Phenethylamine compounds, compositions, and methods of use

Abstract

This disclosure relates to phenethylamine compounds, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs and pharmaceutical compositions thereof, and in some embodiments, to serotonin 5-HT2 receptor agonists and their use in the treatment of diseases related to the 5-HT2 receptor.

Description

[Technical Field]

[0001] cross reference This application claims priority to U.S. Provisional Patent Application No. 63 / 420,265, filed on 28 October 2022, which is incorporated herein by reference in its entirety. This disclosure generally relates to phenethylamine compounds, compositions, and in some embodiments, serotonin 5-HT2 receptor agonists, and their use in the treatment of diseases such as diseases related to the 5-HT2 receptor. [Background technology]

[0002] The “Background Art” descriptions provided herein are for the purpose of generally presenting the contents of this disclosure. To the extent described in this Background Art section, the work of the currently designated inventors, as well as any descriptions that may not be recognized as prior art at the time of filing, are not expressly or implicitly recognized as prior art to the present invention.

[0003] Classic serotonergic hallucinogens such as lysergic acid diethylamide (LSD), psilocybin, and 3,4-methylenedioxymethamphetamine (MDMA) cause many 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), for example, (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 (ii) Psychotherapy for the treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials, Psychopharmacology (Berl) 237, 2485-2497), (ii) Major depressive disorder (MDD), (iii) Treatment-resistant depression (TRD) (Goldberg, SB, Pace, BT, Nicholas, CR, Raison, CL, and Hutson, PR, 2020, The experimental effects of psilocybin on symptoms of anxiety and depression: A meta-analysis, Psychiatry Res 284, 112749), (iv) Obsessive-compulsive disorder (OCD) (Moreno, FA, Wiegand, CB, Taitano, EK, and Delgado, PL)(v) Social anxiety disorder (ClinicalTrials.gov number NCT02008396), (vi) Substance use disorders, e.g., alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder, (vii) Anorexia nervosa, (viii) Bulimia nervosa (ClinicalTrials.gov numbers NCT04454684 and NCT04052568), (ix) Alzheimer's disease (ClinicalTrials.gov number NCT04123314), and (x) Cluster headache and migraine (Nichols, DE, 2016, Psychedelics, Pharmacol Rev) It is being actively investigated by researchers and the medical community to alleviate cluster headaches (68,264-355, Johnson, MW, Hendricks, PS, Barrett, FS, and Griffiths, RR, 2019, Classic psychedelics: An integrative review of epidemiology, therapists, 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).

[0004] These drugs are also being investigated to alleviate autonomic nervous system (ANS) conditions, including, in particular, lung disorders (e.g., asthma and chronic obstructive pulmonary disease (COPD)) and cardiovascular disorders (e.g., atherosclerosis) (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).

[0005] Mechanistically, the therapeutic effect of classic serotonergic hallucinogens is primarily due to the serotonin (5-HT) receptor, particularly 5-HT receptors. 2A It is thought to be mediated by interaction with receptors, but 5-HT 1A Other targets, including receptors, may also be involved (Nichols, DE, 2016, Psychedelics, Pharmacol Rev 68, 264-355; Canal, CE, 2018, Serotonal Psychedelics: Experimental Approaches for Assessing Mechanisms of Action, Handb Exp Pharmacol 252, 227-260). For example, 5-HT 2A Activation of R primarily mediates hallucinogenic effects and induces anti-inflammatory effects, while 5-HT 2C Activation of R reduces feeding behavior and may be involved in the reported anti-addictive properties of classic hallucinogens. (Canal, CE, and Murnane, KS, 2017, The serotonin 5-HT2C receptor and the non-addictive nature of classic hallucinogens, J Psychopharmacol 31, 127-143). However, 5-HT 2B Chronic activation of R is associated with valvular heart disease (VHD), a life-threatening adverse event (AE). Furthermore, the effects of phenethylamines such as MDMA are influenced by their interactions with monoamine transporters, particularly 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).

[0006] One class of serotonergic hallucinogens is the 2C-X family of phenethylamines (phenethylamines that include 2,5-methoxy substitutions of the phenyl group, and most also have substitutions at the 4-position). Members of this class, such as 2,5-dimethoxy-4-bromophenethylamine (2C-B), may be used to treat sexual dysfunction (Shulgin, A., and Shulgin, Ann., 1991, Pihkal: a chemical love story, Transform Press, Berkeley, CA) and neuropsychiatric states, and to induce perceptual, cognitive, affective, and mood changes that may underlie their reported neuropsychotherapeutic benefits (Johnson, MW, Hendricks, PS, Barrett, FS, and Griffiths, RR, 2019, Classic psychedelics: An integrative review of epidemiology, therapists, mystical experience, and brain network function, Pharmacol Ther 197, 83-102).

[0007] However, the development of more extensive clinical trials and practical treatment protocols for 2C-X compounds is hampered by the following factors: 1) poor oral bioavailability, 2) low cerebral permeability, 3) delayed effects from oral administration, 4) significant pharmacokinetic variability among patients, 5) therapeutic effects requiring high doses, and 6) acute psychiatric adverse events (AEs) such as phobias, anxiety, and paranoia, cardiovascular events including tachycardia and hypertension, and gastrointestinal effects including nausea.These properties are thought to be due to 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, as well as their relatively hydrophilic nature (which limits 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, AT, 1978, Psychotomimetic Drugs: Structure-activity relationships. Chapter 6, Handbook of psychopharmacology, V.11-Stimulants, pp 243-333, Plenum Press, New York). [Overview of the Initiative]

[0008] Considering the foregoing, there is a need for novel 2C-X phenethylamine compounds that are orally bioavailable, rapidly express, minimize metabolism-induced changes, and have short-acting, improved pharmacokinetic properties. There is a further need for efficient, more convenient, and controllable 2C-X phenethylamine formulations that provide controlled drug exposure without causing neurological toxicity (e.g., psychotropic toxicity) in plasma concentrations, and maintain drug concentrations within a safe and effective range.

[0009] One object of this disclosure is to provide novel 2C-X phenethylamine compounds and compositions thereof that meet these criteria, as well as methods for using them to treat diseases such as serotonin 5-HT2 receptor-related disorders. More specifically, this disclosure provides novel 2C-X phenethylamine compounds and compositions thereof that can be used to treat other disorders such as neuropsychiatric disorders, central nervous system (CNS) disorders, autonomic nervous system (ANS) disorders, neurodegenerative diseases, and inflammation-related disorders, including neuroinflammation.

[0010] Therefore, this disclosure provides the following: (1) A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, [ka] During the ceremony, X 1 and X <9999999>are each independently hydrogen or deuterium, Y 1 and Y 2 are each independently hydrogen or deuterium, R 3 is hydrogen or deuterium, each R a is independently substituted or unsubstituted C1-C6 alkyl, R 4 is R 7 -S(O)-, R 8 -S(O)2-, R 9 -S-S-, R 10 -C(Z)-, R 11 R 12 -P(O)-, R 13 R 14 -N-, or R 15 -Se-, R 7 、R 8 、R 9 、R 10 、R 11 and R 12 are each independently unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, R 13 and R 14 are each independently unsubstituted C2-C 10 alkyl, substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, or alternatively, R 13 and R 14 optionally combine together with the nitrogen atom to which they are attached to form an unsubstituted or substituted heterocycloalkyl having at least two heteroatoms, R 15 is unsubstituted C2-C 10Alkyl, substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, Z is either S or O, However, R 4 R 7 -S(O)- and X 1 , X 2 , Y 1 , Y 2 , and R 3 Each of them is hydrogen, and each R a If R is methyl, 7 A compound, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, polymorph, or prodrug, provided that is not methyl, n-propyl, 2-hydroxypropyl, or 3-hydroxypropyl. (2)X 1 and X 2 However, the compound described in (1) is hydrogen. (3)Y 1 and Y 2 The compound described in (1) or (2), wherein the compound is hydrogen. (4)R 3 However, the compound is hydrogen, as described in any one of (1) to (3). (5) Each R a The compound is methyl, as described in any one of (1) to (4). (6) Having the structure of formula (II), [ka] During the ceremony, X 1 and X 2 These are independently hydrogen or deuterium, Y 1 and Y 2 These are independently hydrogen or deuterium, R 3 However, it is hydrogen or deuterium, Each R aThese are independently substituted or unsubstituted C1-C6 alkyl groups. R 7 However, it is an unsubstituted or substituted alkyl, an unsubstituted or substituted alkenyl, an unsubstituted or substituted alkynyl, an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocycloalkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl, However, X 1 , X 2 , Y 1 , Y 2 , and R 3 Each of them is hydrogen, and each R a If R is methyl, 7 The compounds described in (1), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs thereof, provided that is not methyl, n-propyl, 2-hydroxypropyl, or 3-hydroxypropyl. (7) [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound described in (6), selected from the group consisting of the above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. (8) Having the structure of formula (III), [ka] During the ceremony, X 1 and X 2 These are independently hydrogen or deuterium, Y 1 and Y 2 These are independently hydrogen or deuterium, R 3 However, it is hydrogen or deuterium, Each R a These are independently substituted or unsubstituted C1-C6 alkyl groups. R 8 The compounds described in (1), which are unsubstituted or substituted alkyls, unsubstituted or substituted alkenyls, unsubstituted or substituted alkynyls, unsubstituted or substituted cycloalkyls, unsubstituted or substituted heterocycloalkyls, unsubstituted or substituted aryls, or unsubstituted or substituted heteroaryls, or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs thereof. (9) [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound described in (8), selected from the group consisting of the above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. (10) Having the structure of formula (IV), [ka] During the ceremony, X 1 and X2 These are independently hydrogen or deuterium, Y 1 and Y 2 These are independently hydrogen or deuterium, R 3 However, it is hydrogen or deuterium, Each R a These are independently substituted or unsubstituted C1-C6 alkyl groups. R 9 The compounds described in (1), which are unsubstituted or substituted alkyls, unsubstituted or substituted alkenyls, unsubstituted or substituted alkynyls, unsubstituted or substituted cycloalkyls, unsubstituted or substituted heterocycloalkyls, unsubstituted or substituted aryls, or unsubstituted or substituted heteroaryls, or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs thereof. (11) [ka] [ka] [ka] [ka] [ka] [ka] A compound described in (10) selected from the group consisting of, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. (12) Having the structure of formula (V), [ka] During the ceremony, X 1 and X 2 These are independently hydrogen or deuterium, Y 1 and Y 2 These are independently hydrogen or deuterium, R 3 However, it is hydrogen or deuterium, Each R a These are independently substituted or unsubstituted C1-C6 alkyl groups. R 10 However, it is an unsubstituted or substituted alkyl, an unsubstituted or substituted alkenyl, an unsubstituted or substituted alkynyl, an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocycloalkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. The compound described in (1), wherein Z is S or O, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. (13) [ka] [ka] [ka] [ka] [ka] A compound described in (12), selected from the group consisting of the above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. (14) Having the structure of formula (VI), [ka] wherein 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, each R a is independently substituted or unsubstituted C1-C6 alkyl, R 11 and R 12 are independently unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, the compound according to (13), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. (15)

Chemical formula

Chemical formula

Chemical formula

[0011] The preceding paragraphs are provided as a general introduction and are not intended to limit the scope of the following claims. The embodiments described, along with their further advantages, will be best understood by referring to the following detailed description, when considered in conjunction with the accompanying drawings. [Brief explanation of the drawing]

[0012] [Figure 1] The 2C-X compound of formula (I) of this disclosure is shown. [Figure 2] The synthesis route to compound II-4 is shown. [Figure 3] The synthesis route to compound II-10 is shown. [Figure 4] The synthesis route to compound II-13 is shown. [Figure 5] The synthesis route to compound III-6 is shown. [Figure 6] The synthesis route to compound III-11 is shown. [Figure 7] The synthesis route to compound III-14 is shown. [Figure 8] The synthesis route to compound III-17 is shown. [Figure 9] The synthesis route to compound IV-6 is shown. [Figure 10] The synthesis route to compound IV-13 is shown. [Figure 11] The synthesis route to compound V-1 is shown. [Figure 12] The synthesis route to compound V-6 is shown. [Figure 13] The synthesis route to compound V-16 is shown. [Figure 14] The synthesis route to compound VI-1 is shown. [Figure 15] The synthesis route to compound VII-3 is shown. [Figure 16] The synthesis route to compound VIII-9 is shown. [Figure 17] This graph shows the competitive binding of agonist-labeled 5-HT2A radioligand ([125I](±)-DOI) using compounds II-10, II-13, III-11, III-14, and III-17. The compounds were tested in pairs at 100 nM or 1 μM, and the results are shown as average values. [Figure 18] This graph shows the competitive binding of agonist-labeled 5-HT2B radioligand ([125I](±)-DOI) using compounds II-10, II-13, III-11, III-14, and III-17. The compounds were tested in pairs at 100 nM or 1 μM, and the results are shown as average values. [Figure 19] This graph shows the competitive binding of agonist-labeled 5-HT1A radioligand ([3H]8-OH-DPAT) using compounds II-10, II-13, III-11, III-14, and III-17. The compounds were tested in pairs at 100 nM or 1 μM, and the results are shown as average values. [Figure 20] This graph shows the dose-response of the 5-HT2A functional assay as a percentage of the control agonist response (5-HT). Compounds III-6, III-14, and III-17 were tested in double series at the indicated concentrations, and EC50 and EMAX values ​​were determined by nonlinear regression analysis of concentration-response curves generated from mean repeat values, either by limiting the highest level to 100% (compound III-6) or by reporting the best-fit values ​​for all parameters (compounds III-14 and III-17). [Figure 21]This graph shows the dose-response of the 5-HT2B functional assay as a percentage of the control agonist response (5-HT). Compounds III-6, III-14, and III-17 were tested in double series at the indicated concentrations, and EC50 and EMAX values ​​were determined by nonlinear regression analysis of concentration-response curves generated from mean repeated values, either by limiting the highest level to 100% (compounds III-6 and III-14) or by reporting the best-fit value for all parameters (compound III-17). [Figure 22] This graph shows the dose-response of the 5-HT2A functional assay as a percentage of the control agonist response (5-HT). Compounds II-4 and II-13 were tested in double series at the indicated concentrations, and EC50 and EMAX values ​​were determined by nonlinear regression analysis of concentration-response curves generated from mean repeated values, either by limiting the highest level to 100% (compound II-4) or by reporting the best-fit value (compound II-13). [Figure 23] This graph shows the dose-response of the 5-HT2B functional assay as a percentage of the control agonist response (5-HT). Compounds II-4 and II-13 were tested in double series at the indicated concentrations, and the EC50 and EMAX values ​​were determined by nonlinear regression analysis of the concentration-response curves generated from mean repeated values, with the best-fit value reported (compound II-13). The curve for compound II-4 did not fit. [Figure 24] This graph shows the dose-response of the 5-HT2A functional assay as a percentage of the control agonist response (5-HT). Compound VI-1 was tested in two consecutive tests at the indicated concentrations, but the concentration-response curve showed an effect of less than 25% at the highest test concentration, so EC50 and EMAX values ​​were not calculated. [Figure 25] This graph shows the dose-response of the 5-HT2B functional assay as a percentage of the control agonist response (5-HT). Compound VI-1 was tested in two consecutive tests at the indicated concentrations, but the concentration-response curve showed an effect of less than 25% at the highest test concentration, so EC50 and EMAX values ​​were not calculated. [Figure 26]This graph shows the dose-response of the 5-HT2A functional assay as a percentage of the control agonist response (5-HT). Compounds V-1 and VIII-9 were tested in double series at the indicated concentrations, and EC50 and EMAX values ​​were determined by nonlinear regression analysis of concentration-response curves generated from mean repeated values, either by limiting the highest level to 100% (compound V-1) or by reporting the best-fit value (compound VIII-9). [Figure 27] This graph shows the dose response of the 5-HT2B functional assay as a percentage of the control agonist response (5-HT). Compounds V-1 and VIII-9 were tested in double series at the indicated concentrations, and EC50 and EMAX values ​​were determined by nonlinear regression analysis of concentration response curves generated from mean repeated values, either by limiting the highest level to 100% (compound V-1) or by reporting the best-fit value (compound VIII-9). [Figure 28] This graph shows the dose-response of the 5-HT2A functional assay as a percentage of the control agonist response (5-HT). Compounds V-6 and VII-3 were tested in double series at the indicated concentrations, and the concentration-response curves were determined by nonlinear regression analysis of the mean repeated values, with EC50 and EMAX values ​​limited to 100% at the highest level (compound V-6). The curve did not fit for compound VII-3. [Figure 29] This graph shows the dose-response of the 5-HT2B functional assay as a percentage of the control agonist response (5-HT). Compounds V-6 and VII-3 were tested in double series at the indicated concentrations, and the concentration-response curves were determined by nonlinear regression analysis of the mean repeated values, with EC50 and EMAX values ​​limited to 100% at the highest level (compound V-6). The curve did not fit for compound VII-3. [Figure 30]This graph shows the competitive binding of agonist-labeled 5-HT2A radioligand ([3H]LSD) to compounds IV-6, IV-13, and serotonin (5-HT). The results are from three independent experiments: 5-HT tested in a double-chain configuration (6 replicates per data point), and compounds IV-6 and IV-13 tested in a triple-chain configuration (9 replicates per data point). The data were analyzed using a two-site fit Ki model. [Figure 31A] The plasma concentration-time curves after intravenous (IV) and oral (PO) administration of compound II-13 at 0.5 mg / kg and 3 mg / kg in mice are shown on a linear scale (Figure 31A) and a logarithmic scale (Figure 31B). [Figure 31B] The plasma concentration-time curves after intravenous (IV) and oral (PO) administration of compound II-13 at 0.5 mg / kg and 3 mg / kg in mice are shown on a linear scale (Figure 31A) and a logarithmic scale (Figure 31B). [Modes for carrying out the invention]

[0013] The following detailed description of embodiments of the Disclosure includes numerous specific details to provide a complete understanding of the embodiments of the Disclosure. However, it will be apparent to those skilled in the art that embodiments of the Disclosure can be carried out without these specific details. In other examples, well-known methods, procedures, components, and circuits are not described in detail so as not to unnecessarily obscure aspects of the embodiments of the Disclosure.

[0014] definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure pertains.

[0015] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, for example, 1 to 8 carbon atoms, i.e., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 to 2 carbon atoms. This term includes, by example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), n-hexyl (CH3CH2CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0016] The term "substituted alkyl" refers to an alkyl group as defined herein, in which one or more carbon atoms in the alkyl chain are optionally -O-, -N-, -S-, -S(O) n Substituted with heteroatoms such as -(n is 0-2), -NR-(R is hydrogen or alkyl), and including deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl, and -NR ’ R ” (R ’And R'' may be the same or different, and the molecule has 1 to 10 substituents selected from the group consisting of hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclic compounds.

[0017] "Alkylene" refers to a divalent aliphatic hydrocarbyl group having 1 to 6 carbon atoms, including 1 to 3 carbon atoms in either a linear or branched chain, and these are -O-, -NR 10 -, -NR 10 C(O)-, -C(O)NR 10 -Optionally interrupted by one or more groups selected from the following. This term includes, for example, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), (-C(CH3)2CH2CH2-), (-C(CH3)2CH2C(O)-), (-C(CH3)2CH2C(O)NH-), (-CH(CH3)CH2-), etc.

[0018] A "substituted alkylene" refers to an alkylene group having 1 to 3 hydrogen atoms substituted by substituents, as described for carbon in the definition of "substitution" below.

[0019] The term "alkane" refers to alkyl and alkylene groups as defined herein.

[0020] The terms "alkylaminoalkyl", "alkylaminoalkenyl", and "alkylaminoalkynyl" are R ’ NHR ” - Refers to the base, R ’ R is an alkyl group as defined herein, ” is an alkylene, alkenylene, or alkynylene group as defined herein.

[0021] The term "alkalyl" or "aralkyl" refers to an alkylene-aryl group and a substituted alkylene-aryl group, and alkylene, substituted alkylene, and aryl are defined herein.

[0022] "Alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. Examples of alkoxys include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and others. The term "alkoxy" also refers to an alkenyl-O-group, a cycloalkyl-O-group, a cycloalkenyl-O-group, and an alkynyl-O-group, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.

[0023] The term "substituted alkoxy" refers to substituted alkyl-O-groups, substituted alkenyl-O-groups, substituted cycloalkyl-O-groups, substituted cycloalkenyl-O-groups, and substituted alkynyl-O-groups, where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl, and substituted alkynyl are as defined herein.

[0024] The term "alkoxyamino" refers to an -NH-alkoxy group, where alkoxy is defined herein.

[0025] The term "haloalkoxy" refers to an alkyl-O- group in which one or more hydrogen atoms on an alkyl group are substituted with a halo group, including, for example, trifluoromethoxy groups.

[0026] The term "haloalkyl" refers to an alkyl group that has been substituted as described above, in which one or more hydrogen atoms on the alkyl group are replaced by a halo group. Examples of such groups include, but are not limited to, fluoroalkyl groups such as trifluoromethyl, difluoromethyl, and trifluoroethyl.

[0027] 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, alkyl, alkylene, and substituted alkylene are as defined herein.

[0028] 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, alkyl, alkyl, and substituted alkylene are as defined herein.

[0029] "Alkenyl" refers to a linear or branched hydrocarbyl group having 2 to 6 carbon atoms, for example, 2 to 4 carbon atoms, and at least one, for example, 1 to 2 double bond unsaturated sites. Examples of this term include vivinyl, allyl, and buta-3-en-1-yl. This term includes cis and trans isomers, or mixtures of these isomers.

[0030] The term "substituted alkenyl" refers to an alkenyl group as defined herein, having 1 to 5 substituents or 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.

[0031] "Alkynyl" refers to a linear or branched monovalent hydrocarbyl group having 2 to 6 carbon atoms, for example 2 to 3 carbon atoms, and at least one, for example 1 to 2 triple bond unsaturated sites. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH).

[0032] The term "substituted alkynyl" refers to an alkynyl group as defined herein having 1 to 5 substituents or 1 to 3 substituents selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.

[0033] "Alkynyloxy" refers to an -O-alkynyl group, where alkynyl is defined herein. Examples of alkynyloxy include ethynyloxy and propynyloxy.

[0034] "Acyl" includes HC(O)- group, alkyl-C(O)- group, substituted alkyl-C(O)- group, alkenyl-C(O)- group, substituted alkenyl-C(O)- group, alkynyl-C(O)- group, substituted alkynyl-C(O)- group, cycloalkyl-C(O)- group, substituted cycloalkyl-C(O)- group, cycloalkenyl-C(O)- group, substituted cycloalkenyl-C(O)- group, aryl-C(O)- group, substituted aryl-C(O)- group, heteroaryl-C (O)-groups, substituted heteroaryl-C(O)-groups, heterocyclyl-C(O)-groups, and substituted heterocyclyl-C(O)-groups refer to 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 contains the "acetyl" group CH3C(O).

[0035] "Acylamino" is -NR 20 C(O) alkyl group, -NR 20 C(O) substituted alkyl group, NR 20 C(O) cycloalkyl group, -NR 20 C(O)-substituted cycloalkyl groups, -NR 20 C(O)cycloalkenyl group, -NR 20 C(O)-substituted cycloalkenyl group, -NR 20 C(O) alkenyl group, -NR 20 C(O) substituted alkenyl group, -NR 20 C(O) alkynyl group, -NR 20 C(O) substituted alkynyl group, -NR 20 C(O)aryl group, -NR 20 C(O) substituted aryl group, -NR 20 C(O) heteroaryl group, -NR 20 C(O)-substituted heteroaryl group, -NR 20 C(O) heterocyclic group, and -NR 20 This refers to a C(O) substituted heterocyclic group, R 20is hydrogen or alkyl, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0036] "Aminocarbonyl" or the term "aminoacyl" is -C(O)NR 21 R 22 It refers to the base, R 21 and R 22 R 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. 21 and R 22 These groups optionally bond with the nitrogen atoms they are bound to to form heterocyclic or substituted heterocyclic groups, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic groups are as defined herein.

[0037] "Aminocarbonylamino" is -NR 21 C(O)NR 22 R 23 It refers to the base, R 21 , R 22 , and R 23 These are independently selected from hydrogen, alkyl, aryl, or cycloalkyl, or two R groups are bonded to form a heterocycline group.

[0038] The term "alkoxycarbonylamino" refers to the -NRC(O)OR group, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl, and alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0039] The term "acyloxy" refers to alkyl-C(O)O-groups, substituted alkyl-C(O)O-groups, cycloalkyl-C(O)O-groups, substituted cycloalkyl-C(O)O-groups, aryl-C(O)O-groups, heteroaryl-C(O)O-groups, and heterocyclyl-C(O)O-groups, where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0040] "Aminosulfonyl" is -SO2NR 21 R 22 It refers to the base, R 21 and R 22 R 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. 21 and R 22 These groups optionally bond with the nitrogen atoms they are bound to to form heterocyclic or 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 groups are as defined herein.

[0041] "Sulfonylamino" is -NR 21 SO2R 22 It refers to the base, R 21 and R 22R 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. 21 and R 22 These atoms may optionally bond with the atoms they are bonded to to form heterocyclic or substituted heterocyclic groups, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic groups are as defined herein.

[0042] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (such as one present in a phenyl group) or a ring system having multiple fused rings, which may or may not be aromatic, as long as the bonding site is through an atom of an aromatic ring (examples of such aromatic ring systems include naphthyl, anthuryl, and indanyl). Examples of this term include phenyl and naphthyl. Unless restricted by the definition of aryl substituents, such aryl groups can be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents, selected from acyloxy, hydroxyl, 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, aryloxy, azide, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamide, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and trihalomethyl.

[0043] "Aryloxy" refers to an -O-aryl group, where aryl includes, as defined herein, for example, phenoxy, naphthoxy, and optionally substituted aryl groups, as also defined herein.

[0044] "Amino" refers to the -NH2 group.

[0045] The term "substituted amino" refers to a -NRR group, where 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, provided that at least one R is not hydrogen.

[0046] The term "azid" refers to the -N3 group.

[0047] "Carboxyl," "carboxy," or "carboxylate" refers to -CO2H or its salts.

[0048] "Carboxyl-ester" or "carboxy-ester," or the term "carboxyalkyl" or "carboxylalkyl" refers to -C(O)O-alkyl group, -C(O)O-substituted alkyl group, -C(O)O-alkenyl group, -C(O)O-substituted alkenyl group, -C(O)O-alkynyl group, -C(O)O-substituted alkynyl group, -C(O)O-aryl group, -C(O)O-substituted aryl group, -C(O)O-cycloalkyl group, -C(O)O-substituted cycloalkyl group, -C(O)O-cycloalkenyl The terms refer to -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-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.

[0049] "(carboxyl-ester)oxy" or "carbonate" refers to -OC(O)O-alkyl groups, -OC(O)O-substituted alkyl groups, -OC(O)O-alkenyl groups, -OC(O)O-substituted alkenyl groups, -OC(O)O-alkynyl groups, -OC(O)O-substituted alkynyl groups, -OC(O)O-aryl groups, -OC(O)O-substituted aryl groups, -OC(O)O-cycloalkyl groups, -OC(O)O-substituted cycloalkyl groups, -OC(O)O-cycloalkenyl groups, -OC(O)O-substituted cy This refers to chloroalkenyl groups, -OC(O)O-heteroaryl groups, -OC(O)O-substituted heteroaryl groups, -OC(O)O-heterocyclic groups, and -OC(O)O-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0050] "Cyano" or "nitrile" refers to the -CN group.

[0051] "Cycloalkyl" refers to a cyclic alkyl group of 3 to 10 carbon atoms having one or more cyclic rings, including fusion, crosslinking, and spiro-ring systems. Examples of suitable cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Such cycloalkyl groups include, for example, single-ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl, or multi-ring structures such as adamantanyl.

[0052] The term "substituted cycloalkyl" includes deuterium, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, 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- This refers to a cycloalkyl group having 1 to 5 substituents selected from alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl groups, or 1 to 3 substituents.

[0053] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group with 3 to 10 carbon atoms, having one or more rings and at least one double bond, for example, one to two double bonds.

[0054] The term "substituted cycloalkenyl" includes deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, 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-This refers to a cycloalkenyl group having 1 to 5 substituents selected from substituted alkyl, -SO2-aryl, and -SO2-heteroaryl groups, or 1 to 3 substituents.

[0055] "Cycloalkynyl" refers to a non-aromatic cycloalkyl group consisting of 5 to 10 carbon atoms, having a single ring or multiple rings and at least one triple bond.

[0056] "Cycloalkoxy" refers to -O-cycloalkyl.

[0057] "Cycloalkenyloxy" refers to -O-cycloalkenyl.

[0058] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodine.

[0059] "Hydroxy" or "hydroxyl" refers to the -OH group.

[0060] A "heteroaryl" refers to an aromatic group having 1 to 15 carbon atoms, for example, 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. Such heteroaryl groups may have a single ring in the ring system (e.g., pyridinyl, imidazolyl, or furyl) or multiple fused rings (e.g., in groups such as indolidinyl, 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 insofar as the bonding site is through an atom of the aromatic ring. In certain embodiments, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Examples of this term include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless restricted by the definition of heteroaryl substituents, such heteroaryl groups can be optionally substituted with 1 to 5 substituents selected from acyloxy, hydroxyl, 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, azide, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamide, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl and trihalomethyl, or 1 to 3 substituents.

[0061] The term "heteroaralkyl" refers to an alkylene-heteroaryl group, where alkylene and heteroaryl are defined herein. Examples of this term include pyridylmethyl, pyridylethyl, and indolylmethyl.

[0062] "Heteroaryloxy" refers to -O-heteroaryl.

[0063] "Heterocyclic," "heterocyclic," "heterocycloalkyl," and "heterocyclyl" refer to saturated or unsaturated groups having a single ring or multiple fused rings, including condensed bridges and spiro-ring systems, and having 3 to 20 ring atoms, including 1 to 10 heterocyclic atoms. 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 may be cycloalkyl, aryl, or heteroaryl, insofar as the bonding site is via a non-aromatic ring. In certain embodiments, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide an N-oxide, -S(O)-, or -SO2- moiety.

[0064] Examples of heterocyclic and heteroaryl compounds include, but are not limited to, aziridine, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, dihydroindole, indazole, purine, quinoridine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carborin, phenantholidine, acridine, phenanthroline, isothiazole, phenazine, and isoxazoline. These include 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, morpholine, thiomorpholine (also called thiamorpholinil), 1,1-dioxothiomorpholine, pyrrolidine, tetrahydrofuran, benzo[d][1,3]oxatiol, benzo[d][1,3]dioxol, etc.

[0065] Unless restricted by the definition of heterocyclic substituents, such heterocyclic groups can be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and condensed heterocycles.

[0066] "Heterocyclyloxy" refers to the -O-heterocyclyl group.

[0067] The term "heterocyclilthio" refers to a heterocyclic -S- group.

[0068] The term "heterocyclene" refers to a diradical group formed from a heterocycle, as defined herein.

[0069] The term "hydroxyamino" refers to the -NHOH group.

[0070] "Nitro" refers to the -NO2 group.

[0071] "Oxo" refers to an oxygen (O) atom.

[0072] "Sulfonyl" refers to SO2-alkyl groups, SO2-substituted alkyl groups, SO2-alkenyl groups, SO2-substituted alkenyl groups, SO2-cycloalkyl groups, SO2-substituted cycloalkyl groups, SO2-cycloalkenyl groups, SO2-substituted cycloalkenyl groups, SO2-aryl groups, SO2-substituted aryl groups, SO2-heteroaryl groups, SO2-substituted heteroaryl groups, SO2-heterocyclic groups, and SO2-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. Examples of sulfonyls include methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.

[0073] "Sulfonyloxy" refers to -OSO2-alkyl groups, OSO2-substituted alkyl groups, OSO2-alkenyl groups, OSO2-substituted alkenyl groups, OSO2-cycloalkyl groups, OSO2-substituted cycloalkyl groups, OSO2-cycloalkenyl groups, OSO2-substituted cycloalkenyl groups, OSO2-aryl groups, OSO2-substituted aryl groups, OSO2-heteroaryl groups, OSO2-substituted heteroaryl groups, OSO2-heterocyclic groups, and OSO2-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.

[0074] The term "aminocarbonyloxy" refers to the -OC(O)NRR group, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic, and alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.

[0075] "Thiol" refers to the -SH group.

[0076] The term "thioxo" or "thioketo" refers to a (=S) atom.

[0077] "Alkylthio" or the term "thioalkoxy" refers to an -S-alkyl group, where alkyl is as defined herein. In certain embodiments, sulfur may be oxidized to -S(O)-. The sulfoxide may exist as one or more stereoisomers.

[0078] The term "substituted thioalkoxy" refers to an -S-substituted alkyl group.

[0079] The term "thioaryloxy" refers to an aryl-S-group, where the aryl group is as defined herein and includes optionally substituted aryl groups as also defined herein.

[0080] The term "thioheteroaryloxy" refers to a heteroaryl-S-group, where the heteroaryl group is as defined herein and includes optionally substituted aryl groups as also defined herein.

[0081] The term "thioheterocyclooxy" refers to a heterocyclyl-S-group, where the heterocyclyl group is as defined herein and includes any optionally substituted heterocyclyl groups as also defined herein.

[0082] In addition to the disclosures herein, when used to modify a particular group or radical, the term “substitution” may also mean that one or more hydrogen atoms of a particular group or radical are each independently of one another substituted with the same or different substituents as defined below.

[0083] In addition to the groups disclosed with respect to individual terms herein, substituents for substituting one or more hydrogens on a saturated carbon atom in a specified group or radical (any two hydrogens on one carbon, =O, =NR) are also available. 70 、=N-OR 70 (Can be replaced with =N2 or =S) Unless otherwise specified, deuterium, -R 60 , halo, =O, -OR 70 , -SR 70 , -NR 80 R 80 , trihalomethyl, -CN, OCN, SCN, NO, NO2, =N2, N3, SO2R 70 ,SO2O - M + ,SO2OR 70 OSO2R 70 OSO2O - M + OSO2OR 70 ,P(O)(O - )2(M + )2,P(O)(OR 70 )O - M + ,P(O)(OR 70 )2,C(O)R 70,C(S)R 70 ,C(NR 70 )R 70 ,C(O)O - M + ,C(O)OR 70 ,C(S)OR 70 ,C(O)NR 80 R 80 ,C(NR 70 )NR 80 R 80 OC(O)R 70 OC(S)R 70 ,OC(O)OM + ,OC(O)OR 70 ,OC(S)OR 70 ,NR 70 C(O)R 70 ,NR 70 C(S)R 70 ,NR 70 CO2 - M + ,NR 70 CO2R 70 ,NR 70 C(S)OR 70 ,NR 70 C(O)NR 80 R 80 ,-NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 And R 60 The group consists of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, and each R 70 Independently, hydrogen or R 60 And each R 80 R is independent of R 70 Alternatively, two R 80These, together with the nitrogen atom to which they are bonded, form a 5, 6, or 7-membered heterocycloalkyl, which optionally comprises the same or different additional 1 to 4 heteroatoms selected from the group consisting of O, N, and S, of which N may have a -H or C1-C3 alkyl substitution, and each M + Each M is a counterion with a single net positive charge. + Independently, for example, K + na + Li + Alkaline ions such as + N(R 60 ) Ammonium ions such as 4, or [Ca 2+ ] 0.5 [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 These may include alkaline earth ions such as (the subscript 0.5 means that one of the counterions of such a divalent alkaline earth ion is the ionized form of the compound of this disclosure and the other is a typical counterion such as a chloride, or that two ionized compounds disclosed herein can play the role of counterions of such a divalent alkaline earth ion, or that a biionized compound disclosed herein can play the role of counterions of such a divalent alkaline earth ion). A specific example is -NR 80 R 80 It is intended to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methylpiperazin-1-yl, and N-morpholinyl.

[0084] In addition to the disclosures herein, substituents on hydrogen atoms on unsaturated carbon atoms in "substituted" alkenes, alkynes, aryls, and heteroaryl groups are deuterium, -R, unless otherwise specified. 60 Hello, -O - M + , -OR 70 , -SR 70 , -S - M + , -NR 80 R 80, trihalomethyl, -CF3, CN, OCN, SCN, NO, NO2, N3, SO2R 70 , SO3 - M + , SO3R 70 , OSO2R 70 , OSO3 - M + , OSO3R 70 , PO3 2 (M + )2, P(O)(OR 70 )O - M + , P(O)(OR 70 )2, C(O)R 70 , C(S)R 70 , C(NR 70 )R 70 , CO2 - M + , CO2R 70 , C(S)OR 70 , C(O)NR 80 R 80 , C(NR 70 )NR 80 R 80 , OC(O)R 70 , OC(S)R 70 , OCO2 - M + , OCO2R 70 , OC(S)OR 70 , NR 70 C(O)R 70 , NR 70 C(S)R 70 , NR 70 , CO2 - M + , NR 70 , CO2R 70 , NR 70 , C(S)OR 70 , NR[[ID=​​​​​​​​​​​​​​​​​​​​​​​80 , and M + This is as previously defined, however, in the case of substituted alkenes or alkynes, the substituent is -O - M + , -OR 70 , -SR 70 , or -S - M + isn't it.

[0085] In addition to the groups disclosed with respect to the individual terms herein, substituents on hydrogen atoms on nitrogen atoms in "substituted" heteroalkyl and cycloheteralkyl groups are, unless otherwise specified, -R 60 ,-OM + , -OR 70 , -SR 70 -SM + , -NR 80 R 80 , trihalomethyl, -CF3, CN,NO,NO2,S(O)2R 70 ,S(O)2OM + ,S(O)2OR 70 OS(O)2R 70 OS(O)2OM + OS(O)2OR 70 ,P(O)(O)2(M + )2,P(O)(OR 70 )OM + ,P(O)(OR 70 )(OR 70 ), C(O)R 70 ,C(S)R 70 ,C(NR 70 )R 70 ,C(O)OR 70 ,C(S)OR 70 ,C(O)NR 80 R 80 ,C(NR 70 )NR 80 R 80 OC(O)R 70 OC(S)R 70 ,OC(O)OR 70 ,OC(S)OR 70 ,NR 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 + This is as defined above.

[0086] In addition to the disclosures herein, in certain embodiments, the substituted group has one, two, three, or four substituents, one, two, or three substituents, one or two substituents, or one substituent.

[0087] Unless otherwise specified, polymers achieved by defining substituents having further substituents on themselves (for example, a substituted aryl having a substituted aryl group as a substituent itself substituted with a substituted aryl group, which is then further substituted with a substituted aryl group) are not intended to be included herein. In such cases, the maximum number of such substitutions is 3. For example, the sequential substitutions of substituted aryl groups specifically intended herein are limited to substituted aryl-(substituted aryl)-substituted aryl. However, substituents defined as polyethers, for example, do not have more than 3 sequential substitutions, such as -O-(CH2CH2O) n -H may be present, and in the formula, n may be 1, 2, 3, or more.

[0088] Unless otherwise indicated, the naming of substituents not explicitly defined herein is achieved by naming the terminal portion of the functional group, followed by the adjacent functional groups toward the bonding site. For example, the substituent "arylalkyloxycarbonyl" refers to the (aryl)-(alkyl)-OC(O)- group.

[0089] It is understood that, with respect to any of the groups disclosed herein that contain one or more substituents, such groups do not include any substitutions or substitution patterns that are sterically unrealizable and / or synthetically unfeasible. Furthermore, the compounds in question include all stereochemical isomers resulting from the substitutions of these compounds.

[0090] As used herein, the term “fat” refers to a compound having a long-chain (linear) hydrophobic moiety consisting of hydrogen and 4 to 26 carbon atoms, which may be fully saturated or partially unsaturated.

[0091] The terms "pharmaceutically acceptable" and "physiologically acceptable" are used herein to refer to compounds, materials, compositions, and / or dosage forms that are within the bounds of sound medical judgment, suitable for use in contact with human tissue without excessive toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit / risk ratio. When referring to salts, the terms "pharmaceutically acceptable salt" and "physiologically acceptable salt" mean salts that are acceptable for administration to mammalian patients (salts having counterions that have acceptable mammalian safety for a given administration regimen). As is well known in the art, such salts can be derived from pharmaceutically acceptable inorganic or organic bases, such as sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts; from addition salts with inorganic acids, such as hydrochlorides, hydrobroms, sulfates, sulfamates, phosphates, nitrates, and perchlorates, if the molecule contains a basic functional group; and from addition salts with organic acids, such as formates, tartrates, besilates, mesilates, acetates, maleates, malons, oxalates, fumarates, benzoates, salicylates, succinates, oxalates, glycolates, hemioxalates, hemifumarates, propions, stearates, lactates, citrates, ascorbicates, pamoates, hydroxymaleates, phenylacetates, glutamates, 2-acetoxybenzoates, tosylates, ethanedisulfonates, and isethionates. The term "salt" 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 pharmaceutically acceptable, although this is not required for salts of intermediate compounds not intended for administration to patients. For example, salts of this compound include those in which the compound is protonated by an inorganic or organic acid to form a cation, and the salt has a conjugate base of the inorganic or organic acid as its anionic component.

[0092] "Solvate" means the physical association of a compound or salt of the Disclosure with one or more solvent molecules, which are organic, inorganic, or a mixture of both. This physical association includes hydrogen bonding. In certain examples, for example, a solvate can be isolated if one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in a solvate may exist in regular and / or irregular arrangements. A solvate may contain either stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both the solution phase and the isolateable solvate. Some examples of solvents include, but are not limited to, methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. When the solvent is water, the solvate formed is a hydrate (e.g., monohydrate, dihydrate, etc.). Thus, exemplary solvates include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, etc. The solvation method is generally known in the art.

[0093] "Stereoisomers" and "stereoisomers" refer to compounds that have the same atomic bonding but different atomic arrangements in space. Stereoiomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. All forms of compounds, such as racemates and optically pure stereoisomers, are contemplated herein. Chemical formulas and compounds that have at least one chiral center but are drawn without reference to stereochemistry are contemplated to include both racemic compounds and distinct stereoisomers, such as R- and / or S-stereoisomers, and each diastereomer substitution, insofar as their diastereomers are geometrically feasible.

[0094] "Tautomer" refers to alternative molecular forms that differ only in the electron bonding of atoms and / or in the position of protons, such as enol-keto, imine-enamine, and neutral / zwitterionic tautomers, or to tautomers of heteroaryl groups containing the -N=C(H)-NH-ring atom configuration, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. Other tautomer ring atom configurations are also possible. For example, a compound containing both an acidic and a basic group within the same molecule shown in its neutral form may also exist in a zwitterionic form, similar to the amino acid / ammonium carboxylate tautomer. A given chemical formula or name shall encompass all of its tautomer forms, to the extent that they exist.

[0095] The term "prodrug" refers to a compound that can be converted under physiological conditions or by solvation to the biologically active compounds described herein. Therefore, the term "prodrug" refers to a precursor of a pharmaceutically acceptable biologically active compound. For example, prodrugs such as esters and phosphate esters may be inactive when administered to a subject but are converted in vivo to active compounds, for example, by hydrolysis, to free carboxylic acids or free hydroxyl groups. Prodrug compounds often offer advantages in solubility, histocompatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). For further discussion of prodrugs, see Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” ACSSymposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon). This is described in Press, 1987, both of which are fully incorporated herein by reference. The term “prodrug” is also intended to include any covalent carrier that releases the active compound in vivo when such a prodrug is administered to a mammalian subject. Prodrugs of active compounds described herein may be prepared by modifying functional groups present in the active compound so that the modification is a routine operation or cleaved in vivo to the parental active compound. Examples of prodrugs include compounds in which a hydroxyl group, amino group, or mercapto group is attached to any group that cleaves to form a free hydroxyl group, a free amino group, or a 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, acetates, formates, benzoates, and dihydrogen phosphate derivatives of alcohols, or acetamide, formamide, and benzamide derivatives of amine functional groups in active compounds.

[0096] 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 therefore exhibits a sharp, characteristic crystalline peak in its X-ray powder diffraction (XRPD) pattern. In some cases, a crystalline solid may exist in different crystalline forms known as "polymorphs," which have the same chemical composition but differ in the packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs can have a variety of solid physical properties that affect, for example, the solubility, dissolution rate, bioavailability, chemical and physical stability, fluidity, and compressibility of a compound, as well as the safety and efficacy of pharmaceuticals based on that compound. Further purification with respect to physical or optical purity can also be achieved in the process of preparing polymorphs. As used herein, the term "amorphous" refers to a solid material that does not substantially have long-range order in the position of its molecules, where the molecules are randomly arranged in a clearly defined arrangement, e.g., there is no effective molecular packing and no long-range order. Amorphous solids are generally isotropic, meaning 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 substantially sharp characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., it is not crystallinity 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. Therefore, an "amorphous" subject compound / material is a compound / material characterized as having substantially no crystallinity as determined by XRPD, i.e., having less than 10% crystallinity, less than 8% crystallinity, less than 6% crystallinity, less than 4% crystallinity, less than 2% crystallinity, less than 1% crystallinity, or 0% crystallinity, i.e., being at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% amorphous. For example, in some embodiments, the degree of crystallinity % may be determined by measuring the intensity of one or more peaks in the XRPD diffractogram compared to a reference peak that may be an internal standard.For example, 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 aforementioned percentages in terms of weight percentage, may be used to determine the percentage of the subject compound / substance that is amorphous or crystalline.

[0097] The compounds described herein may exist in different forms, including salts, solvates, stereoisomers, tautomers, and crystalline / amorphous (including polymorphs), and it will be understood that this disclosure is intended to include all such permutations, e.g., solvates of pharmaceutically acceptable salts of stereoisomers of the subject compound.

[0098] As used herein, the terms “stable,” “stability,” etc., include chemical stability and solid-state (physical) stability. The term “chemical stability” means that a compound can be stored under normal storage conditions in an isolated form or in the form of a formulation provided, for example, mixed with a pharmaceutically acceptable carrier, diluent, or adjuvant as described herein, with little or no chemical degradation or decomposition. “Solid-state stability” means that a compound can be stored under normal storage conditions in an isolated solid form or in the form of a solid formulation provided, for example, mixed with a pharmaceutically acceptable carrier, diluent, or adjuvant as described herein, with little or no change in the solid state (e.g., hydration, dehydration, solvation, desolvation, crystallization, recrystallization, or solid phase transition).

[0099] As used herein, the term “composition” is equivalent to the term “formulation.”

[0100] "Steam" refers to solid matter in the gaseous phase at temperatures below its critical temperature, meaning that steam can condense into a liquid by increasing the pressure on it without lowering its temperature.

[0101] As used herein, “aerosol” is a suspension of fine solid particles or droplets in a gas phase (e.g., air, oxygen, helium, nitrous oxide, and other gases, and mixtures thereof). As used herein, “mist” is a subset of aerosols distinct from vapor, and is a dispersion of 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 portion 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. Mist does not contain solid particles. The aerosols and mists of this disclosure can be produced by any suitable method and apparatus, and examples thereof are described herein, for example, through the use of an inhaler or nebulizer.

[0102] As used herein, the term “inhalation session” describes an administration event in which a subject inhales a given dose of a drug, regardless of the number of breaths required to inhale that given dose. For example, a subject prescribed to take 10 mg of a drug twice daily would perform two inhalation sessions, each inhalation session delivering 10 mg of the drug. The duration and number of breaths of each inhalation session would 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 subject’s breathing pattern.

[0103] As used herein, the term “release period” refers to the time window during which any compound described herein is released from its dosage form (e.g., matrix) to obtain the plasma concentration of the compound described herein. The start time of the release period is defined from the time of administration to the subject, which is considered to be approximately equivalent to gastric entry and initial dissolution by gastric enzymes and acids.

[0104] As used herein, the phrase “maximum sustained release” describes the release window of a particular formulation of the present disclosure formulated to increase the release period to a maximum value, which, in the case of an enteral route, is ultimately limited to the time it takes for the gastrointestinal tract to naturally eliminate all of the drug with food.

[0105] The term "tamper resistance" is understood in the art to describe a form of pharmaceutical formulation that makes it more difficult to abuse the drug portion of the formulation by using the formulation through extraction for purposes such as intravenous or intradermal use, or through crushing for the use of purified cocaine, thereby reducing the risk of drug abuse.

[0106] As used herein, the term “steady state” describes a stable or steady-state level of molecular concentration, such as the concentration of any compound described herein.

[0107] As used herein, the terms “to treat” or “treatment” mean treating or treating a disease or medical condition in a patient, such as a mammal (especially a human), which includes improving the disease or medical condition, such as by eliminating or reducing its regression; suppressing the disease or medical condition, for example by delaying or stopping its onset; or alleviating one or more symptoms of the disease or medical condition. In one embodiment, preventive treatment may prevent the onset of the disease or medical condition in a subject.

[0108] In this specification, the terms “patient” or “subject” as used interchangeably may be any mammal, including, for example, human or non-human subjects. The patient or subject may have the condition being treated, or may be susceptible to the condition being treated.

[0109] As used herein, unless otherwise specified, the terms “prevent,” “prevent,” and “prevention” refer to the prevention of the onset, recurrence, or spread of a disease, disorder, or condition, or one or more of its symptoms. These terms encompass the suppression or reduction of symptoms of a particular disease, disorder, or condition. Subjects with a family history of a disease, disorder, or condition are, in particular, candidates for a preventive regimen in certain embodiments. Furthermore, 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 “preventive treatment.”

[0110] As used herein, and unless otherwise specified, the terms “to manage,” “managing,” and “control” refer to preventing or delaying the progression, spread, or worsening of a disease, disorder, or condition, or one or more of its symptoms. In many cases, the beneficial effects obtained by a subject from preventive and / or therapeutic treatments do not result in a cure for the disease, disorder, or condition. In this regard, the term “managing” includes 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 of its symptoms.

[0111] "Therapeutic effective dose" refers to the amount of a compound sufficient to treat one or more of a specific disorder or disease, or its symptoms, and / or to prevent the onset of the disease or disorder (prophylactic effective dose).

[0112] As used herein, and unless otherwise specified, the “prophylactic effective dose” of an active agent is an amount sufficient to prevent a disease, disorder, or condition, or to prevent its recurrence. The term “prophylactic effective dose” may include an amount that improves overall prevention or enhances the prophylactic effect of another prophylactic agent.

[0113] The term "administration schedule" refers to a plan that outlines the type, amount, duration, and procedure of medication in drug therapy, specifying the dosage, method of administration, order of administration, and administration date for each drug. The dates designated for administration are determined before drug administration begins. Administration is continued by repeating a series of administration schedules, which constitute a "course." A "continuous" administration schedule means administration every day without interruption during a course of treatment. If the administration schedule follows an "intermittent" administration schedule, the number of administration days may be followed by "rest days" or non-administration days during the course. A "drug-free period" indicates a time when the drug is not being administered according to a prescribed administration schedule. For example, after several courses of treatment, a subject may be prescribed a regulated drug-free period as part of the administration schedule, for example, before resuming active treatment.

[0114] The term “toxic spike” is used herein to describe a nerve spike at any concentration of any compound described herein that causes a sedative or psychotropic side effect (e.g., hallucinations, dizziness, and nausea) or any undesirable and / or unintended secondary effect caused by administering a drug to an individual, resulting in a subjective experience qualitatively different from normal consciousness. These experiences may include derealization, depersonalization, hallucinations, and / or distortions of sensation in the visual, auditory, olfactory, tactile, proprioceptive and / or interoceptive ranges, and / or other perceptual alterations, as well as other significant subjective changes in cognition, memory, affect, and consciousness. If undesirable and / or unintended, such side effects may affect not only immediate effects but also compliance with treatment. In particular, side effects may be more pronounced at blood concentration levels of approximately 250, 300, 400, and 500 ng / L or higher.

[0115] As used herein, and unless otherwise specified, “neuropsychiatric disorder or condition” is defined as a behavioral or psychological problem associated with a known neurological condition, typically as a group of co-occurring 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.

[0116] As used herein, “inflammatory condition” or “inflammatory disease” includes rheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthritis), spondyloarthritis (e.g., ankylosing spondylitis, reactive arthritis, Reiter's syndrome), crystalline arthropathy (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, Sjögren's syndrome); and vasculitis (e.g., polymyositis nodosa). This broadly refers to chronic or acute inflammatory diseases, including but not limited to: arteritis, Wegener's granulomatosis, Churg-Strauss syndrome; inflammatory conditions including those resulting from trauma or ischemia; sarcoidosis; atherosclerosis, atherosclerosis, and vascular occlusive diseases (e.g., atherosclerosis, ischemic heart disease, myocardial infarction, stroke, peripheral vascular disease); and vascular diseases including vascular stent restenosis; and eye diseases including but not limited to uveitis, corneal diseases, iritis, iridocyclitis, glaucoma, and cataracts.

[0117] All diseases and disorders listed herein may be defined as those described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) published by the American Psychiatric Association, or in the International Classification of Diseases (ICD) published by the World Health Organization.

[0118] As used herein, the terms "and / or" include any and all combinations of one or more of the related enumerated items. As used throughout this specification and the subsequent claims, "a," "an," and "the" include plural references in addition to singular references unless the context otherwise explicitly indicates. The term "about" in relation to a number means that the value fluctuates by 5 percent above or below. For example, a value of about 100 means 95 to 105 (or any value between 95 and 105).

[0119] compound Equation (I) Compounds of formula (I), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs thereof are disclosed herein. [ka] During the ceremony, X 1 and X 2 These are independently hydrogen or deuterium, Y 1 and Y 2 These are independently hydrogen or deuterium, R 3 However, it is hydrogen or deuterium, Each R a These are independently substituted or unsubstituted C1-C6 alkyl groups. R 4 However, R 7 -S(O)-, R 8 -S(O)2-, R 9 -SS-, R 10 -C(Z)-, R 11 R 12 -P(O)-, R 13 R 14 -N-, or R 15 -Se-, R 7 , R 8 , R 9 , R 10 , R 11 and R 12These are independently unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, R 13 and R 14 These are independent, unsubstituted C2~C 10 Alkyl, substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, or alternatively, R 13 and R 14 However, optionally, they bond together with the nitrogen atoms attached to them to form an unsubstituted heterocycloalkyl or substituted heterocycloalkyl having at least two heterocyclic atoms. R 15 However, unsubstituted C2~C 10 Alkyl, substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, Z is either S or O.

[0120] X 1 and X 2 They may be the same or they may be different. In some embodiments, X 1 and X 2 They are the same. In some embodiments, X 1 and X 2 is hydrogen. In some embodiments, X 1 and X 2 is deuterium. In some embodiments, X 1 and X 2 They are different. In some embodiments, X 1 It is deuterium, X 2 It is hydrogen.

[0121] Y 1and Y 2 They may be the same or they may be different. In some embodiments, Y 1 and Y 2 They are the same. In some embodiments, Y 1 and Y 2 is hydrogen. In some embodiments, Y 1 and Y 2 is deuterium. In some embodiments, Y 1 and Y 2 They are different. In some embodiments, Y 1 It is deuterium, Y 2 It is hydrogen.

[0122] In some embodiments, X 1 , X 2 , Y 1 , and Y 2 is deuterium. In some embodiments, X 1 , X 2 , Y 1 , and Y 2 is hydrogen. In some embodiments, X 1 and X 2 It is deuterium, Y 1 and Y 2 It is hydrogen.

[0123] In some embodiments, R 3 is deuterium. In some embodiments, R 3 It is hydrogen.

[0124] Each R a They may be the same or they may be different. In some embodiments, each R a They are the same. Each R a Each R is independently a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C1-C3 alkyl, or a substituted or unsubstituted C1-C3 alkyl, preferably a substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, -CH3, -CDH2, -CD2H, -CD3, -CFH2, -CF2H, and -CF3. In some embodiments, each R a is -CH3 (methyl). In some embodiments, each Ra is -CD3. In some embodiments, each R a They are different, for example, one R a One is -CH3, and the other is -CD3.

[0125] In some embodiments, R a is -CH3, X 1 , X 2 , Y 1 , and Y 2 is deuterium. In some embodiments, R a is -CD3, X 1 , X 2 , Y 1 , and Y 2 is deuterium. In some embodiments, R a is -CH3, X 1 , X 2 , Y 1 , and Y 2 is hydrogen. In some embodiments, R a is -CD3, X 1 , X 2 , Y 1 , and Y 2 is hydrogen. In some embodiments, each R a is -CH3, X 1 and X 2 It is deuterium, Y 1 and Y 2 is hydrogen. In some embodiments, each R a is -CD3, X 1 and X 2 It is deuterium, Y 1 and Y 2 It is hydrogen.

[0126] In some embodiments, R 4 is, -R 7 It is -S(O)-.

[0127] In some embodiments, R 7 is an unsubstituted or substituted alkyl group. In some embodiments, R 7This is an unsubstituted or substituted C1-C8 alkyl group, for example, an unsubstituted or substituted C1 alkyl group, an unsubstituted or substituted C2 alkyl group, an unsubstituted or substituted C3 alkyl group, an unsubstituted or substituted C4 alkyl group, an unsubstituted or substituted C5 alkyl group, an unsubstituted or substituted C6 alkyl group, an unsubstituted or substituted C7 alkyl group, or an unsubstituted or substituted C8 alkyl group. In some embodiments, R 7 is an unsubstituted or substituted linear alkyl. In some embodiments, R 7 is an unsubstituted or substituted branched alkyl group. In some embodiments, R 7 These are unsubstituted alkyl groups (e.g., unsubstituted C1-C8 alkyl groups), and examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl, with particular mention of t-butyl.

[0128] In some embodiments, R 7The alkyl group is a substituted alkyl group (e.g., a substituted C1-C8 alkyl group). The alkyl group may contain one or more substituents. The alkyl group may be substituted with any one or more substituents listed herein, examples of which include polar substituents such as deuterium, halogens (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), 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, the alkyl group is substituted with one or more deuterium atoms, examples of which include -CDH2, -CD2H, -CD3, -CD2CD3, and -CD2CD2CD3. In some embodiments, the alkyl group is substituted with one or more fluorine atoms, i.e., a fluoroalkyl group. In some embodiments, the fluorine-to-carbon atom ratio in the fluoroalkyl group includes 1:6, 1:5, 1:4, 1:3, 2:5, 1:2, 2:3, 1:1, 4:3, 3:2, 5:3, 2:1, 5:2.3:1, or any range in between. Examples of fluoroalkyl groups include -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CH2CF2CHF2, -CH2CF2CF3, -CH(CF3)2, -CH(CH3)CF3, -CF2CH2CH2F, -CF2CH2CHF2, -CF2CH2CF3, -CF2CH2CH3, -CF2CH2CH2CH3, Examples include, but are not limited to, -CF2CH2CH2CH2CH3 and -CF2CH2CH2CH2CH2CH3. In some embodiments, the alkyl group is substituted with one or more deuterium atoms and one or more fluorine atoms, examples of which include -CD2CH2F, -CD2CHF2, -CD2CF3, -CD2CH2CH2F, -CD2CH2CHF2, -CD2CH2CF3, -CD2CD2CH2, -CD2CD2CHF2, -CD2CD2CF3, -CD2CH2CH2CH2F, -CD2CH2CH2CHF2, -CD2CH2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, Examples include, but are not limited to, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3. In some embodiments, R 7 This refers to substituted C1 alkyl groups, and there is a particular mention of C1 fluoroalkyl groups.

[0129] In some embodiments, R 7 These are unsubstituted or substituted alkenyls, such as unsubstituted or substituted allyls, butenyls, and clotyls.

[0130] In some embodiments, R 7 This is an unsubstituted or substituted alkynyl, for example, an unsubstituted or substituted propargyl.

[0131] In some embodiments, R 7 This refers to unsubstituted or substituted cycloalkyl groups, for example, unsubstituted or substituted C3-C3 groups. 10 It is a cycloalkyl, or an unsubstituted or substituted C4-C8 cycloalkyl, or an unsubstituted or substituted C5-C6 cycloalkyl. In some embodiments, R 7 This refers to unsubstituted cycloalkyl groups (e.g., unsubstituted C3-C3). 10 These are cycloalkyl compounds, and examples include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 7This refers to substituted cycloalkyls (for example, substituted C3-C3). 10 A cycloalkyl group is a cycloalkyl group. The cycloalkyl group may be substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one or more substituents.

[0132] In some embodiments, R 7 is an unsubstituted or substituted heterocycloalkyl group. In some embodiments, the unsubstituted or substituted heterocycloalkyl group may be a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring. In some embodiments, R 7 R is an unsubstituted heterocycloalkyl, such as those described herein, and examples include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, and 1,3-dioxolane. In some embodiments, R 7 The substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), oxo, and hydroxyl, and may be any of those listed herein. The heterocycloalkyl group may contain one or more substituents.

[0133] In some embodiments, R 7 is a non-substituted or substituted aryl. In some embodiments, R 7R is an unsubstituted aryl, and examples include, but are not limited to, phenyl and naphthyl. In some embodiments, R 7 The substituent is a substituted aryl group. The substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl, and any other group listed herein. The aryl group may contain one or more substituents.

[0134] In some embodiments, R 7 is an unsubstituted or substituted heteroaryl. In some embodiments, R 7 R is an unsubstituted heteroaryl, and examples include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, indolyl, benzofuranyl, benzothiophenyl, thiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and pyrazolyl. In some embodiments, R 7 The group is a substituted heteroaryl group. Substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl groups, and any other group listed herein. The heteroaryl group may contain one or more substituents.

[0135] In some embodiments, R 4 R 7 -S(O)- and X 1 , X 2, Y 1 , Y 2 And, R 3 Each of them is hydrogen, and each R a If R is methyl, 7 R is not methyl (CH3-), n-propyl (CH3CH2CH2-), 2-hydroxypropyl (CH3CH(OH)CH2-), or 3-hydroxypropyl (HOCH2CH2CH2-). In some embodiments, R 4 R 7 -S(O)- and X 1 , X 2 , Y 1 , Y 2 And, R 3 Each of them is hydrogen, and each R a If R is methyl, 7 These are methyl, n-propyl, 2-hydroxypropyl, or 3-hydroxypropyl.

[0136] In some embodiments, R 4 R 8 It is -S(O)2-.

[0137] In some embodiments, R 8 is an unsubstituted or substituted alkyl group. In some embodiments, R 8 This is an unsubstituted or substituted C1-C8 alkyl group, for example, an unsubstituted or substituted C1 alkyl group, an unsubstituted or substituted C2 alkyl group, an unsubstituted or substituted C3 alkyl group, an unsubstituted or substituted C4 alkyl group, an unsubstituted or substituted C5 alkyl group, an unsubstituted or substituted C6 alkyl group, an unsubstituted or substituted C7 alkyl group, or an unsubstituted or substituted C8 alkyl group. In some embodiments, R 8 is an unsubstituted or substituted linear alkyl. In some embodiments, R 8 is an unsubstituted or substituted branched alkyl group. In some embodiments, R 8 These are unsubstituted alkyl groups (e.g., unsubstituted C1-C8 alkyl groups), and examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl, with particular mention of t-butyl.

[0138] In some embodiments, R 8 The alkyl group is a substituted alkyl group (e.g., a substituted C1-C8 alkyl group). The alkyl group may contain one or more substituents. The alkyl group may be substituted with any one or more substituents listed herein, examples of which include polar substituents such as deuterium, halogens (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), 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, the alkyl group is substituted with one or more deuterium atoms, examples of which include -CDH2, -CD2H, -CD3, -CD2CD3, and -CD2CD2CD3. In some embodiments, the alkyl group is substituted with one or more fluorine atoms, i.e., a fluoroalkyl group. In some embodiments, the fluorine-to-carbon atom ratio in the fluoroalkyl group includes 1:6, 1:5, 1:4, 1:3, 2:5, 1:2, 2:3, 1:1, 4:3, 3:2, 5:3, 2:1, 5:2.3:1, or any range in between. Examples of fluoroalkyl groups include -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CH2CF2CHF2, -CH2CF2CF3, -CH(CF3)2, -CH(CH3)CF3, -CF2CH2CH2F, -CF2CH2CHF2, -CF2CH2CF3, -CF2CH2CH3, -CF2CH2CH2CH3, Examples include, but are not limited to, -CF2CH2CH2CH2CH3 and -CF2CH2CH2CH2CH2CH3. In some embodiments, the alkyl group is substituted with one or more deuterium atoms and one or more fluorine atoms, examples of which include -CD2CH2F, -CD2CHF2, -CD2CF3, -CD2CH2CH2F, -CD2CH2CHF2, -CD2CH2CF3, -CD2CD2CH2, -CD2CD2CHF2, -CD2CD2CF3, -CD2CH2CH2CH2F, -CD2CH2CH2CHF2, -CD2CH2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, Examples include, but are not limited to, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3. In some embodiments, R 8 This refers to substituted C1 alkyl groups, and there is a particular mention of C1 fluoroalkyl groups.

[0139] In some embodiments, R 8 These are unsubstituted or substituted alkenyls, such as unsubstituted or substituted allyls, butenyls, and clotyls.

[0140] In some embodiments, R 8 This is an unsubstituted or substituted alkynyl, for example, an unsubstituted or substituted propargyl.

[0141] In some embodiments, R 8 This refers to unsubstituted or substituted cycloalkyl groups, for example, unsubstituted or substituted C3-C3 groups. 10 It is a cycloalkyl, or an unsubstituted or substituted C4-C8 cycloalkyl, or an unsubstituted or substituted C5-C6 cycloalkyl. In some embodiments, R 8 This refers to unsubstituted cycloalkyl groups (e.g., unsubstituted C3-C3). 10 These are cycloalkyl compounds, and examples include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 8This refers to substituted cycloalkyls (for example, substituted C3-C3). 10 A cycloalkyl group is a cycloalkyl group. The cycloalkyl group may be substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one or more substituents.

[0142] In some embodiments, R 8 is an unsubstituted or substituted heterocycloalkyl group. In some embodiments, the unsubstituted or substituted heterocycloalkyl group may be a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring. In some embodiments, R 8 R is an unsubstituted heterocycloalkyl, such as those described herein, and examples include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, and 1,3-dioxolane. In some embodiments, R 8 The substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), oxo, and hydroxyl, and may be any of those listed herein. The heterocycloalkyl group may contain one or more substituents.

[0143] In some embodiments, R 8 is a non-substituted or substituted aryl. In some embodiments, R 8R is an unsubstituted aryl, and examples include, but are not limited to, phenyl and naphthyl. In some embodiments, R 8 The substituent is a substituted aryl group. The substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl, and any other group listed herein. The aryl group may contain one or more substituents.

[0144] In some embodiments, R 8 is an unsubstituted or substituted heteroaryl. In some embodiments, R 8 R is an unsubstituted heteroaryl, and examples include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, indolyl, benzofuranyl, benzothiophenyl, thiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and pyrazolyl. In some embodiments, R 8 The group is a substituted heteroaryl group. Substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl groups, and any other group listed herein. The heteroaryl group may contain one or more substituents.

[0145] In some embodiments, R 4 R 8 -S(O)2- and X 1 , X 2, Y 1 , Y 2 And, R 3 Each of them is hydrogen, and each R a If R is methyl, 8 R is not methyl (CH3-), n-propyl (CH3CH2CH2-), 2-hydroxypropyl (CH3CH(OH)CH2-), or 3-hydroxypropyl (HOCH2CH2CH2-). In some embodiments, R 4 R 8 -S(O)2- and X 1 , X 2 , Y 1 , Y 2 And, R 3 Each of them is hydrogen, and each R a If R is methyl, 8 These are methyl, n-propyl, 2-hydroxypropyl, or 3-hydroxypropyl.

[0146] In some embodiments, R 4 R 9 It is -SS-.

[0147] In some embodiments, R 9 is an unsubstituted or substituted alkyl group. In some embodiments, R 9 This is an unsubstituted or substituted C1-C8 alkyl group, for example, an unsubstituted or substituted C1 alkyl group, an unsubstituted or substituted C2 alkyl group, an unsubstituted or substituted C3 alkyl group, an unsubstituted or substituted C4 alkyl group, an unsubstituted or substituted C5 alkyl group, an unsubstituted or substituted C6 alkyl group, an unsubstituted or substituted C7 alkyl group, or an unsubstituted or substituted C8 alkyl group. In some embodiments, R 9 is an unsubstituted or substituted linear alkyl. In some embodiments, R 9 is an unsubstituted or substituted branched alkyl group. In some embodiments, R 9 These are unsubstituted alkyl groups (e.g., unsubstituted C1-C8 alkyl groups), and examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl, with particular mention of t-butyl.

[0148] In some embodiments, R 9 The alkyl group is a substituted alkyl group (e.g., a substituted C1-C8 alkyl group). The alkyl group may contain one or more substituents. The alkyl group may be substituted with any one or more substituents listed herein, examples of which include polar substituents such as deuterium, halogens (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), 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, the alkyl group is substituted with one or more deuterium atoms, examples of which include -CDH2, -CD2H, -CD3, -CD2CD3, and -CD2CD2CD3. In some embodiments, the alkyl group is substituted with one or more fluorine atoms, i.e., a fluoroalkyl group. In some embodiments, the fluorine-to-carbon atom ratio in the fluoroalkyl group includes 1:6, 1:5, 1:4, 1:3, 2:5, 1:2, 2:3, 1:1, 4:3, 3:2, 5:3, 2:1, 5:2.3:1, or any range in between. Examples of fluoroalkyl groups include -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CH2CF2CHF2, -CH2CF2CF3, -CH(CF3)2, -CH(CH3)CF3, -CF2CH2CH2F, -CF2CH2CHF2, -CF2CH2CF3, -CF2CH2CH3, -CF2CH2CH2CH3, Examples include, but are not limited to, -CF2CH2CH2CH2CH3 and -CF2CH2CH2CH2CH2CH3. In some embodiments, the alkyl group is substituted with one or more deuterium atoms and one or more fluorine atoms, examples of which include -CD2CH2F, -CD2CHF2, -CD2CF3, -CD2CH2CH2F, -CD2CH2CHF2, -CD2CH2CF3, -CD2CD2CH2, -CD2CD2CHF2, -CD2CD2CF3, -CD2CH2CH2CH2F, -CD2CH2CH2CHF2, -CD2CH2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, Examples include, but are not limited to, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3. In some embodiments, R 9 This refers to substituted C1 alkyl groups, and there is a particular mention of C1 fluoroalkyl groups.

[0149] In some embodiments, R 9 These are unsubstituted or substituted alkenyls, such as unsubstituted or substituted allyls, butenyls, and clotyls.

[0150] In some embodiments, R 9 This is an unsubstituted or substituted alkynyl, for example, an unsubstituted or substituted propargyl.

[0151] In some embodiments, R 9 This refers to unsubstituted or substituted cycloalkyl groups, for example, unsubstituted or substituted C3-C3 groups. 10 It is a cycloalkyl, or an unsubstituted or substituted C4-C8 cycloalkyl, or an unsubstituted or substituted C5-C6 cycloalkyl. In some embodiments, R 9 This refers to unsubstituted cycloalkyl groups (e.g., unsubstituted C3-C3). 10 These are cycloalkyl compounds, and examples include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 9This refers to substituted cycloalkyls (for example, substituted C3-C3). 10 A cycloalkyl group is a cycloalkyl group. The cycloalkyl group may be substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one or more substituents.

[0152] In some embodiments, R 9 is an unsubstituted or substituted heterocycloalkyl group. In some embodiments, the unsubstituted or substituted heterocycloalkyl group may be a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring. In some embodiments, R 9 R is an unsubstituted heterocycloalkyl, such as those described herein, and examples include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, and 1,3-dioxolane. In some embodiments, R 9 The substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), oxo, and hydroxyl, and may be any of those listed herein. The heterocycloalkyl group may contain one or more substituents.

[0153] In some embodiments, R 9 is a non-substituted or substituted aryl. In some embodiments, R 9R is an unsubstituted aryl, and examples include, but are not limited to, phenyl and naphthyl. In some embodiments, R 9 The substituent is a substituted aryl group. The substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl, and any other group listed herein. The aryl group may contain one or more substituents.

[0154] In some embodiments, R 9 is an unsubstituted or substituted heteroaryl. In some embodiments, R 9 R is an unsubstituted heteroaryl, and examples include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, indolyl, benzofuranyl, benzothiophenyl, thiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and pyrazolyl. In some embodiments, R 9 The group is a substituted heteroaryl group. Substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl groups, and any other group listed herein. The heteroaryl group may contain one or more substituents.

[0155] In some embodiments, R 4 R 10 It is -C(Z)-.

[0156] Z can be O or S. In some embodiments, Z is O. In some embodiments, Z is S.

[0157] In some embodiments, R 10 is an unsubstituted or substituted alkyl group. In some embodiments, R 10 This is an unsubstituted or substituted C1-C8 alkyl group, for example, an unsubstituted or substituted C1 alkyl group, an unsubstituted or substituted C2 alkyl group, an unsubstituted or substituted C3 alkyl group, an unsubstituted or substituted C4 alkyl group, an unsubstituted or substituted C5 alkyl group, an unsubstituted or substituted C6 alkyl group, an unsubstituted or substituted C7 alkyl group, or an unsubstituted or substituted C8 alkyl group. In some embodiments, R 10 is an unsubstituted or substituted linear alkyl. In some embodiments, R 10 is an unsubstituted or substituted branched alkyl group. In some embodiments, R 10 These are unsubstituted alkyl groups (e.g., unsubstituted C1-C8 alkyl groups), and examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl, with particular mention of t-butyl.

[0158] In some embodiments, R 10The alkyl group is a substituted alkyl group (e.g., a substituted C1-C8 alkyl group). The alkyl group may contain one or more substituents. The alkyl group may be substituted with any one or more substituents listed herein, examples of which include polar substituents such as deuterium, halogens (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), 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, the alkyl group is substituted with one or more deuterium atoms, examples of which include -CDH2, -CD2H, -CD3, -CD2CD3, and -CD2CD2CD3. In some embodiments, the alkyl group is substituted with one or more fluorine atoms, i.e., a fluoroalkyl group. In some embodiments, the fluorine-to-carbon atom ratio in the fluoroalkyl group includes 1:6, 1:5, 1:4, 1:3, 2:5, 1:2, 2:3, 1:1, 4:3, 3:2, 5:3, 2:1, 5:2.3:1, or any range in between. Examples of fluoroalkyl groups include -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CH2CF2CHF2, -CH2CF2CF3, -CH(CF3)2, -CH(CH3)CF3, -CF2CH2CH2F, -CF2CH2CHF2, -CF2CH2CF3, -CF2CH2CH3, -CF2CH2CH2CH3, Examples include, but are not limited to, -CF2CH2CH2CH2CH3 and -CF2CH2CH2CH2CH2CH3. In some embodiments, the alkyl group is substituted with one or more deuterium atoms and one or more fluorine atoms, examples of which include -CD2CH2F, -CD2CHF2, -CD2CF3, -CD2CH2CH2F, -CD2CH2CHF2, -CD2CH2CF3, -CD2CD2CH2, -CD2CD2CHF2, -CD2CD2CF3, -CD2CH2CH2CH2F, -CD2CH2CH2CHF2, -CD2CH2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, Examples include, but are not limited to, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3.

[0159] In some embodiments, R 10 These are unsubstituted or substituted alkenyls, such as unsubstituted or substituted butenyls.

[0160] In some embodiments, R 10 These are unsubstituted or substituted alkynyl compounds.

[0161] In some embodiments, R 10 This refers to unsubstituted or substituted cycloalkyl groups, for example, unsubstituted or substituted C3-C3 groups. 10 It is a cycloalkyl, or an unsubstituted or substituted C4-C8 cycloalkyl, or an unsubstituted or substituted C5-C6 cycloalkyl. In some embodiments, R 10 This refers to unsubstituted cycloalkyl groups (e.g., unsubstituted C3-C3). 10 These are cycloalkyl compounds, and examples include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 10 This refers to substituted cycloalkyls (for example, substituted C3-C3). 10A cycloalkyl group is a cycloalkyl group. The cycloalkyl group may be substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one or more substituents.

[0162] In some embodiments, R 10 is an unsubstituted or substituted heterocycloalkyl group. In some embodiments, the unsubstituted or substituted heterocycloalkyl group may be a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring. In some embodiments, R 10 R is an unsubstituted heterocycloalkyl, such as those described herein, and examples include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, and 1,3-dioxolane. In some embodiments, R 10 The substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), oxo, and hydroxyl, and may be any of those listed herein. The heterocycloalkyl group may contain one or more substituents.

[0163] In some embodiments, R 10 is a non-substituted or substituted aryl. In some embodiments, R 10R is an unsubstituted aryl, and examples include, but are not limited to, phenyl and naphthyl. In some embodiments, R 10 The substituent is a substituted aryl group. The substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl, and any other group listed herein. The aryl group may contain one or more substituents.

[0164] In some embodiments, R 10 is an unsubstituted or substituted heteroaryl. In some embodiments, R 10 R is an unsubstituted heteroaryl, and examples include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, indolyl, benzofuranyl, benzothiophenyl, thiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and pyrazolyl. In some embodiments, R 10 The group is a substituted heteroaryl group. Substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl groups, and any other group listed herein. The heteroaryl group may contain one or more substituents.

[0165] In some embodiments, R 4 R 11 R 12 It is -P(O)-.

[0166] R 11 and R 12 They may be the same or they may be different. In some embodiments, R 11 and R 12 They are the same. In some embodiments, R 11 and R 12 They are different. In some embodiments, R 11 and / or R 12 is an unsubstituted or substituted alkyl group. In some embodiments, R 11 and / or R 12 This is an unsubstituted or substituted C1-C8 alkyl group, for example, an unsubstituted or substituted C1 alkyl group, an unsubstituted or substituted C2 alkyl group, an unsubstituted or substituted C3 alkyl group, an unsubstituted or substituted C4 alkyl group, an unsubstituted or substituted C5 alkyl group, an unsubstituted or substituted C6 alkyl group, an unsubstituted or substituted C7 alkyl group, or an unsubstituted or substituted C8 alkyl group. In some embodiments, R 11 and / or R 12 is an unsubstituted or substituted linear alkyl. In some embodiments, R 11 and / or R 12 is an unsubstituted or substituted branched alkyl group. In some embodiments, R 11 and / or R 12 These are unsubstituted alkyl groups (e.g., unsubstituted C1-C8 alkyl groups), and examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl, with particular mention of methyl.

[0167] In some embodiments, R 11 and / or R 12The alkyl group is a substituted alkyl group (e.g., a substituted C1-C8 alkyl group). The alkyl group may contain one or more substituents. The alkyl group may be substituted with any one or more substituents listed herein, examples of which include polar substituents such as deuterium, halogens (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), 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, the alkyl group is substituted with one or more deuterium atoms, examples of which include -CDH2, -CD2H, -CD3, -CD2CD3, and -CD2CD2CD3. In some embodiments, the alkyl group is substituted with one or more fluorine atoms, i.e., a fluoroalkyl group. In some embodiments, the fluorine-to-carbon atom ratio in the fluoroalkyl group includes 1:6, 1:5, 1:4, 1:3, 2:5, 1:2, 2:3, 1:1, 4:3, 3:2, 5:3, 2:1, 5:2.3:1, or any range in between. Examples of fluoroalkyl groups include -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CH2CF2CHF2, -CH2CF2CF3, -CH(CF3)2, -CH(CH3)CF3, -CF2CH2CH2F, -CF2CH2CHF2, -CF2CH2CF3, -CF2CH2CH3, -CF2CH2CH2CH3, Examples include, but are not limited to, -CF2CH2CH2CH2CH3 and -CF2CH2CH2CH2CH2CH3. In some embodiments, the alkyl group is substituted with one or more deuterium atoms and one or more fluorine atoms, examples of which include -CD2CH2F, -CD2CHF2, -CD2CF3, -CD2CH2CH2F, -CD2CH2CHF2, -CD2CH2CF3, -CD2CD2CH2, -CD2CD2CHF2, -CD2CD2CF3, -CD2CH2CH2CH2F, -CD2CH2CH2CHF2, -CD2CH2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, Examples include, but are not limited to, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3.

[0168] In some embodiments, R 11 and / or R 12 These are unsubstituted or substituted alkenyls, such as unsubstituted or substituted allyls, butenyls, and clotyls.

[0169] In some embodiments, R 11 and / or R 12 This is an unsubstituted or substituted alkynyl, for example, an unsubstituted or substituted propargyl.

[0170] In some embodiments, R 11 and / or R 12 This refers to unsubstituted or substituted cycloalkyl groups, for example, unsubstituted or substituted C3-C3 groups. 10 It is a cycloalkyl, or an unsubstituted or substituted C4-C8 cycloalkyl, or an unsubstituted or substituted C5-C6 cycloalkyl. In some embodiments, R 11 and R 12 This refers to unsubstituted cycloalkyl groups (e.g., unsubstituted C3-C3). 10 These are cycloalkyl compounds, and examples include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R11 and / or R 12 This refers to substituted cycloalkyls (for example, substituted C3-C3). 10 A cycloalkyl group is a cycloalkyl group. The cycloalkyl group may be substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one or more substituents.

[0171] In some embodiments, R 11 and / or R 12 is an unsubstituted or substituted heterocycloalkyl group. In some embodiments, the unsubstituted or substituted heterocycloalkyl group may be a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring. In some embodiments, R 11 and / or R 12 R is an unsubstituted heterocycloalkyl, such as those described herein, and examples include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, and 1,3-dioxolane. In some embodiments, R 11 and / or R 12 The substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), oxo, and hydroxyl, and may be any of those listed herein. The heterocycloalkyl group may contain one or more substituents.

[0172] In some embodiments, R 11 and / or R 12 is a non-substituted or substituted aryl. In some embodiments, R 11 and / or R 12 R is an unsubstituted aryl, and examples include, but are not limited to, phenyl and naphthyl. In some embodiments, R 11 and / or R 12 The substituent is a substituted aryl group. The substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl, and any other group listed herein. The aryl group may contain one or more substituents.

[0173] In some embodiments, R 11 and / or R 12 is an unsubstituted or substituted heteroaryl. In some embodiments, R 11 and / or R 12 R is an unsubstituted heteroaryl, and examples include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, indolyl, benzofuranyl, benzothiophenyl, thiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and pyrazolyl. In some embodiments, R 11 and / or R 12The group is a substituted heteroaryl group. Substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl groups, and any other group listed herein. The heteroaryl group may contain one or more substituents.

[0174] In some embodiments, R 4 R 13 R 14 It is -N-.

[0175] R 13 and R 14 They may be the same or they may be different. In some embodiments, R 13 and R 14 They are the same. In some embodiments, R 13 and R 14 They are different.

[0176] In some embodiments, R 13 and / or R 14 is unsubstituted C2~C 10 Alkyl, for example, unsubstituted C2 alkyl, unsubstituted C3 alkyl, unsubstituted C4 alkyl, unsubstituted C5 alkyl, unsubstituted C6 alkyl, unsubstituted C7 alkyl, unsubstituted C8 alkyl, unsubstituted C9 alkyl, or unsubstituted C 10 It is alkyl. In some embodiments, R 13 and / or R 14 This is a non-substituted linear C2~C 10 It is alkyl. In some embodiments, R 13 and / or R 14 This is a non-substituted branched C3~C 10 It is alkyl. Unsubstituted C2~C 10Examples of alkyl groups include, but are not limited to, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl, with particular mention of isopropyl.

[0177] In some embodiments, R 13 and / or R 14 The alkyl group is a substituted alkyl group (e.g., a substituted C1-C8 alkyl group). The substituted alkyl group may be, for example, a substituted C1 alkyl group, a substituted C2 alkyl group, a substituted C3 alkyl group, a substituted C4 alkyl group, a substituted C5 alkyl group, a substituted C6 alkyl group, a substituted C7 alkyl group, or a substituted C8 alkyl group. The alkyl group may contain one or more substituents. The alkyl group may be substituted with any one or more substituents listed herein, examples of which include, but are not limited to, polar substituents such as deuterium, halogens (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), 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, the alkyl group is substituted with one or more deuterium atoms, examples of which include, but are not limited to, -CDH2, -CD2H, -CD3, -CD2CD3, and -CD2CD2CD3. In some embodiments, the alkyl group is substituted with one or more fluorine atoms, i.e., it is a fluoroalkyl group. In some embodiments, the fluorine-to-carbon ratio in the fluoroalkyl group includes 1:6, 1:5, 1:4, 1:3, 2:5, 1:2, 2:3, 1:1, 4:3, 3:2, 5:3, 2:1, 5:2.3:1, or any range in between. Examples of fluoroalkyl groups include -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CH2CF2CHF2, -CH2CF2CF3, -CH(CF3)2, -CH(CH3)CF3, -CF2CH2CH2F 、 -CF2CH2CHF2, -CF2CH2CF3, -CF2CH2CH3, Examples include -CF2CH2CH2CH3, -CF2CH2CH2CH2CH3, and P-CF2CH2CH2CH2CH2CH3, but are not limited to these.

[0178] In some embodiments, the alkyl group is substituted with one or more deuterium atoms and one or more fluorine atoms, examples of which include -CD2CH2FCD2CHF2, CD2CF3, CD2CH2CH2F, CD2CH2CHF2, CD2CH2CF3, CD2CD2CH2, CD2CD2CHF2, CD2CD2CF3, CD2CH2CH2CH2F, CD2CH2CH2CHF2, CD2CH2CH2CF3, CD2CD2CH2CH2F, CD2CD2CH2CHF2, CD2CD2CH2CF3, Examples include, but are not limited to, CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3. In some embodiments, 13 and / or R 14 This refers to substituted C1 alkyl groups, and there is a particular mention of C1 fluoroalkyl groups.

[0179] In some embodiments, R 13 and / or R 14 These are unsubstituted or substituted alkenyls, such as unsubstituted or substituted allyls, butenyls, and clotyls.

[0180] In some embodiments, R 13 and / or R 14 This is an unsubstituted or substituted alkynyl, for example, an unsubstituted or substituted propargyl.

[0181] In some embodiments, R 13 and / or R14 This refers to unsubstituted or substituted cycloalkyl groups, for example, unsubstituted or substituted C3-C3 groups. 10 It is a cycloalkyl, or an unsubstituted or substituted C4-C8 cycloalkyl, or an unsubstituted or substituted C5-C6 cycloalkyl. In some embodiments, R 13 and R 14 This refers to unsubstituted cycloalkyl groups (e.g., unsubstituted C3-C3). 10 These are cycloalkyl compounds, and examples include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 13 and / or R 14 This refers to substituted cycloalkyls (for example, substituted C3-C3). 10 A cycloalkyl group is a cycloalkyl group. The cycloalkyl group may be substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one or more substituents.

[0182] In some embodiments, R 13 and / or R 14 is an unsubstituted or substituted heterocycloalkyl group. In some embodiments, the unsubstituted or substituted heterocycloalkyl group may be a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring. In some embodiments, R 13 and / or R 14R is an unsubstituted heterocycloalkyl, such as those described herein, and examples include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, and 1,3-dioxolane. In some embodiments, R 13 and / or R 14 The substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), oxo, and hydroxyl, and may be any of those listed herein. The heterocycloalkyl group may contain one or more substituents.

[0183] In some embodiments, R 13 and / or R 14 is a non-substituted or substituted aryl. In some embodiments, R 13 and / or R 14 R is an unsubstituted aryl, and examples include, but are not limited to, phenyl and naphthyl. In some embodiments, R 13 and / or R 14 The substituent is a substituted aryl group. The substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl, and any other group listed herein. The aryl group may contain one or more substituents.

[0184] In some embodiments, R 13 and / or R 14is an unsubstituted or substituted heteroaryl. In some embodiments, R 13 and / or R 14 R is an unsubstituted heteroaryl, and examples include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, indolyl, benzofuranyl, benzothiophenyl, thiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and pyrazolyl. In some embodiments, R 13 and / or R 14 The group is a substituted heteroaryl group. Substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl groups, and any other group listed herein. The heteroaryl group may contain one or more substituents.

[0185] In some embodiments, R 13 and R 14 These atoms bond together with the nitrogen atoms attached to them to form an unsubstituted heterocycloalkyl or substituted heterocycloalkyl having at least two heterocyclic atoms.

[0186] In some embodiments, R 13 and R 14 These atoms bond together with the nitrogen atoms bonded to them to form an unsubstituted heterocycloalkyl group having at least two heterocyclic atoms. The unsubstituted heterocycloalkyl group having at least two heterocyclic atoms may be, for example, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., and these may be optionally fused with other rings. The unsubstituted heterocycloalkyl group having at least two heterocyclic atoms has at least one nitrogen ring atom (R 13 and R14 It contains a nitrogen atom interposed therein, together with at least one additional heterocyclic atom, which may be one or more of nitrogen, sulfur, or oxygen, totaling two, three, or four heterocyclic atoms (at least one of which is a nitrogen ring atom). 13 and R 14 However, an example of an unsubstituted heterocycloalkyl group having at least two heterocyclic atoms formed by bonding together with the nitrogen atoms bonded to them is: [ka] These include, but are not limited to, the following:

[0187] In some embodiments, R 13 and R 14 These combine with the nitrogen atoms bonded to them to form a substituted heterocycloalkyl group. The substituted heterocycloalkyl group may be, for example, a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring, and these may be optionally fused with other rings. The substituted heterocycloalkyl group has at least one nitrogen ring atom (R 13 and R 14The substituted heterocycloalkyl groups contain a nitrogen atom interposed between them, and optionally contain additional heterocyclic atoms (e.g., nitrogen, sulfur, or oxygen) totaling 1, 2, 3, or 4 heterocyclic atoms (at least one of which is a nitrogen ring atom). Examples of substituted heterocycloalkyl groups, but not limited to these, include aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, or thiomorpholine, which are substituted with at least one substituent. Substituents include, but are not limited to, any of the substituents listed herein, such as deuterium, halogens (e.g., fluorine), polar substituents such as hydroxyl and oxo, unsubstituted alkoxys, substituted alkoxys (e.g., polyether groups), unsubstituted alkenyls, substituted alkenyls, unsubstituted alkynyls, substituted alkynyls, unsubstituted cycloalkyls, substituted cycloalkyls, unsubstituted heterocycloalkyls, substituted heterocycloalkyls, unsubstituted aryls, substituted aryls, unsubstituted heteroaryls, and substituted heteroaryls. 13 and R 14 However, substituted heterocycloalkyls formed by bonding together with the nitrogen atoms bonded to them include heterocycloalkyls substituted with one, two, three, four, or more substituents. The substituents may be located on the carbocyclic atom or on the heterocyclic atom.

[0188] R 13 and R 14 However, examples of substituted heterocycloalkyl groups formed by bonding together with the nitrogen atoms bonded to them include: [ka] These include, but are not limited to, the following:

[0189] In some embodiments, R 4 R 15 It is -Se-.

[0190] In some embodiments, R 15 is unsubstituted C2~C 10 Alkyl, for example, unsubstituted C2 alkyl, unsubstituted C3 alkyl, unsubstituted C4 alkyl, unsubstituted C5 alkyl, unsubstituted C6 alkyl, unsubstituted C7 alkyl, unsubstituted C8 alkyl, unsubstituted C9 alkyl, or unsubstituted C 10 It is alkyl. In some embodiments, R 15 This is a non-substituted linear C2~C 10 It is alkyl. In some embodiments, R 15 This is a non-substituted branched C3~C 10 It is alkyl. Unsubstituted C2~C 10 Examples of alkyl groups include, but are not limited to, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.

[0191] In some embodiments, R 15The alkyl group is a substituted alkyl group (e.g., a substituted C1-C8 alkyl group). The substituted alkyl group may be, for example, a substituted C1 alkyl group, a substituted C2 alkyl group, a substituted C3 alkyl group, a substituted C4 alkyl group, a substituted C5 alkyl group, a substituted C6 alkyl group, a substituted C7 alkyl group, or a substituted C8 alkyl group. The alkyl group may contain one or more substituents. The alkyl group may be substituted with any one or more substituents listed herein, examples of which include, but are not limited to, polar substituents such as deuterium, halogens (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), 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, the alkyl group is substituted with one or more deuterium atoms, examples of which include, but are not limited to, -CDH2, -CD2H, -CD3, -CD2CD3, and -CD2CD2CD3. In some embodiments, the alkyl group is substituted with one or more fluorine atoms, i.e., it is a fluoroalkyl group. In some embodiments, the fluorine-to-carbon ratio in the fluoroalkyl group includes 1:6, 1:5, 1:4, 1:3, 2:5, 1:2, 2:3, 1:1, 4:3, 3:2, 5:3, 2:1, 5:2.3:1, or any range in between. Examples of fluoroalkyl groups include -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CH2CF2CHF2, -CH2CF2CF3, -CH(CF3)2, -CH(CH3)CF3, -CF2CH2CH2F 、 -CF2CH2CHF2, -CF2CH2CF3, -CF2CH2CH3, Examples include, but are not limited to, -CF2CH2CH2CH3, -CF2CH2CH2CH2CH3, and -CF2CH2CH2CH2CH2CH3. In some embodiments, the alkyl group is substituted with one or more deuterium atoms and one or more fluorine atoms, examples of which include -CD2CH2F, -CD2CHF2, -CD2CF3, -CD2CH2CH2F, -CD2CH2CHF2, -CD2CH2CF3, -CD2CD2CH2, -CD2CD2CHF2, -CD2CD2CF3, -CD2CH2CH2CH2F, -CD2CH2CH2CHF2, -CD2CH2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3 is an example, but is not limited to these. In some embodiments, R 15 This refers to substituted C1 alkyl groups, and there is a particular mention of C1 fluoroalkyl groups.

[0192] In some embodiments, R 15 These are unsubstituted or substituted alkenyls, such as unsubstituted or substituted allyls, butenyls, and clotyls.

[0193] In some embodiments, R 15 This is an unsubstituted or substituted alkynyl, for example, an unsubstituted or substituted propargyl.

[0194] In some embodiments, R 15 This refers to unsubstituted or substituted cycloalkyl groups, for example, unsubstituted or substituted C3-C3 groups. 10 It is a cycloalkyl, or an unsubstituted or substituted C4-C8 cycloalkyl, or an unsubstituted or substituted C5-C6 cycloalkyl. In some embodiments, R 15 This refers to unsubstituted cycloalkyl groups (e.g., unsubstituted C3-C3). 10These are cycloalkyl compounds, and examples include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R 15 This refers to substituted cycloalkyls (for example, substituted C3-C3). 10 A cycloalkyl group is a cycloalkyl group. The cycloalkyl group may be substituted with any one or more substituents listed herein, examples of which include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one or more substituents.

[0195] In some embodiments, R 15 is an unsubstituted or substituted heterocycloalkyl group. In some embodiments, the unsubstituted or substituted heterocycloalkyl group may be a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring. In some embodiments, R 15 R is an unsubstituted heterocycloalkyl, such as those described herein, and examples include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, and 1,3-dioxolane. In some embodiments, R 15The substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), oxo, and hydroxyl, and may be any of those listed herein. The heterocycloalkyl group may contain one or more substituents.

[0196] In some embodiments, R 15 is a non-substituted or substituted aryl. In some embodiments, R 15 R is an unsubstituted aryl, and examples include, but are not limited to, phenyl and naphthyl. In some embodiments, R 15 The substituent is a substituted aryl group. The substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl, and any other group listed herein. The aryl group may contain one or more substituents.

[0197] In some embodiments, R 15 is an unsubstituted or substituted heteroaryl. In some embodiments, R 15 R is an unsubstituted heteroaryl, and examples include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, indolyl, benzofuranyl, benzothiophenyl, thiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and pyrazolyl. In some embodiments, R 15The group is a substituted heteroaryl group. Substituents include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl groups, and any other group listed herein. The heteroaryl group may contain one or more substituents.

[0198] In some embodiments, the compound of formula (I) has the structure of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), or formula (VIII), including any exemplary compound thereof provided below.

[0199] Formula (II) In some embodiments, the compound of formula (I) has the structure of formula (II), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. [ka] During the ceremony, X 1 , X 2 , Y 1 , Y 2 , R 3 , R a , and R 7 This is defined for equation (I). In some embodiments, a compound, for example, the compound of formula (II), [ka] [ka] [ka]

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0200] In some embodiments, X 1 , X 2 , Y 1 , Y 2 , and R 3 are each hydrogen, and when each R a is methyl, R 7 is not methyl, n-propyl, 2-hydroxypropyl, or 3-hydroxypropyl. In some embodiments, the compound is compound II-26 (a compound of formula (II) in which X1 , X 2 , Y 1 , Y 2 , and R 3 are each hydrogen, and each R a is methyl, and R 7 is methyl, is not the compound). In some embodiments, the compound is Compound II-27 (a compound of formula (II) wherein X 1 , X 2 , Y 1 , Y 2 , and R 3 are each hydrogen, and each R a is methyl, and R 7 is n-propyl, is not the compound). In some embodiments, the compound is Compound II-28 (a compound of formula (II) wherein X 1 , X 2 , Y 1 , Y 2 , and R 3 are each hydrogen, and each R a is methyl, and R 7 is 2-hydroxypropyl, is not the compound). In some embodiments, the compound is Compound II-29 (a compound of formula (II) wherein X 1 , X 2 , Y 1 , Y 2 , and R 3 are each hydrogen, and each R a is methyl, and R 7 is 3-hydroxypropyl, is not the compound). In some embodiments, when X 1 , X 2 , Y 1 , Y 2 , and R 3 are each hydrogen, and each R a is methyl, R 7 is methyl, n-propyl, 2-hydroxypropyl, or 3-hydroxypropyl.

[0201] Formula (III) In some embodiments, the compound of formula (I) has the structure of formula (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. [ka] During the ceremony, X 1 , X 2 , Y 1 , Y 2 , R 3 , R a , and R 8 This is defined for equation (I). In some embodiments, a compound, for example, the compound of formula (III), [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Alternatively, a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof may be selected from the group.

[0202] Formula (IV) In some embodiments, the compound of formula (I) has the structure of formula (IV), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. [ka] During the ceremony, X 1 , X 2 , Y 1 , Y 2 , R 3 , R a , and R 9 This is defined for equation (I).

[0203] In some embodiments, a compound, for example, the compound of formula (IV), [ka] [ka] [ka] [ka] [ka] [ka] Alternatively, a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof may be selected from the group.

[0204] Formula (V) In some embodiments, the compound of formula (I) has the structure of formula (V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. [ka] During the ceremony, X 1 , X 2 , Y 1 , Y 2 , R 3 , R a , and R 10 This is defined for equation (I).

[0205] In some embodiments, a compound, for example, a compound of formula (V), [ka] [ka] [ka] [ka] [ka] selected from the group consisting of or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug.

[0206] Formula (VI) In some embodiments, the compound of formula (I) has the structure of formula (VI), or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug,

Chemical formula

[0207] In some embodiments, a compound, for example, a compound of formula (VI)

Chemical formula

Chemical formula

[0208] Formula (VII) In some embodiments, the compound of formula (I) has the structure of formula (VII), or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug,

Chemical formula

[0209] In some embodiments, a compound, for example, a compound of formula (VII), [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Alternatively, a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof may be selected from the group.

[0210] Formula (VIII) In some embodiments, the compound of formula (I) has the structure of formula (VIII), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. [ka] During the ceremony, X 1 , X 2 , Y 1 , Y 2 , R 3 , R a , and R 15 This is defined for equation (I).

[0211] In some embodiments, a compound, for example, a compound of formula (VIII), [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Alternatively, a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof may be selected from the group.

[0212] Compounds of formulas (I) to (VIII) may contain a chiral center. In such cases, formulas (I) to (VIII) are drawn without considering stereochemistry, but the compounds may exist as different stereoisomers. Therefore, this disclosure includes all possible stereoisomers, including not only racemic compounds but also individual enantiomers (enantiomerically pure compounds), individual diastereomers (diastereomerically pure compounds), and non-racemic mixtures thereof. If a compound is desired as a single enantiomer, it can be obtained, for example, by stereospecific synthesis, chiral resolution, or a combination thereof, as is known in the art. One non-limiting example is R 4 However, R 7 R is -S(O)- 4 Examples include compounds of formula (II) containing a sulfoxide functional group represented by . As is known in the art, the bond between the sulfur atom and the oxygen atom in sulfoxides is an intermediate between a coordinate bond and a polarizing double bond. For the sake of simplification (and without considering stereochemistry), the double bond configuration (S=O) is depicted herein, but the sulfur-oxygen interaction has an electrostatic aspect, resulting in a pronounced bipolar property with a negative charge centered on oxygen. A lone pair of electrons resides on the sulfur atom, giving it a tetrahedral electron pair structure and a trigonal pyramidal shape. As a result, the sulfur atom becomes a stereoforming center when the two organic residues bonded to the sulfur atom are different. The energy barrier required to invert this stereocenter is sufficiently high that most sulfoxides are optically stable around room temperature. Accordingly, this disclosure includes all possible stereoisomers of sulfoxide compounds, including not only racemic compounds but also individual enantiomers (enantiomerically pure compounds) and diastereomers of the compounds, as far as they exist.

[0213] In some embodiments, the compounds described herein, for example, the compounds of formulas (I) to (VIII), are nonstereoisomers. In some embodiments, the compounds described herein, for example, the compounds of formulas (I) to (VIII), are racemates. In some embodiments, the compounds described herein, for example, the compounds of formulas (I) to (VIII), are enantiomerically enriched (one enantiomer present in a higher proportion), including being enantiomerically pure. In some embodiments, the compounds described herein, for example, the compounds of formulas (I) to (VIII), are provided as single diastereomers. In some embodiments, the compounds described herein, for example, the compounds of formulas (I) to (VIII), are provided as a mixture of diastereomers. When provided as a mixture of diastereomers, the mixture may include equal mixtures or mixtures enriched with a particular diastereomer (one diastereomer present in a higher proportion than another).

[0214] In some embodiments, the compounds of formulas (I) to (VIII) are agonists of the serotonin 5-HT2 receptor.

[0215] In some embodiments, the compounds of formulas (I) to (VIII) are serotonin 5-HT 2A It is a receptor agonist.

[0216] Furthermore, compounds of the present disclosure, such as pharmaceutically acceptable salts of the compounds of formulas (I) to (VIII), are disclosed herein. The acid used to form pharmaceutically acceptable salts of the compounds of formulas (I) to (VIII) may be monoacid, diacid, triacid, tetraacid, or may contain more acidic groups. The acidic groups may be, for example, carboxylic acids, sulfonic acids, phosphonic acids, or other acidic moieties containing at least one substituteable hydrogen atom.Examples of acids used in the preparation of pharmaceutically acceptable (acid addition) salts disclosed herein include acetic acid, 2,2-dichloroacetic acid, phenylacetic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphtha) (e.g., benzoic acid, p-toluenesulfonic acid, ethanedisulfonic acid), benzoic acid (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-aminosalicylic acid, gentisic acid, etc.), boric acid, (+)-camphoric acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecyl sulfate, formic acid, fumaric acid, galactaric acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, g Licolic 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, sugar acid, succinic acid, sulfuric acid, sulfamic acid, tannic acid, tartaric acid This includes, but is not limited to, fatty acids (including mono- and di-fatty acids, such as adipico(hexanedi)ic acid, laurico(dodecano)ic acid, linoleic acid, myristico(tetradecano)ic acid, capric(decano)ic acid, stearic(octadecano)ic acid, oleic acid, caprylic(octano)ic acid, palmitic(hexadeceno)ic acid, sebacic acid, undecylenic acid, caproic acid, etc.).

[0217] In some embodiments, pharmaceutically acceptable salts of the compounds of formulas (I) to (VIII) are benzenesulfonates, tartrates, hemifumarates, acetates, citrates, malons, fumarates, succinates, oxalates, benzoates, salicylates, ascorbicates, hydrochlorides, maleates, malates, methanesulfonates, toluenesulfonates, glucurons, or glutarates of the compounds of formulas (I) to (VIII). In some embodiments, pharmaceutically acceptable salts of the compounds of formulas (I) to (VIII) are salts formed from sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.). In some embodiments, pharmaceutically acceptable salts of the compounds of formulas (I) to (VIII) are salts formed from benzoic acids (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-aminosalicylic acid, etc.).

[0218] In some embodiments, the pharmaceutically acceptable salts of the compounds of formulas (I) to (VIII) are fatty acid salts. The fatty acids used to produce the fatty acid salts of the compounds of formulas (I) to (VIII) may be fatty monoacids or fatty diacids and may contain hydrogen and a fatty hydrocarbon moiety consisting of 4 to 6 to 8 to 10 to 12 to 14 to 16 to a maximum of 26 to 24 to 22 to 20 to 18 carbon atoms, which may be fully saturated or partially unsaturated. In some embodiments, the pharmaceutically acceptable salts of the compounds of formulas (I) to (VIII) are adipine, laurate, linoleate, myristicate, caprate, stearate, oleate, caprylate, palmitate, sebacinate, undecylenate, or caproate of the compounds of formulas (I) to (VIII).

[0219] Methods for preparing pharmaceutically acceptable salt forms of pharmaceutical compounds are known to those skilled in the art. In some embodiments, the method is: (a) Suspending the compounds of formulas (I) to (VIII) in a solvent or a mixture of solvents, (b) To provide a mixture by contacting an acid with a compound of formula (I) to (VIII), (c) Selectively heating the mixture, (d) Optionally cooling the mixture, (e) including isolating the salt.

[0220] The disclosed method may use a variety of solvents, including one or more protic solvents, one or more aprotic solvents, or mixtures thereof. In some embodiments, the solvent used in the method for preparing the salt is a protic solvent. In some embodiments, the solvent used in the method for preparing the salt is selected from the group consisting of methanol, ethanol, propanol, isopropanol, 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.

[0221] Acids suitable for use in the preparation of pharmaceutically acceptable acid addition salts may include those described above. 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 adipico(hexanedi) acid, laurico(dodecano) acid, linoleic acid, myristico(tetradecano) acid, capric(decano) acid, stearic(octadecano) acid, oleic acid, caprylic(octano) acid, palmitic(hexadeceno) acid, sebacic acid, undecylenic acid, caproic acid, and in particular adipico(hexanedi) acid, laurico(dodecano) acid, linoleic acid, myristico(tetradecano) acid, capric(decano) acid, stearic(octadecano) acid, oleic acid, and caprylic(octano) acid.

[0222] In some embodiments, a stoichiometric (or superstoichiometric) amount of acid is contacted with the compound of formulas (I) to (VIII). In some embodiments, a substoichiometric (e.g., 0.5 molar equivalent) amount of acid is contacted with the compound of formulas (I) to (VIII). For example, if the acid contains at least two acidic protons (e.g., two or more carboxylic acid groups) and the target salt is a hemate, the use of a substoichiometric amount of acid may be desirable.

[0223] In some embodiments, the mixture is heated before cooling, for example, by reflux.

[0224] In some embodiments, the mixture is cooled to allow the salt to precipitate from the solution. In some embodiments, the salt precipitates from the solution in a crystalline form. In some embodiments, the salt precipitates from the solution in an amorphous form.

[0225] The isolation of salts can be carried out by various well-known isolation techniques, such as filtration and decantation. In some embodiments, the isolation step includes filtering the mixture. After isolation, additional crystallization and / or recrystallization steps may be optionally performed as desired, for example, to increase purity, crystallinity, etc.

[0226] In some embodiments, the compounds of the Disclosure, e.g., compounds of formulas (I) to (VIII), or their pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, or prodrugs, are in the form of solvates. Examples of solvate forms include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, etc., with hydrates and ethanolates being preferred. Solvates may be formed from stoichiometric or non-stoichiometric amounts of solvent molecules. Solvates of the compounds herein may also be in the form of isolateable solvates. In one non-limiting example, as a hydrate, the compound may be a monohydrate, dihydrate, etc. Solvates of the compounds herein also include solution phase forms. Accordingly, in some embodiments, the Disclosure provides solution phase compositions of the compounds herein, or any pharmaceutically acceptable salt thereof, in solvated form, preferably in fully solvated form.

[0227] In some embodiments, the compounds of this disclosure, for example, compounds of formulas (I) to (VIII), or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, or prodrugs, are provided in a crystalline form, for example, as determined by XRPD. Thus, pharmaceutical compositions can be prepared from compounds of formulas (I) to (VIII) in a crystalline form comprising one or more polymorphic forms, and can be used in the treatments described herein. The crystalline form is advantageous in that it provides stability and clearly defined physical properties, and is therefore desirable for the preparation and administration of pharmaceuticals.

[0228] In some embodiments, the compounds of the Disclosure, for example, the compounds of formulas (I) to (VIII), or their pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs, are provided in amorphous forms, for example, as determined by XRPD. Thus, pharmaceutical compositions can be prepared from the compounds of formulas (I) to (VIII), or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, or prodrugs, in one or more amorphous forms, and can be used in the treatments described herein. Because amorphous forms typically have higher water solubility and dissolution rates compared to their crystalline equivalents, they may be suitable for fast-acting dosage forms adapted to rapidly release the active ingredient, such as orally dispersible (ODx) and immediate-release (IR) dosage forms.

[0229] The compounds of this disclosure, for example, the compounds of formulas (I) to (VIII), or their pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs, can generally be prepared according to or similar to the synthetic routes exemplified herein. Other synthetic routes may also be used in techniques and procedures known to those skilled in the art.

[0230] Pharmaceutical composition Also disclosed herein are pharmaceutical compositions comprising compounds of formulas (I) to (VIII), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs thereof, and a pharmaceutically acceptable vehicle. A pharmaceutical composition may comprise one or more of the compounds of this disclosure.

[0231] A “pharmaceutically acceptable vehicle” may be a vehicle approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally accepted pharmacopoeia for use in mammals such as humans. The term “vehicle” means a diluent, adjuvant, excipient, or carrier into which the compounds of this disclosure or salts thereof are formulated for administration to mammals. Such pharmaceutically acceptable vehicles may be solid or liquid, such as water and oil, and may be of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Pharmaceutical vehicles may include water, saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Furthermore, auxiliaries, stabilizers, solubilizers, thickeners, smoothers, buffers, colorants, sweeteners, and other pharmaceutically acceptable additives may be included in the disclosed compositions, for example, those described below. The pharmaceutical vehicle may include acids, such as those previously described for use in forming the pharmaceutically acceptable salt forms of the present disclosure, with particular reference to citric acid and / or tartaric acid.

[0232] A pharmaceutical composition may comprise a single compound of formulas (I) to (VIII), or a mixture of compounds of formulas (I) to (VIII). A pharmaceutical composition may be formed from a mixture of isotopologes of the disclosed compounds. In some embodiments, the target compounds of formulas (I) to (VIII) may be present in the pharmaceutical composition with a purity of at least 20% by weight, at least 30% by weight, at least 40% by weight, at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, at least 95% by weight, or at least 99% by weight, based on the total weight of the isotopologes of the compounds of formulas (I) to (VIII) present in the pharmaceutical composition. In some embodiments, the composition comprises the target compounds of formulas (I) to (VIII) and substantially does not contain other isotopologes of the target compounds in any form, such as free bases or salts. For example, the composition has less than 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or 0.5 mole percent of other isotopologes of the target compounds.

[0233] In some embodiments, any position in a deuterium-containing compound has more minimal deuterium incorporations than naturally occurring deuterium in hydrogen (about 0.016 atomic%). In some embodiments, any position in a deuterium-containing compound has at least 10 atomic%, at least 20 atomic%, at least 25 atomic%, at least 30 atomic%, at least 40 atomic%, at least 45 atomic%, at least 50 atomic%, at least 60 atomic%, at least 70 atomic%, at least 80 atomic%, at least 90 atomic%, at least 95 atomic%, and at least 99 atomic% of minimal deuterium incorporations at the deuterated site.

[0234] In some embodiments, the compounds of formulas (I) to (VIII), or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs, are chemically pure and have a chemical purity of, for example, 90%, 92%, 94%, 96%, 97%, 98%, or 99% as measured by UPLC or HPLC. In some embodiments, the compounds of formulas (I) to (VIII), or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs do not contain a single impurity exceeding 1%, 0.5%, 0.4%, 0.3%, or 0.2% as measured by UPLC or HPLC. In some embodiments, the compounds of formulas (I) to (VIII), or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs, have a chemical purity exceeding 97 area%, 98 area%, or 99 area%, as measured by UPLC or HPLC. In some embodiments, the compounds of formulas (I) to (VIII), or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs, as measured by UPLC or HPLC, do not contain a single impurity exceeding 1 area%, 0.5 area%, 0.4 area%, 0.3 area%, or 0.2 area%, respectively.

[0235] Pharmaceutical compositions may be formulated using enantiomerically pure compounds of the Disclosure, e.g., compounds of formulas (I) to (VIII), or racemic mixtures of the compounds. As described herein, racemic compounds of formulas (I) to (VIII) may contain about 50% of the R- and S-stereoisomers based on the molar ratio of one of the isomers (about 48 to about 52 mol%, or about 1:1 ratio). In some embodiments, a composition, drug, or therapeutic method may involve combining separately produced R- and S-stereoisomer compounds in substantially equal molar ratios (e.g., about 48 to 52%). In some embodiments, a drug or pharmaceutical composition may contain mixtures of distinct compounds of the R- and S-stereoisomers in different proportions. In some embodiments, a pharmaceutical composition may contain an excess (more than 50%) of the R-enantiomer. Preferred R / S molar ratios may be about 1.5:1, 2:1, 3:1, 4:1, 5:1, 10:1, or higher. In some embodiments, the pharmaceutical composition may contain an excess of the S-enantiomer by reversing the provided ratio of R / S. Other preferred amounts of R / S may also be selected. For example, the R-enantiomer may be concentrated, for example, in amounts of at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%. In some embodiments, the S-enantiomer may be concentrated, for example, in amounts of at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%. All of these exemplary proportions, as well as larger and smaller proportions, are included within the scope of the disclosure.

[0236] Pharmaceutical compositions may be formulated using one or more polymorphs of the compounds of formulas (I) to (VIII), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, or prodrugs (including crystalline and / or amorphous polymorphs of the compounds or their salts).

[0237] Generally, pharmaceutical compositions containing one or more compounds (based on the active form) disclosed herein may be provided in amounts of approximately 0.001 to approximately 1000 mg, approximately 1 to approximately 500 mg, approximately 2 to approximately 100 mg, approximately 0.001 mg, approximately 0.01 mg, approximately 0.1 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 5 mg, approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 300 mg, approximately 400 mg, and approximately 500 mg. The amount of compound (e.g., compounds of formulas (I) to (VIII)) (based on the active form) in a unit dose preparation may be changed or adjusted within the above ranges if deemed appropriate using sound medical judgment, depending on the specific use, route of administration, potency of the active ingredient, etc. The composition may also contain other suitable therapeutic agents / active ingredients if desired.

[0238] In some embodiments, the pharmaceutical composition contains, based on the total weight of the pharmaceutical composition, at least 0.1% by weight, at least 0.5% by weight, at least 1% by weight, at least 5% by weight, at least 10% by weight, at least 15% by weight, at least 20% by weight, at least 25% by weight, at least 30% by weight, at least 35% by weight, at least 40% by weight, at least 45% by weight, at least 50% by weight, and up to 99.9% by weight, up to 99.5% by weight, up to 99% by weight, up to 98% by weight, up to 97% by weight, up to 95% by weight, up to 90% by weight, up to 85% by weight, up to 80% by weight, up to 75% by weight, up to 70% by weight, up to 65% by weight, up to 60% by weight, and up to 55% by weight of a compound of formula (I) to (VIII).

[0239] The pharmaceutical compositions disclosed herein may be administered in a single dose or in multiple doses at intervals. It is understood that the exact dose and duration of treatment may vary depending on the age, weight, and condition of the patient being treated, and may be determined empirically using known test protocols or by extrapolation from in vivo or in vitro studies or diagnostic data. It is understood that for any particular individual, a specific dosing regimen should be adjusted over time in accordance with the individual needs and the professional judgment of the person administering or supervising the administration of the formulation.

[0240] If the patient's condition does not improve, the compound may, at the physician's discretion, be administered chronically, i.e., over a long period throughout the patient's life, to improve, or otherwise control or limit, the symptoms of the patient's disease or condition.

[0241] If the patient's condition improves, the compound may be administered continuously or temporarily discontinued for a certain period (i.e., a "drug-free period"), at the physician's discretion.

[0242] Once the patient's condition improves, a maintenance dose is administered if desired or necessary. Thereafter, the dose, frequency, or both may be reduced, depending on the symptoms, to a level that maintains the improved impairment. However, if symptoms recur, the patient may require intermittent treatment over a long period.

[0243] Pharmaceutical compositions may take the form of capsules, tablets, pills, pellets, throat lozenges, powders, granules, syrups, elixirs, solutions, suspensions, emulsions, suppositories, or sustained-release formulations thereof, or any other form suitable for administration to mammals. Administration of the compound of interest may be systemic or topical. In some examples, pharmaceutical compositions are formulated for administration according to routine procedures as pharmaceutical compositions suitable for oral, intravenous, intradermal, or inhalation administration to humans, or other routes of administration described herein. Examples of suitable pharmaceutical vehicles and their formulation methods are described in Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995, Chapters 86, 87, 88, 91, and 92, which are incorporated herein by reference. The selection of a vehicle will be determined in part by the specific compound and the specific method used to administer the composition. Therefore, there are a wide variety of suitable formulations of the pharmaceutical composition in question. Preparations in liquid form include solutions and emulsions, such as water, water / propylene glycol solution, or organic solvents. When administered to mammals, the compounds and compositions of this disclosure, as well as pharmaceutically acceptable vehicles, may be sterilized. In some cases, for example, when the compound in question is administered intravenously, intradermally, or by inhalation, aqueous media such as water, saline, and aqueous dextrose and glycerol solutions may be used as vehicles.

[0244] As described below, the pharmaceutical compositions of this disclosure may be specifically formulated for administration in solid, semi-solid, or liquid form, including those conforming to the following: A. Oral administration, e.g., in the form of a trench (aqueous solution, non-aqueous solution, or suspension), tablets, films, or capsules, e.g., those targeting oral, sublingual, and systemic absorption, boluses, powders, granules, syrups, pastes for application to the tongue, etc. B. Parenteral administration, for example by subcutaneous, intradermal, intramuscular, intravenous, or epidural injection, for example, as a sterile solution or suspension, or as a sustained-release formulation; C. Topical application / transdermal administration, for example, as a cream, ointment, or controlled-release patch or spray applied to the skin, or as a pessary, cream, or foam applied to an opening such as the vagina or rectum and / or mucosal surface; D. Modified-release dosage forms such as delayed, extended, prolonged, sustained, pulsating, controlled, accelerated, rapid, targeted, program-released, and intragastric retention dosage forms, such modified-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126 above); and, E. Inhalation administration, for example, an aerosol, preferably a mist.

[0245] A tamper-evident dosage form / packaging for any disclosed pharmaceutical composition is intended.

[0246] A. Oral administration The pharmaceutical compositions disclosed herein may be provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration includes, for example, gastric (enteral) delivery, where the drug is taken in and swallowed by mouth, and intraoral administration via the mucous membrane of the oral cavity, such as buccal, lingual, and sublingual administration. Preferred oral dosage forms include, but are not limited to, tablets, capsules, pills, lozenges, pastilles, cachets, pellets, medicinal chewing gum, granules, powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, films, sprinkles, elixirs, and syrups. In addition to the active ingredient, the pharmaceutical composition may contain one or more pharmaceutically acceptable vehicles (e.g., carriers or excipients), including but not limited to binders, fillers, diluents, disintegrants, wetting agents, lubricants, flow promoters, colorants, pigment migration inhibitors, sweeteners, preservatives, antioxidants, lyoprotectants, stabilizers, solubilizers, complexing agents, and flavoring agents. In some embodiments, the pharmaceutical composition contains the active ingredient in amounts of about 1% to about 95% by weight, 5% to about 70% by weight, or about 10% to about 60% by weight, or about 20% to about 50% by weight, or about 30% to about 40% by weight.

[0247] In some embodiments, the pharmaceutical compositions of this disclosure may be orally disintegrating tablets (ODTs) (sometimes also called rapidly disintegrating tablets, orally dispersible tablets, or rapidly dispersible tablets) or orally dispersible dosage forms (ODx) comprising orally dispersible films (ODFs) (or wafers). Such dosage forms, when administered orally, for example through the inner mucosal layer of the oral cavity, such as buccal, lingual, and sublingual administration, offer increased bioavailability, faster onset of action, and enable pregastric absorption of the compounds / salts herein compared to oral administration via the gastrointestinal tract.

[0248] Orally dispersible dosage forms can be prepared by various techniques, such as freeze-drying (lyophilization), molding, spray-drying, mass extrusion, or compression. Preferably, the orally dispersible dosage form is prepared by freeze-drying. In some embodiments, the orally dispersible dosage form disintegrates in less than 90 seconds, less than 60 seconds, less than 30 seconds, less than 20 seconds, less than 10 seconds, less than 5 seconds, or less than 2 seconds after being received in the oral cavity. In some embodiments, the orally dispersible dosage form dissolves in less than 90 seconds, less than 60 seconds, or less than 30 seconds after being received in the oral cavity. In some embodiments, the orally dispersible dosage form disperses in less than 90 seconds, less than 60 seconds, less than 30 seconds, less than 20 seconds, less than 10 seconds, less than 5 seconds, or less than 2 seconds after being received in the oral cavity. In some embodiments, the pharmaceutical composition undergoes a United States Pharmacopeia (USP) disintegration test of approximately 30 seconds or less, approximately 20 seconds or less, approximately 10 seconds or less, approximately 5 seconds or less, and approximately 2 seconds or less. <701> This refers to an orally dispersible dosage form, such as an orally disintegrating tablet (ODT), that has a disintegration time according to the United States Pharmacopeia (USP) disintegration test. <701> Accordingly, for example, if the purpose is sustained release, oral dispersible dosage forms having disintegration times of 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 60 minutes, or any range in between, or longer, should also be considered.

[0249] In some embodiments, the pharmaceutical composition is in the form of a lyophilized oral dispersible dosage form, such as a lyophilized oral dehydrated drug (ODT). In some embodiments, the lyophilized oral dispersible dosage form (e.g., lyophilized ODT) is prepared by creating a porous matrix by sublimating water from a pre-frozen aqueous formulation of the drug containing a matrix-forming agent and other vehicles as described herein, such as one or more lioprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, etc. In some embodiments, the oral dispersible dosage form includes a two-component framework of a lyophilized matrix system that works together to ensure the successful development of the formulation. In some embodiments, the first component is a water-soluble polymer such as gelatin, dextran, alginate, and maltodextrin. This component maintains its shape and provides mechanical strength to the dosage form (binder). In some embodiments, the second component is a matrix support / disintegration accelerator such as sucrose, lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and / or starch, which acts by bonding a porous framework provided by a water-soluble polymer, thereby accelerating the disintegration of the orally dispersible dosage form. In some embodiments, the lyophilized orally dispersible dosage form (e.g., lyophilized ODT) comprises gelatin and mannitol. In some embodiments, the lyophilized orally dispersible dosage form (e.g., lyophilized ODT) comprises gelatin, mannitol, and one or more of the following: lioprotectant, preservative, antioxidant, stabilizer, solubilizer, flavoring agent, etc., with citric acid being particularly mentioned. A non-limiting example of an ODT formulation is Zydis® Orally Dispersible Tablets (available from Catalent). In some embodiments, the ODT formulation (e.g., Zydis® Oral Dispersible Tablets) comprises one or more water-soluble polymers, e.g., gelatin, one or more matrix materials, fillers, or diluents, e.g., mannitol, compounds of formulas (I) to (VIII), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs thereof, and optionally a lioprotectant, preservative, antioxidant, stabilizer, solubilizer, and / or flavoring agent.In some embodiments, the ODT formulation (e.g., Zydis® Oral Dispersible Tablets) comprises gelatin, mannitol, compounds of formulas (I) to (VIII), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs thereof, and organic acids (non-limiting examples thereof are citric acid and / or tartaric acid, or any preferred organic acid as described herein).

[0250] In some embodiments, the pharmaceutical composition is in the form of a lyophilized oral dispersible film (ODF) (or wafer). In some embodiments, the pharmaceutical composition is in the form of a lyophilized ODF protected for long-term storage by special packaging that excludes moisture, oxygen, and light. In some embodiments, the lyophilized ODF is prepared by creating a porous matrix by sublimating water from a pre-frozen aqueous formulation of the drug containing a matrix-forming agent and one or more other vehicles as described herein, such as lioprotectants, preservatives, antioxidants, stabilizers, solubilizers, and flavoring agents. In some embodiments, the lyophilized ODF comprises a thin, water-soluble film matrix. In some embodiments, the ODF comprises a two-component framework of lyophilized matrix systems that cooperate to ensure the development of a successful formulation. In some embodiments, the first component is a water-soluble polymer such as gelatin, dextran, alginate, and maltodextrin. This component maintains its shape and provides mechanical strength to the film / wafer (binder). In some embodiments, the second component is a matrix support / disintegration accelerator such as sucrose and mannitol, which acts by bonding a porous framework provided by a water-soluble polymer and facilitating the disintegration of the wafer. In some embodiments, the freeze-dried ODF includes gelatin and mannitol. In some embodiments, the freeze-dried ODF includes gelatin, mannitol, and one or more of the following: lioprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, etc., with citric acid being particularly mentioned.

[0251] In some embodiments, the ODF (or wafer) may be single-layer, double-layer, or triple-layer. In some embodiments, a single-layer ODF contains an active agent and one or more pharmaceutically acceptable vehicles (e.g., carriers or excipients). In some embodiments, a double-layer ODF contains one or more excipients, such as solubilizers, in the first layer and an active agent in the second layer. This configuration allows the active agent to be stored separately from the excipients, increasing the stability of the active agent and optionally increasing the shelf life of the composition compared to when the excipients and active agent are contained in a single layer. For triple-layer ODF, each layer may be different, or two layers, such as an upper and lower layer, may have substantially the same composition. In some embodiments, the lower and upper layers surround a core layer containing the active agent. In some embodiments, the lower and upper layers may contain one or more excipients, such as solubilizers. In some embodiments, the lower and upper layers have the same composition. Alternatively, the lower and upper layers may contain different excipients or different amounts of the same excipient. The core layer typically contains an activator and optionally one or more excipients.

[0252] In some embodiments, in addition to the active ingredient, the pharmaceutical composition in the orally dispersible dosage form (ODx) may contain one or more pharmaceutically acceptable vehicles (e.g., carriers or excipients). For example, in some embodiments, the pharmaceutical composition in the orally dispersible dosage form may contain one or more pharmaceutically acceptable lioprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, etc.

[0253] Examples of pharmaceutically acceptable lioprotectants include, but are not limited to, disaccharides such as sucrose and trehalose, anionic polymers such as sulfobutyl ether-β-cyclodextrin (SBECD) and hyaluronic acid, and hydroxylated cyclodextrins.

[0254] Examples of pharmaceutically acceptable preservatives include, but are not limited to, glycerin, methylparaben, and propylparaben, benzoic acid, sodium benzoate, and alcohols.

[0255] Examples of pharmaceutically acceptable antioxidants that may act to further enhance the stability of the composition include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​or its salts (cysteine ​​hydrochloride), sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0256] Examples of pharmaceutically acceptable stabilizers include, but are not limited to, fatty acids, aliphatic alcohols, alcohols, long-chain fatty acid esters, long-chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone, polyvinyl ethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, hygroscopic polymers, glycerin, methionine, monothioglycerin, ascorbic acid, citric acid, polysorbate, arginine, cyclodextrin, microcrystalline cellulose, modified cellulose (e.g., carboxymethylcellulose, sodium salt), sorbitol, and cellulose gels.

[0257] Examples of pharmaceutically acceptable solubilizers (or solubilizers) include citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium stearyl fumarate, methacrylate copolymer LD, methylcellulose, sodium lauryl sulfate, polyoxyl 40 stearate, purified shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbyl stearic acid, L-aspartic acid, adipic acid, aminoalkyl methacrylate copolymer E, propylene glycol alginate, casein, sodium caseinate, carboxyvinyl polymer, carboxymethyl ethylcellulose, agar powder, guar gum, succinic acid, copolividone, cellulose phthalate acetate, tartaric acid, sodium dioctyl sulfosuccinate, zein, skim milk powder, sorbitan trioleate, lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethyl methylcellulose This includes, but is not limited to, cellulose, hydroxypropyl methylcellulose succinate acetate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, poly(4-styrene sulfonate sodium), polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, maleic acid, methacrylate copolymer S, lauromacrogol, sulfuric acid, aluminum sulfate, phosphoric acid, calcium dihydrogen phosphate, sodium dodecylbenzenesulfonate, vinylpyrrolidone-vinyl acetate copolymer, sodium lauroyl sarcosinate, acetyltryptophan, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, and sodium octadecyl sulfate. Of these, citric acid is preferred in some embodiments, such as ODT formulations.

[0258] Flavorings include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that produce desirable tastes and taste-masking effects. Examples of flavorings include, but are not limited to, aspartame, saccharin (as sodium, potassium, or calcium saccharin), cyclamate (as sodium, potassium, or calcium salts), sucralose, acesulfame K, thaumatin, neohisperidin, dihydrochalcone, ammonia-modified glycyrrhizin, glucose, maltodextrin, fructose, levose, sucrose, glucose, wild orange peel, citric acid, tartaric acid, wintergreen oil, peppermint oil, methyl salicylate, spearmint oil, sassafras oil, clove oil, cinnamon, anethole, menthol, thymol, eugenol, eucalyptol, lemon, lime, and lemon-lime.

[0259] Cyclodextrins, such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfated-β-cyclodextrin, sulfated-α-cyclodextrin, sulfobutyl ether-β-cyclodextrin, or other solubilized derivatives, can also be advantageously used to enhance the delivery of the compositions described herein.

[0260] For example, pharmaceutical compositions suitable for oral administration, such as tablets including compressed tablets, can be formulated using a variety of vehicles, including those described herein. Examples of suitable vehicles include, but are not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, flow enhancers, colorants, color transfer inhibitors, sweeteners, preservatives, antioxidants, stabilizers, solubilizers, and flavoring agents.

[0261] The binder or granulator imparts cohesiveness to the tablets, ensuring that they remain intact after compression. Suitable binders or granulators include starch, e.g., corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); gelatin; sugars, e.g., sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic rubbers, e.g., acacia, alginic acid, alginate, Irish moss extract, Panwar rubber, Gatti rubber, Isagol husk mucus, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), bee rubber, larch arabogalactan, tragacanth powder, and guar rubber; cellulose, e.g., ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); microcrystalline cellulose, e.g., AVISEL-PH-101, AVISEL-PH-103, AVISEL This includes, but is not limited to, RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.), and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. Binders or fillers may be present in amounts of about 10% by weight, about 20% by weight, about 30% by weight, about 40% by weight, about 50% by weight, about 60% by weight, about 70% by weight, about 80% by weight, about 90% by weight, about 99% by weight, or any range in between.

[0262] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dried starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantities, can impart the property of disintegrating in the mouth by chewing to some compressed tablets. Such compressed tablets can be used as chewable tablets.

[0263] Suitable disintegrants include, but are not limited to, agar; bentonite; cellulose, e.g., methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; rubber, e.g., guar gum and bee gum HV; citrus fruit pulp; cross-linked cellulose, e.g., croscarmellose; cross-linked polymers, e.g., crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, e.g., sodium starch glycolate; potassium polaritrin; starch, e.g., corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; alyn; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions disclosed herein will vary depending on the type of formulation and will be readily apparent to those skilled in the art. The pharmaceutical compositions disclosed herein may contain, for example, about 0.5 to about 15% by weight, or about 1 to about 5% by weight, of the disintegrant.

[0264] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, e.g., glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; sodium stearyl fumarate; talc; hydrogenated vegetable oils, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; silica or silica gel, e.g., AEROSIL® 200 (WRGrace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co., Boston, Mass.); and mixtures thereof. Pharmaceutical compositions disclosed herein may, for example, contain about 0.1 to about 5% by weight of a lubricant.

[0265] Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co., Boston, Mass.), and asbestos-free talc.

[0266] The colorants include approved, certified, water-soluble FD&C dyes, insoluble FD&C dyes suspended in alumina hydrate, and their color lakes and mixtures. Color lakes are conjugates of water-soluble dyes adsorbed to heavy metal hydrate oxides, resulting in an insoluble form of the dye.

[0267] Sweeteners include sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners such as saccharin and aspartame.

[0268] Suitable emulsifiers include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate.

[0269] The suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, beegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.

[0270] The preservatives include glycerin, methyl and propylparabens, benzoic acid, sodium benzoate, and alcohol.

[0271] The humectants include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0272] Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

[0273] It should be understood that many vehicles (carriers, excipients, etc.) can perform multiple functions even within the same formulation. This specification particularly refers to pharmaceutical compositions comprising citric acid, which may play multiple roles as a stabilizer and, in particular, as a solubilizer to provide faster dissolution of the active substance for rapid onset of action, etc., in dosage forms suitable for rapid onset of action and shorter duration of drug action, such as orally dispersible dosage forms (e.g., ODT and ODF).

[0274] Tablet dosage forms may be prepared from the active ingredient in powder, crystalline, or granular form, either alone or in combination with one or more vehicles (e.g., carriers or excipients) as described herein, which include binders, disintegrants, release-controlled polymers, lubricants, diluents, and / or colorants. Flavoring agents and sweeteners are particularly useful in the formation of chewable tablets and lozenges.

[0275] Pharmaceutical compositions as described herein may be in the form of compressed tablets, crushed tablets, chewable lozenges, rapidly dissolving tablets, multi-compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestines, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammonia-modified shellac, and cellulose phthalate acetate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial for covering unpleasant tastes or odors and protecting the tablet from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose phthalate acetate. Film coatings impart the same general properties as sugar coatings. Multiple compression tablets are compression tablets manufactured using multiple compression cycles and include layered tablets, compression-coated tablets, or dry-coated tablets.

[0276] In some embodiments, the pharmaceutical composition (e.g., a tablet composition formulated for oral administration, such as a single-layer tablet composition) comprises any of the compounds described herein (e.g., compounds of formulas (I) to (VIII)), or pharmaceutically acceptable salts thereof, and a polymer.

[0277] In some embodiments, the tablet composition is a sustained-release, preferably a controlled-release tablet adapted to maximum sustained-release. In some embodiments, in the formulations of the Disclosure, the duration of release of any of the compounds described herein (e.g., compounds of formulas (I) to (VIII)) is greater than 4 hours, greater than 6 hours, greater than 8 hours, greater than 10 hours, greater than 12 hours, greater than 16 hours, greater than 20 hours, greater than 24 hours, greater than 28 hours, greater than 32 hours, greater than 36 hours, or greater than 48 hours.

[0278] In some embodiments, the tablet composition is adapted to prevent tampering. In some embodiments, the tablet composition comprises, for example, polyethylene oxide (PEO) with a MW of about 2,000 to about 7,000 kDa in combination with HPMC. In some embodiments, the tablet composition may further comprise polyethylene glycol (PEG), such as PEG8K. In some embodiments, the tablet composition may further comprise a polymer supporting one or more load groups, such as polyacrylic acid. In some embodiments, the tablet composition containing PEO is further subjected to heating / annealing, such as under extrusion conditions.

[0279] In some embodiments, the pharmaceutical composition comprises a combination of (i) a water-insoluble neutral charged nonionic matrix, (ii) a polymer supporting one or more load groups, and (iii) any of the compounds described herein (e.g., compounds of formulas (I) to (VIII), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs thereof).

[0280] In some embodiments, the polymer supporting one or more load groups is selected from the group consisting of polyacrylic acid, polylactic acid, polyglycolic acid, polymethacrylate carboxylate, cation exchange resin, clay, zeolite, hyaluronic acid, anionic rubber, salts thereof, or mixtures thereof. In some embodiments, the anionic rubber is selected from the group consisting of naturally derived substances and semi-synthetic substances. In some embodiments, the naturally derived substances are selected from the group consisting of alginic acid, pectin, xanthan gum, carrageenan, locust bean gum, acacia gum, karaya gum, guar gum, and tragacanth gum. In some embodiments, the semi-synthetic substances are selected from the group consisting of carboxymethyl chitin and cellulose rubber.

[0281] Furthermore, although we do not wish to be constrained by theory, in some embodiments, the role played by polymers supporting one or more load groups, such as the acidic parts of the acidic polymers described herein, surprisingly results in significant retention of any of the compounds described herein (e.g., compounds of formulas (I) to (VIII), or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs) in the matrix. In some embodiments, this negative charge may be generated in situ, for example, based on the release of protons by pKa and under certain pH conditions, or via electrostatic interactions / negative charge generation. It should also be noted that the acidic polymers may be salts of the corresponding weak acids that become the relevant protonated acids in the stomach. While we do not wish to be constrained by theory, this may neutralize the charge and reduce the interaction between any of the compounds described herein (e.g., compounds of formulas (I) to (VIII), or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs) and the matrix. Furthermore, the release matrix may be further complemented by other inactive pharmaceutically acceptable components to assist in the preparation of suitable solid dosage forms such as fillers, disintegrants, flow improvers, lubricants, colorants, and taste masks.

[0282] In some embodiments, the water-insoluble, neutrally charged, nonionic matrix is ​​selected from cellulosic polymers such as HPMC, either alone or enhanced by mixing with components selected from the group consisting of starch, wax, neutral rubber, polymethacrylate, PVA, PVA / PVP blends, and mixtures thereof. In some embodiments, the cellulosic polymer is hydroxypropyl methylcellulose (HPMC).

[0283] In some embodiments, the cellulosic polymer is hydroxypropyl methylcellulose (HPMC). In some embodiments, the tablet composition comprises about 10-70% by weight, 20-60% by weight, or 30-50% by weight of hydroxypropyl methylcellulose, about 10-30% by weight, or about 15-20% by weight of starch, or any combination thereof.

[0284] Disclosed herein are pharmaceutical compositions in a controlled-release dosage form, comprising the compounds disclosed herein and one or more controlled-release excipients or carriers described herein. Suitable controlled-release dosage form vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separation layer coatings, enteric coatings, osmotic devices, multi-particle devices, and combinations thereof. The pharmaceutical compositions may also contain non-controlled-release excipients or carriers.

[0285] In some embodiments, the oral pharmaceutical composition is intended for low-dose maintenance therapy, which may be constructed using the compounds described herein, taking advantage of the ability of the phenethylamine-type compounds described herein to bind to anionic polymers.

[0286] In some embodiments, the pharmaceutical composition comprises a compound of the Disclosure, which is an orally active, peripherally-restricted 5-HT2 agonist, for the treatment of autonomic nervous system disorders, including lung disorders (e.g., asthma) and cardiovascular disorders (e.g., atherosclerosis).

[0287] Furthermore, this specification discloses pharmaceutical compositions in enteric-coated dosage forms, comprising the compounds disclosed herein and one or more controlled-release excipients or carriers for use in enteric-coated dosage forms. The pharmaceutical compositions may also contain non-controlled-release excipients or carriers.

[0288] Furthermore, this specification discloses effervescent pharmaceutical compositions comprising the compounds disclosed herein and one or more release-controlled excipients or carriers for use in effervescent formulations. The pharmaceutical compositions may also contain non-release-controlled excipients or carriers.

[0289] Furthermore, a pharmaceutical composition in dosage form is disclosed, having an immediate-release component and at least one delayed-release component, capable of discontinuously releasing the compound in the form of at least two consecutive pulses separated by intervals of about 0.1 to a maximum of about 24 hours (e.g., about 0.1, 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 10, 22, or 24 hours). The pharmaceutical composition comprises the compound disclosed herein and one or more release-controlled and release-non-release-controlled excipients or carriers, such as excipients or carriers suitable as destructible semipermeable membranes and swelling substances.

[0290] Pharmaceutical compositions in dosage forms for oral administration to a subject are also disclosed herein, comprising a compound, salt, or solvate disclosed herein, one or more pharmaceutically acceptable vehicles (e.g., excipients or carriers) encapsulated in an intermediate reaction layer comprising an alkali-neutralized, cation-exchangeable, gastric juice-resistant polymer layer material and a gastric juice-resistant outer layer.

[0291] The dosage form may be an immediate-release (IR) dosage form, including, but not limited to, immediate-release (IR) tablets or immediate-release (IR) capsules. In addition to the active ingredient (e.g., compounds of formulas (I) to (VIII)), an immediate-release-compatible dosage form may include one or more pharmaceutically acceptable vehicles that disperse, dissolve, or otherwise decompose readily in the gastric environment so as not to delay or prolong the dissolution / absorption of the active ingredient. Examples of pharmaceutically acceptable vehicles for an immediate-release dosage form include, but are not limited to, one or more binders / granules, matrix materials, fillers, diluents, disintegrants, dispersants, solubilizers, lubricants, and / or performance modifiers. In some embodiments, the immediate-release (IR) dosage form is an immediate-release (IR) tablet containing one or more of the following: microcrystalline cellulose, sodium carboxymethylcellulose, magnesium stearate, mannitol, crospovidone, and sodium stearyl fumarate. In some embodiments, the immediate-release (IR) dosage form comprises microcrystalline cellulose, sodium carboxymethylcellulose, and magnesium stearate. In some embodiments, the immediate-release (IR) dosage form comprises mannitol, crospovidone, and sodium stearyl fumarate.

[0292] The pharmaceutical compositions disclosed herein may be disclosed as flexible or rigid capsules, which may be made from gelatin, methylcellulose, starch, or calcium alginate. Rigid gelatin capsules, also known as dry-filled capsules (DFCs) or powder-encapsulated capsules (PICs), consist of two sections, one of which overlaps the other, thus completely encapsulating the active ingredient. Flexible elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerin, sorbitol, or similar polyols. The flexible gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methylparaben and propylparaben, and sorbic acid. The liquid, semi-solid, and solid dosage forms disclosed herein may be encapsulated. Suitable liquid and semi-solid dosage forms include solutions and suspensions of propylene carbonate, vegetable oil, or triglycerides. The capsules may also be coated, as is known to those skilled in the art, to modify or maintain the dissolution of the active ingredient.

[0293] In some embodiments, the pharmaceutical composition is in the form of an immediate-release capsule for oral administration and may further comprise cellulose, iron oxide, lactose, magnesium stearate, and sodium starch glycolate.

[0294] In some embodiments, the pharmaceutical composition is in the form of a delayed-release capsule for oral administration and may further contain cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide.

[0295] In some embodiments, the pharmaceutical composition is in the form of an enteric-coated delayed-release tablet for oral administration and may further comprise carnauba wax, crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropylcellulose, hypromellose phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, and yellow ferric oxide.

[0296] In some embodiments, the pharmaceutical composition is in the form of an enteric-coated delayed-release tablet for oral administration and may further comprise calcium stearate, crospovidone, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylate copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

[0297] The formulations of this disclosure include orally administered pharmaceutical compositions such as tablets, capsules, caplets, gel caps, and cap compositions, which may include uncoated or coated tablets, caplets, and caps (including film-coated tablets, sugar-coated tablets, and gastric-tolerant / enteric-coated tablets). Oral pharmaceutical compositions for oral use may include any of the compounds described herein (e.g., compounds of formulas (I) to (VIII)) mixed with pharmaceutically acceptable inert excipients such as diluents, disintegrants, binders, smoothing agents, powder flow improvers, wetting agents, sweeteners, flavoring agents, colorants, and preservatives. Furthermore, the oral pharmaceutical compositions of this disclosure are solid dosage forms intended for oral administration, obtained, for example, by dry granulation by single or multiple compressions of powder or granules. In some embodiments, oral pharmaceutical compositions may be obtained using wet granulation techniques. In some embodiments, oral pharmaceutical compositions may be obtained by molding, heating / annealing, or extrusion techniques.

[0298] In some embodiments, the oral tablets are cylindrical, with flat or convex end faces, and the ends may be chamfered. In some embodiments, the surface is convex. Furthermore, they may have lines or division marks (notches), symbols, or other marks.

[0299] In some embodiments, splitting marks are intended to allow for precise splitting of tablets to provide doses less than one tablet. In some embodiments, the tablet composition includes one or more excipients, such as diluents, binders, disintegrants, lubricants, substances that can modify the dosage form and the action of the active ingredient in the gastrointestinal tract, colorants approved by the appropriate national or regional authorities, and flavoring agents. When using such excipients, it is necessary to ensure that they do not adversely affect the stability, dissolution rate, bioavailability, safety, or efficacy of the active ingredient, and there should be no incompatibility between the components of the dosage form.

[0300] Coated tablets are tablets covered with one or more layers of a mixture of substances such as natural or synthetic resins, polymers, rubber, fillers, sugars, plasticizers, polyols, waxes, colorants approved by the appropriate national or regional authorities, and flavorings. Such coating materials do not contain any active ingredients, for example, any of the compounds described herein (e.g., compounds of formulas (I) to (VIII), or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs). Tablets may be coated for a variety of reasons, such as protection of the active ingredient from burst emission from the matrix, air, moisture, or light, masking of unpleasant tastes and odors, or improvement of appearance. The substances used for coating may be applied as solutions or suspensions.

[0301] In some embodiments, the manufacturing process of an oral pharmaceutical composition, such as a tablet, meets the requirements of Good Manufacturing Practices (GMP). In some embodiments, in the manufacture of an oral pharmaceutical composition, one or more measures selected from the following are taken: ensuring that mixing with excipients is carried out in a manner that ensures homogeneity; ensuring that the oral pharmaceutical composition has suitable mechanical strength to avoid crushing or destruction in subsequent processing such as coating, storage, and distribution; minimizing degradation of the active ingredient; minimizing the risk of microbial contamination; and minimizing the risk of secondary contamination. Furthermore, in the manufacture of split tablets (tablets with split marks or multiple marks) intended to be divided to provide doses less than one tablet, measures are taken as necessary to ensure the effectiveness of the split marks on the mass or uniformity of the contents of the divided portion so that the patient receives the intended dose.

[0302] The pharmaceutical compositions disclosed herein may be disclosed in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is dispersed throughout another liquid in the form of small spheres, and may be oil-in-water or water-in-oil. Emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharmaceutically acceptable suspending agent and a preservative. Alcoholic aqueous solutions may contain a pharmaceutically acceptable acetal of a lower alkylaldehyde di(lower alkyl) acetal (the term "lower" means an alkyl having 1 to 6 carbon atoms), such as acetaldehyde diethyl acetal, and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweet, and aqueous-alcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may contain preservatives. In the case of liquid dosage forms, for example, a solution in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, so that it can be easily measured for administration.

[0303] Other useful liquid and semi-solid dosage forms include, but are not limited to, those containing the active ingredients disclosed herein (e.g., compounds of formulas (I) to (VIII)) and dialkylated mono- or polyalkylene glycols, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, and polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weight of polyethylene glycol. These formulations may further contain one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates. In some embodiments, examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0304] Cyclodextrins, such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfated-β-cyclodextrin, sulfated-α-cyclodextrin, sulfobutyl ether-β-cyclodextrin, or other solubilized derivatives, can also be advantageously used to enhance the delivery of the compositions described herein.

[0305] Pharmaceutical compositions disclosed herein for oral administration may also be disclosed in the form of liposomes, micelles, microspheres, or nanosystems.

[0306] The pharmaceutical compositions disclosed herein may be disclosed as non-foaming or foaming granules and powders that can be reconstituted into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-foaming granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in foaming granules or powders may include organic acids and carbon dioxide sources.

[0307] Colorants and flavoring agents may be used in any of the disclosed dosage forms.

[0308] The pharmaceutical compositions disclosed herein may be co-formulated with other active ingredients that do not impair the desired therapeutic effect, or with substances that complement the desired effect, such as hydrocortisone.

[0309] B. Parenteral administration The pharmaceutical compositions disclosed herein may be administered parenterally by injection, infusion, perfusion, or implantation for topical or systemic administration. As used herein, parenteral administration includes, but is not limited to, intravenous, intradermal, intra-arterial, intraperitoneal, subarachnoid, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

[0310] The pharmaceutical compositions disclosed herein may be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquids before injection. Such dosage forms may be prepared according to conventional methods known to those skilled in the art of pharmacy (see Remington: The Science and Practice of Pharmacy, above).

[0311] Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable vehicles (e.g., carriers and excipients), including but not limited to aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial or antiseptic agents against microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspensions and dispersants, wetting or emulsifiers, complexing agents, chelating agents, cryoprotectants, lioprotectants, thickeners, pH adjusters, and inert gases.

[0312] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic glucose injection, sterile water injection, glucose, and Ringer's lactate injection. Non-aqueous vehicles include, but are not limited to, plant-derived fixed oils, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, coconut oil, and medium-chain triglycerides from palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300, polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide.

[0313] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid, thimerosal, benzalkonium chloride, benzethonium chloride, methylparaben and propylparaben, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and glucose. Suitable buffering agents include, but are not limited to, phosphoric acid and citric acid. Suitable antioxidants include those described herein, including bisulfites and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, including sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleic acid. Suitable chelating or sequestering agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-3-cyclodextrin / hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-O-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

[0314] The pharmaceutical compositions disclosed herein may be formulated for single or multi-dose administration. Single-dose formulations are packaged in ampoules, vials, or syringes. Multi-dose parenteral formulations must contain an antimicrobial agent in a bacteriostatic or fungiostatic concentration. All parenteral formulations must be sterile, as is known and practiced in the art.

[0315] In some embodiments, the pharmaceutical composition is disclosed as a ready-to-use sterile solution. In some embodiments, the pharmaceutical composition is disclosed as a sterile-dried soluble product comprising a lyophilized powder and a tablet for subcutaneous injection, which are reconstituted in a vehicle before use. In some embodiments, the pharmaceutical composition is disclosed as a ready-to-use sterile suspension. In some embodiments, the pharmaceutical composition is disclosed as a sterile-dried insoluble product, which are reconstituted in a vehicle before use. In some embodiments, the pharmaceutical composition is disclosed as a ready-to-use sterile emulsion.

[0316] The pharmaceutical compositions may be formulated as suspensions, solids, semi-solids, or thixotropic liquids for administration as implantation depot agents. In some embodiments, the pharmaceutical compositions disclosed herein are insoluble in body fluids but dispersed in a solid inner matrix surrounded by an outer polymer membrane that allows the active ingredients in the pharmaceutical composition to diffuse. Fatty acid salts of the compounds of formulas (I) to (VIII) are well suited to such dosage forms.

[0317] Suitable internal matrices include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as hydrogels of acrylic and methacrylic acid esters, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate.

[0318] Suitable outer polymer films include polyethylene, polypropylene, ethylene-propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, vinylidene chloride, ethylene, and vinyl chloride copolymer with propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol copolymer, and ethylene / vinyl oxyethanol copolymer.

[0319] C. Local administration The pharmaceutical compositions disclosed herein may be administered topically to the skin, orifices, or mucous membranes. The effects may be topical or systemic. Topical administration, as described herein, includes, but is not limited to, conjunctival, intracorneal, intraocular, eye, ear, transdermal, nasal (e.g., intranasal), vaginal, urethral, ​​respiratory, and rectal administration.

[0320] The pharmaceutical compositions disclosed herein may be formulated in any dosage form suitable for topical administration for topical or systemic effects, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, cleansers, sprays, suppositories, bandages, and skin patches. Topical formulations of the pharmaceutical compositions disclosed herein may contain an active ingredient that can be mixed with a pharmaceutically acceptable vehicle under sterile conditions and any preservatives, buffers, absorption enhancers, and propellants as needed. Liposomes, micelles, microspheres, nanosystems, and mixtures thereof may also be used.

[0321] pharmaceutically acceptable vehicles (e.g., carriers and excipients) suitable for use in topical formulations disclosed herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial or antiseptic agents against microbial growth, stabilizers, dissolution accelerators, isotonic agents, buffers, antioxidants, topical anesthetics, suspensions and dispersants, wetting or emulsifiers, complexing agents, chelating or sealing agents, penetration enhancers, antifreeze agents, lioprotectants, thickeners, and inert gases.

[0322] In addition to the active ingredient, ointments, pastes, creams, and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0323] In addition to the active ingredient, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. For example, sprays used for nasal (intravenous) administration may additionally contain common propellants such as fluorohydrocarbons and chlorofluorohydrocarbons, as well as volatile unsubstituted hydrocarbons such as butane and propane.

[0324] Transdermal delivery devices (e.g., patches) may be used. Such dosage forms have the additional advantage of providing controlled delivery of the active ingredient to the body. That is, the compounds of the present disclosure (e.g., compounds of formulas (I) to (VIII), or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs) can be administered via transdermal patches at steady-state concentrations, thereby allowing the active ingredient to be administered gradually over time, avoiding drug spikes and associated adverse events / toxicities.

[0325] The transdermal patch formulations described herein may be formulated with varying amounts of the active ingredient depending on the disease / condition being treated, the active ingredient used, the penetration and size of the transdermal delivery device, the release period, etc. For example, when formulated with compounds of formulas (I) to (VIII), unit dose preparations may be modified or adjusted from compounds of formulas (I) to (VIII) (based on activity type), for example, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg to 200 mg, 175 mg, 150 mg, 125 mg, 100 mg, 95 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, and 55 mg, or otherwise modified or adjusted to be deemed appropriate using reasonable medical judgment according to the specific use and the potency of the compound.

[0326] Transdermal patches formulated with the disclosed compounds may be suitable for microdosing or non-hallucinogenic (also referred to herein as non-psychoactive) administration, which achieve long-term therapeutic benefits while reducing toxicity. In some embodiments, compounds of formulas (I) to (VIII), or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs, are administered via transdermal patches at non-psychoactive concentrations (which may still be potentially serotonergic concentrations) over extended periods, such as 8, 24, 48, 72, 84, 96, or 168 hours.

[0327] In addition to the active ingredient and any optional pharmaceutically acceptable vehicle, the transdermal patch may include one or more of a pressure-sensitive adhesive layer, a backing, and a release liner, as is known to those skilled in the art.

[0328] Transdermal patch formulations can be prepared by dissolving or dispersing the compounds herein in a suitable medium. In some embodiments, the compounds of the disclosed herein may be directly dissolved / dispersed in a polymer matrix forming a pressure-sensitive adhesive layer. Such transdermal patches are called drug-in-adhesive (DIA) patches. A preferred DIA patch configuration is one in which the active ingredient is uniformly distributed throughout the pressure-sensitive adhesive polymer matrix. In some embodiments, the active ingredient may be provided in a layer containing a separate active ingredient and polymer substrate from the pressure-sensitive adhesive layer. In any case, the compounds of the disclosed herein may be optionally formulated with suitable vehicles, such as carriers, penetration / absorption enhancers, and humectants / crystallization inhibitors. They may also be optionally formulated to increase overall skin flow.

[0329] Examples of carriers include C8-C2 acids such as oleic acid, undecanoic acid, valeric acid, heptanoic acid, pelargonic acid, capric acid, lauric acid, and eicosapentaenoic acid. 22 Fatty acids; such as octanol, nonanol, oleyl alcohol, decyl alcohol, and lauryl alcohol, C8-C 22 Fatty alcohols; such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate (C8-C2). 22 Lower alkyl esters of fatty acids; such as diisopropyl adipate, C6-C6 22 Di(low)alkyl esters of diacids; such as glyceryl monolaurate, C8-C 22Examples include, but are not limited to, fatty acid monoglycerides; tetrahydrofuryl alcohol polyethylene glycol ethers; polyethylene glycol, propylene glycol; 2-(2-ethoxyethoxy)ethanol; diethylene glycol monomethyl ethers; alkylaryl ethers of polyethylene oxide; polyethylene oxide monomethyl ethers; polyethylene oxide dimethyl ethers; glycerol; ethyl acetate; acetoacetate esters; N-alkylpyrrolidone; cyclodextrins such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or derivatives such as 2-hydroxypropyl-β-cyclodextrin; and terpenes / terpenoids (including mixtures thereof) such as limonene, linalool, myrcene, pinene such as α-pinene, caryophyllene, citral, and eucoliptol.

[0330] Examples of penetrating agents / absorption enhancers include, but are not limited to, sulfoxides such as dodecylmethyl sulfoxide, octylmethyl sulfoxide, nonylmethyl sulfoxide, decylmethyl sulfoxide, undecylmethyl sulfoxide, 2-hydroxydecylmethyl sulfoxide, 2-hydroxy-undecylmethyl sulfoxide, and 2-hydroxydodecylmethyl sulfoxide; surfactants formed from an aqueous phase having one or more of poloxamer, CARBOPOL, and PEMULEN, a lipid phase formed from one or more of isopropyl palmitate and PPG-2 myristyl ether propionate, and lecithin - lecithin organogel (PLO); fatty acids, esters, and alcohols such as oleic acid and oleyl alcohol; keto acids such as levulinic acid; glycols and glycol ethers, such as diethylene glycol monoethyl ether (including mixtures thereof).

[0331] Examples of water-retaining agents / crystallization inhibitors include, but are not limited to, polyvinylpyrrolidone-co-vinyl acetate, HPMC, polymethacrylate, and mixtures thereof.

[0332] The pressure-sensitive adhesive layer may be formed from polymers including, but not limited to, acrylics (polyacrylates including alkyl acrylics), polyvinyl acetates, natural and synthetic rubbers (e.g., polyisobutylene), ethylene vinyl acetate copolymers, polysiloxanes, polyurethanes, plasticized polyether block amide copolymers, plasticized styrene-butadiene rubber block copolymers, and mixtures thereof. The pressure-sensitive adhesive layer used in the transdermal patch of this disclosure may be formed from an acrylic polymer pressure-sensitive adhesive, preferably an acrylic copolymer pressure-sensitive adhesive. Acrylic copolymer pressure-sensitive adhesives may be obtained by copolymerization of one or more alkyl (meth)acrylates (e.g., 2-ethylhexyl acrylate); aryl (meth)acrylates; arylalkyl (meth)acrylates; and functional (meth)acrylates, such as hydroxyalkyl (meth)acrylates (e.g., hydroxyethyl acrylate, 2-hydroxypropyl acrylate, 3-hydroxypropyl acrylate, 4-hydroxybutyl acrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, 3-hydroxypropyl methacrylate, and 4-hydroxybutyl methacrylate), carboxylic acid-containing (meth)acrylates (e.g., acrylic acid), and alkoxy (meth)acrylates (e.g., methoxyethyl acrylate), or optionally by copolymerization with one or more copolymerizable monomers (e.g., vinylpyrrolidone, vinyl acetate, etc.). Specific examples of acrylic pressure-sensitive adhesives include, but are not limited to, DURO-TAK products (Henkel) such as DURO-TAK 87-900A, DURO-TAK 87-9301, DURO-TAK 87-4098, DURO-TAK 87-2074, DURO-TAK 87-235A, DURO-TAK 87-2510, DURO-TAK 87-2287, DURO-TAK 87-4287, DURO-TAK 87-2516, DURO-TAK 387-2052, and DURO-TAK 87-2677.

[0333] The backing used in the transdermal patch of this disclosure may include flexible backings such as films, nonwovens, Japanese paper, cotton fabrics, knitted fabrics, woven fabrics, and laminated composites of nonwovens and films. Such backings are preferably composed of a soft material that can closely contact the skin and follow skin movements, and a material that can suppress skin rashes and other discomforts after prolonged use of the patch. Examples of backing materials, but not limited to, include polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polystyrene, nylon, cotton, rayon acetate, rayon, rayon / polyethylene terephthalate composites, polyacrylonitrile, polyvinyl alcohol, acrylic polyurethane, ester polyurethane, ether polyurethane, styrene-isoprene-styrene copolymer, styrene-butadiene-styrene copolymer, styrene-ethylene-propylene-styrene copolymer, styrene-butadiene rubber, ethylene vinyl acetate copolymer, or cellophane. Preferred backings do not adsorb or release the active ingredient. To suppress the adsorption and release of active ingredients, improve the transdermal absorption of active ingredients, and suppress skin rashes and other discomforts, the backing preferably consists of one or more layers made of the above-mentioned materials and having water vapor permeability. Specific examples of the backing include, but are not limited to, 3M COTRAN products such as 3M COTRAN ethylene vinyl acetate film 9702, 3M COTRAN ethylene vinyl acetate film 9716, 3M COTRAN polyethylene film 9720, and 3M COTRAN ethylene vinyl acetate film 9728.

[0334] The release liners used in the transdermal patches of this disclosure may include, but are not limited to, polyester films having one or both sides treated with a release coating, polyethylene-laminated high-quality paper treated with a release coating, and glass paper treated with a release coating. The release coating may be a fluoropolymer, silicone, fluorosilicone, or any other release coating known to those skilled in the art. The release liner may have an uneven surface to facilitate removal of the transdermal patch from the package. Examples of release liners may include, but are not limited to, SCOTCHPAK products from 3M, such as 3M SCOTCHPAK 9744, 3M SCOTCHPAK 9755, 3M SCOTCHPAK 9709, and 3M SCOTCHPAK 1022.

[0335] Other layers may also be used, such as abuse deterrents formulated with one or more irritants (e.g., sodium lauryl sulfate, poloxamer, sorbitan monoester, glyceryl monooleate, spice, etc.).

[0336] The methods disclosed herein using transdermal patch formulations provide systemic delivery of small amounts of the active ingredient over preferredly long periods, such as 2 to 96 hours, or 4 to 72 hours, or 8 to 24 hours, or 10 to 18 hours, or 12 to 14 hours, up to a maximum of 168 hours. In particular, the compounds of formulas (I) to (VIII) can be delivered in small, stable, and consistent doses so as to avoid adverse or undesirable side effects. In some embodiments, the compounds of formulas (I) to (VIII) are administered transdermally at concentrations that do not cause hallucinations (but are still potentially serotonergic concentrations).

[0337] Each exemplary drug-containing adhesive (DIA) patch formulation may contain, based on the total weight of the DIA patch formulation, 5 to 30% by weight of a compound of formula (I) to (VIII), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof; 30 to 70% by weight of a pressure-sensitive adhesive (e.g., DURO-TAK 387-2052, DURO-TAK 87-2677, and DURO-TAK 87-4098); 1 to 10% by weight of a penetrating / absorption enhancer (e.g., oleyl oleate, oleyl alcohol, levulinic acid, diethylene glycol monoethyl ether, etc.); and 5 to 35% by weight of a crystallization inhibitor (e.g., polyvinylpyrrolidone-co-vinyl acetate, HPMC, polymethacrylic acid, etc.), but it should be understood that many modifications are possible in light of the teachings herein.

[0338] Automated injectors provide a method for delivering the compositions disclosed herein to a patient. The compositions disclosed herein may be administered to a patient using an automated injector via several known devices, a non-limiting list of which include transdermal, subcutaneous, and intramuscular delivery.

[0339] In some transdermal, subcutaneous, or intramuscular applications, the compositions disclosed herein are absorbed through the skin. Passive transdermal patch devices often include an absorbent layer or membrane placed on the outer layer of the skin. The membrane typically contains a dose of the substance that is acceptable to be absorbed through the skin in order to deliver the composition to the patient. Typically, only substances that are readily absorbed through the outer layer of the skin may be delivered by such transdermal patch devices.

[0340] Other automated injectors disclosed herein are configured to provide increased skin permeability to improve the delivery of the disclosed compositions. Non-limiting examples of structures used to increase permeability to improve the movement of compositions into, across the skin, or into muscle include the use of one or more microneedles, which in some embodiments may be coated with the compositions disclosed herein. Alternatively, hollow microneedles may be used to provide fluid channels for delivering the disclosed compositions beneath the outer layer of the skin. Other devices disclosed herein include transdermal delivery by iontophoresis, sonophoresis, reverse iontophoresis, or a combination thereof, and other techniques known in the art for increasing skin permeability to facilitate drug delivery.

[0341] The pharmaceutical compositions may also be administered topically by electroporation, ion electrophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection, for example, POWDERJECT® (Chiron Corp., Emeryville, Calif.) and BIOJECT® (Bioject Medical Technologies Inc., Tualatin, Oreg.).

[0342] The pharmaceutical compositions disclosed herein may be disclosed in the form of ointments, creams, and gels. Suitable ointment vehicles include, for example, oily or hydrocarbon vehicles containing lard, benzoated lard, olive oil, cottonseed oil, and other oils, and white petrolatum; emulsifying or absorbent vehicles, for example, hydrophilic petrolatum, hydroxystearic acid sulfate, and anhydrous lanolin; water-removing vehicles, for example, hydrophilic ointments; water-soluble ointment vehicles containing polyethylene glycol of various molecular weights; and emulsion vehicles, either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, containing cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see Remington: The Science and Practice of Pharmacy, above). These vehicles are emollients, but generally require the addition of antioxidants and preservatives.

[0343] A suitable cream base may be oil-in-water or water-in-oil. The cream vehicle is washable with water and contains an oil phase, an emulsifier, and an aqueous phase. The oil phase is generally also called the "internal" phase and consists of petrolatum and fatty acid alcohols such as cetyl or stearyl alcohol. The aqueous phase is usually, but not necessarily, larger in volume than the oil phase and generally contains a wetting agent. The emulsifier in the cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.

[0344] A gel is a semi-solid suspension system. A single-phase gel contains an organic polymer substantially uniformly dispersed throughout the liquid carrier. Suitable gelling agents include cross-linked acrylic polymers, e.g., carbomer, carboxypolyalkylene, Carbopol®; hydrophilic polymers, e.g., polyethylene oxide, polyoxyethylene-polyoxypropylene copolymer, and polyvinyl alcohol; cellulosic polymers, e.g., hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, methylcellulose; rubbers, e.g., tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a homogeneous gel, a dispersant such as alcohol or glycerin may be added, or the gelling agent may be dispersed by grinding, mechanical mixing, and / or stirring.

[0345] The pharmaceutical compositions disclosed herein may be administered rectally, urethra, vagina, or perivaginally in the form of suppositories, pessaries, bougies, patches or poultices, pastes, powders, dressings, creams, ointments, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms may be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy (above).

[0346] Rectal, urethral, ​​and vaginal suppositories are solids for insertion into body orifices, which are solid at normal temperatures but melt or soften at body temperature to release the active ingredient into the orifice. Pharmaceutically acceptable carriers used for rectal and vaginal suppositories include bases or vehicles, such as curing agents, that produce a melting point near body temperature when the pharmaceutical compositions disclosed herein are formulated. Antioxidants described herein include bisulfites and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin gelatin, carbowax (polyoxyethylene glycol), whale wax, paraffin, white and yellow waxes, and suitable mixtures of monoglycerides, diglycerides, and triglycerides of fatty acids; hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid; and glycerin gelatin. Various combinations of vehicles may be used. Rectal and vaginal suppositories may be prepared by compression or molding. The typical weight of rectal and vaginal suppositories is approximately 2 to 3 grams.

[0347] The pharmaceutical compositions disclosed herein may be administered ophthalmologically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, intraocular implants, and implants.

[0348] The pharmaceutical compositions disclosed herein may be administered intranasally. The pharmaceutical compositions may be disclosed in the form of aerosols or solutions for delivery, either alone or in combination with suitable sprays, including, but not limited to, fluorohydrocarbons, chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons such as butane, propane, 1,1,1,2-tetrafluoroethane, or 1,1,1,2,3,3,3-heptafluoropropane, using a pressurized vessel, pump, spray, atomizer, or nebulizer to produce a fine mist. The pharmaceutical compositions may be disclosed as dry powders for inhalation, either alone or in combination with an inert carrier such as lactose or phospholipids; and as nasal drops. For intranasal use, the powders may contain a bioadhesive comprising chitosan or cyclodextrin.

[0349] Solutions or suspensions used in pressurized vessels, pumps, sprays, atomizers, or nebulizers may be formulated to contain ethanol, aqueous ethanol, or a suitable alternative or solvent for dispersion, solubilization, or sustained release of the active ingredients disclosed herein; and / or surfactants such as sorbitan triolate, oleic acid, or oligolactic acid.

[0350] The pharmaceutical compositions disclosed herein can be atomized to a size suitable for delivery, for example, about 50 micrometers or less, or about 10 micrometers or less. Particles of such size can be prepared using pulverization methods known to those skilled in the art, such as spiral jet pulverization, fluidized bed jet pulverization, supercritical fluid treatment for forming nanoparticles, high-pressure homogenization, or spray drying.

[0351] Capsules, blisters, and cartridges used in inhalation or injectable formulations may be formulated to contain a powder mixture of the pharmaceutical compositions disclosed herein; a suitable powder base such as lactose or starch; and performance modifiers such as l-leucine, mannitol, or magnesium stearate. Lactose may be anhydrous or in monohydrate form. Other suitable excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. Pharmaceutical compositions disclosed herein for inhalation / intranasal administration may further contain a suitable flavoring agent such as menthol and levomenthol, or a sweetener such as saccharin or sodium saccharin.

[0352] Pharmaceutical compositions disclosed herein for topical administration may be formulated to have immediate release or release modulation including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

[0353] D. Modified release The pharmaceutical compositions disclosed herein may be formulated as controlled-release dosage forms. As used herein, the term “modified-release” refers to a dosage form in which the rate or location of release of the active ingredient differs from that of the immediate-release dosage form when administered via the same route. Pharmaceutical compositions in modified-release dosage forms may be prepared using a variety of controlled-release devices and methods known to those skilled in the art, including, but not limited to, matrix-controlled release devices, osmotic-controlled release devices, multi-particle-controlled release devices, ion-exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. The rate of release of the active ingredient may also be modified by altering the particle size and pleomorphism of the active ingredient.

[0354] 1. Matrix-controlled emission device The pharmaceutical compositions disclosed herein in release-controlled formulations can be prepared using matrix release control devices known to those skilled in the art (see Takada et al. “Encyclopedia of Controlled Drug Delivery,” Vol.2, Mathiowitz ed., Wiley, 1999).

[0355] In some embodiments, the pharmaceutical compositions disclosed herein in release-controlled formulations are formulated using an elution matrix apparatus, which is a water-swellable, erosive, or soluble polymer, including synthetic polymers, natural polymers, and derivatives, such as polysaccharides and proteins.

[0356] Materials useful for forming eluting matrices include chitin, chitosan, dextran, and pullulan; agar gum, acacia gum, karaya gum, locust bean gum, tragacanth gum, carrageenan, gatti gum, guar gum, xanthan gum, and scleroglucan; starch, e.g., dextrin and maltodextrin; hydrophilic colloids, e.g., pectin; phospholipids, e.g., lecithin; alginates; propylene glycol alginate; gelatin; collagen; and cellulose-based materials, e.g., ethylcellulose (EC), methylethylcellulose (MEC), carboxymethylcellulose (CMC), CMEC, and hydroxyethylcellulose (HEC). Hydroxypropylcellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamic acid; degradable lactate-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride.

[0357] In some embodiments, the pharmaceutical composition is formulated using a non-eluting matrix apparatus. The active ingredient is dissolved or dispersed in an inert matrix and, upon administration, is released primarily by diffusion through the inert matrix. Suitable materials for use as a non-eluting matrix apparatus include insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, vinyl acetate, vinylidene chloride, vinyl chloride copolymer with ethylene and propylene, ionomer polyethylene terephthalate, and butyl rubber. Epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, ethylene / vinyl oxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer; and hydrophilic polymers, such as ethylcellulose, cellulose acetate, crospovidone, crosslinked partially hydrolyzed polyvinyl acetate, and aliphatic compounds, such as carnauba wax, microcrystalline wax, and triglycerides, are included but not limited to these.

[0358] In a matrix-controlled release system, the desired release dynamics can be controlled, for example, by the type of polymer used, the polymer viscosity, the particle size of the polymer and / or active ingredient, the ratio of the active ingredient to the polymer, and other excipients or carriers in the composition.

[0359] The pharmaceutical compositions disclosed herein in release-controlled formulations may be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt granulation followed by compression.

[0360] 2. Osmotic pressure controlled release device The pharmaceutical compositions disclosed herein in release-controlled dosage forms may be manufactured using osmotic pressure-controlled release devices, including one-chamber systems, two-chamber systems, asymmetric membrane technology (AMT), and extrusion core systems (ECS). Generally, such devices have at least two components: (a) a core containing the active ingredient, and (b) a semipermeable membrane having at least one delivery port enclosing the core. The semipermeable membrane controls the inflow of water from the aqueous environment at use to the core so as to cause drug release by extrusion through the delivery port.

[0361] In addition to the active ingredient, the core of the osmotic device optionally contains an osmotic agent that generates a driving force for water transport from the operating environment to the core of the device. Water-swellable hydrophilic polymers, also known as "osmopolymers" and "hydrogels," are a type of osmotic agent and include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), and carboxyethylcellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0362] Other types of osmogenic agents are osmogens, which can absorb water and influence the osmotic gradient across the surrounding coating barrier. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars such as glucose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

[0363] By using osmotic agents with different dissolution rates, the rate at which the active ingredient is initially delivered from the dosage form can be influenced. For example, using amorphous sugars such as Mannogeme EZ (SPI Pharma, Lewes, Del.) can provide faster delivery in the first few hours to immediately generate the desired therapeutic effect, and then gradually and continuously release the remaining amount to maintain the desired level of therapeutic or preventive effect over a long period. In this case, the active ingredient is released at a rate that replaces the amount of active ingredient that is metabolized and excreted.

[0364] The core may also contain various other excipients and carriers described herein to enhance the performance of the dosage form or to facilitate its stability or processing.

[0365] Materials useful for forming semipermeable membranes include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives that are water-permeable and water-insoluble at physiologically relevant pH levels, or that are readily water-insoluble through chemical changes such as crosslinking. Examples of suitable polymers useful for forming coatings include plasticized, non-plasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose butyrate acetate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose trimellitate acetate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta-glucan acetate, beta-glucan triacetate, acetaldehyde dimethyl acetate, locust bean rubber triacetate, hydroxylated ethylene vinyl acetate, EC, PEG, PPG, PEG / PPG This includes copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters, poly(methacrylic) acids and esters, and their copolymers, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0366] Semipermeable membranes can also be hydrophobic microporous membranes, as disclosed in U.S. Patent No. 5,798,119, in which the pores are substantially filled with gas and are not moistened by aqueous media, but are permeable to water vapor. Such hydrophobic but water vapor permeable membranes typically consist of hydrophobic polymers, such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyhalogens, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0367] Delivery ports on a semipermeable film may be formed after coating by mechanical or laser drilling. Delivery ports may also be formed in situ by erosion of a water-soluble material plug or by rupture of a thin portion of the film over a core recess. Furthermore, delivery ports may be formed during the coating process, as in the case of asymmetric film coatings of the type disclosed in U.S. Patents 5,612,059 and 5,698,220.

[0368] The total amount and rate of release of the active ingredient can be substantially controlled through the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

[0369] Pharmaceutical compositions in osmotic pressure-controlled release formulations may further include additional conventional excipients or carriers described herein to enhance the performance or processing of the composition.

[0370] Osmotically controlled release formulations can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, Santus and Baker, J. Controlled Release 1995, 35, 1-21, Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708, and Verma et al., J. Controlled Release 2002, 79, 7-27).

[0371] In some embodiments, the pharmaceutical compositions disclosed herein are formulated as AMT-controlled release formulations comprising an asymmetric permeable membrane coating a core containing an active ingredient and other pharmaceutically acceptable vehicles (e.g., excipients or carriers). AMT-controlled release formulations can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and immersion coating.

[0372] In some embodiments, the pharmaceutical compositions disclosed herein are formulated as ESC-controlled release formulations comprising a permeable membrane coating a core containing an active ingredient, hydroxyethylcellulose, and other pharmaceutically acceptable excipients or carriers.

[0373] 3. Multi-particle controlled emission device The pharmaceutical compositions disclosed herein in release-controlled dosage forms may be manufactured as multiparticulate controlled release devices comprising a number of particles, granules, or pellets in diameters ranging from about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, or about 100 μm to about 1 mm. Such multiparticulates may be manufactured by processes known to those skilled in the art, including wet and dry granulation, extrusion / spheroidization, roller compression, melt-solidification, and by spray coating of seed cores. See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994 and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

[0374] Other excipients or carriers described herein may be blended with the pharmaceutical composition to assist in the processing and formation of multiparticles. The resulting particles themselves may constitute a multiparticle device or may be coated with various film-forming materials such as enteric polymers, water-swellable polymers, and water-soluble polymers. The multiparticles may be further processed into capsules or tablets.

[0375] 4. Targeted delivery The pharmaceutical compositions disclosed herein may also be formulated to target specific tissues, receptors, or other areas of the body being treated, and may include liposomes, re-encapsulated red blood cells, and antibody delivery systems.

[0376] E. Inhalation administration The pharmaceutical compositions disclosed herein may be formulated for inhalation administration, for example, pulmonary absorption. Preferred preparations may include the liquid preparations described above, such as solutions and emulsions, and the solvent or carrier may be, for example, water, a water / water miscible vehicle such as a water / propylene glycol solution, or an organic solvent containing an optional buffer, and may be delivered as an aerosol, preferably a mist, together with a carrier gas such as air, oxygen, a mixture of helium and oxygen, or other gases and gas mixtures. The pharmaceutical compositions may be formulated as a dry powder for inhalation, either alone or in combination with an inert carrier such as lactose or a phospholipid.

[0377] The pharmaceutical composition may be in the form of an aerosol or solution for delivery, either by using a pressurized container, pump, sprayer, atomizer such as a sprayer that generates a fine mist using electrohydrodynamics, or nebulizer alone, or in combination with a suitable propellant such as hydrofluoroalkanes such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane (HFA 134A) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), carbon dioxide, perfluorinated hydrocarbons such as perflubron, and other suitable gases.

[0378] Aqueous solutions suitable for inhalation use can be prepared by dissolving the compounds of formulas (I) to (VIII), or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs, in water or other water-based media. Suitable stabilizers and thickeners may also be added. Emulsions suitable for inhalation use can be prepared by solubilizing the compounds of formulas (I) to (VIII), or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs, in an aqueous media and optionally dispersing this solubilized form in a hydrophobic media using viscous materials such as natural or synthetic rubber, resins, methylcellulose, sodium carboxymethylcellulose, and other suspending agents.

[0379] Solutions or suspensions used in pressurized vessels, pumps, sprays, atomizers, or nebulizers may be formulated to contain a surfactant or other suitable co-solvent, or a suitable alternative for the dispersion, solubilization, or sustained release of the active ingredients disclosed herein, and optionally a propellant. Such surfactants or co-solvents may include, but are not limited to, polysorbate 20, 60, and 80; Pluronic® F-68, F-84, and P-103; cyclodextrin; polyoxyl 35 castor oil; sorbitan trioleate, oleic acid, or oligolactic acid. Surfactants and co-solvents may be used optionally at levels of about 0.01% to about 2% by weight of the pharmaceutical composition. Viscosity greater than that of a simple aqueous solution may, in some cases, be desirable to reduce variability when dispensing the formulation, reduce the physical separation of the emulsion components of the formulation, and / or otherwise improve the formulation. Such viscosity-building agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations of the above substances. Such agents are, if desired, typically used at a concentration of about 0.01% to about 2% by weight of the pharmaceutical composition.

[0380] The compounds of this disclosure may also be dissolved in organic solvents or aqueous mixtures of organic solvents. Organic solvents may include, for example, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloromethane (DCE), dichloromethane (DCM), 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, ethanol, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethylene, or xylene, and combinations thereof. Organic solvents may belong to functional group categories such as ester solvents, ketone solvents, alcohol solvents, amide solvents, ether solvents, and hydrocarbon solvents, each of which may be used.

[0381] The compounds of the present disclosure (e.g., compounds of formulas (I) to (VIII)) may be delivered by inhalation as an aerosol, preferably as a mist, for systemic administration to the central nervous system of a patient. Preferably, the aerosol is generated without external heat (this does not exclude a slight temperature rise caused by the formation of the aerosol itself by a vibrating mesh or other nebulizer, etc., however such a slight temperature rise can often be offset by the vaporization of the drug, which results in cooling of the composition). The compounds of the present disclosure may be delivered as an aerosol, preferably as a mist, together with a carrier such as air, oxygen, or a mixture of helium and oxygen, or other gas mixtures including a therapeutic gas mixture. The carrier gas, e.g., air, oxygen, a mixture of helium and oxygen, or other gases and gas mixtures may be heated to about 50°C to about 60°C, or about 55°C to about 56°C. When a mixture of helium and oxygen is used as a carrier, helium may be present in the mixture of oxygen and helium at a volume of about 50%, 60%, 70%, 80%, or 90%, and oxygen may be present in the mixture at a volume of about 50%, 40%, 30%, or 10%, or any range in between.

[0382] Inhalation delivery may further include administering a pre-treatment inhalation therapy prior to the administration of an aerosol containing the compounds of formulas (I) to (VIII). The pre-treatment may include administering to the patient via inhalation a mixture of helium and oxygen heated to about 90°C, about 92°C, about 94°C, about 96°C, about 98°C, about 100°C, about 105°C, about 110°C, about 115°C, about 120°C, or any range in between. For example, an inhalation procedure may include (i) administering to the patient via inhalation a mixture of helium and oxygen heated to about 90°C to about 120°C, and then (ii) administering to the patient via inhalation an aerosol containing a mixture of helium and oxygen heated to about 50°C to about 60°C and the compounds of formulas (I) to (VIII), and then repeating steps (i) and (ii). Steps (i) and (ii) can be repeated 1, 2, 3, 4, 5 or more times.

[0383] The compounds of this disclosure (e.g., compounds of formulas (I) to (VIII)) are, in some embodiments, administered in doses of approximately 1 μg to approximately 200 mg or more (or any range between approximately 1 μg and approximately 200 mg) per inhalation session, for example, approximately 1 μg, 2 μg, 5 μg, 6 μg, 10 μg, 13 μg, 15 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 110 μg, 120 μg, 130 μg, 140 μg, 150 μg, 160 μg, 170 μg, 180 μg, 190 μg, 200 μg, 210 μg It can be administered via aerosol inhalation in doses of μg, 220μg, 230μg, 240μg, 250μg, 260μg, 270μg, 280μg, 290μg, 300μg, 400μg, 500μg, 1.0mg, 2.0mg, 3.0mg, 4.0mg, 5.0mg, 6.0mg, 7.0mg, 8.0mg, 9.0mg, 10.0mg, 20.0mg, 30.0mg, 40.0mg, 50.0mg, 60.0mg, 70.0mg, 80.0mg, 90.0mg, 100.0mg, 150.0mg, and 200.0mg or more. In some embodiments, subjects may have one, two, three, four, or five or more inhalation sessions per day. In some embodiments, the subject may have one, two, three, four, or five or more inhalation sessions every other day, once a week, twice a week, or three times a week. In some embodiments, the subject may have one, two, three, four, or five or more inhalation sessions every other month, twice a month, three times a month, or four times a month. In some embodiments, the subject may have one, two, three, four, five, six, seven, eight, or more inhalation sessions per treatment course, such as within 28 days.

[0384] aerosol Aerosols, preferably mists, can be delivered using air, oxygen, a mixture of oxygen and helium, or other gases and gas mixtures as a carrier gas. The carrier gas may be delivered at room temperature or heated. In some embodiments, aerosols, preferably mists, containing compounds of formulas (I) to (VIII) are delivered via inhalation using a heated helium-oxygen (HELIOX) mixture. Due to the very low viscosity of helium, the mixture of helium and oxygen reaches deep into the lung region and generates a gas flow characterized by laminar flow, a highly desirable feature for reducing drug deposition in the airways, which is one of the major obstacles in dose delivery via inhalation. A patient can inhale the dissolved compounds disclosed herein as a mist into the alveolar region of the patient's lungs. The compounds of formulas (I) to (VIII) can then be delivered into the fluid inner layer of the alveolar region of the lungs and may be systemically absorbed into the patient's blood circulation. Advantageously, once inhaled into the alveolar region of the lungs, these formulations can be effectively delivered into the bloodstream.

[0385] Apparatus suitable for delivering heated or unheated carrier gases (e.g., air, oxygen, or helium-oxygen mixtures) includes, for example, the continuous mode nebulizers Flo-Mist (Phillips) and Hope (B&B Medical Technologies), as well as accessories such as the regulator for the Medipure™ Heliox-LCQ System (PraxAir) and the control box for the Precision Control Flow (PraxAir). In some embodiments, the complete delivery apparatus may be, for example, the apparatus described in Russian Patent No. RU199823U1.

[0386] As used herein, the term “heliox” refers to a mixture of helium gas (He) and oxygen gas (O2) as breathing gases. In some embodiments, the heliox mixture may contain helium in a helium-oxygen mixture at about 50%, 60%, 70%, 80%, or 90% by volume, and oxygen in a helium-oxygen mixture at about 50%, 40%, 30%, or 10% by volume, or any range in between. Thus, the heliox mixture may contain helium and oxygen in volume ratios of 50:50, 60:40, 70:30, 80:20, 90:10, or any range in between. In some embodiments, the heliox may generate less resistance with the airway due to increased laminar flow tendency and reduced resistance in turbulence.

[0387] The use of heat in heliox mixtures can further improve drug delivery by increasing the permeability of key physical barriers for drug absorption. Heating the mucosal surface can increase permeability by improving peripheral blood circulation and relaxing interstitial junctions and other mechanisms. Helium has nearly 10 times higher thermal conductivity than oxygen and nitrogen, and can promote heat transfer more efficiently. Dry heliox mixtures can be safely used as a pretreatment step when heated up to 110°C, which allows the dry heliox mixture to heat the mucosal surfaces of the lungs and airways more efficiently.

[0388] Various types of personal inhalers are known in the art. Generally, personal inhalers are characterized by heating a solid drug or compound. Inhalers can function by directly heating a solid drug or compound to its smoldering point. Vaporization of a solid or solid concentrate can be done by convection or conduction. Convective heating of a solid concentrate involves a heating element in contact with water or another liquid, which then vaporizes. The high-temperature vapor directly heats and smolders the solid or solid concentrate, releasing vapor which is inhaled by the user. Conductive heating involves direct contact between the solid or solid concentrate and the heating element, which brings the solid to its smoldering point, releasing vapor which is inhaled by the user. Vaporizers offer advantages over smoking in terms of lung damage, however the vaporized drug / active ingredient can be significantly degraded by the heat of vaporization.

[0389] In some embodiments, the compounds of formulas (I) to (VIII) are delivered via an aqueous droplet aerosol, preferably a mist-generating nebulizer, containing the compound and optionally combined with a heated helium-oxygen mixture. In some embodiments, the disclosed compounds are delivered via an aqueous droplet aerosol, preferably a mist-generating nebulizer, containing the compound and combined with a driving gas containing nitrous oxide. The driving gas containing nitrous oxide may be nitrous oxide gas itself or a therapeutic gas mixture such as an N2O-O2 mixture or an N2O-air mixture. The therapeutic gas mixture may further contain other gases such as one or more of N2, Ar, CO2, Ne, CH4, He, Kr, H2, Xe, H2O (e.g., vapor). In some embodiments, the driving gas is a therapeutic gas mixture containing N2O, which is present in concentrations ranging from 5% by volume, 10% by volume, 15% by volume, 20% by volume, 25% by volume, 30% by volume, 35% by volume, 40% by volume, 45% by volume, and up to 75% by volume, up to 70% by volume, up to 65% by volume, up to 60% by volume, up to 55% by volume, up to 50% by volume, or any range in between, relative to the total volume of the therapeutic gas mixture. The presence of nitrous oxide (which is an NMDA receptor antagonist) in (or as the driving gas) can enhance the effects of the disclosed compounds and provide the ability to obtain similar levels of effect using lower doses.

[0390] For example, compounds of formulas (I) to (VIII), or preparations thereof that are pharmaceutically acceptable, such as their stereoisomers, tautomers, solvates, polymorphs, or prodrugs, can be placed in a liquid medium and introduced into an aerosol using a device such as a nebulizer. In some embodiments, the nebulizer may be, for example, an air compressor nebulizer, an ultrasonic nebulizer, a vibrating mesh or horn nebulizer, or a microprocessor-controlled exhalation-operated nebulizer. In some embodiments, the nebulizer device may be, for example, the device described in Russian Patent No. RU199823U1.

[0391] A nebulizer is a device that converts drugs, such as compounds of formulas (I) to (VIII) in a solution or suspension, into a fine aerosol, such as a mist, for delivery to the lungs. A nebulizer may also be called a sprayer. Spraying is the process of converting a dissolved drug into an aerosol, such as a mist. To deliver the drug by spraying, the drug may be dispersed in a liquid medium, such as water, ethanol, or propylene glycol. Furthermore, the disclosed compounds may be transported by vehicles such as liposomes, polymers, emulsions, micelles, nanoparticles, or polyethyleneimine (PEI). The liquid drug for nebulizers may be, for example, an aqueous solution or a viscous solution. The dissolved drug is contained in droplets after a force for dispersion (e.g., gas jet, ultrasound, or mesh vibration) is applied, and then these droplets are inhaled. The mist may contain droplets of the drug in the air or in another gas mixture (e.g., a mixture of helium and oxygen).

[0392] A jet nebulizer (also called an air nebulizer or compressor nebulizer) uses compressed gas to produce mist. In some embodiments, the jet nebulizer is a microprocessor-controlled exhalation-operated nebulizer, also called an exhalation-operated nebulizer. Exhalation-operated nebulizers do not produce mist continuously, but only when the patient is inhaling. Mist can be produced, for example, by passing an airflow through a venturi tube in a nebulizer bowl or cup. A venturi tube is a system for accelerating the flow of a fluid by compressing the fluid into a conical tube. In this limitation, the fluid must increase its velocity, thereby decreasing its pressure and creating a partial vacuum. As the fluid exits the constriction, its pressure increases again to ambient or pipe level pressure. This can create a low-pressure region that pulls droplets from the drug solution in the nebulizer bowl through the supply tube, then generating a flow of atomized droplets that flows into the mouthpiece. As the airflow increases, particle size decreases and ejection volume increases. Due to the droplets and solvent that saturate the discharged gas, a jet nebulizer can cool the drug solution within the nebulizer and increase the solute concentration in the residual volume. The baffles in the nebulizer bowl or cup may be affected by larger particles, which will retain them and return them to the solution in the nebulizer bowl or cup for re-atomization. The entrainment of air passing through the nebulizer bowl as the subject inhales may increase the amount of mist produced in the inhaled air. Mist generation is more likely to occur with smaller particle size distributions, but the smaller the particle size used, the longer the atomization time may be.

[0393] The commonly used unit of measurement for droplet size is the median mass diameter (MMD), defined as the average droplet diameter by mass. This unit may also be referred to as mass-mean aerodynamic diameter, or MMAD. MMD droplet sizes for jet nebulizers can be approximately 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0 μm or larger (or any range between approximately 1.0 and 10.0 μm), which can be smaller than those for ultrasonic nebulizers.

[0394] Ultrasonic nebulizers generate mist using the vibration of a piezoelectric crystal, which converts alternating current into high-frequency (approximately 1 to 3 MHz) acoustic energy. The solution is broken down into droplets at the surface, and the resulting mist is drawn out of the device by the patient's inhalation or pushed out by a gas flow through the device generated by a small compressor. Ultrasonic nebulizers can include high-volume and low-volume ultrasonic nebulizers. Droplet sizes tend to be larger in ultrasonic nebulizers than in jet nebulizers. MMD droplet sizes for ultrasonic nebulizers can be approximately 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 10.0 μm or larger (or any range between approximately 2.0 and 10.0 μm). Ultrasonic nebulizers can generate high-density mist with droplets of approximately 100, 150, 200, 250, or 300 μm / L or more.

[0395] Mesh nebulizers indirectly generate mist using the vibration of a piezoelectric crystal. Mesh nebulizers include, for example, active mesh nebulizers and passive mesh nebulizers. Active mesh nebulizers use a piezoelectric element that contracts and expands with the application of an electric current to vibrate a precisely drilled mesh in contact with a drug solution, thereby generating mist. The vibration of the piezoelectric crystal can be used to vibrate a thin metal plate with thousands of holes. One side of the plate is in contact with the liquid to be atomized, and the vibration forces this liquid through the holes to generate a mist of tiny droplets. Passive mesh nebulizers generate mist using a transducer horn that induces passive vibration in a perforated plate with tapered holes. Examples of active mesh nebulizers include Aeroneb® (Aerogen, Galway, Ireland) and eFlow® (PARI, Starnberg, Germany), while Microair NE-U22® (Omron, Bannockburn, IL) is a passive mesh nebulizer. Mesh nebulizers are precise and customizable. The device can be adjusted for use with drug solutions of different viscosities by changing the pore size of the mesh, which alters the rate of ejection. Several advantages can be offered by using this atomization method. Droplet size can be extremely precise, as it can be determined by the size of the holes in the mesh (which can be customized for the application). Nebulizer meshes can be manufactured using methods such as electrodeposition, electroplating, and laser cutting to produce liquid particles in a breathable range of gases. Meshes can be made from metal alloys. Metals used in mesh manufacturing may include platinum, palladium, nickel, and stainless steel. The droplet size is approximately twice the size of the mesh pores. Therefore, the mesh pores can be approximately 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 μm or larger (or any value between approximately 0.1 and 5.0 μm). Mist generation in a mesh nebulizer can also vary based on the mesh shape, the material from which the mesh is made, and the method by which the mesh is produced.In other words, different meshes can generate liquid particles of different sizes that float in the gas. Generally, MMD droplet sizes in mesh nebulizers can be approximately 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0 μm or larger (or any value between approximately 1.0 and 7.0 μm).

[0396] Furthermore, droplet size may be programmable. In particular, geometric modifications can be made to the nebulizer to provide a specific desired droplet size. Moreover, droplet size can be controlled independently of droplet velocity. The volume of atomized liquid and droplet velocity can also be precisely controlled by adjusting the frequency and amplitude of mesh vibration. Furthermore, the number of holes in the mesh and their layout on the mesh can be customized. The mesh nebulizer can be powered by either electricity or batteries.

[0397] The mist output rate in standing cloud mL per minute (for any atomization method described herein) may be, for example, in the range of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 mL / min or more (or any range between approximately 0.1 and 0.9 mL / min), and the residual volume of any type of nebulizer storage unit may be in the range of approximately 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 mL or more (or any range between approximately 0.01 and 2.0 mL). Precise droplet size control may be advantageous because droplet size may directly correlate with dynamic drug release (KDR). Precise control of KDR is achievable by precise control of droplet size. The compounds herein can be delivered via mist using any method with MMD droplet sizes of approximately 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0 μm or larger (or any range between approximately 0.5 and 10.0 μm).

[0398] In some embodiments, compounds of formulas (I) to (VIII) may be delivered via a continuous positive airway pressure (CPAP) device or other pressure-assisted breathing apparatus. A pressure-assisted breathing apparatus continuously pushes a column of compressed air or other gas at a specified constant pressure against the face and nose of a patient wearing a mask or nose cap. When the patient opens their glottis and inhales, the pressure is transmitted throughout the airway, helping to open it. As the patient exhales, the pressure from the contracting lungs and chest wall pushes air against the continuous pressure until the two pressures are equal. The air pressure in the airway at the end of exhalation is equal to the machine's external ai...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, 【Chemistry 1】 During the ceremony, X １ and X ２ These are independently hydrogen or deuterium, Y １ and Y ２ These are independently hydrogen or deuterium, R ３ However, it is hydrogen or deuterium, Each R ａ Independently, substitution or non-substitution C １ ~C ６ It is alkyl, R ４ is R ７ -S(O)-, R ８ -S(O) ２ -, R ９ -S-S-, or R １５ -Se-, and R ７ , R ８ , and R ９ These are independently unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, R １５ However, non-substituted C ２ ~C １０ Alkyl, substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, However, R ４ R ７ -S(O)- and X １ , X ２ , Y １ , Y ２ , and R ３ Each of them is hydrogen, and each R ａ If R is methyl, ７ A compound, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, polymorph, or prodrug, provided that is not methyl, n-propyl, 2-hydroxypropyl, or 3-hydroxypropyl.

2. X １ and X ２ The compound according to claim 1, wherein the compound is hydrogen.

3. Y １ and Y ２ The compound according to claim 1, wherein the compound is hydrogen.

4. R ３ The compound according to claim 1, wherein the compound is hydrogen.

5. Each R ａ The compound according to claim 1, wherein the compound is methyl.

6. Having the structure of formula (II), 【Chemistry 2】 During the ceremony, X １ and X ２ These are independently hydrogen or deuterium, Y １ and Y ２ These are independently hydrogen or deuterium, R ３ However, it is hydrogen or deuterium, Each R ａ Independently, substitution or non-substitution C １ ~C ６ It is alkyl, R ７ However, it is an unsubstituted or substituted alkyl, an unsubstituted or substituted alkenyl, an unsubstituted or substituted alkynyl, an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocycloalkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl, However, X １ , X ２ , Y １ , Y ２ , and R ３ Each of them is hydrogen, and each R ａ If R is methyl, ７ The compound according to claim 1, provided that is not methyl, n-propyl, 2-hydroxypropyl, or 3-hydroxypropyl, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. 【Request Item 7】 【Chemistry 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 A compound according to claim 6, selected from the group consisting of the above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof.

8. It has the structure of formula (III), 【Chemistry 14】 During the ceremony, X １ and X ２ These are independently hydrogen or deuterium, Y １ and Y ２ These are independently hydrogen or deuterium, R ３ However, it is hydrogen or deuterium, Each R ａ Independently, substitution or non-substitution C １ ~C ６ It is alkyl, R ８ The compound according to claim 1, wherein the compound is an unsubstituted or substituted alkyl, an unsubstituted or substituted alkenyl, an unsubstituted or substituted alkynyl, an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocycloalkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. 【Request Item 9】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 A compound according to claim 8, selected from the group consisting of the above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof.

10. Having the structure of formula (IV), 【Chemistry 26】 During the ceremony, X １ and X ２ These are independently hydrogen or deuterium, Y １ and Y ２ These are independently hydrogen or deuterium, R ３ However, it is hydrogen or deuterium, Each R ａ Independently, substitution or non-substitution C １ ~C ６ It is alkyl, R ９ The compound according to claim 1, wherein the compound is an unsubstituted or substituted alkyl, an unsubstituted or substituted alkenyl, an unsubstituted or substituted alkynyl, an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocycloalkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. 【Request Item 11】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 A compound according to claim 10, selected from the group consisting of the above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof.

12. It has the structure of formula (VIII), 【Transformation 33】 During the ceremony, X １ and X ２ These are independently hydrogen or deuterium, Y １ and Y ２ These are independently hydrogen or deuterium, R ３ However, it is hydrogen or deuterium, Each R ａ Independently, substitution or non-substitution C １ ~C ６ It is alkyl, R １５ However, non-substituted C ２ ~C １０ A compound according to claim 1, which is an alkyl, substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. 【Request Item 13】 【Chemistry 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 A compound according to claim 12, selected from the group consisting of the above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof.

14. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, A pharmaceutical composition comprising a pharmaceutically acceptable vehicle, 【Chemistry 44】 During the ceremony, X １ and X ２ These are independently hydrogen or deuterium, Y １ and Y ２ These are independently hydrogen or deuterium, R ３ However, it is hydrogen or deuterium, Each R ａ Independently, substitution or non-substitution C １ ~C ６ It is alkyl, R ４ is R ７ -S(O)-, R ８ -S(O) ２ -, R ９ -S-S-, or R １５ -Se-, and R ７ 、 R ８ 、 and R ９ are each independently unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, R １５ However, non-substituted C ２ ~C １０ A pharmaceutical composition comprising alkyl, substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

15. The pharmaceutical composition according to claim 14, which is suitable for oral administration.

16. The pharmaceutical composition according to claim 14, which is suitable for intravenous or intradermal administration.

17. The pharmaceutical composition according to claim 14, which is suitable for transdermal administration.

18. The pharmaceutical composition according to claim 14, which is adapted for administration by inhalation.

19. A method of treating a subject with a disease or disability, This includes administering a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, to the subject. 【Chemistry 45】 During the ceremony, X １ and X ２ These are independently hydrogen or deuterium, Y １ and Y ２ These are independently hydrogen or deuterium, R ３ However, it is hydrogen or deuterium, Each R ａ Independently, substitution or non-substitution C １ ~C ６ It is alkyl, R ４ However, R ７ -S(O)-, R ８ -S(O) ２ -, R ９ -S-S-, or R １５ -Se-, R ７ , R ８ , and R ９ These are independently unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, R １５ However, non-substituted C ２ ~C １０ A method comprising alkyl, substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

20. Serotonin 5-HT ２ A method for treating a subject having a disease or disorder related to receptors, This includes administering a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, to the subject. 【Chemistry 46】 During the ceremony, X １ and X ２ These are independently hydrogen or deuterium, Y １ and Y ２ These are independently hydrogen or deuterium, R ３ However, it is hydrogen or deuterium, Each R ａ Independently, substitution or non-substitution C １ ~C ６ It is alkyl, R ４ However, R ７ -S(O)-, R ８ -S(O) ２ -, R ９ -S-S-, or R １５ -Se-, R ７ , R ８ , and R ９ These are independently unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, R １５ However, non-substituted C ２ ~C １０ A method comprising alkyl, substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

21. The method according to claim 20, wherein the disease or disorder is a neuropsychiatric disorder or inflammatory disease or disorder.

22. The method according to claim 20, wherein the disease or disorder is a central nervous system (CNS) disorder.

23. The method according to claim 22, wherein the central nervous system (CNS) disorder is at least one selected from the group consisting of major depressive disorder (MDD), treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), bipolar disorder and related disorders, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, substance use disorder, eating disorder, Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset fluency, severe neurocognitive impairment, mild neurocognitive impairment, suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or suicidal behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), chronic fatigue syndrome, Lyme disease, gambling disorder, paraphilic disorder, sexual dysfunction, peripheral neuropathy, and obesity.

24. The method according to claim 22, wherein the central nervous system (CNS) disorder is major depressive disorder (MDD).

25. The method according to claim 22, wherein the central nervous system (CNS) disorder is treatment-resistant depression (TRD).

26. The method according to claim 22, wherein the central nervous system (CNS) disorder is generalized anxiety disorder (GAD).

27. The method according to claim 22, wherein the central nervous system (CNS) disorder is social anxiety disorder.

28. The method according to claim 22, wherein the central nervous system (CNS) disorder is obsessive-compulsive disorder (OCD).

29. The method according to claim 22, wherein the central nervous system (CNS) disorder is cluster headache or migraine.

30. The method according to claim 22, wherein the central nervous system (CNS) disorder is a substance use disorder.

31. The method according to claim 30, wherein the substance use disorder is alcohol use disorder.

32. The method according to claim 30, wherein the substance use disorder is nicotine use disorder.

33. The method according to claim 20, wherein the disease or disorder is characterized by neuroinflammation or otherwise related to neuroinflammation.

34. The method according to claim 20, wherein the disease or disorder is an autonomic nervous system (ANS) state.

35. The method according to claim 20, wherein the disease or disorder is a lung disorder.

36. The method according to claim 20, wherein the disease or disorder is a cardiovascular disorder.

37. The method according to claim 20, wherein the compound is administered orally to the subject.

38. The method according to claim 20, wherein the compound is administered orally to the subject.

39. The method according to claim 20, wherein the compound is administered intravenously or intradermally to the subject.

40. The method according to claim 20, wherein the compound is administered transdermally to the subject.

41. The method according to claim 20, wherein the compound is administered to the subject by inhalation.

42. The method according to claim 20, wherein the compound is administered to the subject in a dose that induces hallucinations, ranging from approximately 0.083 mg / kg to approximately 5 mg / kg.

43. The method according to claim 42, wherein the compound is administered at a dose that induces hallucinations at least once a week throughout the course of treatment.

44. The method according to claim 20, wherein the compound is administered to the subject in a dose that does not cause hallucinations, ranging from about 0.00001 mg / kg to less than about 0.083 mg / kg.

45. The method according to claim 44, wherein the compound is administered at least once a day throughout the course of treatment in a dose that does not cause hallucinations.

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