodiments, R 4 -CF 2 CH 2 CH 2 C≡CH. In some embodiments, R 4 teeth, -CF 2 CH 2 CH 2 CH 2 C≡CH.

[0143] In some embodiments, R 4 -OR b or -SR b and 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 In some embodiments, R 4 -OR b In some embodiments, R 4 -SR b In some embodiments, R b is a substituted or unsubstituted C 1 ~C 6 Alkyl, or substituted or unsubstituted C 3 ~C 10 Cycloalkyl, for example, substituted C1 ~C 6 Alkyl groups, unsubstituted C 1 ~C 6 Alkyl groups, substituted C 3 ~C 10 Cycloalkyl group or unsubstituted C 3 ~C 10 It is a cycloalkyl group.

[0144] In some embodiments, R b is a substituted or unsubstituted C 1 ~C 6 In some embodiments, R b is unsubstituted C 1 ~C 6 and 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 substitution C 1 ~C 6 Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, hydroxyl, or polar substituents such as polyether substituents. 1 ~C 6 The alkyl group may include one or more substituents. In some embodiments, R b is a substitution C 1 is an alkyl group, examples of which include -CDH 2 , -CD 2 H,-CD 3 ,-CFH 2 ,-CF 2 H,-CF 3 , and -CH 2 In some embodiments, R b is a substitution C 2 alkyl groups, examples of which include -CDHCDH 2 , -CDHCD 2 H,-CD 2 CD 3 ,-CH 2 CFH2 ,-CH 2 CF 2 H,-CH 2 CF 3 , and -CH 2 CH 2 In some embodiments, R b is C 2 Substituted C such as fluoroalkyl group 2 For example, in some embodiments, R 4 -OR b or -SR b If R b teeth, -CH 2 CFH 2 , -CH 2 CF 2 H or -CH 2 CF 3 In some embodiments, R b is a substitution C 3 is an alkyl group, examples of which include -CH 2 CH 2 CF 3 , -CH 2 CH 2 CF 2 H, -CH 2 CH 2 CFH 2 ,-CH 2 CF 2 CF 2 H, and -CH 2 CH 2 CH 2 In some embodiments, R b teeth, -CH 2 CH 2 CFH 2 isn't it.

[0145] In some embodiments, R b is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, and the like.

[0146] In some embodiments, R b is substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, and the like. 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 (-CH 2 In some embodiments, R b teeth, -CH 2 CH 2 C≡CH. In some embodiments, R b is -CH 2 CH 2 CH 2 C≡CH. In some embodiments, R b teeth, -CH 2 CH 2 CH 2 CH 2 C≡CH. In some embodiments, R b is substituted alkynyl. In some embodiments, R b is a substituted propargyl (e.g., -CF 2 In some embodiments, R b teeth, -CF 2 CH 2 C≡CH. In some embodiments, R b -CF 2 CH 2 CH 2 C≡CH. In some embodiments, R b teeth, -CF 2 CH 2 CH 2 CH 2 C≡CH.

[0147] In some embodiments, R b is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C 3 ~C10 Cycloalkyl, or substituted or unsubstituted C 4 ~C 8 Cycloalkyl, or substituted or unsubstituted C 5 ~C 6 In some embodiments, R b is an unsubstituted cycloalkyl (e.g., an unsubstituted C 3 ~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 3 ~C 10 Cycloalkyl groups are substituted with any one or more of the 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.

[0148] In some embodiments, R 4 -A(CF 2 ) m (CH 2 ) n Q, where A is S, O, CH 2 , or CF 2 In some embodiments, A is S. In some embodiments, A is O. In some embodiments, A is CH 2 (methylene). In some embodiments, A is CF 2(difluoromethylene). In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, when A is S or O, the sum of m+n is 6 or less, or 5 or less, or 4 or less, or 3 or less, or 2 or less, or 1 or less, or 0. In some embodiments, A is CH 2 or CF 2 In some embodiments, Q is -C≡CH. In some embodiments, Q is -C≡N. -A(CF 2 ) m (CH 2 ) n Representative examples of Q groups include -SC≡CH, -SCH 2 C≡CH, -SCF 2 C≡CH, -SCH 2 C≡N,-SCH 2 CH 2 C≡CH, -SCF 2 CH 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -OCH 2 C≡CH, -OC≡CH, -CH 2 C≡CH, -CF 2 C≡CH, -CH 2 CH 2 C≡CH, -CF 2 CH 2 C≡CH, -CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 C≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH and -CF 2 CH 2 CH 2 CH 2 Examples include, but are not limited to, C≡CH.

[0149] In some embodiments, R 4 -SMe, -SCD 3, -SCF 3, -SCF 2 H,-SCFH 2, SCH 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H, -SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -SEt, -Sn-Pr, -Me,-CD 3 ,-CF 3 ,-t-Bu,-C(CD 3 ) 3 , -Cyclopentyl, -OMe, -OCD 3 ,-OCF 3 ,-OCF 2 H,-OCFH 2 , -OCH 2 CH 2 CF 3 ,-OCH2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 In some embodiments, R 4 -SMe, -SCF 3 , -SCF 2 H, -Me, -OCD 3 , -CF 3 , -t-Bu, or -cyclopentyl. In some embodiments, R 4 -SCF 3 , -SCF 2 H, -SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H,-SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -OCF 3 ,-OCF 2 H,-OCFH2 , -OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 R is selected from the group consisting of C≡CH and -cyclopentyl. 4 Ga-SCF 3 If -SCF 2 H, -SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H,-OCF 3 ,-OCF 2 H, -OCFH 2 ,-OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H, -Cyclopentyl (-C 5H 9 ), or -A(CF 2 ) m (CH 2 ) n Q, where A is S, O, CH 2 , or CF 2 m is 0 to 3, n is 0 to 6, and Q is -C≡CH or -C≡N, and 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 some embodiments, R 4 -SCF 2 H, -SCFH 2 ,-SCH 2 CF 2 CF 2 H,-SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -OCF 3 ,-OCF 2 H,-OCFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 C≡CH and -cyclopentyl (-C 5 H 9 ) is selected from the group consisting of R 4 But -SCF 2H, -SCFH 2 , -SCH 2 CF 2 CF 2 H,-SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -OCF 3 ,-OCF 2 H,-OCFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 C≡CH, or -cyclopentyl (-C 5 H 9 ), 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.

[0150] 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 of R 6 and R 7 are different. In some embodiments, R 6 is hydrogen and R7 is a substituted or unsubstituted C 1 ~C 6 It is 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.

[0151] In some embodiments, R 6 and / or R 7 is unsubstituted C 1 ~C 6 Alkyl, e.g., unsubstituted C 1 Alkyl, unsubstituted C 2 Alkyl, unsubstituted C 3 Alkyl, unsubstituted C 4 Alkyl, unsubstituted C 5 Alkyl or unsubstituted C 6 In some embodiments, R 6 and / or R 7 is an unsubstituted linear C 2 ~C 6 In some embodiments, R 6 and / or R 7 is a non-substituted branch C 3 ~C 10 Alkyl. Unsubstituted C 1 ~C 6 Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.

[0152] In some embodiments, R 6 and / or R 7 is a substitution C 1 ~C 6 Alkyl, e.g., substituted C 1 Alkyl, substituted C 2 Alkyl, substituted C 3 Alkyl, substituted C 4 Alkyl, substituted C 5 Alkyl or substituted C 6is an 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 C substituted with one or more deuterium atoms. 1 ~C 6 alkyl, examples of which include -CDH 2 , -CD 2 H, -C.D. 3 , -CD 2 CD 3 , and -CD 2 CD 2 CD 3 In some embodiments, R 6 and / or R 7 is C substituted with one or more fluorine atoms 1 ~C 6 An example of a fluoroalkyl group is -CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 CH 2 F,-CH 2 CHF 2 , -CH 2 CF 3 ,-CH 2 CH 2 CH 2 F,-CH 2 CH 2 CHF 2 ,-CH 2 CH 2 CF 3 ,-CH2 CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 CHF 2 ,-CH 2 CH 2 CH 2 CF 3 ,-CH 2 CF 2 CHF 2 ,-CH 2 CF 2 CF 3 ,-CH(CF 3 ) 2 , and -CH(CH 3 )CF 3 These include, but are not limited to:

[0153] In some embodiments, R 6 and / or R 7 is a C substituted with one or more deuterium atoms and one or more fluorine atoms. 1 ~C 6 alkyl, examples of which include: -CD 2 CH 2 F, -CD 2 CHF 2 , -CD 2 CF 3 , -CD 2 CH 2 CH 2 F, -CD 2 CH 2 CHF 2 , -CD 2 CH 2 CF 3 , -CD 2 CD 2 CH 2 ,-CD 2 CD 2 CHF 2 ,-CD 2 CD 2 CF 3 ,-CD 2 CH 2 CH2 CH 2 F,-CD 2 CH 2 CH 2 CHF 2 , -CD 2 CH 2 CH 2 CF 3 ,-CD 2 CD 2 CH 2 CH 2 F,-CD 2 CD 2 CH 2 CHF 2 ,-CD 2 CD 2 CH 2 CF 3 , -CD 2 CD 2 CD 2 CH 2 F,-CD 2 CD 2 CD 2 CHF 2 , and -CD 2 CD 2 CD 2 CF 3 These include, but are not limited to:

[0154] In some embodiments, R 6 and / or R 7 is a C substituted with a substituted or unsubstituted cycloalkyl 1 ~C 6 It is an alkyl group. 1 ~C 6 Alkyl can be, for example, substituted or unsubstituted C 3 ~C 10 Cycloalkyl, or substituted or unsubstituted C 4 ~C 8 Cycloalkyl, or substituted or unsubstituted C 5 ~C 6 In some embodiments, C may be substituted with cycloalkyl. 1 ~C 6 Alkyl is an unsubstituted cycloalkyl (e.g., unsubstituted C 3 ~C 10cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, C 1 ~C 6 Alkyl can be substituted cycloalkyl (e.g., substituted C 3 ~C 10 Cycloalkyl groups are substituted with any one or more of the 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 include one or more substituents. In some embodiments, R 6 and / or R 7 is a C substituted with a substituted or unsubstituted cycloalkyl 1 Alkyl, especially cyclopropylmethyl (-CH 2 C 3 H 5 ) is mentioned.

[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 7 is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C 3 ~C 10Cycloalkyl, or substituted or unsubstituted C 4 ~C 8 Cycloalkyl, or substituted or unsubstituted C 5 ~C 6 In some embodiments, R 6 and R 7 is an unsubstituted cycloalkyl (e.g., an unsubstituted C 3 ~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 3 ~C 10 Cycloalkyl groups are substituted with any one or more of the 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. 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 may 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 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.

[0160] In some embodiments, R 6 and / or R7 is substituted or unsubstituted heteroaryl. In some embodiments, R 6 and / or R 7 is an 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 may be any of those enumerated 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. Heteroaryl groups may contain one or more substituents.

[0161] In some embodiments, R 6 is hydrogen and R 7 is unsubstituted or substituted C 1 ~C 6 In some embodiments, R is an 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 is hydrogen and R 7 is a substituted or unsubstituted C 1 ~C 6 In some embodiments, R 6 is hydrogen, and R 7 is unsubstituted C 1 ~C 6 Alkyl, C substituted with one or more deuterium atoms1 ~C 6 Alkyl, C substituted with one or more fluorine atoms 1 ~C 6 C substituted with alkyl, or substituted or unsubstituted cycloalkyl 1 ~C 6 For example, in some embodiments, R 6 is hydrogen, and R 7 is methyl, ethyl, propyl, -CD 3 , or cyclopropylmethyl (-CH 2 C 3 H 5 ).

[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 be optionally fused to other rings. An unsubstituted heterocycloalkyl group can have a minimum of one nitrogen ring atom (R 6 and R 7 R includes a nitrogen atom between the ring atoms, 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 are examples of unsubstituted heterocycloalkyl groups: [ka] These include, but are not limited to:

[0163] In some embodiments, R 6 and R7 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 be optionally fused to other rings. A substituted heterocycloalkyl group can be a substituted heterocycloalkyl group with a minimum of one nitrogen ring atom (R 6 and R 7 and optionally an additional heterocyclic atom (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 of which is substituted with at least one substituent. The substituents may be any of those enumerated 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 Substituted heterocycloalkyl formed from the bonding of a heterocycloalkyl group with the nitrogen atom to which it is attached includes heterocycloalkyl groups substituted with one, two, three, four or more substituents. The substituents 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 are examples of substituted heterocycloalkyl groups: [ka] These include, but are not limited to:

[0165] Each R a can be the same or different. In some embodiments, each R a are the same. a are independently substituted or unsubstituted C 1 ~C 6 Alkyl, preferably substituted or unsubstituted C 1 ~C 3 Alkyl, preferably substituted or unsubstituted C 1 alkyl, examples of which include -CH 3 , -CDH 2 , -CD 2 H, -C.D. 3 , -CFH 2 , -CF 2 H, -CF 3 In some embodiments, each R a is -CH 3 In some embodiments, each R a -CD 3 In some embodiments, each R a are different, for example, one R a Ha-CH 3 and the other is -CD 3 It is.

[0166] In some embodiments, Y 1 and Y 2 are each hydrogen or each deuterium, R 3 is hydrogen, and X 1 and X 2 are each hydrogen or each deuterium, and each R a is -CH 3 or -CD 3 and R 4 -SMe, -SCD 3、 -SCF 3、 -SCF2 H,-SCFH 2 ,SCH 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H, -SCH 2 C≡CH,-SC≡CH,-SCF 2 C≡CH,-SCH 2 CH 2 CH 2 C≡CH,-SCF 2 CH 2 CH 2 C≡CH,-SEt,-Sn-Pr, -Me,-CD 3 ,-CF 3 ,-t-Bu、-C(CD 3 ) 3 、-シクロペンチル、-OMe,-OCD 3 ,-OCF 3 ,-OCF 2 H,-OCFH 2 , -OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH,-OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH,-CF 2 CH 2 CH 2 CH 2 C≡CH,-Cl,-I,or -Br,preferably R4 is -SCF 3 ,-SCF 2 H,-SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H,-SCH 2 C≡CH, -SC≡CH, -OCF 3 ,-OCF 2 H,-OCFH 2 ,-OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 , -OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 C≡CH, and -cyclopentyl, R 6 is hydrogen and R 7 is hydrogen or substituted or unsubstituted C 1 ~C 6 It is an alkyl.

[0167] As noted above, any of the above embodiments of the compound of formula (I) may further comprise: (i) X 1 ,X 2 ,Y 1 ,Y 2 ,R 3 ,R 4 ,R6 ,R 7 , and R a At least one of (ii) R 4 But -SCF 3 , -SCF 2 H, -SCFH 2 , -SCH 2 CH 2 CF 3 , -SCH 2 CH 2 CF 2 H, -SCH 2 CH 2 CFH 2 , -SCH 2 CF 2 CF 2 H,-OCF 3 , -OCF 2 H, -OCFH 2 , -OCH 2 CH 2 CF 3 , -OCH 2 CH 2 CF 2 H, -OCH 2 CH 2 CFH 2 , -OCH 2 CF 2 CF 2 H, -Cyclopentyl (-C 5 H 9 ), and -A(CF 2 ) m (CH 2 ) n Q, where A is selected from the group consisting of S, O, CH 2 , or CF 2 m is 0 to 3, n is 0 to 6, and Q is -C≡CH or In some embodiments, in proviso (ii), R 4 -SCF 2 H, -SCFH 2 ,-SCH 2 CF 2 CF 2 H,-SCH 2C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -OCF 3 ,-OCF 2 H,-OCFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 C≡CH and -cyclopentyl (-C 5 H 9 The above conditions stated with "and / or" mean that the compound falls within the scope when one of conditions (i) or (ii) is met, or when both conditions (i) and (ii) are met. For clarity, when condition (i) is met, i.e., X 1 , X 2 ,Y 1 ,Y 2 ,R 3 ,R 4 ,R 6 ,R 7 , and R a In the case of a compound in which at least one of R 4 -SCF 3 , -SCF 2 H, -SCFH 2 , -SCH 2 CH 2 CF 3 , -SCH 2 CH 2 CF 2 H, -SCH 2 CH 2 CFH2 , -SCH 2 CF 2 CF 2 H, -OCF 3 , -OCF 2 H, -OCFH 2 , -OCH 2 CH 2 CF 3 , -OCH 2 CH 2 CF 2 H, -OCH 2 CH 2 CFH 2 , -OCH 2 CF 2 CF 2 H, -Cyclopentyl (-C 5 H 9 ), and -A(CF 2 ) m (CH 2 ) n Q, where A is S, O, CH 2 , or CF 2 where m is 0 to 3, n is 0 to 6, and Q is -C≡CH or -C≡N. Similarly, compounds satisfying condition (ii) include, for example, R 4 But -SCF 3 , -SCF 2 H,-SCFH 2 ,S.C.H. 2 CH 2 CF 3 , -SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H,-OCF 3 ,-OCF 2 H,-OCFH 2 ,-OCH 2 CH 2 CF 3 , -OCH 2 CH 2 CF2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H, -Cyclopentyl (-C 5 H 9 ), or -A(CF 2 ) m (CH 2 ) n Q, where A is S, O, CH 2 , or CF 2 In the case where m is 0 to 3, n is 0 to 6, and Q is -C≡CH or -C≡N, condition (i) does not need to be satisfied, i.e., other substituents X 1 ,X 2 ,Y 1 ,Y 2 ,R 3 ,R 6 ,R 7 , and R a may or may not contain deuterium.

[0168] Formula (II) In some embodiments, the compound has the structure of formula (II): [ka] or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; During the ceremony, X 1 and X 2 are independently hydrogen or deuterium; Y 1 and Y 2 are independently hydrogen or deuterium; R 4 is halogen, substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 3 ~C 10 Cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR b , or -SR band 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 It is cycloalkyl.

[0169] 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.

[0170] 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.

[0171] In some embodiments, R 4 is a halogen, for example, -Br, -F, -Cl, or -I.

[0172] In some embodiments, R 4 is a substituted or unsubstituted C 1 ~C 6 In some embodiments, R 4 is unsubstituted C 1 ~C 6and 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. Preferred unsubstituted alkyl groups are methyl and t-butyl. In some embodiments, R 4 is a substitution C 1 ~C 6 Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, hydroxyl, or polar substituents such as polyether substituents. 1 ~C 6 The alkyl group may include one or more substituents. In some embodiments, R 4 is a substitution C 1 Alkyl groups (i.e., substituted methyl groups), examples of which include -CDH 2 , -CD 2 H, -C.D. 3 , -CFH 2 , -CF 2 H, -CF 3 , and -CH 2 In some embodiments, R 4 is a substitution C 2 alkyl groups, examples of which include -CDHCDH 2 ,-CDHCD 2 H,-CD 2 CD 3 ,-CH 2 CFH 2 ,-CH 2 CF 2 H, -CH 2 CF 3 , and -CH 2 CH 2 In some embodiments, R 4 is C 2 Substituted C such as fluoroalkyl group 2 For example, in some embodiments, R 4 -CH 2 CFH 2 , -CH2 CF 2 H, or -CH 2 CF 3 In some embodiments, R 4 is a substitution C 3 is an alkyl group, examples of which include CH 2 CH 2 CF 3 ,-CH 2 CH 2 CF 2 H,-CH 2 CH 2 CFH 2 ,-CH 2 CF 2 CF 2 H, and -CH 2 CH 2 CH 2 In some embodiments, R 4 -CH 2 CH 2 CFH 2 isn't it.

[0173] In some embodiments, R 4 is a substituted or unsubstituted C 3 ~C 10 In some embodiments, R 4 is unsubstituted C 3 ~C 10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R 4 is a substitution C 3 ~C 10Cycloalkyl. Cycloalkyl groups can be substituted with any one or more of the 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 can include one or more substituents.

[0174] In some embodiments, R 4 is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, and the like.

[0175] In some embodiments, R 4 is substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, and the like. In some embodiments, R 4 is unsubstituted alkynyl. In some embodiments, R 4 is unsubstituted acetylenyl (-C≡CH). In some embodiments, R 4 is unsubstituted propargyl (-CH 2 In some embodiments, R 4 teeth, -CH 2 CH 2 C≡CH. In some embodiments, R 4 is -CH 2 CH 2 CH 2 C≡CH. In some embodiments, R 4 teeth, -CH 2 CH 2 CH 2 CH 2 C≡CH. In some embodiments, R 4 is substituted alkynyl. In some embodiments, R 4 is a substituted propargyl (e.g., -CF 2In some embodiments, R 4 teeth, -CF 2 CH 2 C≡CH. In some embodiments, R 4 -CF 2 CH 2 CH 2 C≡CH. In some embodiments, R 4 teeth, -CF 2 CH 2 CH 2 CH 2 C≡CH.

[0176] In some embodiments, R 4 -OR b or -SR b and 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 In some embodiments, R 4 -OR b In some embodiments, R 4 -SR b In some embodiments, R b is a substituted or unsubstituted C 1 ~C 6 Alkyl, or substituted or unsubstituted C 3 ~C 10 Cycloalkyl, for example, substituted C 1 ~C 6 Alkyl groups, unsubstituted C 1 ~C 6 Alkyl groups, substituted C 3 ~C 10 Cycloalkyl group or unsubstituted C 3 ~C 10 It is a cycloalkyl group.

[0177] In some embodiments, R b is a substituted or unsubstituted C1 ~C 6 In some embodiments, R b is unsubstituted C 1 ~C 6 and 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 substitution C 1 ~C 6 Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, hydroxyl, or polar substituents such as polyether substituents. 1 ~C 6 The alkyl group may include one or more substituents. In some embodiments, R b is a substitution C 1 is an alkyl group, examples of which include -CDH 2 , -CD 2 H, -C.D. 3 , -CFH 2 , -CF 2 H, -CF 3 , and -CH 2 In some embodiments, R b is a substitution C 2 alkyl groups, examples of which include -CDHCDH 2 , -CDHCD 2 H, -C.D. 2 CD 3 , -CH 2 CFH 2 , -CH 2 CF 2 H, -CH 2 CF 3 , and -CH 2 CH 2 In some embodiments, R b is C 2 Substituted C such as fluoroalkyl group 2For example, in some embodiments, R 4 -OR b or -SR b If R b teeth, -CH 2 CFH 2 , -CH 2 CF 2 H or -CH 2 CF 3 In some embodiments, R b is a substitution C 3 is an alkyl group, examples of which include -CH 2 CH 2 CF 3 , -CH 2 CH 2 CF 2 H, -CH 2 CH 2 CFH 2 , -CH 2 CF 2 CF 2 H, and -CH 2 CH 2 CH 2 In some embodiments, R b teeth, -CH 2 CH 2 CFH 2 isn't it.

[0178] In some embodiments, R b is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, and the like.

[0179] In some embodiments, R b is substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, and the like. 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 (-CH2 In some embodiments, R b teeth, -CH 2 CH 2 C≡CH. In some embodiments, R b -CH 2 CH 2 CH 2 C≡CH. In some embodiments, R b teeth, -CH 2 CH 2 CH 2 CH 2 C≡CH. In some embodiments, R b is substituted alkynyl. In some embodiments, R b is a substituted propargyl (e.g., -CF 2 In some embodiments, R b teeth, -CF 2 CH 2 C≡CH. In some embodiments, R b -CF 2 CH 2 CH 2 C≡CH. In some embodiments, R b teeth, -CF 2 CH 2 CH 2 CH 2 C≡CH.

[0180] In some embodiments, R b is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C 3 ~C 10 Cycloalkyl, or substituted or unsubstituted C 4 ~C 8 Cycloalkyl, or substituted or unsubstituted C 5 ~C 6 In some embodiments, R b is an unsubstituted cycloalkyl (e.g., an unsubstituted C 3 ~C 10cycloalkyl), 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 3 ~C 10 Cycloalkyl groups are substituted with any one or more of the 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.

[0181] In some embodiments, R 4 -A(CF 2 ) m (CH 2 ) n Q, where A is S, O, CH 2 , or CF 2 In some embodiments, A is S. In some embodiments, A is O. In some embodiments, A is CH 2 (methylene). In some embodiments, A is CF 2(difluoromethylene). In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, when A is S or O, the sum of m+n is 6 or less, or 5 or less, or 4 or less, or 3 or less, or 2 or less, or 1 or less, or 0. In some embodiments, A is CH 2 or CF 2 In some embodiments, Q is -C≡CH. In some embodiments, Q is -C≡N. -A(CF 2 ) m (CH 2 ) n Representative examples of Q groups include -SC≡CH, -SCH 2 C≡CH, -SCF 2 C≡CH, -SCH 2 C≡N,-SCH 2 CH 2 C≡CH, -SCF 2 CH 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -OCH 2 C≡CH, -OC≡CH, -CH 2 C≡CH, -CF 2 C≡CH, -CH 2 CH 2 C≡CH, -CF 2 CH 2 C≡CH, -CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 C≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH and -CF 2 CH 2 CH 2 CH 2 Examples include, but are not limited to, C≡CH.

[0182] In some embodiments, R 4 -SMe, -SCD 3, -SCF 3, -SCF 2 H,-SCFH 2, SCH 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H, -SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -SEt, -Sn-Pr, -Me,-CD 3 ,-CF 3 ,-t-Bu,-C(CD 3 ) 3 , -Cyclopentyl, -OMe, -OCD 3 ,-OCF 3 ,-OCF 2 H,-OCFH 2 , -OCH 2 CH 2 CF 3 ,-OCH2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 In some embodiments, R 4 -SMe, -SCF 3, -SCF 2 H,-Me,-OCD 3 ,-CF 3 ,-t-Bu, or -cyclopentyl. In some embodiments, R 4 -SCF 3 , -SCF 2 H, -SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H,-SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -OCF 3 ,-OCF 2 H,-OCFH2 , -OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 C≡CH, and -cyclopentyl. In some embodiments, R 4 -SCF 2 H, -SCFH 2 , -SCH 2 CF 2 CF 2 H,-SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -OCF 3 ,-OCF 2 H,-OCFH 2 , -OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 C≡CH and -cyclopentyl (-C 5 H9 ).

[0183] In some embodiments, Y 1 and Y 2 are each hydrogen or each deuterium, and X 1 and X 2 are each hydrogen or each deuterium, R 4 -SMe, -SCD 3, -SCF 3, -SCF 2 H,-SCFH 2 ,-SCH 2 CH 2 CF 3 , -SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H,-SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -SEt, -Sn-Pr, -Me, -CD 3 ,-CF 3 ,-t-Bu,-C(CD 3 ) 3 , -Cyclopentyl, -OMe, -OCD 3 ,-OCF 3 ,-OCF 2 H,-OCFH 2 ,-OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H, -OCH 2 CH 2 CFH 2 ,-OCH2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 C≡CH, -Cl, -I, or -Br, preferably R 4 -SCF 3 , -SCF 2 H,-SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H,-SCH 2 C≡CH, -SC≡CH, -OCF 3 ,-OCF 2 H, -OCFH 2 ,-OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, and -cyclopentyl.

[0184] -OCD at the 2nd and 5th positions of the phenyl ring 3Compounds of formula (II) containing deuteration in the form of groups may have beneficial effects by slowing or avoiding O-demethylation (mainly mediated by the CYP2D6 enzyme) at these positions, thereby improving pharmacokinetics, particularly bioavailability, and safety as a result of lower exposure to potentially toxic metabolites.

[0185] Formula (III) In some embodiments, the compound has the structure of formula (III): [ka] or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; During the ceremony, X 1 and X 2 are independently hydrogen or deuterium; Y 1 and Y 2 are independently hydrogen or deuterium; R 4 C with one or more deuterium substitutions 1 ~C 6 Alkyl, C substituted with one or more deuterium 3 ~C 10 Cycloalkyl, -OR b , or -SR b and Each R a are independently substituted or unsubstituted C 1 ~C 6 is alkyl, R b is a C substituted with one or more deuterium atoms. 1 ~C 6 Alkyl or C substituted with one or more deuterium 3 ~C 10 It is cycloalkyl.

[0186] X 1 and X 2 may be the same or different. In some embodiments, X 1 and X 2are the same. In some embodiments, X 1 and X 2 is hydrogen. In some embodiments, X 1 and X 2 is deuterium.

[0187] 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.

[0188] In some embodiments, R 4 is a C substituted with one or more deuterium atoms. 1 ~C 6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl groups that contain one or more deuterium substitutions. An alkyl group can contain one or more deuterium substituents, such as 1, 2, 3, 4, 5, 6, 7, 8, or 9 deuterium substituents. Exemplary C groups substituted with one or more deuterium are: 1 ~C 6 The alkyl group is -CD 3 and -C(CD 3 ) 3 These include, but are not limited to:

[0189] In some embodiments, R 4 is a C substituted with one or more deuterium atoms. 3 ~C 10Cycloalkyl, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclooctyl groups substituted with one or more deuterium atoms. The cycloalkyl group can contain one or more substituents, such as 1, 2, 3, 4, 5, 6, 7, 8, or 9 deuterium substituents.

[0190] In some embodiments, R 4 -OR b where R b is C substituted with one or more deuterium atoms as defined and exemplified above. 1 ~C 6 C substituted with alkyl group or one or more deuterium 3 ~C 10 C substituted with one or more deuterium, such as cycloalkyl groups 1 ~C 6 Alkyl or C substituted with one or more deuterium 3 ~C 10 In some embodiments, R b is a C substituted with one or more deuterium atoms. 1 Alkyl groups, for example -CDH 2 , -CD 2 H, and -CD 3 In some embodiments, R b is a C substituted with one or more deuterium atoms. 2 alkyl, examples of which include -CDHCDH 2 , -CDHCD 2 H, -C.D. 2 CD 3 In some embodiments, R b is a C substituted with one or more deuterium atoms. 3 In some embodiments, R 4 -OCD 3 It is.

[0191] In some embodiments, R 4 -SR b where R bis C substituted with one or more deuterium atoms as defined and exemplified above. 1 ~C 6 C substituted with alkyl group or one or more deuterium 3 ~C 10 C substituted with one or more deuterium, such as cycloalkyl groups 1 ~C 6 Alkyl or C substituted with one or more deuterium 3 ~C 10 In some embodiments, R b is a C substituted with one or more deuterium atoms. 1 Alkyl groups, for example -CDH 2 , -CD 2 H, and -CD 3 In some embodiments, R b is a C substituted with one or more deuterium atoms. 2 alkyl, examples of which include -CDHCDH 2 , -CDHCD 2 H, -C.D. 2 CD 3 In some embodiments, R b is a C substituted with one or more deuterium atoms. 3 In some embodiments, R 4 -SCD 3 It is.

[0192] In some embodiments, R 4 is R 4 But -SCD 3 , -CD 3 , -C(CD 3 ) 3 , and -OCD 3 and wherein

[0193] Each R a can be the same or different. In some embodiments, each R a are the same. a are independently substituted or unsubstituted C 1 ~C 6Alkyl, preferably substituted or unsubstituted C 1 ~C 3 Alkyl, preferably substituted or unsubstituted C 1 alkyl, examples of which include -CH 3 , -CDH 2 ,-CD 2 H,-CD 3 ,-CFH 2 ,-CF 2 H,-CF 3 In some embodiments, each R a -CH 3 In some embodiments, each R a -CD 3 In some embodiments, each R a are different, for example, one R a Ha-CH 3 and the other is -CD 3 It is.

[0194] In some embodiments, X 1 and X 2 are each hydrogen or each deuterium, and Y 1 and Y 2 are each hydrogen or each deuterium, and each R a -CH 3 and R 4 -SCD 3 , -CD 3 , -C(CD 3 ) 3 , or -OCD 3 It is.

[0195] R on the phenyl ring 4 Compounds of formula (III) containing a deuterated substituent (e.g., a deuterated alkyl / cycloalkyl group) at position 1 may have a beneficial effect by allowing the incorporation of a lipophilic group for improved brain penetration while at the same time slowing or avoiding metabolism at this position for improved pharmacokinetics, particularly bioavailability.

[0196] Formula (IV) In some embodiments, the compound has the structure of formula (IV): [ka] or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; During the ceremony, Y 1 and Y 2 are independently hydrogen or deuterium; R 4 is halogen, substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 3 ~C 10 Cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR b , or -SR b and Each R a are independently substituted or unsubstituted C 1 ~C 6 is alkyl, 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 It is cycloalkyl.

[0197] 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.

[0198] In some embodiments, R 4 is a halogen, for example, -Br, -F, -Cl, or -I.

[0199] In some embodiments, R 4 is a substituted or unsubstituted C 1 ~C 6 In some embodiments, R 4 is unsubstituted C 1 ~C 6 and 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. Preferred unsubstituted alkyl groups are methyl and t-butyl. In some embodiments, R 4 is a substitution C 1 ~C 6 Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, hydroxyl, or polar substituents such as polyether substituents. 1 ~C 6 The alkyl group may include one or more substituents. In some embodiments, R 4 is a substitution C 1 Alkyl groups (i.e., substituted methyl groups), examples of which include -CDH 2 , -CD 2 H, -C.D. 3 , -CFH 2 , -CF 2 H, -CF 3 , and -CH 2 In some embodiments, R 4 is a substitution C 2 alkyl groups, examples of which include -CDHCDH 2 , -CDHCD 2 H, -C.D. 2 CD 3 , -CH 2 CFH 2 , -CH 2 CF 2 H, -CH 2 CF 3 , and -CH 2 CH 2In some embodiments, R 4 is C 2 Substituted C such as fluoroalkyl group 2 For example, in some embodiments, R 4 -CH 2 CFH 2 , -CH 2 CF 2 H, or -CH 2 CF 3 In some embodiments, R 4 is a substitution C 3 is an alkyl group, examples of which include -CH 2 CH 2 CF 3 , -CH 2 CH 2 CF 2 H, -CH 2 CH 2 CFH 2 , -CH 2 CF 2 CF 2 H, and -CH 2 CH 2 CH 2 In some embodiments, R 4 -CH 2 CH 2 CFH 2 isn't it.

[0200] In some embodiments, R 4 is a substituted or unsubstituted C 3 ~C 10 In some embodiments, R 4 is unsubstituted C 3 ~C 10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R 4 is a substitution C 3 ~C 10Cycloalkyl. Cycloalkyl groups can be substituted with any one or more of the 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 can include one or more substituents.

[0201] In some embodiments, R 4 is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, and the like.

[0202] In some embodiments, R 4 is substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, and the like. In some embodiments, R 4 is unsubstituted alkynyl. In some embodiments, R 4 is unsubstituted acetylenyl (-C≡CH). In some embodiments, R 4 is unsubstituted propargyl (-CH 2 In some embodiments, R 4 teeth, -CH 2 CH 2 C≡CH. In some embodiments, R 4 is -CH 2 CH 2 CH 2 C≡CH. In some embodiments, R 4 teeth, -CH 2 CH 2 CH 2 CH 2 C≡CH. In some embodiments, R 4 is substituted alkynyl. In some embodiments, R 4 is a substituted propargyl (e.g., -CF 2In some embodiments, R 4 teeth, -CF 2 CH 2 C≡CH. In some embodiments, R 4 -CF 2 CH 2 CH 2 C≡CH. In some embodiments, R 4 teeth, -CF 2 CH 2 CH 2 CH 2 C≡CH.

[0203] In some embodiments, R 4 -OR b or -SR b and 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 In some embodiments, R 4 -OR b In some embodiments, R 4 -SR b In some embodiments, R b is a substituted or unsubstituted C 1 ~C 6 Alkyl, or substituted or unsubstituted C 3 ~C 10 Cycloalkyl, for example, substituted C 1 ~C 6 Alkyl groups, unsubstituted C 1 ~C 6 Alkyl groups, substituted C 3 ~C 10 Cycloalkyl group or unsubstituted C 3 ~C 10 It is a cycloalkyl group.

[0204] In some embodiments, R b is a substituted or unsubstituted C1 ~C 6 In some embodiments, R b is unsubstituted C 1 ~C 6 and 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 substitution C 1 ~C 6 Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, hydroxyl, or polar substituents such as polyether substituents. 1 ~C 6 The alkyl group may include one or more substituents. In some embodiments, R b is a substitution C 1 is an alkyl group, examples of which include -CDH 2 , -CD 2 H, -C.D. 3 , -CFH 2 , -CF 2 H, -CF 3 , and -CH 2 In some embodiments, R b is a substitution C 2 alkyl groups, examples of which include -CDHCDH 2 , -CDHCD 2 H, -C.D. 2 CD 3 , -CH 2 CFH 2 , -CH 2 CF 2 H, -CH 2 CF 3 , and -CH 2 CH 2 In some embodiments, R b is C 2 Substituted C such as fluoroalkyl group 2For example, in some embodiments, R 4 -OR b or -SR b If R b teeth, -CH 2 CFH 2 , -CH 2 CF 2 H or -CH 2 CF 3 In some embodiments, R b is a substitution C 3 is an alkyl group, examples of which include -CH 2 CH 2 CF 3 , -CH 2 CH 2 CF 2 H, -CH 2 CH 2 CFH 2 , -CH 2 CF 2 CF 2 H, and -CH 2 CH 2 CH 2 In some embodiments, R b teeth, -CH 2 CH 2 CFH 2 isn't it.

[0205] In some embodiments, R b is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, and the like.

[0206] In some embodiments, R b is substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, and the like. 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 (-CH2 In some embodiments, R b teeth, -CH 2 CH 2 C≡CH. In some embodiments, R b -CH 2 CH 2 CH 2 C≡CH. In some embodiments, R b teeth, -CH 2 CH 2 CH 2 CH 2 C≡CH. In some embodiments, R b is substituted alkynyl. In some embodiments, R b is a substituted propargyl (e.g., -CF 2 In some embodiments, R b teeth, -CF 2 CH 2 C≡CH. In some embodiments, R b -CF 2 CH 2 CH 2 C≡CH. In some embodiments, R b teeth, -CF 2 CH 2 CH 2 CH 2 C≡CH.

[0207] In some embodiments, R b is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C 3 ~C 10 Cycloalkyl, or substituted or unsubstituted C 4 ~C 8 Cycloalkyl, or substituted or unsubstituted C 5 ~C 6 In some embodiments, R b is an unsubstituted cycloalkyl (e.g., an unsubstituted C 3 ~C 10cycloalkyl), 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 3 ~C 10 Cycloalkyl groups are substituted with any one or more of the 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.

[0208] In some embodiments, R 4 -A(CF 2 ) m (CH 2 ) n Q, where A is S, O, CH 2 , or CF 2 In some embodiments, A is S. In some embodiments, A is O. In some embodiments, A is CH 2 (methylene). In some embodiments, A is CF 2(difluoromethylene). In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, when A is S or O, the sum of m+n is 6 or less, or 5 or less, or 4 or less, or 3 or less, or 2 or less, or 1 or less, or 0. In some embodiments, A is CH 2 or CF 2 In some embodiments, Q is -C≡CH. In some embodiments, Q is -C≡N. -A(CF 2 ) m (CH 2 ) n Representative examples of Q groups include -SC≡CH, -SCH 2 C≡CH, -SCF 2 C≡CH, -SCH 2 C≡N,-SCH 2 CH 2 C≡CH, -SCF 2 CH 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -OCH 2 C≡CH, -OC≡CH, -CH 2 C≡CH, -CF 2 C≡CH, -CH 2 CH 2 C≡CH, -CF 2 CH 2 C≡CH, -CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 C≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH and -CF 2 CH 2 CH 2 CH 2 Examples include, but are not limited to, C≡CH.

[0209] In some embodiments, R 4 -SMe, -SCD 3, -SCF 3, -SCF 2 H,-SCFH 2, SCH 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H, -SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -SEt, -Sn-Pr, -Me,-CD 3 ,-CF 3 ,-t-Bu,-C(CD 3 ) 3 , -Cyclopentyl, -OMe, -OCD 3 ,-OCF 3 ,-OCF 2 H,-OCFH 2 , -OCH 2 CH 2 CF 3 ,-OCH2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 In some embodiments, R 4 -SMe, -SCF 3 , -SCF 2 H, -Me, -OCD 3 , -CF 3 , -t-Bu, or -cyclopentyl. In some embodiments, R 4 -SCF 3 , -SCF 2 H, -SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H,-SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -OCF 3 ,-OCF 2 H,-OCFH2 , -OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 C≡CH, and -cyclopentyl. In some embodiments, R 4 -SCF 2 H, -SCFH 2 ,-SCH 2 CF 2 CF 2 H,-SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -OCF 3 ,-OCF 2 H,-OCFH 2 , -OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 C≡CH and -cyclopentyl (-C 5 H9 ).

[0210] Each R a can be the same or different. In some embodiments, each R a are the same. a are independently substituted or unsubstituted C 1 ~C 6 Alkyl, preferably substituted or unsubstituted C 1 ~C 3 Alkyl, preferably substituted or unsubstituted C 1 alkyl, examples of which include -CH 3 , -CDH 2 , -CD 2 H, -C.D. 3 , -CFH 2 , -CF 2 H, -CF 3 In some embodiments, each R a -CH 3 In some embodiments, each R a -CD 3 In some embodiments, each R a are different, for example, one R a Ha-CH 3 and the other is -CD 3 It is.

[0211] In some embodiments, Y 1 and Y 2 are each hydrogen or each deuterium, and each R a -CH 3 or -CD 3 and R 4 -SMe, -SCD 3 , -SCF 3 , -SCF 2 H, -SCFH 2 , -SCH 2 CH 2 CF 3 , -SCH 2 CH 2 CF 2 H, -SCH 2CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H、-SCH 2 C≡CH、-SC≡CH、-SCF 2 C≡CH、-SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH、-SEt、-Sn-Pr、-Me、-CD 3 ,-CF 3 ,-t-Bu,-C(CD 3 ) 3 、-cyclopentyl、-OMe、 -OCD 3 ,-OCF 3 ,-OCF 2 H、-OCFH 2 ,-AS WELL 2 CH 2 CF 3 ,-AS WELL 2 CH 2 CF 2 H、-OCH 2 CH 2 CFH 2 、 -AS WELL 2 CF 2 CF 2 H、-OCH 2 C≡CH、-OC≡CH、-CH 2 CH 2 CH 2 CH 2 C≡CH、-CF 2 CH 2 CH 2 CH 2 C≡CH, -Cl, -I, or -Br is, preferably, R 4 は、-SCF 3 ,-SCF 2 H、-SCFH 2 ,-SCH 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H、 -SCH 2 CH 2 CFH 2 , -SCH 2 CF 2 CF 2 H, -SCH 2 C≡CH, -SC≡CH, -OCF 3 , -OCF 2 H, -OCFH 2 , -OCH 2 CH 2 CF 3 , -OCH 2 CH 2 CF 2 H, -OCH 2 CH 2 CFH 2 , -OCH 2 CF 2 CF 2 H, -OCH 2 C≡CH, -OC≡CH, and -cyclopentyl.

[0212] Compounds of formula (IV) containing deuteration, e.g., α-carbon deuteration, in the ethylene fragment linked to the amino group with the benzene ring in the phenethylamine can advantageously retard enzymatic degradation compared to compounds that may otherwise be susceptible to MAO-mediated deamination / oxidation processes, thereby improving bioavailability and simultaneously enhancing brain levels of the active compound, effectively reducing therapeutic doses and preventing high drug concentrations ("spikes") observed acutely after administration. As a result, such compounds are able to reduce acute adverse effects including anxiety, fear, tachycardia, hypertension, elevated body temperature, nausea and vomiting, as well as 5-HT associated with valvular heart disease. 2B This may result in reduced side effects and toxicity, such as toxicity caused by receptor activation.

[0213] Formula (V) In some embodiments, the compound has the structure of formula (V): [ka] or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; During the ceremony, X 1 and X 2 are independently hydrogen or deuterium; Y 1 and Y 2 are independently hydrogen or deuterium; R 4 is halogen, substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 3 ~C 10 Cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR b , or -SR b 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; R 7 is a 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 substituted or unsubstituted C 1 ~C 6 is alkyl, R b is hydrogen, deuterium, substituted or unsubstituted C 1 ~C 6Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted C 3 ~C 10 It is cycloalkyl.

[0214] In some embodiments, 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 -SCF 3 , -SCF 2 H, -SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H,-OCF 3 ,-OCF 2 H, -OCFH 2 ,-OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H,-Cyclopentyl (-C 5 H 9 ), and -A(CF 2 ) m (CH 2 ) n Q, A is selected from the group consisting of S, O, CH 2 , or CF2 m is 0 to 3, n is 0 to 6, and Q is -C≡CH or -C≡N.

[0215] 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.

[0216] 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.

[0217] In some embodiments, R 4 is a halogen, for example, -Br, -F, -Cl, or -I.

[0218] In some embodiments, R 4 is a substituted or unsubstituted C 1 ~C 6 In some embodiments, R 4 is unsubstituted C 1 ~C 6 and 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. Preferred unsubstituted alkyl groups are methyl and t-butyl. In some embodiments, R 4 is a substitution C 1 ~C 6Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, hydroxyl, or polar substituents such as polyether substituents. 1 ~C 6 The alkyl group may include one or more substituents. In some embodiments, R 4 is a substitution C 1 Alkyl groups (i.e., substituted methyl groups), examples of which include -CDH 2 , -CD 2 H,-CD 3 ,-CFH 2 ,-CF 2 H,-CF 3 , and -CH 2 In some embodiments, R 4 is a substitution C 2 alkyl groups, examples of which include -CDHCDH 2 , -CDHCD 2 H,-CD 2 CD 3 ,-CH 2 CFH 2 ,-CH 2 CF 2 H,-CH 2 CF 3 , and -CH 2 CH 2 In some embodiments, R 4 is C 2 Substituted C such as fluoroalkyl group 2 For example, in some embodiments, R 4 -CH 2 CFH 2 , -CH 2 CF 2 H, or -CH 2 CF 3 In some embodiments, R 4 is a substitution C 3 is an alkyl group, examples of which include CH 2 CH 2 CF 3 ,-CH 2CH 2 CF 2 H,-CH 2 CH 2 CFH 2 ,-CH 2 CF 2 CF 2 H, and -CH 2 CH 2 CH 2 In some embodiments, R 4 -CH 2 CH 2 CFH 2 isn't it.

[0219] In some embodiments, R 4 is a substituted or unsubstituted C 3 ~C 10 In some embodiments, R 4 is unsubstituted C 3 ~C 10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R 4 is a substitution C 3 ~C 10 Cycloalkyl. Cycloalkyl groups can be substituted with any one or more of the 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 can include one or more substituents.

[0220] In some embodiments, R 4 is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, and the like.

[0221] In some embodiments, R 4 is substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, and the like. In some embodiments, R 4 is unsubstituted alkynyl. In some embodiments, R 4 is unsubstituted acetylenyl (-C≡CH). In some embodiments, R 4 is unsubstituted propargyl (-CH 2 In some embodiments, R 4 teeth, -CH 2 CH 2 C≡CH. In some embodiments, R 4 is -CH 2 CH 2 CH 2 C≡CH. In some embodiments, R 4 teeth, -CH 2 CH 2 CH 2 CH 2 C≡CH. In some embodiments, R 4 is substituted alkynyl. In some embodiments, R 4 is a substituted propargyl (e.g., -CF 2 In some embodiments, R 4 teeth, -CF 2 CH 2 C≡CH. In some embodiments, R 4 -CF 2 CH 2 CH 2 C≡CH. In some embodiments, R 4 teeth, -CF 2 CH 2 CH 2 CH 2 C≡CH.

[0222] In some embodiments, R 4 -OR b or -SR b and R bis 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 In some embodiments, R 4 -OR b In some embodiments, R 4 -SR b In some embodiments, R b is a substituted or unsubstituted C 1 ~C 6 Alkyl, or substituted or unsubstituted C 3 ~C 10 Cycloalkyl, for example, substituted C 1 ~C 6 Alkyl groups, unsubstituted C 1 ~C 6 Alkyl groups, substituted C 3 ~C 10 Cycloalkyl group or unsubstituted C 3 ~C 10 It is a cycloalkyl group.

[0223] In some embodiments, R b is a substituted or unsubstituted C 1 ~C 6 In some embodiments, R b is unsubstituted C 1 ~C 6 and 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 substitution C 1 ~C 6 Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, hydroxyl, or polar substituents such as polyether substituents. 1 ~C 6The alkyl group may include one or more substituents. In some embodiments, R b is a substitution C 1 is an alkyl group, examples of which include -CDH 2 , -CD 2 H, -C.D. 3 , -CFH 2 , -CF 2 H, -CF 3 , and -CH 2 In some embodiments, R b is a substitution C 2 alkyl groups, examples of which include -CDHCDH 2 , -CDHCD 2 H,-CD 2 CD 3 ,-CH 2 CFH 2 ,-CH 2 CF 2 H,-CH 2 CF 3 , and -CH 2 CH 2 In some embodiments, R b is C 2 Substituted C such as fluoroalkyl group 2 For example, in some embodiments, R 4 -OR b or -SR b If R b teeth, -CH 2 CFH 2 , -CH 2 CF 2 H or -CH 2 CF 3 In some embodiments, R b is a substitution C 3 is an alkyl group, examples of which include CH 2 CH 2 CF 3 ,-CH 2 CH 2 CF 2 H, -CH 2 CH 2CFH 2 ,-CH 2 CF 2 CF 2 H, and -CH 2 CH 2 CH 2 In some embodiments, R b teeth, -CH 2 CH 2 CFH 2 isn't it.

[0224] In some embodiments, R b is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, and the like.

[0225] In some embodiments, R b is substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, and the like. 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 (-CH 2 In some embodiments, R b teeth, -CH 2 CH 2 C≡CH. In some embodiments, R b is -CH 2 CH 2 CH 2 C≡CH. In some embodiments, R b teeth, -CH 2 CH 2 CH 2 CH 2 C≡CH. In some embodiments, R b is substituted alkynyl. In some embodiments, R b is a substituted propargyl (e.g., -CF 2 In some embodiments, Rb teeth, -CF 2 CH 2 C≡CH. In some embodiments, R b -CF 2 CH 2 CH 2 C≡CH. In some embodiments, R b teeth, -CF 2 CH 2 CH 2 CH 2 C≡CH.

[0226] In some embodiments, R b is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C 3 ~C 10 Cycloalkyl, or substituted or unsubstituted C 4 ~C 8 Cycloalkyl, or substituted or unsubstituted C 5 ~C 6 In some embodiments, R b is an unsubstituted cycloalkyl (e.g., an unsubstituted C 3 ~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 3 ~C 10 Cycloalkyl groups are substituted with any one or more of the 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.

[0227] In some embodiments, R 4 -A(CF 2 ) m (CH 2 ) n Q, where A is S, O, CH 2 , or CF 2 In some embodiments, A is S. In some embodiments, A is O. In some embodiments, A is CH 2 (methylene). In some embodiments, A is CF 2 (difluoromethylene). In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, when A is S or O, the sum of m+n is 6 or less, or 5 or less, or 4 or less, or 3 or less, or 2 or less, or 1 or less, or 0. In some embodiments, A is CH 2 or CF 2 In some embodiments, Q is -C≡CH. In some embodiments, Q is -C≡N. -A(CF 2 ) m (CH 2 ) n Representative examples of Q groups include -SC≡CH, -SCH 2 C≡CH, -SCF 2 C≡CH, -SCH 2 C≡N,-SCH 2 CH 2 C≡CH, -SCF 2 CH 2 C≡CH, -SCH2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -OCH 2 C≡CH, -OC≡CH, -CH 2 C≡CH, -CF 2 C≡CH, -CH 2 CH 2 C≡CH, -CF 2 CH 2 C≡CH, -CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 C≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH and -CF 2 CH 2 CH 2 CH 2 Examples include, but are not limited to, C≡CH.

[0228] In some embodiments, R 4 -SMe, -SCD 3, -SCF 3, -SCF 2 H,-SCFH 2, SCH 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H, -SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -SEt, -Sn-Pr, -Me,-CD 3 ,-CF 3 ,-t-Bu,-C(CD 3 ) 3 , -Cyclopentyl, -OMe, -OCD 3 ,-OCF 3 ,-OCF 2 H,-OCFH 2 , -OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 In some embodiments, R 4 -SMe, -SCF 3, -SCF 2 H,-Me,-OCD 3 ,-CF 3 ,-t-Bu, or -cyclopentyl. In some embodiments, R 4 -SCF 3 , -SCF 2 H, -SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H,-SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -OCF 3 ,-OCF 2 H,-OCFH 2 , -OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 R is selected from the group consisting of C≡CH and -cyclopentyl. 4 But -SCF 3 , -SCF 2 H,-SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H, -OCF 3 ,-OCF 2 H,-OCFH 2 ,-OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H, -Cyclopentyl (-C 5 H 9 ), or -A(CF 2 ) m (CH 2 ) n Q (wherein A is S, O, CH 2 , or CF 2 wherein m is 0 to 3, n is 0 to 6, and Q is -C≡CH or -C≡N), other substituents (i.e., X 1 , X 2 , Y 1 , Y 2 , R 6 , R 7 , and R a ) may or may not contain deuterium. In some embodiments, R 4 teeth, -SCF 2 H, -SCFH 2 ,-SCH 2 CF 2 CF 2 H,-SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -OCF 3 ,-OCF 2 H,-OCFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 C≡CH and -cyclopentyl (-C 5 H 9 ) is selected from the group consisting of R 4 But -SCF 2 H, -SCFH 2 ,-SCH 2 CF 2 CF 2 H,-SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -OCF 3 ,-OCF 2 H,-OCFH 2 ,-OCH 2 CF 2 CF 2 H, -OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH 2 C≡CH or -cyclopentyl (-C 5 H 9 In embodiments where X is an integer from 1 to 5, 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.

[0229] R 6 and R 7 can be the same or different. In some embodiments, R 6 and R 7 are the same. In some embodiments, R 6 and R 7 are different. In some embodiments, R 6 is hydrogen and R 7 is a substituted or unsubstituted C 1 ~C 6 It is 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.

[0230] In some embodiments, R 6 and / or R 7 is unsubstituted C 1 ~C 6 Alkyl, e.g., unsubstituted C 1 Alkyl, unsubstituted C 2 Alkyl, unsubstituted C 3 Alkyl, unsubstituted C 4 Alkyl, unsubstituted C 5 Alkyl or unsubstituted C 6 In some embodiments, R 6 and / or R 7 is an unsubstituted linear C 2 ~C 6 In some embodiments, R 6 and / or R 7 is a non-substituted branch C 3 ~C 10 Alkyl. Unsubstituted C 1 ~C 10 Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.

[0231] In some embodiments, R 6 and / or R 7 is a substitution C 1 ~C 6 Alkyl, e.g., substituted C 1 Alkyl, substituted C 2 Alkyl, substituted C 3 Alkyl, substituted C 4 Alkyl, substituted C 5 Alkyl or substituted C 6 is an 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 C substituted with one or more deuterium atoms. 1 ~C 6 alkyl, examples of which include -CDH 2 , -CD 2 H, -C.D. 3 , -CD 2 CD 3 , and -CD 2 CD 2 CD 3 In some embodiments, R 6 and / or R 7 is C substituted with one or more fluorine atoms 1 ~C 6 An example of a fluoroalkyl group is -CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 CH 2 F,-CH 2 CHF2 , -CH 2 CF 3 ,-CH 2 CH 2 CH 2 F,-CH 2 CH 2 CHF 2 ,-CH 2 CH 2 CF 3 ,-CH 2 CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 CHF 2 ,-CH 2 CH 2 CH 2 CF 3 ,-CH 2 CF 2 CHF 2 ,-CH 2 CF 2 CF 3 ,-CH(CF 3 ) 2 , and -CH(CH 3 )CF 3 These include, but are not limited to:

[0232] In some embodiments, R 6 and / or R 7 is a C substituted with one or more deuterium atoms and one or more fluorine atoms. 1 ~C 6 alkyl, examples of which include: -CD 2 CH 2 F, -CD 2 CHF 2 ,-CD 2 CF 3 ,-CD 2 CH 2 CH 2 F,-CD 2 CH 2 CHF 2 ,-CD 2 CH 2 CF3 , -CD 2 CD 2 CH 2 ,-CD 2 CD 2 CHF 2 ,-CD 2 CD 2 CF 3 ,-CD 2 CH 2 CH 2 CH 2 F,-CD 2 CH 2 CH 2 CHF 2 , -CD 2 CH 2 CH 2 CF 3 ,-CD 2 CD 2 CH 2 CH 2 F,-CD 2 CD 2 CH 2 CHF 2 ,-CD 2 CD 2 CH 2 CF 3 , -CD 2 CD 2 CD 2 CH 2 F,-CD 2 CD 2 CD 2 CHF 2 , and -CD 2 CD 2 CD 2 CF 3 These include, but are not limited to:

[0233] In some embodiments, R 6 and / or R 7 is a C substituted with a substituted or unsubstituted cycloalkyl 1 ~C 6 It is an alkyl group. 1 ~C 6 Alkyl can be, for example, substituted or unsubstituted C 3 ~C 10Cycloalkyl, or substituted or unsubstituted C 4 ~C 8 Cycloalkyl, or substituted or unsubstituted C 5 ~C 6 In some embodiments, C may be substituted with cycloalkyl. 1 ~C 6 Alkyl is an unsubstituted cycloalkyl (e.g., unsubstituted C 3 ~C 10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, C 1 ~C 6 Alkyl can be substituted cycloalkyl (e.g., substituted C 3 ~C 10 Cycloalkyl groups are substituted with any one or more of the 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 include one or more substituents. In some embodiments, R 6 and / or R 7 is a C substituted with a substituted or unsubstituted cycloalkyl 1 Alkyl, especially cyclopropylmethyl (-CH 2 C 3 H 5 ) is mentioned.

[0234] 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.

[0235] In some embodiments, R 6and / or R 7 is substituted or unsubstituted, for example, substituted or unsubstituted propargyl.

[0236] In some embodiments, R 6 and / or R 7 is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C 3 ~C 10 Cycloalkyl, or substituted or unsubstituted C 4 ~C 8 Cycloalkyl, or substituted or unsubstituted C 5 ~C 6 In some embodiments, R 6 and R 7 is an unsubstituted cycloalkyl (e.g., an unsubstituted C 3 ~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 3 ~C 10 Cycloalkyl groups are substituted with any one or more of the 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.

[0237] In some embodiments, R 6 and / or R 7is 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. 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 may contain one or more substituents.

[0238] 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 7is 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.

[0239] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted heteroaryl. In some embodiments, R 6 and / or R 7 is an 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 may be any of those enumerated 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. Heteroaryl groups may contain one or more substituents.

[0240] In some embodiments, R 6 is hydrogen and R 7 is unsubstituted or substituted C 1 ~C6 In some embodiments, R is an 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 is hydrogen and R 7 is a substituted or unsubstituted C 1 ~C 6 In some embodiments, R 6 is hydrogen, and R 7 is unsubstituted C 1 ~C 6 Alkyl, C substituted with one or more deuterium atoms 1 ~C 6 Alkyl, C substituted with one or more fluorine atoms 1 ~C 6 C substituted with alkyl, or substituted or unsubstituted cycloalkyl 1 ~C 6 For example, in some embodiments, R 6 is hydrogen, and R 7 is methyl, ethyl, propyl, -CD 3 , or cyclopropylmethyl (-CH 2 C 3 H 5 ).

[0241] 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 be optionally fused to other rings. An unsubstituted heterocycloalkyl group can have a minimum of one nitrogen ring atom (R 6 and R 7R includes a nitrogen atom between the ring atoms, 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 are examples of unsubstituted heterocycloalkyl groups: [ka] These include, but are not limited to:

[0242] 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 be optionally fused to other rings. A substituted heterocycloalkyl group can be a substituted heterocycloalkyl group with a minimum of one nitrogen ring atom (R 6 and R 7and optionally an additional heterocyclic atom (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 of which is substituted with at least one substituent. The substituents may be any of those enumerated 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 Substituted heterocycloalkyl formed from the bonding of a heterocycloalkyl group with the nitrogen atom to which it is attached includes heterocycloalkyl groups substituted with one, two, three, four or more substituents. The substituents may be located on carbon or hetero ring atoms.

[0243] R 6 and R 7 together with the nitrogen atom to which they are attached are examples of substituted heterocycloalkyl groups: [ka] These include, but are not limited to:

[0244] Each R a can be the same or different. In some embodiments, each Ra are the same. a are independently substituted or unsubstituted C 1 ~C 6 Alkyl, preferably substituted or unsubstituted C 1 ~C 3 Alkyl, preferably substituted or unsubstituted C 1 alkyl, examples of which include -CH 3 , -CDH 2 ,-CD 2 H,-CD 3 ,-CFH 2 ,-CF 2 H,-CF 3 In some embodiments, each R a is -CH 3 In some embodiments, each R a -CD 3 In some embodiments, each R a are different, for example, one R a Ha-CH 3 and the other is -CD 3 It is.

[0245] In some embodiments, Y 1 and Y 2 are each hydrogen or each deuterium, and X 1 and X 2 are each hydrogen or each deuterium, and each R a is -CH 3 or -CD 3 and R 4 -SMe, -SCD 3, -SCF 3, -SCF 2 H, -SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2CF 2 H,-SCH 2 C≡CH, -SC≡CH,-SCF 2 C≡CH,-SCH 2 CH 2 CH 2 C≡CH,-SCF 2 CH 2 CH 2 C≡CH,-SEt,-Sn-Pr,-Me,-CD 3 、 -CF 3 ,-t-Bu,-C(CD 3 ) 3 、-シロロペンチル、-OMe、-OCD 3 ,-OCF 3 ,-OCF 2 H,-OCFH 2 ,-AS WELL 2 CH 2 CF 3 , -AS WELL 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-AS WELL 2 CF 2 CF 2 H,-OCH 2 C≡CH,-OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH,-CF 2 CH 2 CH 2 CH 2 C≡CH, -Cl, -I, or -Br is, preferably, R 4 は、-SCF 3 ,-SCF 2 H,-SCFH 2 ,SCH 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH2 CF 2 CF 2 H,-SCH 2 C≡CH, -SC≡CH, -OCF 3 ,-OCF 2 H,-OCFH 2 ,-OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 , -OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, and -cyclopentyl; R 6 is hydrogen and R 7 is a substituted or unsubstituted C 1 ~C 6 It is an alkyl.

[0246] In some embodiments, the compound of formula (V) can be provided by: (i) adding X 1 , X 2 ,Y 1 ,Y 2 ,R 4 ,R 6 , R 7 , and R a at least one of R 4 -SCF 3 , -SCF 2 H,-SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H,-OCF 3 ,-OCF 2H,-OCFH 2 ,-OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H, -OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H, -Cyclopentyl (-C 5 H 9 ), and -A(CF 2 ) m (CH 2 ) n Q, where A is S, O, CH 2 , or CF 2 wherein m is 0 to 3, n is 0 to 6, and Q is -C≡CH or -C≡N. In some embodiments, in proviso (ii), R 4 -SCF 2 H, -SCFH 2 ,-SCH 2 CF 2 CF 2 H, -SCH 2 C≡CH, -SC≡CH, -SCF 2 C≡CH, -SCH 2 CH 2 CH 2 C≡CH, -SCF 2 CH 2 CH 2 C≡CH, -OCF 3 , -OCF 2 H,-OCFH 2 ,-OCH 2 CF 2 CF 2 H,-OCH 2 C≡CH, -OC≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 CH2 C≡CH and -cyclopentyl (-C 5 H 9 The above conditions stated with "and / or" mean that the compound falls within the scope when one of conditions (i) or (ii) is met, or when both conditions (i) and (ii) are met. For clarity, when condition (i) is met, i.e., X 1 , X 2 , Y 1 , Y 2 , R 3 , R 4 , R 6 , R 7 , and R a A compound in which at least one of R 4 teeth, -SCF 3 , -SCF 2 H,-SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 ,-SCH 2 CF 2 CF 2 H, -OCF 3 ,-OCF 2 H,-OCFH 2 ,-OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 ,-OCH 2 CF 2 CF 2 H, -Cyclopentyl (-C 5 H 9 ), and -A(CF 2 ) m (CH 2 )n Q, where A is S, O, CH 2 , or CF 2 where m is 0 to 3, n is 0 to 6, and Q is -C≡CH or -C≡N. Similarly, compounds satisfying condition (ii) include, for example, R 4 But -SCF 3 , -SCF 2 H, -SCFH 2 ,S.C.H. 2 CH 2 CF 3 ,-SCH 2 CH 2 CF 2 H,-SCH 2 CH 2 CFH 2 , -SCH 2 CF 2 CF 2 H,-OCF 3 ,-OCF 2 H,-OCFH 2 ,-OCH 2 CH 2 CF 3 ,-OCH 2 CH 2 CF 2 H,-OCH 2 CH 2 CFH 2 , -OCH 2 CF 2 CF 2 H, -Cyclopentyl (-C 5 H 9 ), or -A(CF 2 ) m (CH 2 ) n Q, where A is S, O, CH 2 , or CF 2 In the case where m is 0 to 3, n is 0 to 6, and Q is -C≡CH or -C≡N, condition (i) does not have to be satisfied, i.e., other substituents X 1 , X 2 , Y 1 , Y 2 , R 3 , R 6, R 7 , and R a may or may not contain deuterium. In some embodiments, compounds of formula (V) are provided without the above provisos.

[0247] In some embodiments, the compound, e.g., the compound of Formula (I)-(V), is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0248] A list of compound numbers, IUPAC names, and substituents for some of the compounds identified above is provided in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0249] In some embodiments, R 4 -OR b or -SR b and R b is a substitution C 2 Alkyl groups, e.g., C 2 In some embodiments, X is not a fluoroalkyl group. 1 , X 2 ,Y 1 ,Y 2 ,R 3 ,R 6 , and R 7 are each hydrogen, and each R a is methyl, R 4 -SCH 2 CH 2 CFH 2 , -SCH 2 C≡CH, -SCFH 2 , -SCF 2 H, or -SCF 3 In some embodiments, for example, X 1 ,X 2 ,Y 1 ,Y 2 ,R 3 , R6 , and R 7 are each hydrogen, and each R a is methyl (e.g., in some embodiments, the compound is not compound I-4), R 4 -SCH 2 CH 2 CFH 2 In some embodiments, for example, X 1 , X 2 ,Y 1 ,Y 2 ,R 3 ,R 6 , and R 7 are each hydrogen, and each R a is methyl (e.g., in some embodiments, the compound is not compound I-11), R 4 -SCH 2 C≡CH. In some embodiments, for example, X 1 , X 2 ,Y 1 ,Y 2 ,R 3 , R 6 , and R 7 are each hydrogen, and each R a is methyl (e.g., in some embodiments, the compound is not compound I-9), R 4 -SCFH 2 In some embodiments, for example, X 1 , X 2 ,Y 1 ,Y 2 ,R 3 ,R 6 , and R 7 are each hydrogen, and each R a is methyl (e.g., in some embodiments, the compound is not compound I-8), R 4 -SCF 2 is not H. In some embodiments, for example, X 1 ,X 2 ,Y 1 ,Y 2 ,R 3 , R 6 , and R 7 are each hydrogen, and each R ais methyl (e.g., in some embodiments, the compound is not compound I-1), R 4 -SCF 3 isn't it.

[0250] Formula (VI) A compound according to formula (VI), [ka] or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is disclosed herein, During the ceremony, X 1 and X 2 are independently hydrogen or deuterium; Y 1 and Y 2 are independently hydrogen or deuterium; R 3 is hydrogen or deuterium, R 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 substituted or unsubstituted C 1 ~C 6 is alkyl, Each R b are independently substituted or unsubstituted C 1 ~C 2 or alternatively, two R b together with the carbon atom to which they are attached are optionally joined to form a substituted or unsubstituted cycloalkyl.

[0251] 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.

[0252] 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.

[0253] In some embodiments, R 3 is deuterium. In some embodiments, R 3 is hydrogen.

[0254] 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 of R 6 and R 7 are different. In some embodiments, R 6 is hydrogen and R 7 is a substituted or unsubstituted C 1 ~C 6 It is 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.

[0255] In some embodiments, R 6 and / or R 7 is unsubstituted C 1 ~C 6 Alkyl, e.g., unsubstituted C 1 Alkyl, unsubstituted C 2 Alkyl, unsubstituted C 3 Alkyl, unsubstituted C 4 Alkyl, unsubstituted C 5 Alkyl or unsubstituted C 6 In some embodiments, R 6 and / or R 7 is an unsubstituted linear C 2 ~C 6 In some embodiments, R 6 and / or R 7 is a non-substituted branch C 3 ~C 10 Alkyl. Unsubstituted C 1 ~C 10 Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.

[0256] In some embodiments, R 6 and / or R 7 is a substitution C 1 ~C 6 Alkyl, e.g., substituted C 1 Alkyl, substituted C 2 Alkyl, substituted C 3 Alkyl, substituted C 4 Alkyl, substituted C 5 Alkyl or substituted C 6is an 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 C substituted with one or more deuterium atoms. 1 ~C 6 alkyl, examples of which include -CDH 2 , -CD 2 H, -C.D. 3 , -CD 2 CD 3 , and -CD 2 CD 2 CD 3 In some embodiments, R 6 and / or R 7 is C substituted with one or more fluorine atoms 1 ~C 6 An example of a fluoroalkyl group is -CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 CH 2 F,-CH 2 CHF 2 , -CH 2 CF 3 ,-CH 2 CH 2 CH 2 F,-CH 2 CH 2 CHF 2 ,-CH 2 CH 2 CF 3 ,-CH2 CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 CHF 2 ,-CH 2 CH 2 CH 2 CF 3 ,-CH 2 CF 2 CHF 2 ,-CH 2 CF 2 CF 3 ,-CH(CF 3 ) 2 , and -CH(CH 3 )CF 3 These include, but are not limited to:

[0257] In some embodiments, R 6 and / or R 7 is a C substituted with one or more deuterium atoms and one or more fluorine atoms. 1 ~C 6 alkyl, examples of which include: -CD 2 CH 2 F, -CD 2 CHF 2 ,-CD 2 CF 3 ,-CD 2 CH 2 CH 2 F,-CD 2 CH 2 CHF 2 ,-CD 2 CH 2 CF 3 , -CD 2 CD 2 CH 2 ,-CD 2 CD 2 CHF 2 ,-CD 2 CD 2 CF 3 ,-CD 2 CH 2 CH2 CH 2 F,-CD 2 CH 2 CH 2 CHF 2 , -CD 2 CH 2 CH 2 CF 3 ,-CD 2 CD 2 CH 2 CH 2 F,-CD 2 CD 2 CH 2 CHF 2 ,-CD 2 CD 2 CH 2 CF 3 , -CD 2 CD 2 CD 2 CH 2 F,-CD 2 CD 2 CD 2 CHF 2 , and -CD 2 CD 2 CD 2 CF 3 These include, but are not limited to:

[0258] In some embodiments, R 6 and / or R 7 is a C substituted with a substituted or unsubstituted cycloalkyl 1 ~C 6 It is an alkyl group. 1 ~C 6 Alkyl can be, for example, substituted or unsubstituted C 3 ~C 10 Cycloalkyl, or substituted or unsubstituted C 4 ~C 8 Cycloalkyl, or substituted or unsubstituted C 5 ~C 6 In some embodiments, C may be substituted with cycloalkyl. 1 ~C 6 Alkyl is an unsubstituted cycloalkyl (e.g., unsubstituted C 3 ~C 10cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, C 1 ~C 6 Alkyl can be substituted cycloalkyl (e.g., substituted C 3 ~C 10 Cycloalkyl groups are substituted with any one or more of the 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 include one or more substituents. In some embodiments, R 6 and / or R 7 is a C substituted with a substituted or unsubstituted cycloalkyl 1 Alkyl, especially cyclopropylmethyl (-CH 2 C 3 H 5 ) is mentioned.

[0259] 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.

[0260] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted, for example, substituted or unsubstituted propargyl.

[0261] In some embodiments, R 6 and / or R 7 is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C 3 ~C 10Cycloalkyl, or substituted or unsubstituted C 4 ~C 8 Cycloalkyl, or substituted or unsubstituted C 5 ~C 6 In some embodiments, R 6 and R 7 is an unsubstituted cycloalkyl (e.g., an unsubstituted C 3 ~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 3 ~C 10 Cycloalkyl groups are substituted with any one or more of the 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.

[0262] 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. 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 may contain one or more substituents.

[0263] 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.

[0264] In some embodiments, R 6 and / or R7 is substituted or unsubstituted heteroaryl. In some embodiments, R 6 and / or R 7 is an 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 may be any of those enumerated 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. Heteroaryl groups may contain one or more substituents.

[0265] In some embodiments, R 6 is hydrogen and R 7 is unsubstituted or substituted C 1 ~C 6 In some embodiments, R is an 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 is hydrogen and R 7 is a substituted or unsubstituted C 1 ~C 6 In some embodiments, R 6 is hydrogen, and R 7 is unsubstituted C 1 ~C 6 Alkyl, C substituted with one or more deuterium atoms1 ~C 6 Alkyl, C substituted with one or more fluorine atoms 1 ~C 6 C substituted with alkyl, or substituted or unsubstituted cycloalkyl 1 ~C 6 For example, in some embodiments, R 6 is hydrogen, and R 7 is methyl, ethyl, propyl, -CD 3 , or cyclopropylmethyl (-CH 2 C 3 H 5 ).

[0266] 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 be optionally fused to other rings. An unsubstituted heterocycloalkyl group can have a minimum of one nitrogen ring atom (R 6 and R 7 R includes a nitrogen atom between the ring atoms, 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 are examples of unsubstituted heterocycloalkyl groups: [ka] These include, but are not limited to:

[0267] In some embodiments, R 6 and R7 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 be optionally fused to other rings. A substituted heterocycloalkyl group can be a substituted heterocycloalkyl group with a minimum of one nitrogen ring atom (R 6 and R 7 and optionally an additional heterocyclic atom (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 of which is substituted with at least one substituent. The substituents may be any of those enumerated 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 Substituted heterocycloalkyl formed from the bonding of a heterocycloalkyl group with the nitrogen atom to which it is attached includes heterocycloalkyl groups substituted with one, two, three, four or more substituents. The substituents may be located on carbon or hetero ring atoms.

[0268] R 6 and R 7 together with the nitrogen atom to which they are attached are examples of substituted heterocycloalkyl groups: [ka] These include, but are not limited to:

[0269] Each R a can be the same or different. In some embodiments, each R a are the same. a are independently substituted or unsubstituted C 1 ~C 6 Alkyl, preferably substituted or unsubstituted C 1 ~C 3 Alkyl, preferably substituted or unsubstituted C 1 alkyl, examples of which include -CH 3 , -CDH 2 ,-CD 2 H,-CD 3 ,-CFH 2 ,-CF 2 H,-CF 3 In some embodiments, each R a -CH 3 In some embodiments, each R a -CD 3 In some embodiments, each R a are different, for example, one R a Ha-CH 3 and the other is -CD 3 It is.

[0270] Each R b can be the same or different. In some embodiments, each R b are the same. b are independently substituted or unsubstituted C 1 ~C 2 Alkyl, preferably substituted or unsubstituted C 1 and alkyl, examples of which include -CH 3 , -CDH 2 ,-CD 2 H,-CD 3 ,-CFH 2 ,-CF2 H,-CF 3 In some embodiments, each R b -CDH 2 , -CD 2 H, -C.D. 3 , and -CH 3 In some embodiments, each R b is -CH 3 In some embodiments, each R b -CD 3 In some embodiments, at least one R b Unlike the others, for example, one R b is -CH 2 CH 3 and the other two are -CH 3 In some embodiments, one R b -CF 3 and the other two are -CH 3 In some embodiments, one R b is -CH 3 and the other two are -CF 3 It is.

[0271] In some embodiments, two R b are joined together with the nitrogen atom to which they are attached to form a substituted or unsubstituted cycloalkyl group. b The substituted or unsubstituted cycloalkyl groups formed from, together with the carbon atom attached thereto, can be, for example, a substituted or unsubstituted C 3 ~C 10 Cycloalkyl, or substituted or unsubstituted C 4 ~C 8 Cycloalkyl, or substituted or unsubstituted C 5 ~C 6 In some embodiments, two R b are joined together with the carbon atom to which they are attached to form an unsubstituted cycloalkyl (e.g., an unsubstituted C 3 ~C 10cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, two R b may be joined together with the carbon atom to which it is attached to form a substituted cycloalkyl (e.g., a substituted C 3 ~C 10 Cycloalkyl groups form cycloalkyl groups. The cycloalkyl groups can be substituted with any one or more of the 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 groups can contain one or more substituents. Two R b When, together with the carbon atom to which it is attached, forms a substituted or unsubstituted cycloalkyl group, the remaining R b As described above, for example, -CH 3 , -CDH 2 ,-CD 2 H,-CD 3 ,-CFH 2 ,-CF 2 H, -CF 3 is selected from.

[0272] In some embodiments, Y 1 and Y 2 are each hydrogen or each deuterium, R 3 is hydrogen, and X 1 and X 2 are each hydrogen or each deuterium, and each R a is -CH 3 or -CD 3 And each R b -CD 3 , or -CH 3 It is.

[0273] In some embodiments, a compound, e.g., a compound of formula (VI), [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0274] Compounds of formula (VI) which contain a quaternary carbon atom attached to the 4-position of the phenyl ring, in particular a lipophilic tertiary alkyl group (e.g., a t-butyl group) in the 4-position of the phenyl ring, tend to exhibit a greater inhibition of 5-HT, especially when compared with compounds lacking a quaternary carbon in the same position, such as in the case of a cyclopentyl group. 2 5-HT such as A 2 It has been found that the compounds of formula (VI) have surprisingly strong binding affinity to the receptor. In addition to their excellent pharmacodynamic properties, the compounds of formula (VI) having a quaternary carbon atom attached to the 4-position of the phenyl ring can also provide advantageous pharmacokinetics by slowing or avoiding metabolism at this position, leading to improved bioavailability, exposure, and brain penetration.

[0275] Formula (VII) A compound according to formula (VII), [ka] or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is disclosed herein, During the ceremony, X 1 and X 2 are independently hydrogen or deuterium; Y 1 and Y 2 are independently hydrogen or deuterium; R 6 is hydrogen, substituted or unsubstituted C 1 ~C 6alkyl, 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; R 7 is a 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 substituted or unsubstituted C 1 ~C 6 is alkyl, 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 It is cycloalkyl.

[0276] 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.

[0277] Y 1 and Y 2 can be the same or different. In some embodiments, Y 1 and Y 2are the same. In some embodiments, Y 1 and Y 2 is hydrogen. In some embodiments, Y 1 and Y 2 is deuterium.

[0278] In some embodiments, R b is a substituted or unsubstituted C 1 ~C 6 In some embodiments, R b is unsubstituted C 1 ~C 6 and 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 substitution C 1 ~C 6 Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, hydroxyl, or polar substituents such as polyether substituents. 1 ~C 6 The alkyl group may include one or more substituents. In some embodiments, R b is a substitution C 1 is an alkyl group, examples of which include -CDH 2 , -CD 2 H, -C.D. 3 , -CFH 2 , -CF 2 H, -CF 3 , and -CH 2 In some embodiments, R b is a substitution C 2 alkyl groups, examples of which include -CDHCDH 2 , -CDHCD 2 H,-CD 2 CD 3 ,-CH 2 CFH 2 ,-CH 2 CF 2 H,-CH2 CF 3 , and -CH 2 CH 2 In some embodiments, R b is C 2 Substituted C such as fluoroalkyl group 2 For example, in some embodiments, R 4 -OR b or -SR b If R b teeth, -CH 2 CFH 2 , -CH 2 CF 2 H or -CH 2 CF 3 In some embodiments, R b is a substitution C 3 is an alkyl group, examples of which include -CH 2 CH 2 CF 3 , -CH 2 CH 2 CF 2 H, -CH 2 CH 2 CFH 2 , -CH 2 CF 2 CF 2 H, and -CH 2 CH 2 CH 2 In some embodiments, R b teeth, -CH 2 CH 2 CFH 2 isn't it.

[0279] In some embodiments, R b is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted allyl, butenyl, crotyl, and the like.

[0280] In some embodiments, R bis substituted or unsubstituted alkynyl, such as substituted or unsubstituted acetylenyl, propargyl, homopropargyl, and the like. 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 (-CH 2 In some embodiments, R b teeth, -CH 2 CH 2 C≡CH. In some embodiments, R b -CH 2 CH 2 CH 2 C≡CH. In some embodiments, R b teeth, -CH 2 CH 2 CH 2 CH 2 C≡CH. In some embodiments, R b is substituted alkynyl. In some embodiments, R b is a substituted propargyl (e.g., -CF 2 In some embodiments, R b teeth, -CF 2 CH 2 C≡CH. In some embodiments, R b -CF 2 CH 2 CH 2 C≡CH. In some embodiments, R b teeth, -CF 2 CH 2 CH 2 CH 2 C≡CH.

[0281] In some embodiments, R b is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C 3 ~C 10Cycloalkyl, or substituted or unsubstituted C 4 ~C 8 Cycloalkyl, or substituted or unsubstituted C 5 ~C 6 In some embodiments, R b is an unsubstituted cycloalkyl (e.g., an unsubstituted C 3 ~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 3 ~C 10 Cycloalkyl groups are substituted with any one or more of the 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.

[0282] In some embodiments, R b -C≡CH, -CH 2 C≡N, -CH 2 C≡CH, -CF 2 C≡CH, -CH 2 CH 2 C≡CH, -CF 2 CH 2 C≡CH, -CH 2 CH 2 CH 2 C≡CH, -CF 2 CH 2 CH 2 C≡CH, -CH 2 CH 2 CH 2 CH 2 C≡CH, and -CF2 CH 2 CH 2 CH 2 C≡CH.

[0283] R 6 and R 7 can be the same or different. In some embodiments, R 6 and R 7 are the same. In some embodiments, R 6 and R 7 are different. In some embodiments, R 6 is hydrogen and R 7 is a substituted or unsubstituted C 1 ~C 6 It is 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.

[0284] In some embodiments, R 6 and / or R 7 is unsubstituted C 1 ~C 6 Alkyl, e.g., unsubstituted C 1 Alkyl, unsubstituted C 2 Alkyl, unsubstituted C 3 Alkyl, unsubstituted C 4 Alkyl, unsubstituted C 5 Alkyl or unsubstituted C 6 In some embodiments, R 6 and / or R 7 is an unsubstituted linear C 2 ~C 6 In some embodiments, R 6 and / or R 7 is a non-substituted branch C 3 ~C 10 Alkyl. Unsubstituted C 1 ~C 10Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.

[0285] In some embodiments, R 6 and / or R 7 is a substitution C 1 ~C 6 Alkyl, e.g., substituted C 1 Alkyl, substituted C 2 Alkyl, substituted C 3 Alkyl, substituted C 4 Alkyl, substituted C 5 Alkyl or substituted C 6 is an 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 C substituted with one or more deuterium atoms. 1 ~C 6 alkyl, examples of which include -CDH 2 , -CD 2 H, -C.D. 3 , -CD 2 CD 3 , and -CD 2 CD 2 CD 3 In some embodiments, R 6 and / or R 7 is C substituted with one or more fluorine atoms 1 ~C 6An example of a fluoroalkyl group is -CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 CH 2 F,-CH 2 CHF 2 , -CH 2 CF 3 ,-CH 2 CH 2 CH 2 F,-CH 2 CH 2 CHF 2 ,-CH 2 CH 2 CF 3 ,-CH 2 CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 CHF 2 ,-CH 2 CH 2 CH 2 CF 3 ,-CH 2 CF 2 CHF 2 ,-CH 2 CF 2 CF 3 ,-CH(CF 3 ) 2 , and -CH(CH 3 )CF 3 These include, but are not limited to:

[0286] In some embodiments, R 6 and / or R 7 is a C substituted with one or more deuterium atoms and one or more fluorine atoms. 1 ~C 6 alkyl, examples of which include: -CD 2 CH 2 F, -CD 2 CHF 2 ,-CD 2CF 3 ,-CD 2 CH 2 CH 2 F,-CD 2 CH 2 CHF 2 ,-CD 2 CH 2 CF 3 , -CD 2 CD 2 CH 2 ,-CD 2 CD 2 CHF 2 ,-CD 2 CD 2 CF 3 ,-CD 2 CH 2 CH 2 CH 2 F,-CD 2 CH 2 CH 2 CHF 2 , -CD 2 CH 2 CH 2 CF 3 ,-CD 2 CD 2 CH 2 CH 2 F,-CD 2 CD 2 CH 2 CHF 2 ,-CD 2 CD 2 CH 2 CF 3 , -CD 2 CD 2 CD 2 CH 2 F, -CD 2 CD 2 CD 2 CHF 2 , and -CD 2 CD 2 CD 2 CF 3 These include, but are not limited to:

[0287] In some embodiments, R 6 and / or R7 is a C substituted with a substituted or unsubstituted cycloalkyl 1 ~C 6 It is an alkyl group. 1 ~C 6 Alkyl can be, for example, substituted or unsubstituted C 3 ~C 10 Cycloalkyl, or substituted or unsubstituted C 4 ~C 8 Cycloalkyl, or substituted or unsubstituted C 5 ~C 6 In some embodiments, C may be substituted with cycloalkyl. 1 ~C 6 Alkyl is an unsubstituted cycloalkyl (e.g., unsubstituted C 3 ~C 10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, C 1 ~C 6 Alkyl can be substituted cycloalkyl (e.g., substituted C 3 ~C 10 Cycloalkyl groups are substituted with any one or more of the 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 include one or more substituents. In some embodiments, R 6 and / or R 7 is a C substituted with a substituted or unsubstituted cycloalkyl 1 Alkyl, especially cyclopropylmethyl (-CH 2 C 3 H 5 ) is mentioned.

[0288] 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.

[0289] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted, for example, substituted or unsubstituted propargyl.

[0290] In some embodiments, R 6 and / or R 7 is a substituted or unsubstituted cycloalkyl, for example, a substituted or unsubstituted C 3 ~C 10 Cycloalkyl, or substituted or unsubstituted C 4 ~C 8 Cycloalkyl, or substituted or unsubstituted C 5 ~C 6 In some embodiments, R 6 and R 7 is an unsubstituted cycloalkyl (e.g., an unsubstituted C 3 ~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 3 ~C 10 Cycloalkyl groups are substituted with any one or more of the 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.

[0291] 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. 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 may contain one or more substituents.

[0292] 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 7is 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.

[0293] In some embodiments, R 6 and / or R 7 is substituted or unsubstituted heteroaryl. In some embodiments, R 6 and / or R 7 is an 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 may be any of those enumerated 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. Heteroaryl groups may contain one or more substituents.

[0294] In some embodiments, R 6 is hydrogen and R 7 is unsubstituted or substituted C 1 ~C6 In some embodiments, R is an 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 is hydrogen and R 7 is a substituted or unsubstituted C 1 ~C 6 In some embodiments, R 6 is hydrogen, and R 7 is unsubstituted C 1 ~C 6 Alkyl, C substituted with one or more deuterium atoms 1 ~C 6 Alkyl, C substituted with one or more fluorine atoms 1 ~C 6 C substituted with alkyl, or substituted or unsubstituted cycloalkyl 1 ~C 6 For example, in some embodiments, R 6 is hydrogen, and R 7 is methyl, ethyl, propyl, -CD 3 , or cyclopropylmethyl (-CH 2 C 3 H 5 ).

[0295] 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 be optionally fused to other rings. An unsubstituted heterocycloalkyl group can have a minimum of one nitrogen ring atom (R 6 and R 7R includes a nitrogen atom between the ring atoms, 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 are examples of unsubstituted heterocycloalkyl groups: [ka] These include, but are not limited to:

[0296] 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 be optionally fused to other rings. A substituted heterocycloalkyl group can be a substituted heterocycloalkyl group with a minimum of one nitrogen ring atom (R 6 and R 7and optionally an additional heterocyclic atom (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 of which is substituted with at least one substituent. The substituents may be any of those enumerated 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 Substituted heterocycloalkyl formed from the bonding of a heterocycloalkyl group with the nitrogen atom to which it is attached includes heterocycloalkyl groups substituted with one, two, three, four or more substituents. The substituents may be located on carbon or hetero ring atoms.

[0297] R 6 and R 7 together with the nitrogen atom to which they are attached are examples of substituted heterocycloalkyl groups: [ka] These include, but are not limited to:

[0298] Each R a can be the same or different. In some embodiments, each Ra are the same. a are independently substituted or unsubstituted C 1 ~C 6 Alkyl, preferably substituted or unsubstituted C 1 ~C 3 Alkyl, preferably substituted or unsubstituted C 1 alkyl, examples of which include -CH 3 , -CDH 2 , -CD 2 H, -C.D. 3 , -CFH 2 , -CF 2 H, -CF 3 In some embodiments, each R a is -CH 3 In some embodiments, each R a -CD 3 In some embodiments, each R a are different, for example, one R a Ha-CH 3 and the other is -CD 3 It is.

[0299] In some embodiments, a compound, e.g., a compound of formula (VII), [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0300] The compounds of formulae (I)-(VII) may contain asymmetric centers. In such cases, although formulae (I)-(VII) are drawn without regard to stereochemistry, the compounds may exist as different stereoisomers. Thus, the present disclosure includes 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, as known in the art. Resolution of the final product, intermediate, or starting material may be carried out by any suitable method in the art.

[0301] In some embodiments, the compounds described herein, e.g., compounds of Formulas (I)-(VII), are racemic. In some embodiments, the compounds described herein, e.g., compounds of Formulas (I)-(VII), are enantiomerically pure.

[0302] In some embodiments, the compound is serotonin 5-HT 2In some embodiments, the compound is an agonist of the serotonin 5-HT 2A In some embodiments, the compound is an agonist of the serotonin 5-HT 1A In some embodiments, the compound is an agonist of the serotonin 5-HT 2C The compound is an agonist of the receptor. 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 a dose that would classically produce a hallucinogenic effect).

[0303] Also disclosed herein are pharma- ceutically acceptable salts of the compounds of the present disclosure, for example, the compounds of formula (I)-(VII). The acid used to form the pharma- ceutically acceptable salts of the compounds of formula (I)-(VII) may be a monoacid, diacid, triacid, tetraacid, or may contain more acid groups. The acid group may be, for example, a carboxylic acid, sulfonic acid, phosphonic acid, or other acidic moiety that contains at least one replaceable hydrogen atom.Examples of acids that may be used to prepare the pharma- ceutically 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, naphthylsulfonic acid, phenylsulfonic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthylsulfonic acid, phenyl ... 1,5-toluenesulfonic 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, glucuronic acid, glyceric ... 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, such as 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.).

[0304] In some embodiments, the pharma- ceutically acceptable salt of a compound of Formulae (I)-(VII) is a benzenesulfonate, tartrate, hemifumarate, acetate, citrate, malonate, fumarate, succinate, oxalate, benzoate, salicylate, ascorbate, hydrochloride, maleate, malate, methanesulfonate, toluenesulfonate, glucuronate, or glutarate salt of a compound of Formulae (I)-(VII). In some embodiments, the pharma- ceutically acceptable salt of the compound of Formula (I)-(VII) is a salt formed from a sulfonic acid (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, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.). In some embodiments, the pharma- ceutically acceptable salt of the compound of Formula (I)-(VII) is a salt formed from a benzoic acid (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-aminosalicylic acid, etc.).

[0305] In some embodiments, the pharma- ceutically acceptable salt of the compound of Formula (I)-(VII) is a fatty acid salt. The fatty acid used to prepare the fatty acid salt of the compound of Formula (I)-(VII) may be a fatty mono- or di-acid, may contain a fatty hydrocarbon moiety consisting of hydrogen and 4, 6, 8, 10, 12, 14, 16, and up to 26, up to 24, up to 22, up to 20, up to 18 carbon atoms, and may be fully saturated or partially unsaturated. In some embodiments, the pharma- ceutically acceptable salt of the compound of Formula (I)-(VII) is an adipate, laurate, linoleate, myristate, caprate, stearate, oleate, caprylate, palmitate, sebacate, undecylenate, or caproate salt of the compound of Formula (I)-(VII).

[0306] Methods for preparing pharma- ceutically acceptable salt forms of pharmaceutical compounds are known to those of skill in the art. In some embodiments, the methods include: (a) suspending a compound of formula (I)-(VII) in a solvent or mixture of solvents; (b) contacting an acid with a compound of Formulae (I)-(VII) to provide a mixture; (c) optionally heating the mixture; (d) optionally cooling the mixture; (e) isolating the salt.

[0307] 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), ether solvents (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.

[0308] Suitable acids for use in preparing pharma-ceutically acceptable acid addition salts may include those previously described. The acid may be an inorganic acid, such as hydrochloric acid, or an organic acid, with organic acids being preferred. 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 (hexane di) 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, and the like, with particular mention being made of adipic (hexane di) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, and caprylic (octanoic) acid.

[0309] In some embodiments, a stoichiometric (or superstoichiometric) amount of acid is contacted with a compound of Formulae (I)-(VII). In some embodiments, a substoichiometric (e.g., 0.5 molar equivalent) amount of acid is contacted with a compound of Formulae (I)-(VII). 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, it may be desirable to use a substoichiometric amount of acid.

[0310] In some embodiments, the mixture is heated, for example to reflux, before cooling.

[0311] In some embodiments, the mixture is cooled and the salt is allowed 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.

[0312] 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.

[0313] After isolation, additional crystallization and / or recrystallization steps may also be optionally performed, as desired, to, for example, increase purity, crystallinity, and the like.

[0314] In some embodiments, the compounds of the present disclosure, such as compounds of formula (I)-(VII), or pharma- ceutically acceptable salts, stereoisomers, or prodrugs thereof, are in the form of a solvate. Examples of solvate forms include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, and the like, with hydrates and ethanolates being preferred. Solvates may be formed from stoichiometric or non-stoichiometric amounts of solvent molecules. The solvates of the compounds of the present disclosure may be in the form of an isolable solvate. In one non-limiting example, as a hydrate, the compounds may be monohydrates, dihydrates, and the like. The solvates of the compounds of the present disclosure also include solution-phase forms. Thus, in some embodiments, the present disclosure provides a solution-phase composition of the compounds of the present disclosure, or any pharma- ceutically acceptable salt thereof, in a solvated form, preferably a fully solvated form.

[0315] In some embodiments, the compounds of the present disclosure, e.g., compounds of Formula (I)-(VII), or pharma- ceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, are provided in crystalline form, e.g., as determined by XRPD. Thus, pharmaceutical compositions may be prepared from compounds of Formula (I)-(VII) 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.

[0316] In some embodiments, the compounds of the present disclosure, e.g., compounds of formula (I)-(VII), or pharma- ceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, are provided in amorphous form, e.g., as determined by XRPD. Thus, pharmaceutical compositions may be prepared from compounds of formula (I)-(VII), or pharma- ceutically 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 may therefore 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.

[0317] Compounds of the present disclosure, such as compounds of formulae (I)-(VII), or pharma-ceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, may generally be prepared according to or similar to the synthetic routes exemplified herein. Other synthetic routes may also be used in accordance with techniques and procedures known to those skilled in the art.

[0318] 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)-(VII), or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof). In some embodiments, the disease or disorder is a serotonin 5-HT2 Receptor related.

[0319] 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 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.

[0320] Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans may be formulated to achieve a concentration found to be effective in animals. A dose in humans may be adjusted by monitoring the response to treatment and adjusting the dose upward (titrating) or downward (tapering).

[0321] Dosages may vary depending on the requirements of the subject and the active ingredient being used (e.g., a compound of Formula (I)-(VII), or a pharma-ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof). In the context of the pharmaceutical compositions presented herein, the dosage administered to a subject should be sufficient to effect a beneficial therapeutic response in the subject over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the active ingredient. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.

[0322] Dosage amount and interval can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated, which will provide a treatment regime commensurate with the severity of the individual's disease state.

[0323] Routes of administration may 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.

[0324] 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)-(VII), or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, may be performed once a day (QD), or in divided doses throughout the day, such as twice a day (BID), three times a day (TID), four times a day (QID), or more. In some embodiments, administration may be performed nightly (QHS). In some embodiments, administration is performed as needed (PRN). Administration may also be performed on a weekly basis, such as once a week, twice a week, three times a week, four times a week, every other week, every two weeks, or less. The dosing schedule may specify a set number of treatments per course of treatment, for example, a compound of Formulae (I)-(VII), or a pharma-ceutically 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 reasonable medical judgment.

[0325] Administration can be continuous (7 days administration 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 administration and 3 days off (rest days) per week, or other intermittent administration schedules deemed appropriate based on sound medical judgment. For example, intermittent administration can involve 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 (one month), which can be repeated with or without a rest period. Longer or shorter courses can also be used, such as 14 days, 18 days, 21 days, 24 days, 35 days, 42 days, 48 ​​days, or more, or any range therebetween. 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.

[0326] Utilizing the teachings provided herein, one can design an effective prophylactic or therapeutic treatment regimen that does not cause substantial toxic or adverse side effects (e.g., caused by sedative or psychotomimetic toxic spikes in the plasma concentration of any of the compounds of formula (I)-(VII)) and is fully effective in treating the clinical symptoms exhibited by a particular patient. This plan should include careful selection of the active ingredient by considering factors such as the potency of the compound, the 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.

[0327] A therapeutically effective amount of a compound of the present disclosure can vary depending on the various factors discussed above, but typically, a compound of Formulas (I)-(VII) is administered in an amount of about 0.00001 mg to about 10 mg per kilogram of the subject's 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, The compound of formula (I) to (VII) 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 (based on active form).

[0328] The compounds of the present disclosure (e.g., a compound of Formula (I)-(VII), or a pharma- ceutically acceptable salt, solvate, stereoisomer, or prodrug thereof) may be administered at a hallucinogenic dose. Hallucinogenic doses, by oral or other means, may, 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 about 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 Formula (I)-(VII) (on an active basis). As mentioned above, higher doses may be used in some embodiments. Some hallucinogenic doses may be administered orally or by other means once and may be repeated at intervals of at least one week. In some cases, five or fewer doses are administered in any one treatment course. The course may be repeated as needed, with or without a rest period. Such acute treatment regimes may involve psychotherapy before, during, and / or after administration of the hallucinogenic dose. These treatments are appropriate for a variety of mental health disorders disclosed herein, examples of which include, but are 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).

[0329] Compounds of the present disclosure (e.g., compounds of Formulae (I)-(VII), or pharma- ceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof) may be administered at non-hallucinogenic (yet potentially serotonergic) concentrations, with low toxicity, and long-term therapeutic benefits, and thus may be suitable for microdosing. Non-hallucinogenic doses, by oral or other means, may, in some embodiments, be 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 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, about 0.02 mg / kg of a compound of formula (I)-(VII) (on an active basis). 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 at a non-hallucinogenic dose, and administration may be less frequent or more frequent if deemed appropriate. The course may be repeated as necessary, with or without a rest period.

[0330] Non-hallucinogenic doses may also be achieved by transdermal delivery, subcutaneous administration, etc., via modified, controlled, sustained, or extended release dosage forms, including, but not limited to, depot dosage forms, implants, patches, and pumps, which may optionally be remotely controlled, where the dose will achieve similar blood levels as a low oral dose, but will nevertheless not produce hallucinations.

[0331] 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.

[0332] The compounds of the present disclosure (e.g., compounds of Formulae (I)-(VII), or pharma- ceutically acceptable salts, solvates, stereoisomers, or prodrugs 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., compounds of Formulae (I)-(VII), or pharma- ceutically acceptable salts, solvates, stereoisomers, or prodrugs 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 drug 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, where the first and second drugs are different. For example, a patient is administered a treatment regimen with a first drug that is not a compound of the present disclosure (the first drug is, 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, a 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 treatment 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 a maintenance regimen can also be performed continuously, e.g., over a period of days, weeks, months, or years. Additionally, a maintenance dose can be administered to a patient on a chronic or long-term basis.

[0333] The subjects treated herein are those who have serotonin 5-HT 2 The person may have a disease or disorder associated with the receptor.

[0334] 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.

[0335] 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), and other conditions. and DHD), pain and neuropathic pain, aphantasia, childhood-onset fluency disorder, severe neurocognitive impairment, mild neurocognitive impairment, 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, paraphilia 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, and obesity.

[0336] In some embodiments, the methods provided herein are used to treat subjects with depressive disorders. As used herein, the term "depressive disorder" or "depression" refers to a group of disorders characterized by a low mood that lasts for a period of time and can affect a person's thoughts, behaviors, emotions, and well-being. In some embodiments, depressive disorders disrupt a person's physical and mental functioning. In some embodiments, depressive disorders cause physical symptoms, such as weight loss, aches or pains, headaches, cramps, or indigestion. In some embodiments, depressive disorders cause mental symptoms, such as persistent sadness, hopelessness and irritability, feelings of guilt, lethargy or helplessness, loss of interest or pleasure in hobbies and activities, difficulty concentrating, memory difficulties, 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).

[0337] 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 normally enjoyable activities, low energy, and pain without clear cause. In some instances, the definition of major depression is characterized by symptoms of depression lasting at least two weeks. In some instances, an individual experiences periods of depression several years apart. In some instances, an individual experiences symptoms of depression almost 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 the symptoms are less severe but last longer. Examples of symptoms of major depressive disorder include, but are not limited to, feelings of sadness, fear, emptiness or hopelessness, angry outbursts, irritability or frustration over small things, loss of interest or pleasure in most or all usual activities, sleep disorders including insomnia or excessive sleepiness, fatigue and lack of energy, loss of appetite, weight loss or gain, anxiety, agitation or restlessness, diminished ability to think, speak or move around, 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.

[0338] As used herein, the term "atypical depression" refers to a condition in which an individual shows a long-term pattern of signs of mood reactivity (i.e., mood brightens in response to actual or potential positive events), significant weight gain, increased appetite, hypersomnia, heavy and sluggish feeling 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 sadness or depression, loss of pleasure in things that were once enjoyable, significant changes (increase or decrease) in weight or appetite, nearly daily insomnia or hypersomnia, physical restlessness or exhaustion that is noticeable to others, daily fatigue or low energy, nearly daily feelings of hopelessness, helplessness or excessive guilt, nearly daily concentration or decision-making problems, recurrent thoughts of death or suicide, suicide attempts, or suicide attempts.

[0339] 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 abnormal 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 typical mood and behavior for that person. Examples of symptoms of mania and excessive behavior include, but are not limited to, abnormally cheerful, erratic, or irritable behavior; increased activity, energy, or irritability, feelings of exaggerated happiness and confidence, decreased need for sleep, abnormal 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 lack of enjoyment of all or nearly all activities, a marked weight loss or weight gain, or a 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, decreased ability to think or concentrate, or indecisiveness, and thoughts of suicide attempts or attempts. 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 that require hospitalization. Subjects with bipolar I disorder may also experience depressive episodes, which typically last at least 2 weeks. Depressive episodes of mixed characteristics are also possible, i.e., depressive and manic symptoms are present at the same time. 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 (elevated and euphoric mood) and depressive symptoms lasting for at least two years.The mood changes are not sufficient in number, severity, or duration to meet the full criteria for a hypomanic or depressive episode.

[0340] As used herein, the term "catatonic depression" refers to a state in which an individual is silent and immobile for long periods of time.Examples of symptoms of catatonic depression include, but are not limited to, a feeling of sadness that may occur every day, loss of interest in most activities, sudden weight gain or loss, appetite changes, difficulty falling asleep, difficulty getting up, a feeling of restlessness, irritability, helplessness, guilt, fatigue, difficulty concentrating, difficulty thinking, difficulty making decisions, thoughts of suicide or death, and / or suicide attempts.

[0341] As used herein, the term "depressive disorder caused by physical illness" refers to a condition in which an individual experiences depressive symptoms due to another illness. Examples of physical illnesses that are known to cause depressive disorders include, but are not limited to, HIV / AIDS, diabetes, arthritis, stroke, brain disorders such as Parkinson's disease, Huntington's disease, multiple sclerosis and Alzheimer's disease, metabolic diseases (e.g., vitamin B12 deficiency), autoimmune diseases (e.g., lupus erythematosus and rheumatoid arthritis), viral or other infectious diseases (hepatitis, mononucleosis, herpes), back pain, and cancer (e.g., pancreatic cancer).

[0342] As used herein, the term "postpartum depression" refers to a condition resulting from childbirth and hormonal changes, psychological adjustment to parenthood, and / or fatigue. Although postpartum depression is often associated with women, men can suffer from postpartum depression as well. Examples of symptoms of postpartum depression include, but are not limited to, feelings of sadness, hopelessness, emptiness, or heaviness; crying more often than usual or for no apparent reason; worrying or feeling excessive anxiety; feeling cranky, irritable, or restless; excessive sleepiness or being unable to sleep even when the baby is sleeping; difficulty concentrating, remembering details, or making decisions; experiencing anger or frustration; losing interest in usually enjoyable activities; suffering from physical aches and pains, including frequent headaches, stomach problems, and muscle aches; overeating or eating too little; withdrawing from or avoiding friends and family; difficulty bonding or forming an emotional attachment with the baby; intermittent doubts about one's ability to care for the baby; and thoughts of harming oneself or the baby.

[0343] As used herein, the term "premenstrual dysphoric disorder" refers to a condition in which an individual experiences symptoms of mood instability, irritability, depression and anxiety that occur recurrently during the premenstrual phase of the menstrual cycle, and that remit around the time of the onset of menstruation or shortly thereafter. Examples of symptoms of premenstrual dysphoric disorder include, but are not limited to, instability (e.g., mood swings), irritability or anger, depression, anxiety and tension, decreased interest in normal activities, difficulty concentrating, moodiness and low energy, changes in appetite (e.g., overeating or craving certain foods), excessive or insomnia, feeling of being overwhelmed or out of control, physical symptoms (e.g., breast tenderness or swelling, joint or muscle pain, abdominal bloating and weight gain), self-deprecating thoughts, tension or tingling sensations, decreased interest in normal activities (e.g., work, school, friends, hobbies, etc.), subjective difficulty concentrating, and easy fatigue.

[0344] As used herein, the term "seasonal affective disorder" refers to a condition in which an individual experiences mood changes based on the time of year. In some instances, an individual experiences low mood, low energy, or other depressive symptoms during the fall and / or winter seasons. In some instances, an individual experiences low mood, low energy, or other depressive symptoms during the spring and / or summer seasons. Examples of seasonal affective disorder symptoms include, but are not limited to, feeling depressed most of the day or almost every day, losing interest in activities that were once enjoyable, low energy, difficulty sleeping, changes in appetite or weight, feelings of lethargy or irritability, difficulty concentrating, feelings of hopelessness, helplessness, or guilt, and frequent thoughts of death or suicide.

[0345] In some embodiments, a depressive disorder comprises a medical diagnosis based on the criteria and classification of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. In some embodiments, a depressive disorder comprises a medical diagnosis based on an independent medical evaluation.

[0346] In some embodiments, the methods described herein are provided to a subject with treatment-resistant depression. In some embodiments, the subject is diagnosed with treatment-resistant depression (TRD). The term "treatment-resistant depression" refers to a type of depression that is unresponsive or resistant to at least one or more treatment attempts of appropriate dose and duration. In some embodiments, a subject with treatment-resistant depression has not responded to one treatment attempt, two treatment attempts, three treatment attempts, four treatment attempts, five treatment attempts, or more. In some embodiments, a subject with treatment-resistant depression has been diagnosed with major depressive disorder and has not responded to three or more treatment attempts. In some embodiments, a subject with treatment-resistant depression has been diagnosed with bipolar disorder and has not responded to one treatment attempt.

[0347] In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder by about 5% to about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% or more, compared to before treatment.

[0348] In some embodiments, the disease or disorder is an anxiety disorder. As used herein, the term "anxiety disorder" refers to a state of worry, uncertainty, and / or fear resulting from the anticipation of an event and / or situation. Anxiety disorders cause physiological and mental signs or symptoms. Non-limiting examples of physiological symptoms include muscle tension, palpitations, sweating, dizziness, shortness of breath, tachycardia, tremors, fatigue, anxiety, irritability, and sleep disorders. Non-limiting examples of mental symptoms include fear of dying, fear of embarrassment or humiliation, fear of an event occurring, and the like. Anxiety disorders also impair a subject's cognition, information processing, stress levels, and immune response. In some embodiments, the methods disclosed herein treat chronic anxiety disorders. As used herein, "chronic" anxiety disorders are recurrent. Examples of anxiety disorders include, but are not limited to, generalized anxiety disorder (GAD), social anxiety disorder, panic disorder, panic attacks, phobia-related disorders (e.g., phobias related to flying, heights, certain animals such as spiders / dogs / snakes, receiving injections, blood, etc., agoraphobia), separation anxiety disorder, selective mutism, anxiety due to physical illness, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), substance-induced anxiety disorder, etc.

[0349] In some embodiments, the subject in need thereof develops an anxiety disorder after experiencing the effects of a disease, including the individual's diagnosis of having the disease, the individual's loved ones' diagnosis of the disease, social isolation due to the disease, isolation from the disease, or social distancing as a result of the disease. In some embodiments, the individual is quarantined to prevent the spread of the disease. In some embodiments, the disease is COVID-19, SARS, or MERS. In some embodiments, the subject develops an anxiety disorder after losing a job, losing a home, or fear of not being able to find work.

[0350] In some embodiments, the disease or disorder is generalized anxiety disorder (GAD). Generalized anxiety disorder is characterized by excessive anxiety and worry, fatigue, restlessness, increased muscle pain or pain, poor concentration, irritability, and / or difficulty sleeping. In some embodiments, the subject with generalized anxiety disorder does not have associated panic attacks. In some embodiments, the subject has generalized anxiety disorder with depression. In some embodiments, the methods herein are provided to a subject with generalized anxiety disorder who also has symptoms of depression. In some embodiments, after treatment, symptoms are reduced by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to before treatment.

[0351] In some embodiments, the disease or disorder is social anxiety disorder. As used herein, "social anxiety disorder" is a significant fear or anxiety of one or more social situations in which an individual is exposed to potential staring by others. Non-limiting examples of situations that induce social anxiety include social interactions (e.g., conversations, meeting unfamiliar people, etc.), being observed (e.g., eating and drinking), and performing in front of others (e.g., giving a speech). In some embodiments, the social anxiety disorder is limited to speaking or acting in public. In some embodiments, treatment according to the methods of the present disclosure reduces or improves the symptoms of social anxiety disorder. In some embodiments, after treatment, symptoms are reduced by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to before treatment.

[0352] In some embodiments, the disease or disorder is an obsessive-compulsive disorder, such as obsessive-compulsive disorder (OCD), body-focused repetitive behavior disorder, hoarding disorder, gambling disorder, compulsive shopping, compulsive internet use, compulsive video gaming, compulsive sexual behavior, binge eating, exercise addiction, body dysmorphic disorder, hoarding disorder, self-injurious dermatopathy, trichotillomania, excoriation, substance-induced obsessive-compulsive disorder and related disorders, or obsessive-compulsive disorder due to another physical illness, or a combination thereof. In some embodiments, the disease or disorder is obsessive-compulsive disorder (OCD).

[0353] In some embodiments, at least one sign or symptom of an anxiety disorder is improved following administration of a compound disclosed herein, in some embodiments, the sign or symptom of an anxiety disorder is measured according to a diary assessment, a physician or caregiver assessment, or a clinical scale. In some embodiments, treatment results in a measurable improvement in one or more of the following: State-Trait Anxiety Inventory (STAI), Beck Anxiety Inventory (BAI), Hospital Anxiety and Depression Scale (HADS), Generalized Anxiety Disorder questionnaire-IV (GADQ- IV), Hamilton Anxiety Rating Scale (HARS), Leibowitz Social Anxiety Scale (LSAS), Overall Anxiety Severity and Impairment Scale (OASIS), Hospital Anxiety and Depression Scale (HADS), Patient Heal...

Claims

1. A compound having the structure of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, During the ceremony, X １ and X ２ are independently hydrogen or deuterium; Y １ and Y ２ are independently hydrogen or deuterium; R ３ is hydrogen or deuterium, R ４ is selected from the group consisting of -SCF2H, -SCFH2, -SCH2CF2CF2H, -OCF3, -OCF2H, -OCFH2, -OCH2CF2CF2H, -cyclopentyl (-C5H9), or -A(CF2)m(CH2)nQ, where A is S, O, CH2, or CF2, m is 0-3, n is 0-6, and Q is -C≡CH or -C≡N; 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, and Each R ａ are independently substituted or unsubstituted C １ ~C ６ is alkyl, A compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

2. R ４ But, -SCH ２ CF ２ CF ２ 2. The compound of claim 1, wherein R is H. 【Request Item 3】 【Chemistry 2】 2. The compound of claim 1, wherein:

4. The compound of claim 1, wherein R 4 is —SCF 2 H. 【Request Item 5】 【Chemistry 3】 2. The compound of claim 1, wherein:

6. having the structure of formula (II): 【Chemistry 4】 During the ceremony, X １ and X ２ are independently hydrogen or deuterium; Y １ and Y ２ are independently hydrogen or deuterium, and R ４ is selected from the group consisting of -SCF2H, -SCFH2, -SCH2CF2CF2H, -OCF3, -OCF2H, -OCFH2, -OCH2CF2CF2H, -cyclopentyl (-C5H9), or -A(CF2)m(CH2)nQ, where A is S, O, CH2, or CF2, m is 0-3, n is 0-6, and Q is -C≡CH or -C≡N 2. The compound of claim 1, wherein:

7. R ４ But, -SCH ２ CF ２ CF ２ 7. The compound of claim 6, wherein:

8. R ４ But, -SCF ２ 7. The compound of claim 6, wherein:

9. having the structure of formula (IV): 【Transformation 5】 During the ceremony, Y １ and Y ２ are independently hydrogen or deuterium; R ４ is selected from the group consisting of -SCF2H, -SCFH2, -SCH2CF2CF2H, -OCF3, -OCF2H, -OCFH2, -OCH2CF2CF2H, -cyclopentyl (-C5H9), or -A(CF2)m(CH2)nQ, where A is S, O, CH2, or CF2, m is 0-3, n is 0-6, and Q is -C≡CH or -C≡N and Each R ａ are independently substituted or unsubstituted C １ ~C ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein R is alkyl.

10. having the structure of formula (V): 【Transformation 6】 During the ceremony, X １ and X ２ are independently hydrogen or deuterium; Y １ and Y ２ are independently hydrogen or deuterium; R ４ is halogen, substituted or unsubstituted C １ ~C ６ Alkyl, substituted or unsubstituted C ３ ~C １０ cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR ｂ , or -SR ｂ 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; R ７ is a 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 substituted or unsubstituted C １ ~C ６ is alkyl, 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 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 R ４ But, -SCF ３ , -SCF ２ H. -SCFH ２ ,SCH ２ CH ２ CF ３ ,-SCH ２ CH ２ CF ２ H,-SCH ２ CH ２ CFH ２ ,-SCH ２ CF ２ CF ２ H,-OCF ３ ,-OCF ２ H, -OCFH ２ ,-OCH ２ CH ２ CF ３ ,-OCH ２ CH ２ CF ２ H, - OCH ２ CH ２ CFH ２ ,-OCH ２ CF ２ CF ２ H、 -Cyclopentyl (-C ５ H ９ ), and -A(CF ２ ) ｍ (CH ２ ) ｎ Q; A is selected from the group consisting of S, O, CH ２ , or CF ２ and m is 0-3, n is 0-6, and Q is —C≡CH or —C≡N, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

11. R ６ is hydrogen, and R ７ is unsubstituted C １ ~C ６ Alkyl, C substituted with one or more deuterium atoms １ ~C ６ alkyl, C substituted with one or more fluorine atoms １ ~C ６ C substituted with alkyl or substituted or unsubstituted cycloalkyl １ ~C ６ The compound of claim 10, wherein the compound is alkyl.

12. The compound of claim 10, wherein R 6 is hydrogen and R 7 is C 1 -C 6 alkyl substituted with a substituted or unsubstituted cycloalkyl. 【Request Item 13】 【Chemistry 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 11. The compound of claim 10, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

14. A compound having the structure of formula (VI): 【Chemistry 25】 During the ceremony, X 1 and X 2 are independently hydrogen or deuterium; Y 1 and Y 2 are independently hydrogen or deuterium; R 3 is hydrogen or deuterium; R 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; A compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein each R b is independently a substituted or unsubstituted C 1 -C 2 alkyl, or alternatively, two R b s, together with the carbon atom to which they are attached, are optionally joined to form a substituted or unsubstituted cycloalkyl. 【Request Item 15】 【Chemistry 26】 15. The compound of claim 14, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

16. A compound having the structure of formula (VII): 【Chemistry 27】 During the ceremony, X 1 and X 2 are independently hydrogen or deuterium; Y 1 and Y 2 are independently hydrogen or deuterium; 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; R 7 is 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; and A compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein 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 17】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 17. The compound of claim 16, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 and a pharmaceutically acceptable excipient.

19. 20. The pharmaceutical composition of claim 18, formulated for oral administration.

20. 20. The pharmaceutical composition of claim 18, formulated for administration via inhalation.

21. Serotonin 5-HT ２ A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 for use in the treatment of a receptor-related disease or disorder.

22. Serotonin 5-HT ２ The disease or disorder associated with the receptor is (i) a neuropsychiatric disease or disorder or an 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, 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) autonomic nervous system (ANS) disorders, or (vii) a pulmonary disorder or a cardiovascular disorder.

23. A monolayer orally administered tablet composition comprising a compound according to any one of claims 1 to 17 and a polymer.

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

25. 1) the pharmaceutical composition of claim 18, and 2) serotonin 5-HT ２ A kit for treating a subject, comprising instructions for use in treating a receptor-associated disease or disorder.

26. A transdermal patch comprising a compound according to any one of claims 1 to 17.

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