Tryptamine compounds, compositions, and methods of use

Abstract

The present disclosure relates to tryptamine compounds, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs thereof, pharmaceutical compositions, and in some embodiments, to serotonin 5-HT2 receptor agonists and their use in treating disorders, such as disorders associated with the 5-HT2 receptor.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 402,650, filed August 31, 2022, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates generally to tryptamine compounds, compositions, and in some embodiments, to serotonin 5-HT2 receptor agonists and their use in treating disorders associated with the 5-HT2 receptor. [Background technology]

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

[0004] Serotonin 5-HT2 receptors (5-HT2Rs) include three closely related subtypes: 5-HT 2A , 5-HT 2B , and 5-HT 2C These are the primary targets of classical serotonergic hallucinogens such as lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-bromoamphetamine (DOB), N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), psilocybin, and its active dephosphorylated form, psilocin. Each subtype is expressed in a unique pattern in mammals (both peripheral tissues and the central nervous system) and, when stimulated, produces unique biochemical, physiological, and behavioral effects. For example, 5-HT 2A Activation of Rs primarily mediates hallucinogenic effects and causes anti-inflammatory effects, whereas 5-HT 2C Activation of Rs reduces feeding behavior. However, 5-HT 2BChronic activation of Rs is associated with valvular heart disease (VHD), a life-threatening adverse event (AE).

[0005] Classical serotonergic hallucinogens and entactogens have been shown to be effective in treating a number of central nervous system (CNS) disorders (Reiff, CM, Richman, EE, Nemeroff, CB, Carpenter, LL, Widge, AS, Rodriguez, CI, Kalin, NH, and McDonald, WM, 2020, Psychedelics and Psychedelic-Assisted Psychotherapy, Am J Psychiatry 177, 391-410), such as: (i) post-traumatic stress disorder (PTSD) (Jerome, L., Feduccia, AA, Wang, JB, Hamilton, S., Yazar-Klosinski, B., Emerson, A., Mithoefer, MC, and Doblin, R., 2020, Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials, Psychopharmacology (Berl) 237, 2485-2497), (ii) major depressive disorder (MDD), (iii) treatment-resistant depression (TRD) (Goldberg, SB, Pace, BT, Nicholas, CR, Raison, CL, and Hutson, PR, 2020, The experimental effects of psilocybin on symptoms of anxiety and depression: A meta-analysis, Psychiatry Res 284, 112749), (iv) obsessive-compulsive disorder (OCD) (Moreno, FA, Wiegand, CB, Taitano, EK, and Delgado, PL, 2006, Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder, J Clin Psychiatry 67, 1735-1740), and (v) social anxiety disorder (Clinical Trials.gov, number NCT02008396), (vi) substance use disorders, such as alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder, (vii) anorexia nervosa, (viii) bulimia nervosa (ClinicalTrials.gov, numbers NCT04454684 and NCT04052568), (ix) Alzheimer's disease (ClinicalTrials.gov, number NCT04123314), (x) cluster headache and migraine (Nichols, DE, 2016, Psychedelics, Pharmacol Rev 68, 264-355; Johnson, MW, Hendricks, PS, Barrett, FS, and Griffiths, RR, 2019, Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain It has been actively investigated by the research and medical community for alleviating conditions such as: (1) network function, Pharmacol Ther 197, 83-102; (2) Sewell, RA, Halpern, JH, and Pope, HG, Jr., 2006, Response of cluster headache to psilocybin and LSD, Neurology 66, 1920-1922; (3) ClinicalTrials.gov, number NCT04218539.

[0006] These agents are also being investigated to alleviate conditions of the autonomic nervous system (ANS), including pulmonary disorders (e.g., asthma and chronic obstructive pulmonary disorder (COPD)) and cardiovascular disorders (e.g., atherosclerosis), among others (Nichols, DE, Johnson, MW, and Nichols, CD, 2017, Psychedelics as Medicines: An Emerging New Paradigm, Clin Pharmacol Ther 101, 209-219; Flanagan, TW, Sebastian, MN, Battaglia, DM, Foster, TP, Cormier, SA, and Nichols, CD, 2019, 5-HT2 receptor activation alleviates airway inflammation and structural remodeling in a chronic mouse asthma model, Life Sci 236, 116-790; Flanagan, TW, Sebastian, MN, Battaglia, DM, Foster, TP, Maillet, EL, and Nichols, CD, 2019, Activation of 5-HT2 Receptors Reduces Inflammation in Vascular Tissue and Cholesterol Levels in High-Fat Diet-Fed Apolipoprotein E Knockout Mice,Sci Rep 9,13444;Sexton,JD,Nichols,CD,and Hendricks,PS,2019,Population Survey Data Informing the Therapeutic Potential of Classic and Novel Phenethylamine,Tryptamine,and Lysergamide Psychedelics, Front Psychiatry 10,896).

[0007] Despite their high potency at serotonin 5-HT2Rs (in some cases, subnanomolar affinity), the therapeutic value of certain tryptamine hallucinogens is hindered by accelerated metabolism in the liver and gastrointestinal tract, particularly by monoamine oxidase (MAO) enzymes. For example, DMT is not orally active and is converted to inactive metabolites before sufficient brain penetration can occur. Similarly, 5-MeO-DMT lacks oral bioavailability and is instead typically vaporized and inhaled to produce its hallucinogenic effects. Psilocybin and psilocin also undergo MAO-mediated metabolism in vivo, which is thought to contribute to the large variability in pharmacokinetics between patients. Furthermore, the duration of action of certain tryptamine hallucinogens is very short—5–15 minutes in the case of DMT and 5-MeO-DMT—limiting their use in effective therapy. Summary of the Invention

[0008] In view of the foregoing, there is a need for novel tryptamine hallucinogens that are orally bioavailable, brain penetrable, and have clinically effective durations of action, such as those with affinity for distinct conformations or populations of 5-HT receptors, and improved pharmacokinetic properties. There is a further need for efficient, more convenient, and controllable tryptamine formulations that provide controlled drug exposure and maintain drug concentrations in a safe and effective range.

[0009] One objective of the present disclosure is to provide novel tryptamine compounds that meet these criteria, compositions thereof, and methods of using the same to treat disorders, such as those associated with the serotonin 5-HT2 receptor. More specifically, the present disclosure provides novel fluorinated tryptamine analogs and compositions thereof that can be used to treat neuropsychiatric disorders, central nervous system (CNS) disorders, neurodegenerative diseases, and other disorders, such as disorders associated with inflammation.

[0010] Thus, the present disclosure provides: (1) A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 is selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and -OPO3H2; R5 is hydrogen, deuterium, hydroxyl, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, unsubstituted alkoxy, alkoxy substituted with one or more deuterium atoms, unsubstituted alkylthio, alkylthio substituted with one or more deuterium atoms, -OR f , and -SR f is selected from the group consisting of R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R8 is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R f is selected from the group consisting of R9 is unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, R f , -S(O)R f , and -S(O)R f is selected from the group consisting of or alternatively, R8 and R9 together with the nitrogen atom to which they are attached optionally join to form a heterocycloalkyl substituted with at least one fluorine; and R f is a fluoroalkyl group, and each R f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium, At least one of R5, R8, and R9 is a fluoroalkyl group, R f and / or R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with at least one fluorine; and A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, with the proviso that (i) when X1, X2, Y1, Y2, R2, R4, R5, R6, and R7 are hydrogen and R8 is hydrogen or methyl, R9 is not -CH2CF3, and (ii) when X1, X2, Y1, Y2, R2, R4, R5, R6, and R7 are hydrogen, R8 and R9 do not combine with the nitrogen atom to which they are bound to form a 4,4-difluoropiperidinyl group. (2) The compound according to (1), wherein X1, X2, Y1, and Y2 are hydrogen. (3) The compound according to (1) or (2), wherein R2 is hydrogen. (4) The compound according to any one of (1) to (3), wherein R4 is hydrogen. (5) The compound according to any one of (1) to (3), wherein R4 is hydroxyl. (6) R5 is hydrogen, unsubstituted alkoxy, alkoxy substituted with one or more deuterium atoms, unsubstituted alkylthio, alkylthio substituted with one or more deuterium atoms, -OR f , and -SR f The compound according to any one of (1) to (5), selected from the group consisting of: (7) The compound according to any one of (1) to (6), wherein R5 is hydrogen. (8) R5 is an unsubstituted alkoxy, an alkoxy substituted with one or more deuterium atoms, or -OR f The compound according to any one of (1) to (6), selected from the group consisting of: (9) R5 is unsubstituted alkylthio, alkylthio substituted with one or more deuterium atoms, or -SR f The compound according to any one of (1) to (6), selected from the group consisting of: (10) R5 is -OR f or -SR f The compound according to any one of (1) to (6), (11) The compound according to (10), wherein n is 0. (12) The compound according to any one of (1) to (11), wherein R6 and R7 are hydrogen. (13) The compound according to any one of (1) to (12), wherein R8 is hydrogen or unsubstituted C1-C6 alkyl. (14) R8 is R f The compound according to any one of (1) to (12), (15)H x is hydrogen and n is 2. (16) The compound according to any one of (1) to (15), wherein R9 is unsubstituted C1-C6 alkyl. (17) R9 is R f The compound according to any one of (1) to (15), (18)H x is hydrogen and n is 2. (19) R9 is -S(O)R f or -S(O)2R fThe compound according to any one of (1) to (15), (20) The compound according to (19), wherein n is 0. (twenty one) [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, according to any one of (1) to (20). (22) A compound according to (1), having the structure of formula (II), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof: [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R8 is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R f is selected from the group consisting of R9 is unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, R f , -S(O)R f , and -S(O)R f is selected from the group consisting of or alternatively, R8 and R9 together with the nitrogen atom to which they are attached optionally join to form a heterocycloalkyl substituted with at least one fluorine; and R f is a fluoroalkyl group, and each R f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium, At least one of R8 and R9 is a fluoroalkyl group, R f or R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with at least one fluorine; and However, (i) when X1, X2, Y1, and Y2 are hydrogen and R8 is hydrogen or methyl, R9 is not -CH2CF3, and (ii) when X1, X2, Y1, and Y2 are hydrogen, R8 and R9 do not combine with the nitrogen atom to which they are bound to form a 4,4-difluoropiperidinyl group, the compound described in (1). (23) The compound according to (22), wherein X1, X2, Y1, and Y2 are hydrogen. (24) The compound according to (22) or (23), wherein R8 is hydrogen or unsubstituted C1-C6 alkyl. (25) R8 is R f The compound according to (22) or (23), (26)H x is hydrogen and n is 2. (27) R9 is R f The compound according to any one of (22) to (26), (28)H x is hydrogen and n is 2. (29) R9 is -S(O)R f or -S(O)2R f The compound according to any one of (22) to (26), (30) The compound according to (29), wherein n is 0. (31) [ka] [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. (32) The compound according to (1), having the structure of formula (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof: [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R8 is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R f is selected from the group consisting of R9 is unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, R f , -S(O)R f , and -S(O)R f is selected from the group consisting of or alternatively, R8 and R9 together with the nitrogen atom to which they are attached optionally join to form a heterocycloalkyl substituted with at least one fluorine; and R f is a fluoroalkyl group, and each R f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium, At least one of R8 and R9 is a fluoroalkyl group, R f or R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with at least one fluorine. (33) The compound according to (32), wherein X1, X2, Y1, and Y2 are hydrogen. (34) The compound according to (32) or (33), wherein R8 is hydrogen or unsubstituted C1-C6 alkyl. (35) R8 is R f The compound according to (32) or (33), (36)H x is hydrogen and n is 2. (37) R9 is R f The compound according to any one of (32) to (36), (38)H x is hydrogen and n is 2. (39) R9 is -S(O)R f or -S(O)2R f The compound according to any one of (32) to (36), (40) The compound according to (39), wherein n is 0. (41) [ka] [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. (42) A compound according to (1) having the structure of formula (IV), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof: [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R5 is an unsubstituted alkoxy, an alkoxy substituted with one or more deuterium atoms, or -OR f is selected from the group consisting of R8 is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R f is selected from the group consisting of R9 is unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, R f , -S(O)R f , and -S(O)R f is selected from the group consisting of or alternatively, R8 and R9 together with the nitrogen atom to which they are attached optionally join to form a heterocycloalkyl substituted with at least one fluorine; and R f is a fluoroalkyl group, and each R f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium, At least one of R5, R8, and R9 is a fluoroalkyl group, R f and / or R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with at least one fluorine. (43) The compound according to (42), wherein X1, X2, Y1, and Y2 are hydrogen. (44) The compound according to (42) or (43), wherein R5 is an unsubstituted C1-C6 alkoxy group. (45) R5 is -OR f The compound according to (42) or (43), (46) The compound according to (45), wherein n is 0. (47) The compound according to any one of (42) to (46), wherein R8 is hydrogen or unsubstituted C1-C6 alkyl. (48) R8 is R f The compound according to any one of (42) to (46), (49)H x is hydrogen and n is 2. (50) The compound according to any one of (42) to (49), wherein R9 is unsubstituted C1-C6 alkyl. (51) R9 is R f The compound according to any one of (42) to (49), (52)H x is hydrogen and n is 2. (53) R9 is -S(O)R f or -S(O)2R f The compound according to any one of (42) to (49), (54) The compound according to (53), wherein n is 0. (55) [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. (56) A compound according to (1), having the structure of formula (V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof: [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R8 is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R f is selected from the group consisting of R9 is unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, R f , -S(O)R f , and -S(O)R f is selected from the group consisting of or alternatively, R8 and R9 together with the nitrogen atom to which they are attached optionally join to form a heterocycloalkyl substituted with at least one fluorine; and R f is a fluoroalkyl group, and each R f are independently -(CH x 2) n CH2F, -(CH x 2) nCHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium, At least one of R8 and R9 is a fluoroalkyl group, R f or R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with at least one fluorine. (57) The compound according to (56), wherein X1, X2, Y1, and Y2 are hydrogen. (58) The compound according to (56) or (57), wherein R8 is hydrogen or unsubstituted C1-C6 alkyl. (59) R8 is R f The compound according to (56) or (57), (60)H x is hydrogen and n is 2. (61) R9 is R f The compound according to any one of (56) to (60), (62)H x is hydrogen and n is 2. (63) R9 is -S(O)R f or -S(O)2R f The compound according to any one of (56) to (60), (64) The compound according to (63), wherein n is 0. (65) [ka] [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof. (66) A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, and a pharmaceutically acceptable vehicle, [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 is selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and -OPO3H2; R5 is hydrogen, deuterium, hydroxyl, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, unsubstituted alkoxy, alkoxy substituted with one or more deuterium atoms, unsubstituted alkylthio, alkylthio substituted with one or more deuterium atoms, -OR f , and -SR f is selected from the group consisting of R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R8 is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R f is selected from the group consisting of R9 is unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, R f , -S(O)R f , and -S(O)R f is selected from the group consisting of or alternatively, R8 and R9 together with the nitrogen atom to which they are attached optionally join to form a heterocycloalkyl substituted with at least one fluorine; and R f is a fluoroalkyl group, and each R f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium, At least one of R5, R8, and R9 is a fluoroalkyl group, R f and / or R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with at least one fluorine. (67) The pharmaceutical composition according to (66), which is adapted for oral administration. (68) A method for treating a subject having a disease or disorder, comprising: administering to a subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof; [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 is selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and -OPO3H2; R5 is hydrogen, deuterium, hydroxyl, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, unsubstituted alkoxy, alkoxy substituted with one or more deuterium atoms, unsubstituted alkylthio, alkylthio substituted with one or more deuterium atoms, -OR f , and -SR f is selected from the group consisting of R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R8 is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R f is selected from the group consisting of R9 is unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, R f , -S(O)R f , and -S(O)R f is selected from the group consisting of or alternatively, R8 and R9 together with the nitrogen atom to which they are attached optionally join to form a heterocycloalkyl substituted with at least one fluorine; and R f is a fluoroalkyl group, and each R f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium, At least one of R5, R8, and R9 is a fluoroalkyl group, R f and / or R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with at least one fluorine. (69) A method for treating a subject having a disease or disorder associated with the serotonin 5-HT2 receptor, comprising: administering to a subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof; [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 is selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and -OPO3H2; R5 is hydrogen, deuterium, hydroxyl, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, unsubstituted alkoxy, alkoxy substituted with one or more deuterium atoms, unsubstituted alkylthio, alkylthio substituted with one or more deuterium atoms, -OR f , and -SR f is selected from the group consisting of R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R8 is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R f is selected from the group consisting of R9 is unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, R f , -S(O)R f , and -S(O)R f is selected from the group consisting of or alternatively, R8 and R9 together with the nitrogen atom to which they are attached optionally join to form a heterocycloalkyl substituted with at least one fluorine; and R f is a fluoroalkyl group, and each R f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) nCF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium, At least one of R5, R8, and R9 is a fluoroalkyl group, R f and / or R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with at least one fluorine. (70) The method according to (69), wherein the disease or disorder is a neuropsychiatric disease or disorder or an inflammatory disease or disorder. (71) The method according to (69), wherein the disease or disorder is a disorder of the central nervous system (CNS). (72) The method according to (71), 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 dysphagia, severe neurocognitive disorder, mild neurocognitive disorder, suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), chronic fatigue syndrome, Lyme disease, gambling disorder, paraphilic disorder, sexual dysfunction, peripheral neuropathy, and obesity. (73) The method according to (71), wherein the central nervous system (CNS) disorder is major depressive disorder (MDD). (74) The method according to (71), wherein the central nervous system (CNS) disorder is treatment-resistant depression (TRD). (75) The method according to (71), wherein the central nervous system (CNS) disorder is generalized anxiety disorder (GAD). (76) The method according to (71), wherein the central nervous system (CNS) disorder is social anxiety disorder. (77) The method according to (71), wherein the central nervous system (CNS) disorder is obsessive-compulsive disorder (OCD). (78) The method according to (71), wherein the central nervous system (CNS) disorder is cluster headache or migraine. (79) The method according to (71), wherein the central nervous system (CNS) disorder is a substance use disorder. (80) The method according to (79), wherein the substance use disorder is alcohol use disorder. (81) The method according to (79), wherein the substance use disorder is nicotine use disorder. (82) The method according to (69), wherein the disease or disorder is a condition of the autonomic nervous system (ANS). (83) The method according to (69), wherein the disease or disorder is a pulmonary disorder. (84) The method according to (69), wherein the disease or disorder is a cardiovascular disorder. (85) The method according to any one of (69) to (84), wherein the compound is orally administered to the subject. (86) The method according to any one of (69) to (85), wherein the compound is administered to the subject orally. (87) The method according to any one of (69) to (86), wherein the compound is administered to the subject at a hallucinogenic dose of about 0.083 mg / kg to about 5 mg / kg. (88) The method of (87), wherein the compound is administered at a hallucinogenic dose no more than once a week over the course of treatment. (89) The method according to (69) to (86), wherein the compound is administered to the subject at a dose that does not cause hallucinations of about 0.00001 mg / kg to less than about 0.083 mg / kg. (90) The method of (89), wherein the compound is administered at a non-hallucinogenic dose at least once daily over the course of treatment. (91) Use of a compound of formula (I), including any of formulas (II) to (V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, for treating a subject having a disease or disorder associated with the serotonin 5-HT2 receptor, [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 is selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and -OPO3H2; R5 is hydrogen, deuterium, hydroxyl, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, unsubstituted alkoxy, alkoxy substituted with one or more deuterium atoms, unsubstituted alkylthio, alkylthio substituted with one or more deuterium atoms, -OR f , and -SR f is selected from the group consisting of R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R8 is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R f is selected from the group consisting of R9 is unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, R f , -S(O)R f , and -S(O)R f is selected from the group consisting of or alternatively, R8 and R9 together with the nitrogen atom to which they are attached optionally join to form a heterocycloalkyl substituted with at least one fluorine; and R f is a fluoroalkyl group, and each R f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium, At least one of R5, R8, and R9 is a fluoroalkyl group, R f and / or R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with at least one fluorine. [Brief explanation of the drawings]

[0011] The foregoing paragraphs have been provided by way of general introduction and are not intended to limit the scope of the claims that follow. The described embodiments, together with further advantages, will be best understood by reference to the following detailed description when considered in conjunction with the accompanying drawings.

[0012] [Figure 1] FIG. 1 shows examples of general synthetic routes that can be used to access compounds of the present disclosure, where LG = leaving group, e.g., chloride, bromide, tosylate, etc. [Figure 2] FIG. 2 shows a synthetic route to compound I-3. [Figure 3] FIG. 3 shows a synthetic route to compound II-2. [Figure 4] FIG. 4 shows a synthetic route to compound II-3. [Figure 5] FIG. 5 shows a synthetic route to compound II-6. [Figure 6] FIG. 6 shows a synthetic route to compound II-10. [Figure 7] FIG. 7 shows a synthetic route to compound II-12. [Figure 8] FIG. 8 shows a synthetic route to compound II-15. [Figure 9] FIG. 9 shows a synthetic route to compound II-19. [Figure 10] FIG. 10 shows a synthetic route to compound II-20. [Figure 11] FIG. 11 shows a synthetic route to compound II-21. [Figure 12] FIG. 12 shows a synthetic route to compound III-2. [Figure 13] FIG. 13 shows a synthetic route to compound III-3. [Figure 14] FIG. 14 shows a synthetic route to compound III-6. [Figure 15] FIG. 15 shows a synthetic route to compound III-10. [Figure 16] FIG. 16 shows a synthetic route to compound III-12. [Figure 17] FIG. 17 shows a synthetic route to compound III-13. [Figure 18] FIG. 18 shows a synthetic route to compound III-14. [Figure 19] FIG. 19 shows a synthetic route to compound IV-3. [Figure 20] FIG. 20 shows a synthetic route to compound IV-21. [Figure 21] FIG. 21 shows a synthetic route to compound IV-40. [Figure 22] Figure 22 is a graph of agonist-labeled human serotonin 5-HT2A receptor radioligand ([H]LSD) competitive binding using compound II-19 and serotonin (5-HT); results are from four independent experiments tested in duplicate (N=8 replicates) with 5-HT and in triplicate (N=12 replicates) with II-19; data analyzed using a one-site fitted K model. [Figure 23]Figure 23 is a graph of agonist-labeled human serotonin 5-HT2A receptor radioligand ([H]LSD) competitive binding using compounds II-10 and II-20 and serotonin (5-HT); results are from four independent experiments with 5-HT tested in duplicate (N=08 replicates) and II-10 and II-20 in triplicate (N=12 replicates); data analyzed using a one-site fitted K model. [Figure 24] Figure 24 is a graph of agonist-labeled human serotonin 5-HT receptor radioligand ([H]LSD) competitive binding using compounds II-6 and III-6 and serotonin (5-HT); results are from three independent experiments with 5-HT tested in duplicate (N=06 replicates) and II-6 and III-6 in triplicate (N=09 replicates); data analyzed using a one-site fitted K model. [Figure 25] Figure 25 is a graph showing the effects of compounds II-6 and III-6 (10 mg / kg PO) compared to the positive control (±) 2,5-dimethoxy-4-iodoamphetamine (DOI, 10 mg / kg PO) on serotonin 5-HT2A receptor-dependent head twitch response (HTR) in adult male C57B1 / 6J mice. [Figure 26] FIG. 26 is a graph showing the results of the 5-HT2A receptor functional assay as percent maximum 5-HT change from baseline, where compounds were tested in triplicate at concentrations of 500 nM and 50 μM. [Figure 27] Figure 27 is a graph showing the results of the dose-response 5-HT2A functional assay as a percentage of the control agonist response for Compound II-2, tested in duplicate at the concentrations shown, with the EC50 determined by nonlinear regression analysis of concentration-response curves generated with average replicate values ​​using Hill equation curve fitting. [Figure 28]Figure 28 is a graph showing the results of the dose-response 5-HT2A functional assay as a percentage of the control agonist response for compounds III-2 and IV-21, which were tested in duplicate at the concentrations shown and the EC50 was determined by nonlinear regression analysis of the concentration-response curves generated with average replicate values ​​using Hill equation curve fitting. [Figure 29] Figure 29 is a graph showing the results of the dose-response 5-HT2B functional assay as a percentage of the control agonist response for compounds III-2 and IV-21, which were tested in duplicate at the concentrations shown and the EC50 was determined by nonlinear regression analysis of the concentration-response curves generated with average replicate values ​​using Hill equation curve fitting. DETAILED DESCRIPTION OF THE INVENTION

[0013] Detailed Description In the following detailed description of embodiments of the present disclosure, numerous specific details are set forth in order to provide a thorough understanding of embodiments of the present disclosure. However, it will be apparent to those skilled in the art that embodiments of the present disclosure may be practiced without these specific details. In other instances, well-known methods, procedures, components, and circuits have not been described in detail as not to unnecessarily obscure aspects of the embodiments of the present disclosure.

[0014] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0015] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, such as 1 to 6 carbon atoms, or 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or 1 to 2 carbon atoms. This term includes, by way of example, straight-chain and branched hydrocarbyl groups such as methyl (CH-), ethyl (CHCH-), n-propyl (CHCHCH-), isopropyl ((CH)CH-), n-butyl (CHCHCHCH-), isobutyl ((CH)CHCH-), sec-butyl ((CH)(CHCH)CH-), t-butyl (t-Bu) ((CH)C-), n-pentyl (CHCHCHCHCHCH-), and neopentyl ((CH)CCH-).

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

[0017] "Alkylene" is -O-, -NR 10 -, -NR 10 C(O)-, -C(O)NR 10 - refers to a divalent aliphatic hydrocarbyl group having 1 to 6 carbon atoms, either straight or branched, including 1 to 3 carbon atoms, optionally interrupted with one or more groups selected from, for example, methylene (-CH-), ethylene (-CHCH-), n-propylene (-CHCHCH-), iso-propylene (-CHCH(CH)-), (-C(CH)CHCH-), (-C(CH)CHC(O)-), (-C(CH)CHC(O)NH-), (-CH(CH)CH-), and the like.

[0018] "Substituted alkylene" refers to an alkylene group having 1 to 3 hydrogens replaced with a substituent, as described for carbon in the definition of "substituted" below.

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

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

[0021] The terms "alkaryl" or "aralkyl" refer to the groups -alkylene-aryl and -substituted alkylene-aryl, where alkylene, substituted alkylene, and aryl are defined herein.

[0022] "Alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like. The term "alkoxy" also refers to the groups alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.

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

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

[0025] The term "haloalkoxy" refers to an alkyl-O- group in which one or more hydrogen atoms on the alkyl group have been replaced with a halo group and includes, by way of example, groups such as trifluoromethoxy.

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

[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, alkylene, and substituted alkylene are as defined herein.

[0028] The term "alkylthioalkoxy" refers to the groups -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl, and substituted alkylene-S-substituted alkyl, where alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0029] "Alkenyl" refers to a straight or branched chain hydrocarbyl group having from 2 to 6 carbon atoms, e.g., from 2 to 4 carbon atoms, and having at least one site of double bond unsaturation, e.g., from 1 to 2. The term includes, by way of example, bivinyl, allyl, and but-3-en-1-yl. The term includes cis and trans isomers or mixtures of these isomers.

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

[0031] "Alkynyl" refers to a straight-chain or branched monovalent hydrocarbyl group having from 2 to 6 carbon atoms, e.g., 2 to 3 carbon atoms, and having at least 1 site of triple bond unsaturation, e.g., 1 or 2. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CHC≡CH).

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

[0033] "Alkynyloxy" refers to the group -O-alkynyl, where alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like.

[0034] "Acyl" includes HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, ... "C(O)-," "substituted heteroaryl-C(O)-," "heterocyclyl-C(O)-," and "substituted heterocyclyl-C(O)-" groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, acyl includes the "acetyl" group CHC(O).

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

[0036] "Aminocarbonyl" or the term "aminoacyl" refers to -C(O)NR 21 R 22 R refers to the group 21 and R 22 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 is optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

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

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

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

[0040] "Aminosulfonyl" is -SO2NR 21 R 22 R refers to the group 21 and R 22 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0041] "Sulfonylamino" is -NR 21 SO2R 22 R refers to the group 21 and R 22is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 are optionally joined together with the atoms to which they are bound to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0042] "Aryl" or "ar" refers to a monovalent aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (e.g., as in a phenyl group) or a ring system having multiple fused rings, which may or may not be aromatic, provided that the point of attachment is through an aromatic ring atom (examples of such aromatic ring systems include naphthyl, anthryl, and indanyl). This term includes, by way of example, phenyl and naphthyl. Unless constrained by the definition of an aryl substituent, such aryl groups may be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents, selected from acyloxy, hydroxyl, thiol, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamido, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and trihalomethyl.

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

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

[0045] The term "substituted amino" refers to the group -NRR, where if at least one R is not hydrogen, then each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl.

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

[0047] "Carboxyl", "carboxy" or "carboxylate" refers to -CO2H or a salt thereof.

[0048] "Carboxyl-ester" or "carboxy-ester", or the term "carboxyalkyl" or "carboxylalkyl" refers to a -C(O)O-alkyl group, a -C(O)O-substituted alkyl group, a -C(O)O-alkenyl group, a -C(O)O-substituted alkenyl group, a -C(O)O-alkynyl group, a -C(O)O-substituted alkynyl group, a -C(O)Oaryl group, a -C(O)O-substituted aryl group, a -C(O)O-cycloalkyl group, a -C(O)O-substituted cycloalkyl group, a -C(O)O-cycloalkenyl ...substituted cycloalkyl group, a -C(O)O-cycloalkenyl group, a -C(O)O-substituted cycloalkyl group, a -C(O)O-substituted cycloalkyl group, a -C(O)O-cycloalkenyl group, a -C(O)O-substituted cycloalkyl group, a -C(O)O-substituted cycloalkyl group, a -C(O) "C(O)O" refers to alkyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0049] "(Carboxyl-ester)oxy" or "carbonate" refers to an -OC(O)O-alkyl group, an -OC(O)O-substituted alkyl group, an -OC(O)O-alkenyl group, an -OC(O)O-substituted alkenyl group, an -OC(O)O-alkynyl group, an -OC(O)O-substituted alkynyl group, an -OC(O)O-aryl group, an -OC(O)O-substituted aryl group, an -OC(O)O-cycloalkyl group, an -OC(O)O-substituted cycloalkyl group, an -OC(O)O-cycloalkenyl group, an -OC(O)O-substituted cycloalkyl group, an -OC(O)O-substituted cycloalkenyl ... refers to a cycloalkenyl group, an -OC(O)O-heteroaryl group, an -OC(O)O-substituted heteroaryl group, an -OC(O)O-heterocyclic group, and an -OC(O)O-substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

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

[0051] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings, including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like. Such cycloalkyl groups include, for example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl.

[0052] The term "substituted cycloalkyl" includes but is not limited to deuterium, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2- Alkyl, -SO 2- It refers to a cycloalkyl group having 1 to 5 substituents, or 1 to 3 substituents, selected from substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.

[0053] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group of from 3 to 10 carbon atoms having single or multiple rings and at least one double bond, eg, 1 to 2 double bonds.

[0054] The term "substituted cycloalkenyl" includes but is not limited to deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2- Alkyl, -SO2- It refers to a cycloalkenyl group having 1 to 5 substituents, or 1 to 3 substituents, selected from substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

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

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

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

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

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

[0060] "Heteroaryl" refers to an aromatic group of 1 to 15 carbon atoms, such as 1 to 10 carbon atoms, and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl, imidazolyl, or furyl) or multiple condensed rings within the ring system (e.g., in groups such as indolizinyl, quinolinyl, benzofuran, benzimidazolyl, or benzothienyl), provided that at least one ring within the ring system is aromatic and the point of attachment is through an aromatic ring atom. In certain embodiments, the nitrogen and / or sulfur ring atoms of a heteroaryl group are optionally oxidized to provide N-oxide (N→O), sulfinyl, or sulfonyl moieties. This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless constrained by the definition of a heteroaryl substituent, such heteroaryl groups can include acyloxy, 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, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamido, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2- Alkyl, -SO 2- It may be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents selected from substituted alkyl, -SO2-aryl and -SO2-heteroaryl, and trihalomethyl.

[0061] The term "heteroaralkyl" refers to the group alkylene-heteroaryl, where alkylene and heteroaryl are defined herein. This term includes, by way of example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.

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

[0063] "Heterocycle," "heterocyclic," "heterocycloalkyl," and "heterocyclyl" refer to saturated or unsaturated groups having a single ring or multiple fused rings, including fused bridged 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; in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided the point of attachment is through a non-aromatic ring. In certain embodiments, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide the N-oxide, -S(O)-, or -SO2- moieties.

[0064] Examples of heterocycles and heteroaryls include, but are not limited to, aziridine, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazolidine, and the like. These include benzo[b]thiophene, ...

[0065] Unless constrained by the definition of a heterocyclic substituent, such heterocyclic groups may 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, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and fused heterocycle.

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

[0067] The term "heterocyclylthio" refers to the group heterocyclic -S-.

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

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

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

[0071] "Oxo" refers to the (=O) atom.

[0072] "Sulfonyl" refers to an SO2 alkyl group, an SO2-substituted alkyl group, or a SO 2- Alkenyl group, SO2-substituted alkenyl group, SO 2-Cycloalkyl groups, SO2-substituted cycloalkyl groups, SO 2- Cycloalkenyl groups, SO2-substituted cycloalkenyl groups, SO 2- Aryl groups, SO2-substituted aryl groups, SO 2- Heteroaryl groups, SO2-substituted heteroaryl groups, SO 2- Sulfonyl refers to heterocyclic and SO-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Sulfonyl includes, by way of example, methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-.

[0073] "Sulfonyloxy" refers to an OSO2 alkyl group, an OSO2-substituted alkyl group, or an OSO 2- Alkenyl group, OSO2-substituted alkenyl group, OSO 2- Cycloalkyl groups, OSO2-substituted cycloalkyl groups, OSO 2- Cycloalkenyl group, OSO2-substituted cycloalkenyl group, OSO 2- Aryl group, OSO2-substituted aryl group, OSO 2- Heteroaryl groups, OSO2-substituted heteroaryl groups, OSO 2- refers to 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 group -OC(O)NRR, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic, where alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.

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

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

[0077] The term "alkylthio" or "thioalkoxy" refers to an -S-alkyl group, where alkyl is as defined herein. In certain embodiments, sulfur may be oxidized to -S(O)-. Sulfoxides can 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 aryl is as defined herein, including an optionally substituted aryl group, as defined herein.

[0080] The term "thioheteroaryloxy" refers to the group --S-heteroaryl, where heteroaryl is as defined herein, including an optionally substituted aryl group, as defined herein.

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

[0082] Further to the disclosure herein, when used to modify a particular group or radical, the term "substituted" can also mean that one or more hydrogen atoms of the particular group or radical are each, independently of one another, replaced with the same or different substituents as defined below.

[0083] In addition to the groups disclosed for individual terms herein, substituents (such as ═O, ═NR) to replace one or more hydrogens on a saturated carbon atom in a particular group or radical are also included. 70 , =N-OR70 , =N2 or =S) is, 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 80R 80 , -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 and R 60 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups; and each R 70 are independently hydrogen or R 60 and each R 80 are independent, R 70 or alternatively, two R taken together with the nitrogen atom to which they are attached 80’ and forming a 5-, 6-, or 7-membered heterocycloalkyl, which optionally contains 1 to 4 additional heteroatoms, which may be the same or different, selected from the group consisting of O, N, and S, wherein N may have —H or C1-C3 alkyl substitution; and each M + is a counter ion with a net single positive charge. + are independent, e.g., K + , Na + , Li + Alkaline ions such as + N(R 60 )4, or ammonium ions such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 (The subscript 0.5 means that one of the counterions of such divalent alkaline earth ions is the ionized form of the compounds of the present disclosure, and the other typical counterion, such as chloride, or a doubly ionized compound disclosed herein, can serve as the counterion of such divalent alkaline earth ion, or a doubly ionized compound disclosed herein can serve as the counterion of such divalent alkaline earth ion.) A specific example is -NR 80 R80 is intended to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, N-methyl-piperazin-1-yl, and N-morpholinyl.

[0084] Further to the disclosure herein, the substituents of hydrogen on unsaturated carbon atoms in "substituted" alkene, alkyne, aryl, and heteroaryl groups can be deuterium, -R, unless otherwise specified. 60 , halo, -O - M + , -OR 70 , -SR 70 , -S - M + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R 70 , -SO3 - M + , -SO3R 70 , -OSO2R 70 , -OSO3 - M + , -OSO3R 70 , -PO3 -2 (M + )2, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 - 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 70C(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 , R 70 , R 80 and M + is as previously defined, except that in the case of a substituted alkene or alkyne, the substituent is -O - M + , -OR 70 , -SR 70 , or -S - M + isn't it.

[0085] In addition to the groups disclosed for each individual term herein, the substituent of a hydrogen on a nitrogen in a "substituted" heteroalkyl and cycloheteroalkyl group is, unless otherwise specified, an -R 60 , -OM + , -OR 70 , -SR 70 , -SM + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R 70 , -S(O)2O-M + , -S(O)2OR 70 , -OS(O)2R 70 , -OS(O)2O-M + , -OS(O)2OR 70 , -P(O)(O-)2(M + )2, -P(O)(OR 70 )OM +, -P(O)(OR 70 )(OR 70 ), -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -C(O)OR 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OC(O)OR 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 C(O)OR 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 and R 60, R 70 , R 80 and M + is as previously defined.

[0086] Further to the disclosure herein, in certain embodiments, a substituted group has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0087] Unless otherwise specified, it is understood that polymers defined herein are not intended to encompass any of the above-defined substituents, achieved by defining the substituents to have further substituents thereon (e.g., a substituted aryl having a substituted aryl group as a substituent itself substituted with a substituted aryl group, which in turn is substituted with a substituted aryl group, etc.). In such cases, the maximum number of such substitutions is three. For example, the sequential substitution of substituted aryl groups specifically contemplated herein is limited to substituted aryl-(substituted aryl)-substituted aryl. However, for example, a substituent defined as a polyether may have more than three sequential substitutions, e.g., -O-(CHCHO). n It may contain -H, where n can be 1, 2, 3, or more.

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

[0089] For any group disclosed herein that contains one or more substituents, it is of course understood that such group does not include any substitutions or substitution patterns that are sterically infeasible and / or synthetically impractical. Furthermore, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0090] The substituent or group "contains a fluoroalkyl group" (as used herein, R fWhen a substituent or group is described as a fluoroalkyl group (sometimes depicted as a fluoroalkyl group), it should be understood that the substituent or group may itself be a fluoroalkyl group or may contain a fluoroalkyl group within its chemical structure, but the presence of a fluoroalkyl group is consistent with the other specified requirements of the substituent or group being discussed. For example, when the substituent "-R" is defined to include a fluoroalkyl group, it should be understood that -R may itself be a fluoroalkyl group (e.g., -CF3) or a group containing a fluoroalkyl group (e.g., -SCF3) consistent with the other specified requirements for -R.

[0091] As used herein, the term "fat" refers to a compound having a long-chain (linear) hydrophobic moiety composed of hydrogen and 4 to 26 carbon atoms, and can be fully saturated or partially unsaturated.

[0092] The phrases "pharmaceutically acceptable," "physiologically acceptable," and the like are used herein to refer to compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment, suitable for use in contact with human tissues without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. When referring to salts, the phrases "pharmaceutically acceptable salt," "physiologically acceptable salt," and the like mean salts that are acceptable for administration to a patient, such as a mammal (salts having counterions that have acceptable mammalian safety for a given administration regimen). As is well known in the art, such salts can be derived from pharmaceutically acceptable inorganic or organic bases such as sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts, and, where the molecule contains a basic functional group, from addition salts with inorganic acids such as hydrochlorides, hydrobromides, sulfates, sulfamate, phosphates, nitrates, perchlorates, and the like, as well as from addition salts with organic acids such as formates, tartrates, besylates, mesylates, acetates, maleates, malonates, oxalates, fumarates, benzoates, salicylates, succinates, oxalates, glycolates, hemixalates, hemifumarates, propionates, stearates, lactates, citrates, ascorbates, pamoates, hydroxymaleates, phenylacetates, glutamates, 2-acetoxybenzoates, tosylates, ethanedisulfonates, isethionates, and the like. The term "salt thereof" refers to a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation. Where applicable, the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient. As an example, salts of the present compounds include those in which the compound is protonated with an inorganic or organic acid to form a cation and has a conjugate base of the inorganic or organic acid as the anionic component of the salt.

[0093] "Solvate" refers to a physical association of a compound or salt of the present disclosure with one or more solvent molecules, whether organic, inorganic, or a mixture of both. This physical association includes hydrogen bonding. In certain instances, a solvate is capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in a solvate may be present in an ordered and / or irregular arrangement. A solvate may contain either stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. Some examples of solvents include, but are not limited to, methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. When the solvent is water, the solvate formed is a hydrate (e.g., monohydrate, dihydrate, etc.). Thus, exemplary solvates include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, etc. Methods of solvation are generally known in the art.

[0094] "Stereoisomer" and "stereoisomers" refer to compounds that have the same atomic connectivity but different atomic arrangements in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers.

[0095] "Tautomer" refers to alternative forms of molecules that differ only in the electronic bonding of atoms and / or in the position of protons, such as enol-keto, imine-enamine, and neutral / zwitterionic tautomers, or tautomeric forms of heteroaryl groups containing the -N=C(H)-NH- ring atom configuration, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. Other tautomeric ring atom configurations are possible. For example, compounds containing acid and base groups in the same molecule shown in their neutral form may exist in zwitterionic form, as in the case of amino acid / ammonium carboxylate tautomers. Thus, compounds of the present disclosure shown in their neutral form to contain both amino phosphate and dihydrogen phosphate (-OPO3H2) functionalities, such as compounds of Formula (I), Formula (V), etc., may exist in zwitterionic form as the ammonium monohydrogen phosphate zwitterion. A given chemical formula or name is intended to encompass all tautomeric forms thereof, if any exist.

[0096] "Prodrug" is meant to refer to a compound that can be converted under physiological conditions or by solvation into a biologically active compound described herein. Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. For example, prodrugs such as esters, phosphate esters, etc., may be inactive when administered to a subject, but are converted in vivo to an active compound, e.g., by hydrolysis to a free carboxylic acid or a free hydroxyl group. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). For a discussion of prodrugs, see Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 2004). Press, 1987, both of which are incorporated herein by reference in their entireties. The term "prodrug" is also intended to include any covalently bonded carrier that releases an active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the active compounds described herein can be prepared by modifying functional groups present in the active compound such that the modifications are cleaved to the parent active compound by routine manipulation or in vivo. Prodrugs include compounds in which a hydroxyl group, an amino group, or a mercapto group is bonded 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, acetate, formate, benzoate, and dihydrogen phosphate derivatives of alcohols, or acetamide, formamide, and benzamide derivatives of amine functional groups in the active compound.

[0097] A "crystalline" solid is a type of solid whose fundamental three-dimensional structure consists of a highly regular pattern of atoms or molecules forming a crystal lattice with long-range order, and therefore exhibits sharp, characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern. In some cases, a crystalline solid can 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 various solid-state physical properties that affect, for example, the solubility, dissolution rate, bioavailability, chemical and physical stability, flowability, and compressibility of the compound, as well as the safety and efficacy of pharmaceuticals based on the compound. In the process of preparing polymorphs, further refinement can also be achieved with respect to physical or optical purity. As used herein, the term "amorphous" refers to a solid material that has substantially no long-range order in its molecular positions; the molecules are arranged randomly, e.g., so that there is effectively no well-defined arrangement, e.g., no molecular packing, and no long-range order. Amorphous solids are generally isotropic, i.e., they exhibit similar properties in all directions, and do not have a distinct melting point. For example, an amorphous material is a solid material that does not have substantially sharp, characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in the XRPD pattern. Broad peaks are characteristic of amorphous solids. Thus, an "amorphous" subject compound / material is a compound / material characterized as having less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, or 0% crystallinity, i.e., being at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% amorphous, as determined by XRPD, for example. For example, in some embodiments, the percent crystallinity may be determined by measuring the intensity of one or more peaks in an XRPD diffractogram relative to a reference peak, which 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 percent, may be used to determine the percentage of the subject compounds / materials that are amorphous or crystalline.

[0098] It will be understood that the compounds herein may exist in different salt, solvate, stereoisomer, tautomer, crystalline / amorphous (or polymorphic) forms, and that the present disclosure is intended to encompass all such variations, for example, solvates of pharmaceutically acceptable salts of stereoisomers of the subject compounds.

[0099] As used herein, the terms "stable," "stability," and the like include chemical stability and solid-state (physical) stability. The term "chemical stability" means that a compound can be stored under normal storage conditions, either in isolated form or in the form of a formulation provided in admixture with, for example, a pharmaceutically acceptable carrier, diluent, or adjuvant described herein, with little or no chemical degradation or decomposition. "Solid-state stability" means that a compound can be stored under normal storage conditions, either in isolated solid form or in the form of a solid formulation provided in admixture with, for example, a pharmaceutically acceptable carrier, diluent, or adjuvant described herein, with little or no solid-state change (e.g., hydration, dehydration, solvation, desolvation, crystallization, recrystallization, or solid-state phase transition).

[0100] As used herein, the term "composition" is equivalent to the term "formulation."

[0101] A "vapor" is a solid substance in the gas phase at a temperature below its critical temperature, meaning that the vapor can be condensed to a liquid by increasing the pressure on it without decreasing the temperature.

[0102] As used herein, an "aerosol" is a suspension of fine solid particles or liquid droplets in a gas phase (e.g., air, oxygen, helium, nitrous oxide, and other gases, and mixtures thereof). As used herein, a "mist" is a subset of aerosol, distinct from vapor, and is a dispersion of liquid droplets (liquid phase) suspended in a gas phase (e.g., air, oxygen, helium, and mixtures thereof). The liquid droplets of an aerosol or mist may contain a drug moiety dissolved in an aqueous liquid, an organic solvent, or a mixture thereof. The gas phase of an aerosol or mist may contain other gases, including air, oxygen, helium, or mixtures thereof. A mist does not contain solid particles. The aerosols and mists of the present disclosure can be generated by any suitable method and device, examples of which are described herein, for example, through the use of an inhaler or nebulizer.

[0103] As used herein, the term "inhalation session" describes the administration event in which a subject inhales a given dose of drug, regardless of the number of breaths required to inhale the given dose.For example, a subject prescribed to take 10 mg of drug twice a day will perform two inhalation sessions, each inhalation session providing 10 mg of drug.The duration and number of breaths of each inhalation session will depend on factors such as the inhalation device used, the amount of drug inhaled per breath, the drug concentration of the dosage form, and the breathing pattern of the subject.

[0104] As used herein, the term "treating" or "treatment" means treating or treating a disease or medical condition in a patient, e.g., a mammal (particularly a human), including ameliorating a disease or medical condition, such as, for example, eliminating or causing regression of the disease or medical condition in a patient, inhibiting a disease or medical condition, e.g., by slowing or arresting the onset of the disease or medical condition in a patient, or alleviating one or more symptoms of a disease or medical condition in a patient. In one embodiment, prophylactic treatment may prevent the occurrence of a disease or medical condition in a subject.

[0105] A "patient" or "subject," as used interchangeably herein, can be any mammal, including, for example, a human or non-human subject. The patient or subject can have the condition being treated or can be susceptible to the condition being treated.

[0106] As used herein, unless otherwise specified, the terms "prevent," "preventing," and "prevention" refer to the prevention of the onset, recurrence, or spread of a disease, disorder, or condition, or one or more symptoms thereof. The term encompasses the inhibition or reduction of symptoms of a particular disease, disorder, or condition. Subjects with a family history of a disease, disorder, or condition are particularly, in certain embodiments, candidates for a preventative regimen. Additionally, subjects with a history of recurrent symptoms are also potential candidates for prevention. In this regard, the term "prevention" may be used interchangeably with the term "prophylactic treatment."

[0107] A "therapeutically effective amount" refers to an amount of a compound sufficient to treat a particular disorder or disease, or one or more of its symptoms, and / or prevent the occurrence of the disease or disorder (a prophylactically effective amount).

[0108] As used herein, and unless otherwise specified, a "prophylactically effective amount" of an active agent is an amount sufficient to prevent a disease, disorder, or condition, or to prevent its recurrence. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic effect of another prophylactic agent.

[0109] The term "administration schedule" refers to a plan that chronologically shows the type, amount, duration, and procedure of drug treatment, including the dosage, administration method, administration order, and administration date of each drug. The designated administration date is determined before the start of drug administration. Administration is continued by repeating a series of administration schedules, each of which is considered a "course." A "continuous" administration schedule means that the drug is administered daily without interruption during the treatment course. If the administration schedule follows an "intermittent" administration schedule, the days of administration may be followed by "rest days" or non-administration days of the drug during the course. A "drug holiday" indicates that the drug is not administered according to a predetermined administration schedule. For example, after receiving several treatment courses, a subject may be prescribed a regulated drug holiday as part of the administration schedule, for example, before resuming active treatment.

[0110] The term "toxic spike" is used herein to describe a neurological spike in the concentration of any compound described herein that may result in side effects such as sedation or psychotomimetic effects such as hallucinations, dizziness, and nausea, which may have immediate effects as well as impact treatment compliance. In particular, side effects may be more pronounced at blood concentration levels of about 250, 300, 400, or 500 ng / L or greater.

[0111] As used herein, and unless otherwise specified, a "neuropsychiatric disease or disorder" is a behavioral or psychological problem associated with a known neurological condition, typically defined as a constellation of coexisting symptoms. Examples of neuropsychiatric disorders include, but are not limited to, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder, and manic depression, depression, or any combination thereof.

[0112] As used herein, "inflammatory condition" and "inflammatory disease" include rheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthritis), spondyloarthropathies (e.g., ankylosing spondylitis, reactive arthritis, Reiter's syndrome), crystalline arthropathies (e.g., gout, pseudogout, calcium pyrophosphate deposition disease), multiple sclerosis, Lyme disease, polymyalgia rheumatica, connective tissue diseases (e.g., systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, Sjogren's syndrome), vasculitis (e.g., nodular polyposis), and the like. It refers broadly to chronic or acute inflammation, including, but not limited to, inflammatory conditions including those resulting from trauma or ischemia (arteritis, Wegener's granulomatosis, Churg-Strauss syndrome), sarcoidosis; vascular diseases including atherosclerosis, and vascular occlusive diseases (e.g., atherosclerosis, ischemic heart disease, myocardial infarction, stroke, peripheral vascular disease), and vascular stent restenosis; and ophthalmic diseases including uveitis, corneal disease, iritis, iridocyclitis, glaucoma, and cataracts.

[0113] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. As used throughout this description and the claims that follow, the meaning of "a," "an," and "the" includes plural references as well as singular references unless the context clearly indicates otherwise. The term "about" in connection with a numerical value means that the value varies above and below 5%. For example, a value of about 100 means 95 to 105 (or any value between 95 and 105).

[0114] compound Formula (I) Disclosed herein are compounds of formula (I), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs thereof: [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 is selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and -OPO3H2; R5 is hydrogen, deuterium, hydroxyl, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, unsubstituted alkoxy, alkoxy substituted with one or more deuterium atoms, unsubstituted alkylthio, alkylthio substituted with one or more deuterium atoms, -OR f , and -SR f is selected from the group consisting of R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R8 is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R f is selected from the group consisting of R9 is unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, R f , -S(O)R f , and -S(O)R f is selected from the group consisting of or alternatively, R8 and R9 together with the nitrogen atom to which they are attached optionally join to form a heterocycloalkyl substituted with at least one fluorine; and R f is a fluoroalkyl group, and each R f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium, At least one of R5, R8, and R9 is a fluoroalkyl group, R f and / or R8 and R9 together with the nitrogen atom to which they are attached form a heterocycloalkyl substituted with at least one fluorine.

[0115] X1 and X2 can be the same or different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium. In some embodiments, X1 and X2 are different. In some embodiments, X1 is hydrogen or deuterium, and X2 is unsubstituted or substituted alkyl (e.g., unsubstituted or substituted C1-C6 alkyl). In some embodiments, X2 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X2 is substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group can be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, one of X1 and X2 is deuterium and the other is hydrogen. In some embodiments, X1 and / or X2 are unsubstituted or substituted alkenyl, such as unsubstituted or substituted allyl. In some embodiments, X1 and / or X2 are unsubstituted or substituted alkynyl. In some embodiments, X1 and / or X2 are unsubstituted or substituted C3-C 10 In some embodiments, X and / or X are unsubstituted C-C 10 In some embodiments, X and / or X are substituted C-C alkyl groups, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. 10 Cycloalkyl. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents.

[0116] In some embodiments, X1 and / or X2 are unsubstituted or substituted heterocycloalkyl. In some embodiments, X1 and / or X2 are unsubstituted or substituted aryl. In some embodiments, X1 and / or X2 are unsubstituted or substituted heteroaryl.

[0117] Y1 and Y2 can be the same or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y1 and Y2 are different. In some embodiments, one of Y1 and Y2 is deuterium and the other is hydrogen.

[0118] In some embodiments, R2 is hydrogen. In some embodiments, R2 is deuterium. In some embodiments, R2 is halogen, such as fluoro, chloro, bromo, and iodo. In some embodiments, R2 is unsubstituted or substituted alkyl (e.g., unsubstituted or substituted C1-C6 alkyl). In some embodiments, R2 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R2 is substituted alkyl (e.g., C1-C6 alkyl). When R2 is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The alkyl group may contain one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group can be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R2 is an unsubstituted or substituted alkenyl, such as an unsubstituted or substituted allyl. In some embodiments, R2 is an unsubstituted or substituted alkynyl. In some embodiments, R2 is an unsubstituted or substituted C3-C 10In some embodiments, R2 is an unsubstituted C3-C 10 In some embodiments, R2 is a substituted C3-C6 alkyl group, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. 10 It is cycloalkyl. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R2 is unsubstituted or substituted heterocycloalkyl. In some embodiments, R2 is unsubstituted or substituted aryl. In some embodiments, R2 is unsubstituted or substituted heteroaryl.

[0119] In some embodiments, R4 is hydrogen. In some embodiments, R4 is deuterium. In some embodiments, R4 is hydroxyl. In some embodiments, R4 is an unsubstituted alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy. In some embodiments, R4 is a substituted alkoxy. When R4 is a substituted alkoxy, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The alkoxy group may contain one or more substituents. For example, when the alkoxy group is a C1 alkoxy group (i.e., a methoxy group), the substituted C1 alkoxy group may be -OCDH2, -OCD2H, -OCD3, -OCFH2, -OCF2H, -OCF3, etc. In some embodiments, R4 is -OPO3H2.

[0120] In some embodiments, R5 is hydrogen. In some embodiments, R5 is deuterium. In some embodiments, R5 is hydroxyl. In some embodiments, R5 is unsubstituted alkyl (e.g., unsubstituted C1-C6 alkyl), examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R5 is methyl. In some embodiments, R5 is alkyl substituted with one or more deuterium atoms, e.g., a C1-C6 alkyl group substituted with one or more deuterium atoms. The alkyl group may contain one or more deuterium substitutions. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the deuterium-substituted C1 alkyl group may be -CDH2, -CD2H, and -CD3, with particular reference to -CD3. In some embodiments, R5 is an unsubstituted alkoxy group, such as an unsubstituted C1-C6 alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy. In some embodiments, R5 is an alkoxy group substituted with one or more deuterium atoms. The alkoxy group may contain one or more deuterium substitutions. For example, when the alkoxy group is a C1 alkoxy group (i.e., a methoxy group), the deuterium-substituted C1 alkoxy group may be -OCDH2, -OCD2H, and -OCD3. In some embodiments, R5 is an unsubstituted alkylthio group, examples of which include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, t-butylthio, n-pentylthio, neopentylthio, and hexylthio. In some embodiments, R5 is an alkylthio group substituted with one or more deuterium atoms. The alkylthio group may contain one or more deuterium substitutions. For example, if the alkylthio group is a C1 alkylthio group (i.e., a methyl group), the deuterium-substituted C1 alkylthio group may be -SCDH2, -SCDH2, and -SCDH3.

[0121] In some embodiments, R5 is -OR f Examples include -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, -OCH2CH2CH2CH2F, -OCH2CH2CH2CH F2 In some embodiments, R5 is -SR f and examples include, but are not limited to, -SCHF, -SCHF, -SCF, -SCHCHF, -SCHCHF, -SCHCF, -SCHCHCHF, -SCHCHCF, -SCHCHCHF, -SCHCHCF, -SCHCHCHCHF, -SCHCHCHCF, -SCHCHCHCHF, -SCHCHCHCHF, and -SCHCHCHCF, with particular reference to -SCHF, -SCHF, -SCF.

[0122] R6 and R7 can be the same or different. In some embodiments, R6 and R7 are the same. In some embodiments, R6 and R7 are different. In some embodiments, R6 is hydrogen. In some embodiments, R6 is deuterium. In some embodiments, R6 is halogen, such as fluoro, chloro, bromo, and iodo. In some embodiments, R6 is unsubstituted or substituted alkyl (e.g., unsubstituted or substituted C1-C6 alkyl). In some embodiments, R6 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R6 is substituted C1-C6 alkyl. When R6 is substituted C1-C6 alkyl, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R6 is an unsubstituted or substituted alkenyl, such as an unsubstituted or substituted allyl. In some embodiments, R6 is an unsubstituted or substituted alkynyl. In some embodiments, R6 is an unsubstituted or substituted C3-C 10 In some embodiments, R is an unsubstituted C-C 10 In some embodiments, R6 is a substituted C3-C6 alkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. 10It is cycloalkyl. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R6 is unsubstituted or substituted heterocycloalkyl. In some embodiments, R6 is unsubstituted or substituted aryl. In some embodiments, R6 is unsubstituted or substituted heteroaryl.

[0123] In some embodiments, R7 is hydrogen. In some embodiments, R7 is deuterium. In some embodiments, R7 is halogen, such as fluoro, chloro, bromo, and iodo. In some embodiments, R7 is unsubstituted or substituted alkyl (e.g., unsubstituted or substituted C1-C6 alkyl). In some embodiments, R7 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R7 is substituted C1-C6 alkyl. When R7 is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The alkyl group may contain one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group can be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R7 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl. In some embodiments, R7 is an unsubstituted or substituted alkynyl. In some embodiments, R7 is an unsubstituted or substituted C3-C 10 In some embodiments, R7 is an unsubstituted C3-C 10In some embodiments, R7 is a substituted C3-C6 alkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. 10 It is cycloalkyl. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R7 is unsubstituted or substituted heterocycloalkyl. In some embodiments, R7 is unsubstituted or substituted aryl. In some embodiments, R7 is unsubstituted or substituted heteroaryl.

[0124] R and R may be the same or different. In some embodiments, R and R are the same. In some embodiments, R and R are different. In some embodiments, R is hydrogen. In some embodiments, R is unsubstituted alkyl. In some embodiments, R is unsubstituted C-C alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl, with specific reference to methyl. In some embodiments, R is alkyl substituted with one or more deuterium atoms, e.g., a C-C alkyl group substituted with one or more deuterium atoms. The alkyl group may contain one or more deuterium substitutions. For example, if the alkyl group is a C alkyl group (i.e., a methyl group), the deuterium-substituted C alkyl group may be -CDH, -CDH, and -CD, with specific reference to -CD.

[0125] In some embodiments, R is R f R fExamples include, but are not limited to, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, and -CH2CH2CH2CF3, with particular reference to -CH2CH2CH2F, -CH2CH2CHF2, and -CH2CH2CF3.

[0126] In some embodiments, R is unsubstituted alkyl. In some embodiments, R is unsubstituted C-C alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl, with particular reference to methyl. In some embodiments, R is alkyl substituted with one or more deuterium atoms, e.g., a C-C alkyl group substituted with one or more deuterium atoms. The alkyl group may contain one or more deuterium substitutions. For example, if the alkyl group is a C alkyl group (i.e., a methyl group), the deuterium-substituted C alkyl group may be -CDH, -CDH, and -CD, with particular reference to -CD.

[0127] In some embodiments, R is R f and examples include, but are not limited to, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, and -CH2CH2CH2CF3, with particular reference to -CH2CH2CH2F, -CH2CH2CHF2, and -CH2CH2CF3.

[0128] In some embodiments, R9 is —S(O)R fand examples include, but are not limited to, -S(O)CHF, -S(O)CHF, -S(O)CF, -S(O)CHCHF, -S(O)CHCHF, -S(O)CHCF, -S(O)CHCHCHF, -S(O)CHCHCF, -S(O)CHCHCHF, -S(O)CHCHCF, -S(O)CHCHCHCHF, -S(O)CHCHCHCHF, and -S(O)CHCHCHCF, with particular reference to -S(O)CHF, -S(O)CHF, and -S(O)CF.

[0129] In some embodiments, R9 is —S(O)R f Examples include -S(O)2CH2F, -S(O)2CHF2, -S(O)2CF3, -S(O)2CH2CH2F, -S(O)2CH2CHF2, -S(O)2CH2CF3, Including, but not limited to, -S(O)2CH2CH2CH2F, -S(O)2CH2CH2CHF2, -S(O)2CH2CH2CF3, -S(O)2CH2CH2CH2CH2F, -S(O)2CH2CH2CH2CHF2, and -S(O)2CH2CH2CH2CF3, with particular reference to -S(O)2CH2F, -S(O)2CHF2, and -S(O)2CF3.

[0130] In some embodiments, R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl group substituted with at least one fluorine. In some embodiments, the heterocycloalkyl group can be a 3-membered ring. In some embodiments, the heterocycloalkyl group can be a 4-membered ring. In some embodiments, the heterocycloalkyl group can be a 5-membered ring. In some embodiments, the heterocycloalkyl group can be a 6-membered ring. In some embodiments, the heterocycloalkyl group can be a 7-membered ring. In some embodiments, the heterocycloalkyl group can be an 8-membered ring. The heterocycloalkyl group contains at least one nitrogen ring atom (the nitrogen atom between R8 and R9) and may optionally contain additional heterocyclic atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 heterocyclic atoms (at least one of which is a nitrogen ring atom). Examples of heterocycloalkyl groups 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, and thiomorpholine, with particular reference to aziridine, azetidine, pyrrolidine, and piperidine. When R and R, together with the nitrogen atom to which they are attached, form a heterocycloalkyl group, the heterocycloalkyl group can be substituted with one fluorine atom, two fluorine atoms, three fluorine atoms, four fluorine atoms, or more. In some embodiments, the heterocycloalkyl group is substituted with two fluorine atoms.

[0131] Examples of heterocycloalkyl groups substituted with at least one fluorine atom formed by combining R8 and R9 together with the nitrogen atom to which they are attached include: [ka] These include, but are not limited to:

[0132] In some embodiments, R and R do not combine with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine, such as those exemplified above. In some embodiments, R and R do not combine with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine, such as those exemplified above, when X, X, Y, Y, R, R, R, R, R, and R are hydrogen. In some embodiments, R and R do not combine with the nitrogen atom to which they are attached to form a 4,4-difluoropiperidinyl group (shown below) when X, X, Y, Y, R, R, R, R, R, and R are hydrogen. [ka]

[0133] In the compounds of the present disclosure, R f represents a fluoroalkyl group, and at least one of R, R, and R is a fluoroalkyl group; f Each R present in the disclosed compounds includes f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium. In some embodiments, H x is hydrogen. In some embodiments, H x is deuterium. In some embodiments, at least one H x is deuterium and at least one H x is hydrogen. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0134] R fExamples of aryl include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CD2CH2F, -CD2CHF2, -CD2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CD2CH2CH2F, -CD2CH2CHF2, -CD2CH2CF3, -CD2CD2CH2F, -CD2CD2CHF2, -CD2CD2C F3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CD2CH2CH2CH2F, -CD2CH2CH2CHF2, -CD2CH2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3.

[0135] In some embodiments, the compound has one R f In some embodiments, R5 comprises a fluoroalkyl group, R f R and R are fluoroalkyl groups; f For example, R and R are each —CH or —CD, or R and R, together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with at least one fluorine. In some embodiments, R represents a fluoroalkyl group, R f R5 and R8 are fluoroalkyl groups, R f For example, R5 is H, —OCH3, —OCD3, —SCH3, or —SCD3, and R8 is —CH3 or CD3.

[0136] In some embodiments, two of R, R, and R are fluoroalkyl groups, R f In some embodiments, R and R comprise a fluoroalkyl group, R f which may be the same or different, R5 is a fluoroalkyl group, R fFor example, R5 is H, -OCH3, -OCD3, -SCH3, or -SCD3. In some embodiments, R5 and R9 represent a group that does not contain a fluoroalkyl group, R f which may be the same or different, R is a fluoroalkyl group, R f For example, R8 is -CH3 or CD3.

[0137] In some embodiments, each of R, R, and R is a fluoroalkyl group, R f which may all be the same, all may be different, or two R f The groups are the same, and the third R f The groups may be different.

[0138] In some embodiments, when X1, X2, Y1, Y2, R2, R4, R5, R6, and R7 are hydrogen and R8 is hydrogen or methyl, R9 is not -CH2CF3. In some embodiments, when X1, X2, Y1, Y2, R2, R4, R5, R6, and R7 are hydrogen and R8 is hydrogen or methyl, R9 is -CH2CF3.

[0139] In some embodiments, the compound, e.g., the compound of formula (I), [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof.

[0140] In some embodiments, the compound of Formula (I) has the structure of Formula (II), Formula (III), Formula (IV), or Formula (V), including any exemplary compounds thereof, provided below.

[0141] Formula (II) In some embodiments, the compound of Formula (I) has the structure of Formula (II): [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R8 is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R f is selected from the group consisting of R9 is unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, R f , -S(O)R f , and -S(O)R fis selected from the group consisting of or alternatively, R8 and R9 together with the nitrogen atom to which they are attached optionally join to form a heterocycloalkyl substituted with at least one fluorine; and R f is a fluoroalkyl group, and each R f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium, At least one of R8 and R9 is a fluoroalkyl group, R f or R8 and R9 together with the nitrogen atom to which they are attached form a heterocycloalkyl substituted with at least one fluorine.

[0142] X1 and X2 can be the same or different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium. In some embodiments, X1 and X2 are different. In some embodiments, X1 is hydrogen or deuterium, and X2 is unsubstituted or substituted alkyl (e.g., unsubstituted or substituted C1-C6 alkyl). In some embodiments, X2 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X2 is substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group can be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, one of X1 and X2 is deuterium and the other is hydrogen. In some embodiments, X1 and / or X2 are unsubstituted or substituted alkenyl, such as unsubstituted or substituted allyl. In some embodiments, X1 and / or X2 are unsubstituted or substituted alkynyl. In some embodiments, X1 and / or X2 are unsubstituted or substituted C3-C 10 In some embodiments, X and / or X are unsubstituted C-C 10 In some embodiments, X and / or X are substituted C-C alkyl groups, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. 10 Cycloalkyl. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents.

[0143] In some embodiments, X1 and / or X2 are unsubstituted or substituted heterocycloalkyl. In some embodiments, X1 and / or X2 are unsubstituted or substituted aryl. In some embodiments, X1 and / or X2 are unsubstituted or substituted heteroaryl.

[0144] Y1 and Y2 can be the same or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y1 and Y2 are different. In some embodiments, one of Y1 and Y2 is deuterium and the other is hydrogen.

[0145] R and R may be the same or different. In some embodiments, R and R are the same. In some embodiments, R and R are different. In some embodiments, R is hydrogen. In some embodiments, R is unsubstituted alkyl. In some embodiments, R is unsubstituted C-C alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl, with specific reference to methyl. In some embodiments, R is alkyl substituted with one or more deuterium atoms, e.g., a C-C alkyl group substituted with one or more deuterium atoms. The alkyl group may contain one or more deuterium substitutions. For example, if the alkyl group is a C alkyl group (i.e., a methyl group), the deuterium-substituted C alkyl group may be -CDH, -CDH, and -CD, with specific reference to -CD.

[0146] In some embodiments, R is R f R fExamples include, but are not limited to, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, and -CH2CH2CH2CF3, with particular reference to -CH2CH2CH2F, -CH2CH2CHF2, and -CH2CH2CF3.

[0147] In some embodiments, R is unsubstituted alkyl. In some embodiments, R is unsubstituted C-C alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl, with particular reference to methyl. In some embodiments, R is alkyl substituted with one or more deuterium atoms, e.g., a C-C alkyl group substituted with one or more deuterium atoms. The alkyl group may contain one or more deuterium substitutions. For example, if the alkyl group is a C alkyl group (i.e., a methyl group), the deuterium-substituted C alkyl group may be -CDH, -CDH, and -CD, with particular reference to -CD.

[0148] In some embodiments, R is R f and examples include, but are not limited to, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, and -CH2CH2CH2CF3, with particular reference to -CH2CH2CH2F, -CH2CH2CHF2, and -CH2CH2CF3.

[0149] In some embodiments, R9 is —S(O)R fand examples include, but are not limited to, -S(O)CHF, -S(O)CHF, -S(O)CF, -S(O)CHCHF, -S(O)CHCHF, -S(O)CHCF, -S(O)CHCHCHF, -S(O)CHCHCF, -S(O)CHCHCHF, -S(O)CHCHCF, -S(O)CHCHCHCHF, -S(O)CHCHCHCHF, and -S(O)CHCHCHCF, with particular reference to -S(O)CHF, -S(O)CHF, and -S(O)CF.

[0150] In some embodiments, R9 is —S(O)R f Examples include -S(O)2CH2F, -S(O)2CHF2, -S(O)2CF3, -S(O)2CH2CH2F, -S(O)2CH2CHF2, -S(O)2CH2CF3, Including, but not limited to, -S(O)2CH2CH2CH2F, -S(O)2CH2CH2CHF2, -S(O)2CH2CH2CF3, -S(O)2CH2CH2CH2CH2F, -S(O)2CH2CH2CH2CHF2, and -S(O)2CH2CH2CH2CF3, with particular reference to -S(O)2CH2F, -S(O)2CHF2, and -S(O)2CF3.

[0151] In some embodiments, R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl group substituted with at least one fluorine. In some embodiments, the heterocycloalkyl group can be a 3-membered ring. In some embodiments, the heterocycloalkyl group can be a 4-membered ring. In some embodiments, the heterocycloalkyl group can be a 5-membered ring. In some embodiments, the heterocycloalkyl group can be a 6-membered ring. In some embodiments, the heterocycloalkyl group can be a 7-membered ring. In some embodiments, the heterocycloalkyl group can be an 8-membered ring. The heterocycloalkyl group contains at least one nitrogen ring atom (the nitrogen atom between R8 and R9) and may optionally contain additional heterocyclic atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 heterocyclic atoms (at least one of which is a nitrogen ring atom). Examples of heterocycloalkyl groups 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, and thiomorpholine, with particular reference to aziridine, azetidine, pyrrolidine, and piperidine. When R and R, together with the nitrogen atom to which they are attached, form a heterocycloalkyl group, the heterocycloalkyl group can be substituted with one fluorine atom, two fluorine atoms, three fluorine atoms, four fluorine atoms, or more. In some embodiments, the heterocycloalkyl group is substituted with two fluorine atoms.

[0152] Examples of heterocycloalkyl groups substituted with at least one fluorine atom formed by combining R8 and R9 together with the nitrogen atom to which they are attached include: [ka] These include, but are not limited to:

[0153] In some embodiments, R and R do not combine with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine, such as those exemplified above. In some embodiments, R and R do not combine with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine, such as those exemplified above, when X, X, Y, and Y are hydrogen. In some embodiments, R and R do not combine with the nitrogen atom to which they are attached to form a 4,4-difluoropiperidinyl group (shown below) when X, X, Y, and Y are hydrogen. [ka]

[0154] R f In the compound of formula (II), at least one of R8 and R9 is a fluoroalkyl group, R f Each R present in the disclosed compounds includes f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium. In some embodiments, H x is hydrogen. In some embodiments, H x is deuterium. In some embodiments, at least one H x is deuterium and at least one H x is hydrogen. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0155] R fExamples of aryl include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CD2CH2F, -CD2CHF2, -CD2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CD2CH2CH2F, -CD2CH2CHF2, -CD2CH2CF3, -CD2CD2CH2F, -CD2CD2CHF2, -CD2CD2C F3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CD2CH2CH2CH2F, -CD2CH2CH2CHF2, -CD2CH2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3.

[0156] In some embodiments, the compound has one R f In some embodiments, R is a fluoroalkyl group, R f R8 is a fluoroalkyl group; R f For example, R is —CH or CD. In some embodiments, both R and R represent a fluoroalkyl group, R f which may be the same or different.

[0157] In some embodiments, when X 1 , X 2 , Y 1 , and Y 2 are hydrogen and R 8 is hydrogen or methyl, R 9 is not —CH 2 CF 3 .

[0158] In some embodiments, the compound, e.g., the compound of formula (II), [ka] [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof.

[0159] In some embodiments, the compound is [ka] isn't it.

[0160] In some embodiments, the compound is [ka] isn't it.

[0161] In some embodiments, the compound is [ka] isn't it.

[0162] Formula (III) In some embodiments, the compound of Formula (I) has the structure of Formula (III): [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R8 is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R f is selected from the group consisting of R9 is unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, R f , -S(O)R f , and -S(O)R f is selected from the group consisting of or alternatively, R8 and R9 together with the nitrogen atom to which they are attached optionally join to form a heterocycloalkyl substituted with at least one fluorine; and R f is a fluoroalkyl group, and each R f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium, At least one of R8 and R9 is a fluoroalkyl group, R f or R8 and R9 together with the nitrogen atom to which they are attached form a heterocycloalkyl substituted with at least one fluorine.

[0163] X1 and X2 can be the same or different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium. In some embodiments, X1 and X2 are different. In some embodiments, X1 is hydrogen or deuterium, and X2 is unsubstituted or substituted alkyl (e.g., unsubstituted or substituted C1-C6 alkyl). In some embodiments, X2 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X2 is substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group can be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, one of X1 and X2 is deuterium and the other is hydrogen. In some embodiments, X1 and / or X2 are unsubstituted or substituted alkenyl, such as unsubstituted or substituted allyl. In some embodiments, X1 and / or X2 are unsubstituted or substituted alkynyl. In some embodiments, X1 and / or X2 are unsubstituted or substituted C3-C 10 In some embodiments, X and / or X are unsubstituted C-C 10 In some embodiments, X and / or X are substituted C-C alkyl groups, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. 10 Cycloalkyl. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents.

[0164] In some embodiments, X1 and / or X2 are unsubstituted or substituted heterocycloalkyl. In some embodiments, X1 and / or X2 are unsubstituted or substituted aryl. In some embodiments, X1 and / or X2 are unsubstituted or substituted heteroaryl.

[0165] Y1 and Y2 can be the same or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y1 and Y2 are different. In some embodiments, one of Y1 and Y2 is deuterium and the other is hydrogen.

[0166] R and R may be the same or different. In some embodiments, R and R are the same. In some embodiments, R and R are different. In some embodiments, R is hydrogen. In some embodiments, R is unsubstituted alkyl. In some embodiments, R is unsubstituted C-C alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl, with specific reference to methyl. In some embodiments, R is alkyl substituted with one or more deuterium atoms, e.g., a C-C alkyl group substituted with one or more deuterium atoms. The alkyl group may contain one or more deuterium substitutions. For example, if the alkyl group is a C alkyl group (i.e., a methyl group), the deuterium-substituted C alkyl group may be -CDH, -CDH, and -CD, with specific reference to -CD.

[0167] In some embodiments, R is R f R fExamples include, but are not limited to, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, and -CH2CH2CH2CF3, with particular reference to -CH2CH2CH2F, -CH2CH2CHF2, and -CH2CH2CF3.

[0168] In some embodiments, R is unsubstituted alkyl. In some embodiments, R is unsubstituted C-C alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl, with particular reference to methyl. In some embodiments, R is alkyl substituted with one or more deuterium atoms, e.g., a C-C alkyl group substituted with one or more deuterium atoms. The alkyl group may contain one or more deuterium substitutions. For example, if the alkyl group is a C alkyl group (i.e., a methyl group), the deuterium-substituted C alkyl group may be -CDH, -CDH, and -CD, with particular reference to -CD.

[0169] In some embodiments, R is R f and examples include, but are not limited to, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, and -CH2CH2CH2CF3, with particular reference to -CH2CH2CH2F, -CH2CH2CHF2, and -CH2CH2CF3.

[0170] In some embodiments, R9 is —S(O)R fand examples include, but are not limited to, -S(O)CHF, -S(O)CHF, -S(O)CF, -S(O)CHCHF, -S(O)CHCHF, -S(O)CHCF, -S(O)CHCHCHF, -S(O)CHCHCF, -S(O)CHCHCHF, -S(O)CHCHCF, -S(O)CHCHCHCHF, -S(O)CHCHCHCHF, and -S(O)CHCHCHCF, with particular reference to -S(O)CHF, -S(O)CHF, and -S(O)CF.

[0171] In some embodiments, R9 is —S(O)R f and examples include, but are not limited to, -S(O)2CH2F, -S(O)2CHF2, -S(O)2CF3, -S(O)2CH2CH2F, -S(O)2CH2CHF2, -S(O)2CH2CF3, -S(O)2CH2CH2CH2F, -S(O)2CH2CH2CHF2, -S(O)2CH2CH2CF3, -S(O)2CH2CH2CH2F, -S(O)2CH2CH2CH2CHF2, -S(O)2CH2CH2CH2CHF2, and -S(O)2CH2CH2CH2CF3, and particular reference is made to -S(O)2CH2F, -S(O)2CHF2, and -S(O)2CF3.

[0172] In some embodiments, R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl group substituted with at least one fluorine. In some embodiments, the heterocycloalkyl group can be a 3-membered ring. In some embodiments, the heterocycloalkyl group can be a 4-membered ring. In some embodiments, the heterocycloalkyl group can be a 5-membered ring. In some embodiments, the heterocycloalkyl group can be a 6-membered ring. In some embodiments, the heterocycloalkyl group can be a 7-membered ring. In some embodiments, the heterocycloalkyl group can be an 8-membered ring. The heterocycloalkyl group contains at least one nitrogen ring atom (the nitrogen atom between R8 and R9) and may optionally contain additional heterocyclic atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 heterocyclic atoms (at least one of which is a nitrogen ring atom). Examples of heterocycloalkyl groups 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, and thiomorpholine, with particular reference to aziridine, azetidine, pyrrolidine, and piperidine. When R and R, together with the nitrogen atom to which they are attached, form a heterocycloalkyl group, the heterocycloalkyl group can be substituted with one fluorine atom, two fluorine atoms, three fluorine atoms, four fluorine atoms, or more. In some embodiments, the heterocycloalkyl group is substituted with two fluorine atoms.

[0173] Examples of heterocycloalkyl groups substituted with at least one fluorine atom formed by combining R8 and R9 together with the nitrogen atom to which they are attached include: [ka] These include, but are not limited to:

[0174] In some embodiments, R and R do not combine with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine, such as those exemplified above. In some embodiments, R and R do not combine with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine, such as those exemplified above, when X, X, Y, and Y are hydrogen. In some embodiments, R and R do not combine with the nitrogen atom to which they are attached to form a 4,4-difluoropiperidinyl group (shown below) when X, X, Y, and Y are hydrogen. [ka]

[0175] R f In the compound of formula (III), at least one of R8 and R9 is a fluoroalkyl group, R f Each R present in the disclosed compounds includes f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium. In some embodiments, H x is hydrogen. In some embodiments, H x is deuterium. In some embodiments, at least one H x is deuterium and at least one H x is hydrogen. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0176] R fExamples of aryl include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CD2CH2F, -CD2CHF2, -CD2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CD2CH2CH2F, -CD2CH2CHF2, -CD2CH2CF3, -CD2CD2CH2F, -CD2CD2CHF2, -CD2CD2C F3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CD2CH2CH2CH2F, -CD2CH2CH2CHF2, -CD2CH2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3.

[0177] In some embodiments, the compound has one R f In some embodiments, R is a fluoroalkyl group, R f R8 is a fluoroalkyl group; R f For example, R is —CH or CD. In some embodiments, both R and R represent a fluoroalkyl group, R f which may be the same or different.

[0178] In some embodiments, the compound, e.g., the compound of formula (III), [ka] [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof.

[0179] Formula (IV) In some embodiments, the compound of Formula (I) has the structure of Formula (IV): [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R5 is an unsubstituted alkoxy, an alkoxy substituted with one or more deuterium atoms, or -OR f is selected from the group consisting of R8 is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R f is selected from the group consisting of R9 is unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, R f , -S(O)R f , and -S(O)R f is selected from the group consisting of or alternatively, R8 and R9 together with the nitrogen atom to which they are attached optionally join to form a heterocycloalkyl substituted with at least one fluorine; and R f is a fluoroalkyl group, and each R f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium, At least one of R5, R8, and R9 is a fluoroalkyl group, R f and / or R8 and R9 together with the nitrogen atom to which they are attached form a heterocycloalkyl substituted with at least one fluorine.

[0180] X1 and X2 can be the same or different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium. In some embodiments, X1 and X2 are different. In some embodiments, X1 is hydrogen or deuterium, and X2 is unsubstituted or substituted alkyl (e.g., unsubstituted or substituted C1-C6 alkyl). In some embodiments, X2 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X2 is substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group can be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, one of X1 and X2 is deuterium and the other is hydrogen. In some embodiments, X1 and / or X2 are unsubstituted or substituted alkenyl, such as unsubstituted or substituted allyl. In some embodiments, X1 and / or X2 are unsubstituted or substituted alkynyl. In some embodiments, X1 and / or X2 are unsubstituted or substituted C3-C 10 In some embodiments, X and / or X are unsubstituted C-C 10 In some embodiments, X and / or X are substituted C-C alkyl groups, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. 10Cycloalkyl. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents.

[0181] In some embodiments, X1 and / or X2 are unsubstituted or substituted heterocycloalkyl. In some embodiments, X1 and / or X2 are unsubstituted or substituted aryl. In some embodiments, X1 and / or X2 are unsubstituted or substituted heteroaryl.

[0182] Y1 and Y2 can be the same or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y1 and Y2 are different. In some embodiments, one of Y1 and Y2 is deuterium and the other is hydrogen.

[0183] In some embodiments, R5 is an unsubstituted alkoxy group, such as an unsubstituted C1-C6 alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy. In some embodiments, R5 is an alkoxy group substituted with one or more deuterium atoms. The alkoxy group may contain one or more deuterium substitutions. For example, if the alkoxy group is a C1 alkoxy group (i.e., a methoxy group), the deuterium-substituted C1 alkoxy group may be -OCDH2, -OCD2H, and -OCD3.

[0184] In some embodiments, R5 is -OR fExamples include -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, -OCH2CH2CH2CH2F, -OCH2CH2CH2CH F2 and -OCH2CH2CH2CF3, with particular reference to -OCH2F, -OCHF2, and -OCF3.

[0185] R and R may be the same or different. In some embodiments, R and R are the same. In some embodiments, R and R are different. In some embodiments, R is hydrogen. In some embodiments, R is unsubstituted alkyl. In some embodiments, R is unsubstituted C-C alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl, with specific reference to methyl. In some embodiments, R is alkyl substituted with one or more deuterium atoms, e.g., a C-C alkyl group substituted with one or more deuterium atoms. The alkyl group may contain one or more deuterium substitutions. For example, if the alkyl group is a C alkyl group (i.e., a methyl group), the deuterium-substituted C alkyl group may be -CDH, -CDH, and -CD, with specific reference to -CD.

[0186] In some embodiments, R is R f R f Examples include, but are not limited to, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, and -CH2CH2CH2CF3, with particular reference to -CH2CH2CH2F, -CH2CH2CHF2, and -CH2CH2CF3.

[0187] In some embodiments, R is unsubstituted alkyl. In some embodiments, R is unsubstituted C-C alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl, with particular reference to methyl. In some embodiments, R is alkyl substituted with one or more deuterium atoms, e.g., a C-C alkyl group substituted with one or more deuterium atoms. The alkyl group may contain one or more deuterium substitutions. For example, if the alkyl group is a C alkyl group (i.e., a methyl group), the deuterium-substituted C alkyl group may be -CDH, -CDH, and -CD, with particular reference to -CD.

[0188] In some embodiments, R is R f and examples include, but are not limited to, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, and -CH2CH2CH2CF3, with particular reference to -CH2CH2CH2F, -CH2CH2CHF2, and -CH2CH2CF3.

[0189] In some embodiments, R9 is —S(O)R f and examples include, but are not limited to, -S(O)CHF, -S(O)CHF, -S(O)CF, -S(O)CHCHF, -S(O)CHCHF, -S(O)CHCF, -S(O)CHCHCHF, -S(O)CHCHCF, -S(O)CHCHCHF, -S(O)CHCHCF, -S(O)CHCHCHCHF, -S(O)CHCHCHCHF, and -S(O)CHCHCHCF, with particular reference to -S(O)CHF, -S(O)CHF, and -S(O)CF.

[0190] In some embodiments, R9 is —S(O)R fand examples include, but are not limited to, -S(O)2CH2F, -S(O)2CHF2, -S(O)2CF3, -S(O)2CH2CH2F, -S(O)2CH2CHF2, -S(O)2CH2CF3, -S(O)2CH2CH2CH2F, -S(O)2CH2CH2CHF2, -S(O)2CH2CH2CF3, -S(O)2CH2CH2CH2F, -S(O)2CH2CH2CH2CHF2, -S(O)2CH2CH2CH2CHF2, and -S(O)2CH2CH2CH2CF3, and particular reference is made to -S(O)2CH2F, -S(O)2CHF2, and -S(O)2CF3.

[0191] In some embodiments, R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl group substituted with at least one fluorine. In some embodiments, the heterocycloalkyl group can be a 3-membered ring. In some embodiments, the heterocycloalkyl group can be a 4-membered ring. In some embodiments, the heterocycloalkyl group can be a 5-membered ring. In some embodiments, the heterocycloalkyl group can be a 6-membered ring. In some embodiments, the heterocycloalkyl group can be a 7-membered ring. In some embodiments, the heterocycloalkyl group can be an 8-membered ring. The heterocycloalkyl group contains at least one nitrogen ring atom (the nitrogen atom between R8 and R9) and may optionally contain additional heterocyclic atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 heterocyclic atoms (at least one of which is a nitrogen ring atom). Examples of heterocycloalkyl groups 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, and thiomorpholine, with particular reference to aziridine, azetidine, pyrrolidine, and piperidine. When R and R, together with the nitrogen atom to which they are attached, form a heterocycloalkyl group, the heterocycloalkyl group can be substituted with one fluorine atom, two fluorine atoms, three fluorine atoms, four fluorine atoms, or more. In some embodiments, the heterocycloalkyl group is substituted with two fluorine atoms.

[0192] Examples of heterocycloalkyl groups substituted with at least one fluorine atom formed by combining R8 and R9 together with the nitrogen atom to which they are attached include: [ka] These include, but are not limited to:

[0193] In some embodiments, R and R do not combine with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine, such as those exemplified above. In some embodiments, R and R do not combine with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine, such as those exemplified above, when X, X, Y, and Y are hydrogen. In some embodiments, R and R do not combine with the nitrogen atom to which they are attached to form a 4,4-difluoropiperidinyl group (shown below) when X, X, Y, and Y are hydrogen. [ka]

[0194] R f In the compound of formula (IV), at least one of R5, R8, and R9 is a fluoroalkyl group, R f Each R present in the disclosed compounds includes f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium. In some embodiments, H x is hydrogen. In some embodiments, H x is deuterium. In some embodiments, at least one H x is deuterium and at least one H x is hydrogen. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0195] R fExamples of aryl include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CD2CH2F, -CD2CHF2, -CD2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CD2CH2CH2F, -CD2CH2CHF2, -CD2CH2CF3, -CD2CD2CH2F, -CD2CD2CHF2, -CD2CD2C F3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CD2CH2CH2CH2F, -CD2CH2CH2CHF2, -CD2CH2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3.

[0196] In some embodiments, the compound has one R f In some embodiments, R5 comprises a fluoroalkyl group, R f R and R are fluoroalkyl groups; f For example, R and R are each —CH or —CD. In some embodiments, R represents a fluoroalkyl group, R f R5 and R8 are fluoroalkyl groups, R f For example, R5 is -OCH3 or -OCD3, and R8 is -CH3 or CD3.

[0197] In some embodiments, two of R, R, and R are fluoroalkyl groups, R f In some embodiments, R and R comprise a fluoroalkyl group, R f which may be the same or different, R5 is a fluoroalkyl group, R f For example, R5 is -OCH3 or -OCD3. In some embodiments, R5 and R9 represent a group that does not contain a fluoroalkyl group, R fwhich may be the same or different, R is a fluoroalkyl group, R f For example, R8 is -CH3 or CD3.

[0198] In some embodiments, each of R, R, and R is a fluoroalkyl group, R f which may all be the same, all may be different, or two R f The groups are the same, and the third R f The groups may be different.

[0199] In some embodiments, the compound, e.g., the compound of formula (IV), [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof.

[0200] Formula (V) In some embodiments, the compound of Formula (I) has the structure of Formula (V): [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R8 is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R f is selected from the group consisting of R9 is unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, R f , -S(O)R f , and -S(O)R f is selected from the group consisting of or alternatively, R8 and R9 together with the nitrogen atom to which they are attached optionally join to form a heterocycloalkyl substituted with at least one fluorine; and R f is a fluoroalkyl group, and each R f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium, At least one of R8 and R9 is a fluoroalkyl group, R f or R8 and R9 together with the nitrogen atom to which they are attached form a heterocycloalkyl substituted with at least one fluorine.

[0201] X1 and X2 can be the same or different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium. In some embodiments, X1 and X2 are different. In some embodiments, X1 is hydrogen or deuterium, and X2 is unsubstituted or substituted alkyl (e.g., unsubstituted or substituted C1-C6 alkyl). In some embodiments, X2 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X2 is substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group can be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, one of X1 and X2 is deuterium and the other is hydrogen. In some embodiments, X1 and / or X2 are unsubstituted or substituted alkenyl, such as unsubstituted or substituted allyl. In some embodiments, X1 and / or X2 are unsubstituted or substituted alkynyl. In some embodiments, X1 and / or X2 are unsubstituted or substituted C3-C 10 In some embodiments, X and / or X are unsubstituted C-C 10 In some embodiments, X and / or X are substituted C-C alkyl groups, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. 10Cycloalkyl. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents.

[0202] In some embodiments, X1 and / or X2 are unsubstituted or substituted heterocycloalkyl. In some embodiments, X1 and / or X2 are unsubstituted or substituted aryl. In some embodiments, X1 and / or X2 are unsubstituted or substituted heteroaryl.

[0203] Y1 and Y2 can be the same or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y1 and Y2 are different. In some embodiments, one of Y1 and Y2 is deuterium and the other is hydrogen.

[0204] R and R may be the same or different. In some embodiments, R and R are the same. In some embodiments, R and R are different. In some embodiments, R is hydrogen. In some embodiments, R is unsubstituted alkyl. In some embodiments, R is unsubstituted C-C alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl, with specific reference to methyl. In some embodiments, R is alkyl substituted with one or more deuterium atoms, e.g., a C-C alkyl group substituted with one or more deuterium atoms. The alkyl group may contain one or more deuterium substitutions. For example, if the alkyl group is a C alkyl group (i.e., a methyl group), the deuterium-substituted C alkyl group may be -CDH, -CDH, and -CD, with specific reference to -CD.

[0205] In some embodiments, R is R f R f Examples include, but are not limited to, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, and -CH2CH2CH2CF3, with particular reference to -CH2CH2CH2F, -CH2CH2CHF2, and -CH2CH2CF3.

[0206] In some embodiments, R is unsubstituted alkyl. In some embodiments, R is unsubstituted C-C alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl, with particular reference to methyl. In some embodiments, R is alkyl substituted with one or more deuterium atoms, e.g., a C-C alkyl group substituted with one or more deuterium atoms. The alkyl group may contain one or more deuterium substitutions. For example, if the alkyl group is a C alkyl group (i.e., a methyl group), the deuterium-substituted C alkyl group may be -CDH, -CDH, and -CD, with particular reference to -CD.

[0207] In some embodiments, R is R f and examples include, but are not limited to, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, and -CH2CH2CH2CF3, with particular reference to -CH2CH2CH2F, -CH2CH2CHF2, and -CH2CH2CF3.

[0208] In some embodiments, R9 is —S(O)R fand examples include, but are not limited to, -S(O)CHF, -S(O)CHF, -S(O)CF, -S(O)CHCHF, -S(O)CHCHF, -S(O)CHCF, -S(O)CHCHCHF, -S(O)CHCHCF, -S(O)CHCHCHF, -S(O)CHCHCF, -S(O)CHCHCHCHF, -S(O)CHCHCHCHF, and -S(O)CHCHCHCF, with particular reference to -S(O)CHF, -S(O)CHF, and -S(O)CF.

[0209] In some embodiments, R9 is —S(O)R f and examples include, but are not limited to, -S(O)2CH2F, -S(O)2CHF2, -S(O)2CF3, -S(O)2CH2CH2F, -S(O)2CH2CHF2, -S(O)2CH2CF3, -S(O)2CH2CH2CH2F, -S(O)2CH2CH2CHF2, -S(O)2CH2CH2CF3, -S(O)2CH2CH2CH2F, -S(O)2CH2CH2CH2CHF2, -S(O)2CH2CH2CH2CHF2, and -S(O)2CH2CH2CH2CF3, and particular reference is made to -S(O)2CH2F, -S(O)2CHF2, and -S(O)2CF3.

[0210] In some embodiments, R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl group substituted with at least one fluorine. In some embodiments, the heterocycloalkyl group can be a 3-membered ring. In some embodiments, the heterocycloalkyl group can be a 4-membered ring. In some embodiments, the heterocycloalkyl group can be a 5-membered ring. In some embodiments, the heterocycloalkyl group can be a 6-membered ring. In some embodiments, the heterocycloalkyl group can be a 7-membered ring. In some embodiments, the heterocycloalkyl group can be an 8-membered ring. The heterocycloalkyl group contains at least one nitrogen ring atom (the nitrogen atom between R8 and R9) and may optionally contain additional heterocyclic atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 heterocyclic atoms (at least one of which is a nitrogen ring atom). Examples of heterocycloalkyl groups 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, and thiomorpholine, with particular reference to aziridine, azetidine, pyrrolidine, and piperidine. When R and R, together with the nitrogen atom to which they are attached, form a heterocycloalkyl group, the heterocycloalkyl group can be substituted with one fluorine atom, two fluorine atoms, three fluorine atoms, four fluorine atoms, or more. In some embodiments, the heterocycloalkyl group is substituted with two fluorine atoms.

[0211] Examples of heterocycloalkyl groups substituted with at least one fluorine atom formed by combining R8 and R9 together with the nitrogen atom to which they are attached include: [ka] These include, but are not limited to:

[0212] In some embodiments, R and R do not combine with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine, such as those exemplified above. In some embodiments, R and R do not combine with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine, such as those exemplified above, when X, X, Y, and Y are hydrogen. In some embodiments, R and R do not combine with the nitrogen atom to which they are attached to form a 4,4-difluoropiperidinyl group (shown below) when X, X, Y, and Y are hydrogen. [ka]

[0213] R f In the compound of formula (V), at least one of R8 and R9 is a fluoroalkyl group, R f Each R present in the disclosed compounds includes f are independently -(CH x 2) n CH2F, -(CH x 2) n CHF2, and -(CH x 2) n CF3, wherein n is 0 to 3, and each H x are independently hydrogen or deuterium. In some embodiments, H x is hydrogen. In some embodiments, H x is deuterium. In some embodiments, at least one H x is deuterium and at least one H x is hydrogen. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0214] R fExamples of aryl include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CD2CH2F, -CD2CHF2, -CD2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CD2CH2CH2F, -CD2CH2CHF2, -CD2CH2CF3, -CD2CD2CH2F, -CD2CD2CHF2, -CD2CD2C F3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, -CH2CH2CH2CF3, -CD2CH2CH2CH2F, -CD2CH2CH2CHF2, -CD2CH2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CH2CH2F, -CD2CD2CH2CHF2, -CD2CD2CH2CF3, -CD2CD2CD2CH2F, -CD2CD2CD2CHF2, and -CD2CD2CD2CF3.

[0215] In some embodiments, the compound has one R f In some embodiments, R is a fluoroalkyl group, R f R8 is a fluoroalkyl group; R f For example, R is —CH or CD. In some embodiments, both R and R represent a fluoroalkyl group, R f which may be the same or different.

[0216] In some embodiments, the compound, e.g., the compound of formula (V), [ka] [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof.

[0217] Compounds of Formulas (I)-(V) may contain stereocenters. In such cases, although Formulas (I)-(V) are drawn without regard to stereochemistry, the compounds may exist in different stereoisomeric forms. Accordingly, the present disclosure encompasses all possible stereoisomers, including not only racemates 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 may be obtained, for example, by stereospecific synthesis as known in the art.

[0218] In some embodiments, the compounds described herein, e.g., compounds of Formulas (I)-(V), are non-stereoisomeric. In some embodiments, the compounds described herein, e.g., compounds of Formulas (I)-(V), are racemic. In some embodiments, the compounds described herein, e.g., compounds of Formulas (I)-(V), are enantiomerically enriched (one enantiomer is present in a greater proportion), including enantiomerically pure. In some embodiments, the compounds described herein, e.g., compounds of Formulas (I)-(V), are provided as a single diastereomer. In some embodiments, the compounds described herein, e.g., compounds of Formulas (I)-(V), are provided as a mixture of diastereomers. When provided as a mixture of diastereomers, the mixture can include an equal mixture or a mixture enriched in a particular diastereomer (one diastereomer is present in a greater proportion than another).

[0219] In some embodiments, the compounds of Formulae (I)-(V) are agonists of the serotonin 5-HT2 receptor.

[0220] In some embodiments, the compounds of Formulas (I)-(V) are serotonin 5-HT 2A It is an agonist of the receptor.

[0221] Also disclosed herein are pharmaceutically acceptable salts of the compounds of the present disclosure, e.g., compounds of Formulas (I)-(V). When the pharmaceutically acceptable salt is an acid addition salt, the acid used to form the pharmaceutically acceptable salt of a compound of Formulas (I)-(V) can be a mono-, di-, tri-, tetra-, or higher-number acid group. The acid group can be, for example, a carboxylic acid, sulfonic acid, phosphonic acid, or other acidic moiety containing at least one replaceable hydrogen atom.Examples of acids that may be used in the preparation of pharmaceutically acceptable (acid addition) salts disclosed herein include acetic acid, 2,2-dichloroacetic acid, phenylacetic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthyl 2-sulfonic acid, benzophenone-1,2-dione ... toluene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.), benzoic acids (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, etc.), boric acid, (+)-camphoric acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, formic acid, fumaric acid, galactaric acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glutamic acid, Licholic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (-)-D-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, (+)-D-malic acid, hydroxymaleic acid, malonic acid, (±)-DL-mandelic acid, isethionic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, succinic acid, sulfuric acid, sulfamic acid, tannic acid, tartaric acid (e.g., DL-tartaric acid, (+)-L-tartaric acid, (-)-D-tartaric acid), thiocyanic acid, propionic acid, valeric acid, and fatty acids (including fatty mono- and di-acids, e.g., adipic (hexanedio) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, caprylic (octanoic) acid, palmitic (hexadecenoic) acid, sebacic acid, undecylenic acid, caproic acid, etc.).

[0222] In some embodiments, the pharmaceutically acceptable salt of a compound of Formulas (I)-(V) is a benzenesulfonate, tartrate, hemifumarate, acetate, citrate, malonate, fumarate, succinate, oxalate, benzoate, salicylate, ascorbate, hydrochloride, maleate, malate, methanesulfonate, toluenesulfonate, glucuronate, or glutarate salt of a compound of Formulas (I)-(V). In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (I)-(V) is a salt formed with a sulfonic acid (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.). In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (I)-(V) is a salt formed with a benzoic acid (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-aminosalicylic acid, etc.).

[0223] In some embodiments, the pharmaceutically acceptable salts of the compounds of Formulas (I)-(V) are fatty acid salts. The fatty acids used to prepare the fatty acid salts of the compounds of Formulas (I)-(V) may be fatty mono- or di-acids and may contain a fatty hydrocarbon moiety consisting of hydrogen and 4, 6, 8, 10, 12, 14, 16, and up to 26, up to 24, up to 22, up to 20, or up to 18 carbon atoms, and may be fully saturated or partially unsaturated. In some embodiments, the pharmaceutically acceptable salts of the compounds of Formulas (I)-(V) are adipate, laurate, linoleate, myristate, caprate, stearate, oleate, caprylate, palmitate, sebacate, undecylenate, or caproate salts of the compounds of Formulas (I)-(V).

[0224] Methods for preparing pharmaceutically acceptable salt forms of pharmaceutical compounds are known to those skilled in the art. In some embodiments, the method comprises: (a) suspending a compound of Formula (I)-(V) in a solvent or mixture of solvents; (b) contacting an acid with a compound of Formula (I)-(V) to provide a mixture; (c) optionally heating the mixture; (d) optionally cooling the mixture; and (e) isolating the salt.

[0225] A variety of solvents can be used in the disclosed methods, including one or more protic solvents, one or more aprotic solvents, or mixtures thereof. In some embodiments, the solvent used in the method of preparing the salt is a protic solvent. In some embodiments, the solvent used in the method of preparing the salt is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, acetone, butanone, dioxane (1,4-dioxane), water, tetrahydrofuran (THF), acetonitrile (MeCN), an ether solvent (e.g., t-butyl methyl ether (TBME)), hexane, heptane, octane, and combinations thereof. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is tetrahydrofuran.

[0226] Acids suitable for use in preparing pharmaceutically acceptable acid addition salts can include those previously described. The acid can be an inorganic acid, such as hydrochloric acid, or an organic acid, preferably an organic acid. In some embodiments, the acid is an organic acid selected from the group consisting of ascorbic acid, citric acid, fumaric acid, maleic acid, malonic acid, (-)-L-malic acid, (+)-L-tartaric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, benzoic acid, salicylic acid, succinic acid, oxalic acid, D-glucuronic acid, glutarate, and acetic acid. In some embodiments, the acid is an organic acid selected from the group consisting of benzenesulfonic acid, (+)-L-tartaric acid, fumaric acid, acetic acid, citric acid, malonic acid, succinic acid, oxalic acid, benzoic acid, and salicylic acid. In some embodiments, the acid is a fatty acid, such as adipic (hexanedio) acid, lauric (dodecano) acid, linoleic acid, myristic (tetradecano) acid, capric (decano) acid, stearic (octadecano) acid, oleic acid, caprylic (octano) acid, palmitic (hexadeceno) acid, sebacic acid, undecylenic acid, caproic acid, and the like, with particular mention being made of adipic (hexanedio) acid, lauric (dodecano) acid, linoleic acid, myristic (tetradecano) acid, capric (decano) acid, stearic (octadecano) acid, oleic acid, and caprylic (octano) acid.

[0227] In some embodiments, a stoichiometric (or superstoichiometric) amount of acid is contacted with a compound of Formulae (I)-(V). In some embodiments, a substoichiometric (e.g., 0.5 molar equivalent) amount of acid is contacted with a compound of Formulae (I)-(V). For example, when the acid contains at least two acidic protons (e.g., two or more carboxylic acid groups) and the target salt is a hemi-acid salt, using a substoichiometric amount of acid may be desirable.

[0228] In some embodiments, the mixture is heated, for example, to reflux, before cooling.

[0229] In some embodiments, the mixture is cooled and the salt precipitates from solution. In some embodiments, the salt precipitates from solution in a crystalline form. In some embodiments, the salt precipitates from solution in an amorphous form.

[0230] Isolation of the salt can be accomplished by a variety of well-known isolation techniques, such as filtration, decantation, etc. In some embodiments, the isolation step comprises filtering the mixture.

[0231] After isolation, additional crystallization and / or recrystallization steps may also be optionally performed, if desired, to, for example, increase purity, crystallinity, etc.

[0232] In some embodiments, the compounds of the present disclosure, e.g., compounds of Formulas (I)-(V), or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, or prodrugs thereof, are in the form of a solvate. Examples of solvate forms include, but are not limited to, hydrates, methanoates, ethanolates, isopropanolates, and the like, with hydrates and ethanolates being preferred. Solvates may be formed from stoichiometric or non-stoichiometric amounts of solvent molecules. The solvates of the compounds of the present disclosure may be in the form of an isolatable solvate. In one non-limiting example, as a hydrate, the compound may be a monohydrate, a dihydrate, or the like. The solvates of the compounds of the present disclosure also include solution-phase forms. Thus, in some embodiments, the present disclosure provides solution-phase compositions of the compounds of the present disclosure, or any pharmaceutically acceptable salt thereof, in a solvated form, preferably a fully solvated form.

[0233] In some embodiments, compounds of the present disclosure, e.g., compounds of Formulas (I)-(V), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, or prodrugs thereof, are provided in crystalline form, e.g., as determined by XRPD. Accordingly, pharmaceutical compositions may be prepared from compounds of Formulas (I)-(V) in crystalline form, including one or more polymorphic forms, and used in the treatments described herein. Crystalline forms are advantageous in terms of stability and provide well-defined physical properties that are desirable for pharmaceutical preparation and administration.

[0234] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, are provided in amorphous form, as determined, for example, by XRPD. Accordingly, pharmaceutical compositions may be prepared from compounds of Formulas (I)-(V), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, or prodrugs thereof, in one or more amorphous forms and used in the treatments described herein. Amorphous forms typically have higher aqueous solubility and dissolution rates than their crystalline counterparts, and therefore may be suitable for fast-acting dosage forms adapted to rapidly release the active agent, such as orodispersible dosage forms (ODx), immediate-release (IR) dosage forms, and the like.

[0235] Compounds of the present disclosure, for example, compounds of Formulas (I)-(V), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs thereof, can generally be prepared according to, or similar to, the general synthetic route illustrated in Figure 1, or the synthetic routes illustrated below. Other synthetic routes can also be used in accordance with techniques and procedures known to those skilled in the art.

[0236] Pharmaceutical Composition Also disclosed herein are pharmaceutical compositions comprising a compound of Formulas (I)-(V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, and a pharmaceutically acceptable vehicle. The pharmaceutical composition may include one or more compounds of the present disclosure.

[0237] A "pharmaceutically acceptable vehicle" can be a vehicle approved by a federal or state regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in mammals, such as humans. The term "vehicle" refers to a diluent, adjuvant, excipient, or carrier with which the disclosed compounds or salts thereof are formulated for administration to a mammal. Such pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Pharmaceutical vehicles can be water, saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. Additionally, adjuvants, stabilizers, solubilizers, thickeners, lubricants, colorants, sweeteners, and other pharmaceutical additives can be included in the disclosed compositions, such as those described below. Pharmaceutical vehicles may include acids such as those previously described for use in forming pharmaceutically acceptable salt forms of the present disclosure, with particular reference to citric acid and / or tartaric acid.

[0238] The pharmaceutical composition may comprise a single compound of Formula (I)-(V) or a mixture of compounds of Formula (I)-(V). The pharmaceutical composition may be formed from an isotopologue mixture of the disclosed compounds. In some embodiments, the subject compound of Formula (I)-(V) may be present in the pharmaceutical composition with a purity of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight, based on the total weight of isotopic substitution of the compound of Formula (I)-(V) present in the pharmaceutical composition (i.e., isotopic purity). In some embodiments, the composition comprises a subject compound of Formula (I)-(V) and is substantially free of other isotopologues of the subject compound in either free base or salt form; e.g., the composition has less than 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0.5 mole percent of other isotopologues of the subject compound.

[0239] In some embodiments, any position in a deuterium-bearing compound has a minimum deuterium bonding that is greater than the naturally occurring percentage in hydrogen (about 0.016 atomic %), hi some embodiments, any position in a deuterium-bearing compound has a minimum deuterium incorporation of 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 %, or at least 99 atomic % at the deuteration site.

[0240] Pharmaceutical compositions can be formulated using enantiomerically pure compounds of the present disclosure, such as compounds of Formulas (I)-(V), or racemic mixtures of compounds. As described herein, racemic compounds of Formulas (I)-(V) can contain about 50% of the R- and S-stereoisomers based on a molar ratio of one of the isomers (about 48 to about 52 mole %, or about a 1:1 ratio). In some embodiments, a composition, medicament, or method of treatment can involve combining separately produced R- and S-stereoisomers of a compound in an approximately equal molar ratio (e.g., about 48 to 52%). In some embodiments, a medicament or pharmaceutical composition can include a mixture of different ratios of R- and S-stereoisomers of distinct compounds. In some embodiments, a pharmaceutical composition contains an excess (greater than 50%) of the R-enantiomer. Suitable R / S molar ratios can be about 1.5:1, 2:1, 3:1, 4:1, 5:1, 10:1, or higher. In some embodiments, the pharmaceutical composition can contain an excess of S-enantiomer, reversing the provided ratio of R / S. Other suitable amounts of R / S can also be selected. For example, the R-enantiomer can be enriched, e.g., 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 can be enriched, e.g., 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%. Ratios between all of these exemplary embodiments, as well as larger and smaller ratios, are all encompassed within the scope of the disclosure.

[0241] Pharmaceutical compositions may be formulated with one or more polymorphs of the compounds of Formulas (I)-(V), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, or prodrugs thereof, including crystalline and / or amorphous polymorphs of the compounds or salts thereof.

[0242] Generally, pharmaceutical compositions containing about 0.001 to about 1000 mg, about 1 to about 500 mg, about 2 to about 100 mg, about 0.001 mg, about 0.01 mg, about 0.1 mg, about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg of one or more compounds disclosed herein (on an active basis) can be provided herein. The amount (on an active basis) of the compound of Formulas (I)-(V) in a unit dose preparation can be varied or adjusted within the above ranges as deemed appropriate using sound medical judgment, depending on the particular application, route of administration, potency of the active ingredient, etc. The compositions can also contain other compatible therapeutic agents / active ingredients, if desired.

[0243] In some embodiments, the pharmaceutical composition comprises at least 0.1%, at least 0.5%, at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, and up to 99.9%, up to 99.5%, up to 99%, up to 98%, up to 97%, up to 95%, up to 90%, up to 85%, up to 80%, up to 75%, up to 70%, up to 65%, up to 60%, or up to 55% by weight of a compound of Formulae (I)-(V), based on the total weight of the pharmaceutical composition.

[0244] The pharmaceutical compositions disclosed herein may be administered at once or multiple times at intervals.It is understood that the exact dosage and duration of treatment may vary depending on the age, weight, and condition of the patient being treated, and can be empirically determined using known testing protocols or by extrapolation from in vivo or in vitro testing or diagnostic data.It is understood that for any particular individual, specific dosage regimens should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the formulation.

[0245] If the patient's condition does not improve, at the physician's discretion, the compounds may be administered chronically, i.e., over an extended period throughout the patient's life, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0246] If the patient's condition improves, the compound may be continued or temporarily discontinued for a period of time (i.e., a "drug holiday"), at the physician's discretion.

[0247] Once improvement of the patient's condition has occurred, a maintenance dose is administered as needed. Thereafter, the dose or frequency of administration, or both, may be reduced, depending on the symptoms, to a level at which the improved condition is maintained. However, patients may require intermittent treatment on a long-term basis if symptoms recur.

[0248] Pharmaceutical compositions can take the form of capsules, tablets, pills, pellets, lozenges, powders, granules, syrups, elixirs, solutions, suspensions, emulsions, suppositories, or sustained-release formulations thereof, or any other form suitable for administration to a mammal. In some instances, pharmaceutical compositions are formulated for administration in accordance with routine procedures as pharmaceutical compositions adapted for oral, intravenous, intradermal, or inhalation administration to humans, or other routes of administration described herein. Examples of suitable pharmaceutical vehicles and methods for their formulation 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 choice of vehicle will be determined in part by the particular compound and the particular method used to administer the composition. Accordingly, there are a wide variety of suitable formulations of the subject pharmaceutical compositions. Liquid form preparations include solutions and emulsions, such as water, water / propylene glycol solutions, or organic solvents. When administered to mammals, the compounds and compositions of the present disclosure and pharmaceutically acceptable vehicles may be sterilized. In some cases, for example, when the subject compounds are administered intravenously or via inhalation, aqueous media such as water, saline, aqueous dextrose, and glycerol solutions are used as vehicles.

[0249] As described below, the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid, semi-solid, or liquid form, including those compatible with the following: A. Oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets, films, or capsules, such as those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, syrups, pastes for application to the tongue, etc.; B. Parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, intradermal, or epidural injection, e.g., as a sterile solution or suspension, or sustained-release formulation; C. Topical / transdermal administration, e.g., creams, ointments, or controlled-release patches or sprays applied to the skin or to orifices and / or mucosal surfaces such as in the vagina or rectum, e.g., pessaries, creams, or foams; D. Modified-release dosage forms, such as delayed-, extended-, prolonged-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-, etc., modified-release dosage forms and gastroretentive 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, supra; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126); and E. Inhalation administration, eg, aerosol, preferably mists. Tamper-resistant dosage forms / packaging of any of the disclosed pharmaceutical compositions are contemplated.

[0250] A. Oral Administration The pharmaceutical compositions disclosed herein can be provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration includes, for example, enteral delivery, in which the drug is ingested and swallowed, as well as oral administration through the mucosal lining of the oral cavity, for example, buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, films, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical compositions 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, glidants, colorants, dye migration inhibitors, sweeteners, preservatives, antioxidants, lyoprotectants, stabilizers, solubilizers, complexing agents, and flavoring agents.

[0251] In some embodiments, the pharmaceutical compositions of the present disclosure may be orodispersible dosage forms (ODxs), including orodispersible tablets (ODTs) (sometimes also referred to as rapidly disintegrating tablets, orodispersible tablets, or fast-dispersing tablets) or orodispersible films (ODFs) (or wafers). Such dosage forms, when administered intraorally through the mucosal lining of the oral cavity, e.g., buccal, lingual, and sublingual administration, may provide increased bioavailability, more rapid onset of action, and allow pregastric absorption of the compounds / salts herein, as compared to oral administration via the gastrointestinal tract.

[0252] Oral dispersible dosage forms can be prepared by different techniques, such as, for example, freeze-drying (lyophilization), molding, spray-drying, bulk extrusion, or compression. Orally disintegrating tablets are preferably prepared by freeze-drying. In some embodiments, the orodispersible dosage form disintegrates in less than about 90 seconds, less than about 60 seconds, less than about 30 seconds, less than about 20 seconds, less than about 10 seconds, less than about 5 seconds, or less than about 2 seconds after being received in the oral cavity. In some embodiments, the orodispersible dosage form dissolves in less than about 90 seconds, less than about 60 seconds, or less than about 30 seconds after being received in the oral cavity. In some embodiments, the orodispersible dosage form disperses in less than about 90 seconds, less than about 60 seconds, less than about 30 seconds, less than about 20 seconds, less than about 10 seconds, less than about 5 seconds, or less than about 2 seconds after being received in the oral cavity. In some embodiments, the pharmaceutical composition has a disintegration test of about 30 seconds or less, about 20 seconds or less, about 10 seconds or less, about 5 seconds or less, or about 2 seconds or less in the United States Pharmacopeia (USP). <701> The disintegration time is in the form of an orodispersible dosage form such as an orally disintegrating tablet (ODT) that conforms to the United States Pharmacopeia (USP) Disintegration Test. <701> In accordance with the above, orodispersible dosage forms having longer disintegration times, for example, 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 therebetween, or longer, are also contemplated, for example, when adapted for sustained release.

[0253] In some embodiments, the pharmaceutical composition is in the form of a lyophilized orodispersible dosage form, such as a lyophilized ODT. In some embodiments, the lyophilized orodispersible dosage form (e.g., a 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 lyoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, etc. In some embodiments, the orodispersible dosage form comprises a two-component framework of a lyophilized matrix system that cooperates to ensure successful formulation development. In some embodiments, the first component is a water-soluble polymer such as gelatin, dextran, alginate, and maltodextrin. This component maintains shape and provides mechanical strength to the dosage form (binder). In some embodiments, the second component is a matrix support / disintegration promoter, such as sucrose, lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and / or starch, which acts by adhering the porous framework provided by the water-soluble polymer and promotes disintegration of the orodispersible dosage form. In some embodiments, the freeze-dried orodispersible dosage form (e.g., freeze-dried ODT) comprises gelatin and mannitol. In some embodiments, the freeze-dried orodispersible dosage form (e.g., freeze-dried ODT) comprises gelatin, mannitol, and one or more of a cryoprotectant, a preservative, an antioxidant, a stabilizer, a solubilizer, a flavoring agent, etc., with particular mention being made of citric acid. 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® orally dispersible tablets) comprises one or more water-soluble polymers, e.g., gelatin, one or more matrix materials, fillers, or diluents, e.g., mannitol, a compound of Formula (I)-(V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, and optionally a cryoprotectant, preservative, antioxidant, stabilizer, solubilizer, and / or flavoring agent.In some embodiments, the ODT formulation (e.g., Zydis® orally dispersible tablets) comprises gelatin, mannitol, a compound of Formulas (I)-(V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, and an organic acid (non-limiting examples of which are citric acid and / or tartaric acid), or any suitable organic acid described herein.

[0254] In some embodiments, the pharmaceutical composition is in the form of a lyophilized orodispersible 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 other vehicles as described herein, such as one or more cryoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, etc. In some embodiments, the lyophilized ODF comprises a thin, water-soluble film matrix. In some embodiments, the ODF comprises a two-component framework of a lyophilized matrix system that cooperates to ensure successful formulation development. In some embodiments, the first component is a water-soluble polymer such as gelatin, dextran, alginate, and maltodextrin. This component maintains shape and provides mechanical strength to the film / wafer (binder). In some embodiments, the second component is a matrix support / disintegration promoter, such as sucrose and mannitol, which acts by adhering the porous framework provided by the water-soluble polymer and promotes 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 a cryoprotectant, a preservative, an antioxidant, a stabilizer, a solubilizer, a flavoring agent, etc., with particular reference to citric acid.

[0255] In some embodiments, an ODF (or wafer) can comprise a single layer, a double layer, or a triple layer. In some embodiments, a single-layer ODF comprises an active agent and one or more pharmaceutically acceptable vehicles (e.g., carriers or excipients). In some embodiments, a double-layer ODF comprises one or more excipients, such as a solubilizer, in a first layer and an active agent in a 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 ODFs, each layer can be different, or two layers, such as an upper and lower layer, can 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 can include one or more excipients, such as a solubilizer. 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 excipients.The core layer typically contains an active agent and, optionally, one or more excipients.

[0256] In some embodiments, in addition to the active ingredient, the pharmaceutical composition in the orodispersible dosage form (ODx) may include one or more pharmaceutically acceptable vehicles (e.g., carriers or excipients). For example, in some embodiments, the pharmaceutical composition in the orodispersible dosage form includes one or more of a pharmaceutically acceptable cryoprotectant, preservative, antioxidant, stabilizer, solubilizer, flavoring agent, etc.

[0257] Examples of pharmaceutically acceptable cryoprotectants include, but are not limited to, disaccharides such as sucrose and trehalose, anionic polymers such as sulfobutylether-β-cyclodextrin (SBECD) and hyaluronic acid, and hydroxylated cyclodextrins.

[0258] Examples of pharmaceutically acceptable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol.

[0259] Examples of pharmaceutically acceptable antioxidants that may serve to further enhance the stability of the compositions include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​or its salts (cysteine ​​hydrochloride), sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0260] Examples of pharmaceutically acceptable stabilizers include, but are not limited to, fatty acids, fatty alcohols, alcohols, long-chain fatty acid esters, long-chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone, polyvinyl ethers, polyvinyl alcohol, hydrocarbons, hydrophobic polymers, hygroscopic polymers, glycerin, methionine, monothioglycerin, ascorbic acid, citric acid, polysorbates, arginine, cyclodextrin, microcrystalline cellulose, modified cellulose (e.g., carboxymethylcellulose, sodium salt), sorbitol, and cellulose gel.

[0261] Examples of pharmaceutically acceptable solubilizers (or dissolution aids) include citric acid, hydroxypropyl cellulose, hydroxypropylmethylcellulose, sodium stearyl fumarate, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, polyoxyl 40 stearate, purified shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbyl stearate, L-aspartic acid, adipic acid, aminoalkyl methacrylate copolymer E, propylene glycol alginate, casein, sodium caseinate, carboxyvinyl polymer, carboxymethylethylcellulose, powdered agar, guar gum, succinic acid, copolyvidone, cellulose acetate phthalate, tartaric acid, sodium dioctyl sulfosuccinate, zein, nonfat powdered milk, sorbitan trioleate, lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethyl methacrylate, methylcellulose ... Examples of suitable cellulose acetates include, but are not limited to, cellulose, hydroxypropyl methylcellulose acetate succinate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, poly(sodium 4-styrenesulfonate), polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, maleic acid, methacrylic acid 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.

[0262] Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that produce a pleasant taste and taste-masking effect. Examples of flavoring agents include, but are not limited to, aspartame, saccharin (as sodium, potassium, or calcium saccharin), cyclamate (as sodium, potassium, or calcium salt), sucralose, acesulfame K, thaumatin, neohisperidin, dihydrochalcone, ammoniated glycyrrhizin, glucose, maltodextrin, fructose, levulose, 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.

[0263] 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 delivery of the compositions described herein.

[0264] For example, pharmaceutical compositions adapted for oral administration, such as tablets, including compressed tablets, can be formulated with a variety of vehicles, such as those described herein. Examples of suitable vehicles include, but are not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye transfer inhibitors, sweeteners, preservatives, antioxidants, stabilizers, solubilizers, and flavoring agents.

[0265] Binders or granulating agents impart cohesive properties to the tablet and ensure that the tablet remains intact after compression. Suitable binders or granulating agents include starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage of isagol husk, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), bee gum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses such as ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); microcrystalline celluloses such as AVICEL-PH-101, AVICEL-PH-103, AVICEL 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, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler may be present in 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 therebetween, based on the weight of the pharmaceutical compositions disclosed herein.

[0266] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.When present in sufficient amounts, certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, can impart the properties of some compressed tablets that can be disintegrated in the mouth by chewing.Such compressed tablets can be used as chewable tablets.

[0267] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and Bee Gum HV; citrus pulp; cross-linked celluloses such as croscarmellose; cross-linked polymers such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline celluloses such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clays; alain; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions disclosed herein varies depending on the type of formulation and is readily discernible by 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 disintegrant.

[0268] Suitable lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycols such as 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 such as AEROSIL® 200 (WR Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co., Boston, Mass.), and mixtures thereof. The pharmaceutical compositions disclosed herein may contain, for example, about 0.1 to about 5% by weight of a lubricant.

[0269] Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co., Boston, Mass.), and asbestos-free talc.

[0270] Coloring agents include any of the approved, certified, water-soluble FD&C dyes and insoluble FD&C dyes suspended on alumina hydrate, as well as color lakes and mixtures thereof. Color lakes are combinations of water-soluble dyes by adsorption to hydrous heavy metal oxides, resulting in an insoluble form of the dye.

[0271] Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweetening agents, such as saccharin and aspartame.

[0272] Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate.

[0273] Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, beegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.

[0274] Preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol.

[0275] Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0276] Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids utilized 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.

[0277] It should be understood that many vehicles (carriers, excipients, etc.) can serve multiple functions, even within the same formulation. Particular reference is made herein to pharmaceutical compositions herein that contain citric acid, which can serve multiple roles as a stabilizer, particularly as a solubilizer to provide faster dissolution of the active substance for rapid onset of action, etc., in dosage forms adapted for rapid onset of action and shorter duration of drug action, such as orodispersible dosage forms (e.g., ODT and ODF).

[0278] The pharmaceutical compositions herein may be in the form of compressed tablets, crushed tablets, chewable lozenges, quick-dissolving tablets, multiple compressed tablets, or enteric-coated, sugar-coated, 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 intestine, thus protecting the active ingredient from the acidic stomach environment. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in masking unpleasant tastes or odors and protecting the tablets 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 acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets made by multiple compression cycles, including layered tablets, press coated or dry coated tablets.

[0279] Tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular form, alone or in combination with one or more vehicles (e.g., carriers or excipients) described herein, including binders, disintegrants, release-controlling polymers, lubricants, diluents, and / or colorants. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0280] Disclosed herein are pharmaceutical compositions in a modified release dosage form comprising a compound disclosed herein and one or more release-controlling excipients or carriers described herein. Suitable modified release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof. The pharmaceutical composition may also contain non-release-controlling excipients or carriers.

[0281] Further disclosed herein are enteric-coated pharmaceutical compositions comprising a compound disclosed herein and one or more controlled-release excipients or carriers for use in enteric-coated dosage forms. The pharmaceutical compositions may also include non-controlled-release excipients or carriers.

[0282] Further disclosed herein are effervescent dosage form pharmaceutical compositions comprising a compound disclosed herein and one or more controlled-release excipients or carriers for use in effervescent dosage forms. The pharmaceutical compositions may also include non-controlled-release excipients or carriers.

[0283] Further disclosed are pharmaceutical compositions in dosage forms having an immediate release component and at least one delayed release component, capable of discontinuously releasing a compound in at least two successive pulses separated by about 0.1 up to 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 compositions include a compound disclosed herein and one or more controlled-release and non-controlled-release excipients or carriers, such as excipients or carriers suitable for disrupting semipermeable membranes and swellable materials.

[0284] Also disclosed herein is a pharmaceutical composition in a dosage form for oral administration to a subject, comprising a compound, salt, or solvate disclosed herein and one or more pharmaceutically acceptable vehicles (e.g., excipients or carriers) encapsulated in an intermediate reaction layer comprising a gastric juice-resistant polymeric layered material that has been partially neutralized with alkali and has cation exchange capacity, and a gastric juice-resistant outer layer.

[0285] The dosage form may be an immediate release (IR) dosage form, examples of which include, but are not limited to, immediate release (IR) tablets or immediate release (IR) capsules. In addition to the active ingredient (e.g., a compound of Formulas (I)-(V)), dosage forms adapted for immediate release may contain one or more pharmaceutically acceptable vehicles that readily disperse, dissolve, or otherwise degrade in the gastric environment so as not to delay or prolong dissolution / absorption of the active ingredient. Examples of pharmaceutically acceptable vehicles for immediate release dosage forms include, but are not limited to, one or more binders / granulating agents, 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 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.

[0286] The pharmaceutical compositions disclosed herein may be disclosed as soft or hard capsules, which may be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs) or powder-filled capsules (PICs), consist of two compartments, one sliding over the other to completely enclose the active ingredient. Soft elastic capsules (SECs) are soft, globular shells, such as gelatin shells, plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives include those described herein, including methylparaben, propylparaben, and sorbic acid. Liquid, semisolid, and solid dosage forms disclosed herein may be encapsulated. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. The capsules may also be coated as known by those skilled in the art to modify or maintain dissolution of the active ingredient.

[0287] 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.

[0288] In some embodiments, the pharmaceutical composition is in the form of a delayed-release capsule for oral administration and may further comprise cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide.

[0289] 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 monoglyceride, ethyl cellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, and yellow ferric oxide.

[0290] 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, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

[0291] The pharmaceutical compositions disclosed herein may be in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems, in which one liquid is dispersed in the form of small globules throughout another liquid, 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 preservative. Aqueous alcoholic solutions may contain a pharmaceutically acceptable di(lower alkyl)acetal of a lower alkyl aldehyde (the term "lower" means an alkyl having 1 to 6 carbon atoms), e.g., acetaldehyde diethyl acetal, and a water-miscible solvent having one or more hydroxyl groups, e.g., propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, e.g., sucrose, and may contain a preservative. For a liquid dosage form, the solution, for example, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be easily measured for administration.

[0292] Other useful liquid and semisolid dosage forms include those containing an active ingredient disclosed herein (e.g., a compound of Formulas (I)-(V)) and a dialkylated mono- or poly-alkylene glycol, including, but not limited to, 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 weights of the 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, 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 chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0293] 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 delivery of the compositions described herein.

[0294] The pharmaceutical compositions disclosed herein for oral administration may also be disclosed in the form of liposomes, micelles, microspheres, or nanosystems.

[0295] The pharmaceutical compositions disclosed herein may be disclosed as non-effervescent or effervescent granules and powders to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and a carbon dioxide source.

[0296] Coloring and flavoring agents can be used in any of the disclosed dosage forms.

[0297] The pharmaceutical compositions disclosed herein may be co-formulated with other active ingredients that do not impair the desired therapeutic action, or with substances that supplement the desired action, such as hydrocortisone.

[0298] B. Parenteral Administration The pharmaceutical compositions disclosed herein can be administered parenterally by injection, infusion, perfusion, or implantation for local or systemic administration. As used herein, parenteral administration includes, but is not limited to, intravenous, intradermal, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

[0299] The pharmaceutical compositions disclosed herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solution or suspension in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmacy (see Remington: The Science and Practice of Pharmacy, supra).

[0300] 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 agents or preservatives against microbial growth, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, cryoprotectants, thickening agents, pH-adjusting agents, and inert gases.

[0301] Suitable aqueous vehicles include, but are not limited to, water, saline, normal saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, 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 of palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300, polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide.

[0302] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride, benzethonium chloride, methyl and propylparaben, and sorbic acid. Suitable isotonicity agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citric acid. Suitable antioxidants include those described herein, including bisulfite 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 emulsifying agents include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating 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, sulfobutylether-β-cyclodextrin, and sulfobutylether-7-O-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

[0303] The pharmaceutical compositions disclosed herein can be formulated for single or multiple dose administration. Single dose formulations are packaged in ampoules, vials, or syringes. Multiple dose parenteral formulations must contain antimicrobial agents at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as is known and practiced in the art.

[0304] In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile solutions. In some embodiments, the pharmaceutical compositions are disclosed as sterile dry soluble products, including lyophilized powders and hypodermic tablets, which are reconstituted with a vehicle before use. In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile suspensions. In some embodiments, the pharmaceutical compositions are disclosed as sterile dry insoluble products, which are reconstituted with a vehicle before use. In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile emulsions.

[0305] The pharmaceutical composition can be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implanted depot. In some embodiments, the pharmaceutical composition disclosed herein is insoluble in body fluids but dispersed in a solid internal matrix surrounded by an outer polymer membrane that allows the active ingredient in the pharmaceutical composition to diffuse. The fatty acid salts of the compounds of Formulas (I) to (V) may be well suited to such dosage forms.

[0306] Suitable inner 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 esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[0307] Suitable outer polymeric membranes include polyethylene, polypropylene, ethylene-propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate copolymers with vinyl chloride, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers.

[0308] C. Topical administration The pharmaceutical compositions disclosed herein can be administered topically to the skin, orifices, or mucous membranes. The effect can be local or systemic. As described herein, topical administration includes, but is not limited to, conjunctival, intracorneal, intraocular, ophthalmic, otic, transdermal, nasal (e.g., intranasal), vaginal, urethral, ​​respiratory, and rectal administration.

[0309] The pharmaceutical compositions disclosed herein can be formulated in any dosage form suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, washes, sprays, suppositories, bandages, and skin patches. Topical formulations of the pharmaceutical compositions disclosed herein can contain the active ingredient, which can be mixed under sterile conditions with a pharmaceutically acceptable vehicle and any preservatives, buffers, absorption enhancers, and propellants that may be required. Liposomes, micelles, microspheres, nanosystems, and mixtures thereof can also be used.

[0310] Pharmaceutically acceptable vehicles (e.g., carriers and excipients) suitable for use in the topical formulations disclosed herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, cryoprotectants, thickening agents, and inert gases.

[0311] The ointments, pastes, creams, and gels may contain, in addition to the active ingredient, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0312] Powders and sprays can contain, in addition to the active ingredient, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays, such as those used for nasal (intra)nasal administration, can additionally contain customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0313] Transdermal delivery devices (e.g., patches) may also be used. Such dosage forms have the additional advantage of providing controlled delivery of the active ingredient to the body. That is, a compound of the present disclosure (e.g., a compound of Formulas (I) to (V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof) can be administered via a transdermal patch at a steady-state concentration, thereby gradually administering the active ingredient over time and avoiding drug spikes and adverse events / toxicity associated with the active ingredient.

[0314] The transdermal patch dosage forms herein may be formulated with various amounts of active ingredient depending on the disease / condition being treated, the active ingredient used, the permeability and size of the transdermal delivery device, the release period, etc. For example, when formulated with a compound of Formulas (I)-(V), a unit dose preparation may be varied or adjusted from, 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, 55 mg of a compound of Formulas (I)-(V) (based on the active form), or otherwise varied or adjusted as may be deemed appropriate using reasonable medical judgment according to the particular application and potency of the compound.

[0315] Transdermal patches formulated with the disclosed compounds may be suitable for microdosing or non-psychotropic (also referred to herein as non-psychotropic) administration to achieve long-term therapeutic benefit with reduced toxicity. In some embodiments, a compound of Formulas (I)-(V) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof is administered via a transdermal patch at non-psychotropic (yet potentially serotonergic) concentrations for an extended period of time, such as, for example, 8, 24, 48, 72, 84, 96, or 168 hours.

[0316] In addition to the active ingredient(s) and optional pharmaceutically acceptable vehicle, a transdermal patch may comprise one or more of a pressure-sensitive adhesive layer, a backing, and a release liner, as known to those of ordinary skill in the art.

[0317] A transdermal patch dosage form can be prepared by dissolving or dispersing the compound of the present disclosure in a suitable medium. In some embodiments, the compound of the present disclosure may be directly dissolved / dispersed in a polymer matrix forming a pressure-sensitive adhesive layer. Such a transdermal patch is called a drug-in-adhesive (DIA) patch. A preferred DIA patch form 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 comprising the active ingredient and the polymer matrix that is separate from the pressure-sensitive adhesive layer. In either case, the compound of the present disclosure may optionally be formulated with a suitable vehicle, such as a carrier substance, a penetration agent / absorption enhancer, a moisturizer / crystallization inhibitor, etc. It may also be optionally formulated to increase flux across the skin.

[0318] Examples of carrier agents include C8-C12 fatty acids such as oleic acid, undecanoic acid, valeric acid, heptanoic acid, pelargonic acid, capric acid, lauric acid, and eicosapentaenoic acid. 22 Fatty acids; C8-C such as octanol, nonanol, oleyl alcohol, decyl alcohol, and lauryl alcohol 22 Fatty alcohols; C8-C such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate 22 Lower alkyl esters of fatty acids; C6-C such as diisopropyl adipate 22 Di(lower) alkyl esters of diacids; C8-C such as glyceryl monolaurate 22These include, but are not limited to, monoglycerides of fatty acids; tetrahydrofuryl alcohol polyethylene glycol ethers; polyethylene glycol, propylene glycol; 2-(2-ethoxyethoxy)ethanol; diethylene glycol monomethyl ether; alkyl aryl ethers of polyethylene oxide; polyethylene oxide monomethyl ether; polyethylene oxide dimethyl ether; glycerol; ethyl acetate; acetoacetate esters; N-alkylpyrrolidones; cyclodextrins such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or derivatives such as 2-hydroxypropyl-β-cyclodextrin; and terpenes / terpenoids such as limonene, linalool, myrcene, pinenes such as α-pinene, caryophyllene, citral, eucoliptol, and mixtures thereof.

[0319] Examples of permeation agents / absorption enhancers include, but are not limited to, sulfoxides such as dodecyl methyl sulfoxide, octyl methyl sulfoxide, nonyl methyl sulfoxide, decyl methyl sulfoxide, undecyl methyl sulfoxide, 2-hydroxydecyl methyl sulfoxide, 2-hydroxy-undecyl methyl sulfoxide, 2-hydroxydodecyl methyl sulfoxide; surfactant-lecithin organogel (PLO) formed from an aqueous phase having one or more of poloxamer, CARBOPOL, and PEMULEN, an oily phase formed from one or more of isopropyl palmitate and PPG-2 myristyl ether propionate, and lecithin; fatty acids, esters, and alcohols such as oleic acid and oleyl alcohol; keto acids such as levulinic acid; glycols and glycol ethers, for example, diethylene glycol monoethyl ether; including mixtures thereof.

[0320] Examples of humectants / crystallization inhibitors include, but are not limited to, polyvinylpyrrolidone-co-vinyl acetate, HPMC, polymethacrylate, and mixtures thereof.

[0321] The pressure-sensitive adhesive layer may be formed from polymers including, but not limited to, acrylics (polyacrylates including alkyl acrylics), polyvinyl acetate, 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 patches of the present disclosure may be formed from an acrylic polymer pressure-sensitive adhesive, preferably an acrylic copolymer pressure-sensitive adhesive. The acrylic copolymer pressure-sensitive adhesive may be obtained by copolymerization of one or more alkyl(meth)acrylates (e.g., 2-ethylhexyl acrylate); aryl(meth)acrylates; arylalkyl(meth)acrylates; and (meth)acrylates with functional groups 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), optionally with one or more copolymerizable monomers (e.g., vinylpyrrolidone, vinyl acetate, etc.). Specific examples of acrylic pressure-sensitive adhesives may 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.

[0322] The backing used in the transdermal patch of the present disclosure may include flexible backings such as films, nonwoven fabrics, Japanese paper, woven cotton fabrics, knitted fabrics, woven fabrics, and laminated composites of nonwoven fabrics and films. Such backings are preferably constructed of soft materials that can closely contact the skin and conform to the skin's movements, and materials that can prevent skin rashes and other discomfort after prolonged use of the patch. Examples of backing materials include, but are not limited to, 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. In order to prevent the adsorption and release of the active ingredient, improve the percutaneous absorption of the active ingredient, and prevent skin rashes and other discomfort, the backing preferably comprises one or more layers made of the above-mentioned materials and having water vapor permeability.Specific examples of the backing may include, but are not limited to, 3M COTRAN products such as 3M COTRAN ethylene vinyl acetate membrane film 9702, 3M COTRAN ethylene vinyl acetate membrane film 9716, 3M COTRAN polyethylene membrane film 9720, and 3M COTRAN ethylene vinyl acetate membrane film 9728.

[0323] The release liner used in the transdermal patch of the present disclosure may include, but is not limited to, polyester film with 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 easy removal of the transdermal patch from the package. Examples of release liners 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.

[0324] Other layers may also be used, such as an abuse-deterrent layer formulated with one or more irritants (eg, sodium lauryl sulfate, poloxamer, sorbitan monoester, glyceryl monooleate, spices, etc.).

[0325] The methods disclosed herein using transdermal patch dosage forms provide systemic delivery of low amounts of active ingredient, preferably over extended periods of time, for example, up to 168 hours, such as 2-96 hours, or 4-72 hours, or 8-24 hours, or 10-18 hours, or 12-14 hours. In particular, the compounds of Formulae (I)-(V) can be delivered in low, stable, and consistent doses, so as to avoid harmful or undesirable side effects. In some embodiments, the compounds of Formulae (I)-(V) are administered transdermally at non-hallucinogenic (yet potentially serotonergic) concentrations.

[0326] Exemplary drug-in-adhesive (DIA) patch formulations may each comprise, based on the total weight of the DIA patch formulation, 5-30 wt. % of a compound of Formulas (I)-(V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof; 30-70 wt. % of a pressure-sensitive adhesive (e.g., DURO-TAK 387-2052, DURO-TAK 87-2677, and DURO-TAK 87-4098); 1-10 wt. % of a permeation / absorption enhancer (e.g., oleyl oleate, oleyl alcohol, levulinic acid, diethylene glycol monoethyl ether, etc.); and 5-35 wt. % of a crystallization inhibitor (e.g., polyvinylpyrrolidone-co-vinyl acetate, HPMC, polymethacrylic acid, etc.), although it will be understood that many variations are possible in light of the teachings herein.

[0327] The automatic injection device provides a method of delivering the compositions disclosed herein to a patient. The compositions disclosed herein may be administered to a patient using an automatic injection device via several known devices, a non-limiting list of which includes transdermal, subcutaneous, and intramuscular delivery.

[0328] 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 a substance that is acceptable for absorption through the skin to deliver the composition to the patient. Typically, only substances that are easily absorbed through the outer layer of the skin may be delivered by such transdermal patch devices.

[0329] Other automatic injection devices disclosed herein are configured to provide increased skin permeability to improve delivery of the disclosed compositions. Non-limiting examples of structures used to increase permeability to improve movement of the compositions into, across, or into the 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 a fluid channel for delivering the disclosed compositions below the outer layer of the skin. Other devices disclosed herein include transdermal delivery via iontophoresis, sonophoresis, reverse iontophoresis, or a combination thereof, and other techniques known in the art for increasing skin permeability to facilitate drug delivery.

[0330] Pharmaceutical compositions may also be administered locally by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection, e.g., POWDERJECT™ (Chiron Corp., Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, Oreg.).

[0331] The pharmaceutical compositions disclosed herein can be in the form of ointments, creams, and gels.Suitable ointment vehicles include, for example, oily or hydrocarbon vehicles, including lard, benzoated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifying or absorbing vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removing vehicles, such as hydrophilic ointments; water-soluble ointment vehicles, including polyethylene glycols of various molecular weights; emulsion vehicles, either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollients, but generally require the addition of antioxidants and preservatives.

[0332] Suitable cream bases can be oil-in-water or water-in-oil. Cream vehicles are water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also called the "internal" phase, is generally composed of petrolatum and fatty acid alcohols such as cetyl or stearyl alcohol. The aqueous phase usually, but not necessarily, exceeds the oil phase in volume and generally contains a humectant. The emulsifier in a cream formulation can be a nonionic, anionic, cationic, or amphoteric surfactant.

[0333] Gels are semi-solid suspensions. Single-phase gels contain organic polymers dispersed substantially uniformly throughout the liquid carrier. Suitable gelling agents include cross-linked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, Carbopol®; hydrophilic polymers, such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulose-based polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a uniform gel, dispersants such as alcohol or glycerin can be added, or the gelling agent can be dispersed by grinding, mechanical mixing, and / or stirring.

[0334] The pharmaceutical compositions disclosed herein may be administered rectally, urethrally, vaginally, or perivaginally in the form of a suppository, pessary, bougie, poultice or cataplasm, paste, powder, dressing, cream, plaster, contraceptive, ointment, solution, emulsion, suspension, tampon, gel, foam, spray, or enema. These dosage forms can be prepared using conventional processes as described in Remington: The Science and Practice of Pharmacy (supra).

[0335] Rectal, urethral, ​​and vaginal suppositories are solids for insertion into bodily orifices; they are solid at normal temperatures but melt or soften at body temperature, releasing the active ingredient into the orifice. Pharmaceutically acceptable carriers for rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, that produce melting points near body temperature when formulated with the pharmaceutical compositions disclosed herein. Antioxidants described herein include bisulfite and sodium metabisulfite. Suitable vehicles include cocoa butter (theobroma oil), glycerinated gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow waxes, and appropriate mixtures of mono-, di-, and triglycerides of fatty acids; hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid; and glycerinated gelatin. Combinations of various vehicles may be used, including, but not limited to, cocoa butter (theobroma oil), glycerinated gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow waxes, and appropriate mixtures of mono-, di-, and triglycerides of fatty acids; hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid; and glycerinated gelatin. Rectal and vaginal suppositories may be prepared by compression or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

[0336] The pharmaceutical compositions disclosed herein may be administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solution, gels, intraocular inserts, and implants.

[0337] The pharmaceutical compositions disclosed herein may be administered intranasally. The pharmaceutical compositions may be disclosed in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to generate a fine mist, or nebulizer, either alone or in combination with a suitable propellant, 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. The pharmaceutical compositions may be disclosed as dry powders for inhalation, alone or in combination with an inert carrier, such as lactose or phospholipids; and as nasal drops. For intranasal use, the powder may contain a bioadhesive agent, including chitosan or cyclodextrin.

[0338] Solutions or suspensions for use in pressurized containers, pumps, sprays, atomizers, or nebulizers can be formulated to contain ethanol, aqueous ethanol, or a suitable substitute for dispersing, solubilizing, or sustaining the release of the active ingredients disclosed herein, a propellant as a solvent; and / or a surfactant such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0339] The pharmaceutical compositions disclosed herein may be micronized to a size suitable for delivery, such as about 50 microns or less, or about 10 microns or less, etc. Particles of such sizes may be prepared using comminution methods known to those skilled in the art, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0340] Capsules, blisters, and cartridges for use in inhalants or insufflators can be formulated to contain a powder mix of the pharmaceutical compositions disclosed herein; a suitable powder base such as lactose or starch; and a performance modifier such as l-leucine, mannitol, or magnesium stearate. Lactose can be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. Pharmaceutical compositions disclosed herein for inhalation / intranasal administration can further contain a suitable flavoring agent, such as menthol and levomenthol, or a sweetener, such as saccharin or saccharin sodium.

[0341] The pharmaceutical compositions disclosed herein for topical administration may be formulated to be immediate or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release.

[0342] D. Modified release The pharmaceutical compositions disclosed herein can be formulated as modified release dosage forms.As used herein, the term "modified release" refers to a dosage form in which the release rate or release location of the active ingredient is different from that of an immediate dosage form when administered by the same route.The pharmaceutical composition of modified release dosage form can be prepared using various modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof.The release rate of the active ingredient can also be modified by changing the particle size and polymorphism of the active ingredient.

[0343] 1. Matrix controlled release device The pharmaceutical compositions disclosed herein in modified release dosage forms may be prepared using matrix release-controlling devices known to those skilled in the art (see Takada et al., "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz ed., Wiley, 1999).

[0344] In one embodiment, the pharmaceutical compositions disclosed herein in modified controlled dosage form are formulated using a dissolving matrix device, which is a water-swellable, erodible, or soluble polymer, including synthetic polymers, natural polymers and derivatives, such as polysaccharides and proteins.

[0345] Materials useful for forming a dissolving matrix include chitin, chitosan, dextran, and pullulan; agar gum, gum arabic, karaya gum, locust bean gum, tragacanth gum, carrageenan, ghatti gum, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phospholipids, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and cellulosics, such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC). , hydroxypropyl cellulose (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 hydroxyethyl cellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm Copolymers of L-glutamic acid and ethyl-L-glutamic acid; degradable lactic acid-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, but are not limited to these.

[0346] In some embodiments, the pharmaceutical composition is formulated as a non-eluting matrix device. The active ingredient is dissolved or dispersed in an inert matrix and, upon administration, is released primarily by diffusion through the inert matrix. Materials suitable for use as a non-eluting matrix device 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 chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber. These include, but are not limited to, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, ethylene / vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer; and hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone, cross-linked partially hydrolyzed polyvinyl acetate, aliphatic compounds such as carnauba wax, microcrystalline wax, and triglycerides.

[0347] In a matrix controlled release system, the desired release kinetics can be controlled, for example, through the type of polymer used, the polymer viscosity, the particle size of the polymer and / or the active ingredient, the ratio of active ingredient to polymer, and other excipients or carriers in the composition.

[0348] The pharmaceutical compositions disclosed herein in modified-release dosage form 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.

[0349] 2. Osmotic Controlled Release Devices The pharmaceutical compositions disclosed herein in modified-release dosage forms can be manufactured using osmotic controlled release devices, including one-chamber systems, two-chamber systems, asymmetric membrane technology (AMT), and extruded core systems (ECS). Generally, such devices have at least two components: (a) a core containing the active ingredient, and (b) a semipermeable membrane with at least one delivery port that encapsulates the core. The semipermeable membrane controls the influx of water from an aqueous environment into the core during use, causing drug release by extrusion through the delivery port.

[0350] In addition to the active ingredient, the core of the osmotic device optionally includes an osmotic agent that generates a driving force for water transport from the environment of use into the core of the device. Water-swellable hydrophilic polymers, a type of osmotic agent, also referred to as "osmopolymers" and "hydrogels," 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, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0351] Another type of osmotic agent is an osmogen, which can absorb water and affect the osmotic pressure gradient across the barrier of the surrounding coating. 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.

[0352] Osmotic agents with different dissolution rates can be used to affect the rate at which the active ingredient is initially delivered from the dosage form. For example, amorphous sugars such as Mannogeme EZ (SPI Pharma, Lewis, Del.) can be used to provide more rapid delivery in the first few hours to produce a desired therapeutic effect immediately, with the remaining amount gradually and continuously released to maintain a desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient is released at a rate that replaces the amount of active ingredient that is metabolized and excreted.

[0353] The core may also include various other excipients and carriers described herein to enhance the performance of the dosage form or to facilitate stability or processing.

[0354] Materials useful for forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives that are water-permeable and water-insoluble at physiologically relevant pH, or susceptible to being rendered water-insoluble by chemical changes such as crosslinking. Examples of suitable polymers useful for forming the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta-glucan acetate, beta-glucan triacetate, acetaldehyde dimethyl acetate, locust bean gum triacetate, ethylene vinyl acetate, EC, PEG, PPG, PEG / PPG. copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters, poly(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0355] The semipermeable membrane may also be a hydrophobic microporous membrane whose pores are substantially gas-filled and not wetted by aqueous media but are permeable to water vapor, as disclosed in U.S. Patent No. 5,798,119. Such hydrophobic but water vapor-permeable membranes are typically made of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0356] Delivery ports on the semipermeable membrane can be formed after coating by mechanical or laser drilling. Delivery ports can be formed in situ by erosion of a plug of water-soluble material or by rupture of a thin section of the membrane over a core cavity. Additionally, delivery ports can be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patents 5,612,059 and 5,698,220.

[0357] The total amount and rate of release of the active ingredient can be substantially controlled via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

[0358] The osmotic controlled-release dosage form of the pharmaceutical composition may further comprise additional conventional excipients or carriers as described herein to facilitate performance or processing of the composition.

[0359] Osmotic controlled 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, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

[0360] In some embodiments, the pharmaceutical compositions disclosed herein are formulated as AMT controlled-release dosage forms comprising an asymmetric osmotic membrane coating a core containing the active ingredient and other pharmaceutically acceptable vehicles (e.g., excipients or carriers). The AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip-coating methods.

[0361] In some embodiments, the pharmaceutical compositions disclosed herein are formulated as ESC controlled-release dosage forms comprising an osmotic membrane coating a core comprising the active ingredient(s), hydroxyethyl cellulose, and other pharmaceutically acceptable excipients or carriers.

[0362] 3. Multiparticulate controlled release devices The pharmaceutical compositions disclosed herein in modified-release dosage forms can be manufactured as multiparticulate controlled-release devices comprising a multiplicity of particles, granules, or pellets ranging in diameter from about 10 μm to about 3 mm, from about 50 μm to about 2.5 mm, or from about 100 μm to about 1 mm. Such multiparticulates can be manufactured by processes known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller compaction, melt congealing, and by spray coating seed cores. See, e.g., Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994, and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

[0363] Other excipients or carriers described herein may be blended with the pharmaceutical composition to aid in the processing and formation of the multiparticulates. The resulting particles themselves may constitute the multiparticulate device, or they may be coated with various film-forming materials, such as enteric polymers, water-swellable polymers, and water-soluble polymers. The multiparticulates can be further processed as capsules or tablets.

[0364] 4. Targeted delivery The pharmaceutical compositions disclosed herein can also be formulated to target specific tissues, receptors, or other areas of the body of the subject being treated, including using liposomes, resealed red blood cells, and antibody-based delivery systems.

[0365] E. Inhalation Administration The pharmaceutical compositions disclosed herein can be formulated for inhalation administration, e.g., pulmonary absorption. Suitable preparations may include the liquid form 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, optionally containing a buffer, and can 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 composition can be formulated as a dry powder for inhalation, alone or in combination with an inert carrier such as lactose or phospholipids.

[0366] The pharmaceutical compositions may be in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as a nebulizer that uses electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as a hydrofluoroalkane such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoromethane, 1,1,1,2-tetrafluoroethane (HFA 134A) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), carbon dioxide, perfluorinated hydrocarbons such as perflubron, and other suitable gases.

[0367] Aqueous solutions suitable for inhalation use can be prepared by dissolving a compound of Formulas (I)-(V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, in water or other water-based medium. Suitable stabilizers and thickeners may also be added. Emulsions suitable for inhalation use can be made by solubilizing a compound of Formulas (I)-(V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, in an aqueous medium and dispersing the solubilized form in a hydrophobic medium, optionally with the aid of viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other suspending agents.

[0368] Solutions or suspensions for use in pressurized containers, pumps, sprays, atomizers, or nebulizers may be formulated to contain a surfactant or other suitable cosolvent, or a suitable substitute for dispersing, solubilizing, or sustained-release of the active ingredients disclosed herein, and optionally a propellant. Such surfactants or cosolvents may include, but are not limited to, polysorbates 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 cosolvents may optionally be used at concentrations of about 0.01% to about 2% by weight of the pharmaceutical composition. Viscosities greater than those of simple aqueous solutions may be desirable in some cases to reduce variability in dispensing the formulation, reduce physical separation of emulsion components of the formulation, and / or otherwise improve formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations of the above. Such agents, if desired, are typically used at a concentration of about 0.01% to about 2% by weight of the pharmaceutical composition.

[0369] The compounds of the present disclosure can also be dissolved in an organic solvent or an aqueous mixture of organic solvents. The organic solvent can be, for example, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloromethane, dichloromethane, 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. The organic solvent can belong to a functional group category, such as an ester solvent, a ketone solvent, an alcohol solvent, an amide solvent, an ether solvent, or a hydrocarbon solvent, and each can be used.

[0370] The compounds of the present disclosure (e.g., compounds of Formulas (I)-(V)) can be delivered as an aerosol, preferably a mist, via inhalation for systemic administration to a patient's central nervous system. Preferably, the aerosol is generated without external heat (this does not exclude a slight temperature increase caused by the formation of the aerosol itself, such as by a vibrating mesh or other nebulizer; however, such a slight temperature increase can often be offset by vaporization of the agent, resulting in cooling of the composition). The compounds of the present disclosure can be delivered as an aerosol, preferably a mist, with a carrier gas, such as air, oxygen, or a mixture of helium and oxygen, or other gas mixtures, including therapeutic gas mixtures. The carrier gas, e.g., air, oxygen, a mixture of helium and oxygen, or other gases and gas mixtures, can 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 the carrier, the helium can be present in the mixture of oxygen and helium at about 50%, 60%, 70%, 80%, or 90% by volume, and the oxygen can be present in the mixture at about 50%, 40%, 30%, or 10% by volume, or any range therebetween.

[0371] Inhalation delivery can further include administering a pretreatment inhalation regimen prior to administration of the aerosol containing a compound of Formulas (I)-(V). The pretreatment can 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 therebetween. For example, an inhalation procedure can include (i) administering to the patient via inhalation a mixture of helium and oxygen heated to about 90°C to about 120°C, followed by (ii) administering to the patient via inhalation a mixture of helium and oxygen heated to about 50°C to about 60°C and a compound of Formulas (I)-(V), and then repeating steps (i) and (ii). Steps (i) and (ii) may be repeated 1, 2, 3, 4, 5, or more times.

[0372] In some embodiments, compounds of the present disclosure (e.g., compounds of Formulas (I)-(V)) can be administered via aerosol inhalation at doses of about 1 μg to about 200 mg or more (or any range between about 1 μg and about 200 mg) per inhalation session, e.g., about 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, 220 μg, 230 μg, 240 μg, 250 μg, 260 μg, 270 μg, 280 μg, 290 μg, 300 μg, 310 μg, 320 μg, 330 μg, 340 μg, 350 μg, 360 μg, 370 μg, 380 μg, 390 μg, 400 μg, 410 μg, 420 μg, 430 μg, 440 μg, 450 μg, 460 μg, 470 μg, 480 μg, 490 μg, 500 μg, 510 μg, 520 μg, 530 μg, 540 μg, 550 μg, 560 μg, 570 μg, 580 In some embodiments, a dose of 00 μg, 210 μg, 220 μg, 230 μg, 240 μg, 250 μg, 260 μg, 270 μg, 280 μg, 290 μg, 300 μg, 400 μg, 500 μg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10.0 mg, 20.0 mg, 30.0 mg, 40.0 mg, 50.0 mg, 60.0 mg, 70.0 mg, 80.0 mg, 90.0 mg, 100.0 mg, 150.0 mg, 200.0 mg, or more can be administered. In some embodiments, a subject can have 1, 2, 3, 4, 5, or more inhalation sessions per day. In some embodiments, a subject may have 1, 2, 3, 4, 5, or more inhalation sessions every other day, once a week, twice a week, or three times a week. In some embodiments, a subject may have 1, 2, 3, 4, 5, or more inhalation sessions every other month, twice a month, three times a month, or four times a month. In some embodiments, a subject may have 1, 2, 3, 4, 5, 6, 7, 8, or more inhalation sessions per treatment course, such as within a 28-day period.

[0373] 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 can be delivered at room temperature or heated. In some embodiments, aerosols, preferably mists containing compounds of Formulas (I)-(V), are delivered via inhalation using a heated helium-oxygen (HELIOX) mixture. Due to the very low viscosity of helium, the helium and oxygen mixture produces a gas flow characterized by laminar flow, a highly desirable feature for reaching the deep lung region and reducing drug deposition in the airways, one of the major obstacles to dose delivery via inhalation. Patients can inhale the dissolved compounds disclosed herein as mists into the alveolar region of their lungs. The compounds of Formulas (I)-(V) can then be delivered to the fluid lining of the alveolar region of the lungs and systemically absorbed into the patient's blood circulation. Advantageously, these formulations can be effectively delivered to the bloodstream when inhaled into the alveolar region of the lungs.

[0374] Suitable devices for delivery of heated or unheated carrier gas (e.g., air, oxygen, or helium-oxygen mixtures) include, for example, continuous mode nebulizers Flo-Mist (Phillips) and Hope (B&B Medical Technologies), as well as accessories such as regulators for the Medipure™ Heliox-LCQ System (PraxAir) and control boxes for the Precision Control Flow (PraxAir). In some embodiments, the complete delivery device can be, for example, a device described in Russian Patent No. RU199823U1.

[0375] As used herein, the term "heliox" refers to a mixture of helium gas (He) and oxygen gas (O 2)Heliox refers to a mixture of respiratory gases. In some embodiments, a heliox mixture may contain helium in a mixture of helium and oxygen at about 50%, 60%, 70%, 80%, or 90% by volume, and oxygen in a mixture of helium and oxygen at about 50%, 40%, 30%, or 10% by volume, or any range therebetween. Thus, a heliox mixture may contain helium and oxygen in a volume ratio of 50:50, 60:40, 70:30, 80:20, 90:10, or any range therebetween. In some embodiments, heliox may create less resistance with the airways due to increased tendency for laminar flow and decreased resistance in turbulent flow.

[0376] The use of heat in heliox mixtures can further improve drug delivery by increasing the permeability of important physical barriers for drug absorption. Heating mucosal surfaces can increase permeability by improving peripheral blood circulation and relaxing interstitial junctions and other mechanisms. Helium has a thermal conductivity nearly 10 times higher than oxygen and nitrogen, which can promote heat transfer more efficiently. Dry heliox mixtures can be safely used as a pretreatment step when heated up to 110°C, allowing them to more efficiently heat the mucosal surfaces of the lungs and airways.

[0377] Various types of personal inhalers are known in the art. Generally, personal inhalers are characterized by heating a solid medicament or compound. Inhalers can function by directly heating the solid medicament or compound to the smoldering point. Vaporization of the solid or solid concentrate can be achieved by convection or conduction. Convection heating of the solid concentrate involves a heating element in contact with water or another liquid, which then vaporizes. The hot steam directly heats the solid or solid concentrate to smolder, releasing a vapor that is inhaled by the user. Conductive heating involves direct contact between the solid or solid concentrate and a heating element, which brings the solid to the smoldering point, releasing a vapor that is inhaled by the user. While inhalers offer advantages over smoking in terms of lung injury, the vaporized medicament / active ingredient can be significantly degraded by the heat of vaporization.

[0378] In some embodiments, the compounds of Formulas (I)-(V) are delivered via a nebulizer that generates an aqueous droplet aerosol, preferably a mist, containing the compound, optionally combined with a heated helium-oxygen mixture. In some embodiments, the disclosed compounds are delivered via a nebulizer that generates an aqueous droplet aerosol, preferably a mist, containing the compound, which is combined with a drive gas comprising nitrous oxide. The drive gas comprising nitrous oxide can be nitrous oxide gas itself or a therapeutic gas mixture, such as an NO-O mixture or an NO-air mixture. The therapeutic gas mixture can further include other gases, such as one or more of N, Ar, CO, Ne, CH, He, Kr, H, Xe, HO (e.g., vapor), and the like. In some embodiments, the driving gas is a therapeutic gas mixture comprising NO, which is present in a concentration of 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 therebetween, based on 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, providing the ability to use lower doses thereof to achieve a similar level of effect.

[0379] For example, a preparation of a compound of Formulas (I)-(V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, can be placed in a liquid medium and aerosolized by a device such as a nebulizer. In some embodiments, the nebulizer can be, for example, an air compressor nebulizer, an ultrasonic nebulizer, a vibrating mesh or horn nebulizer, or a microprocessor-controlled breath-actuated nebulizer. In some embodiments, the nebulizer device can be, for example, a device described in Russian Patent No. RU199823U1.

[0380] A nebulizer is a device that converts a drug, such as a compound of Formulas (I)-(V), in solution or suspension into a fine aerosol, such as a mist, for delivery to the lungs. A nebulizer may also be referred to as a nebulizer. Nebulization refers to the process of dissolving a dissolved drug into an aerosol form, such as a mist. To deliver a drug by nebulization, the drug can be dispersed in a liquid medium, such as water, ethanol, or propylene glycol. Furthermore, the disclosed compounds can be carried in vehicles such as liposomes, polymers, emulsions, micelles, nanoparticles, or polyethyleneimine (PEI). Liquid drug formulations for nebulizers can be, for example, aqueous or viscous solutions. After applying a dispersing force (e.g., a gas jet, ultrasound, or mesh vibration), the dissolved drug is contained within droplets, which are then inhaled. The mist can include droplets containing the drug in air or another gas mixture (e.g., a mixture of helium and oxygen).

[0381] Jet nebulizers (also called air nebulizers or compressor nebulizers) use compressed gas to generate mist. In some embodiments, jet nebulizers are microprocessor-controlled, breath-activated nebulizers, also called breath-activated nebulizers. Breath-activated nebulizers do not produce mist continuously, but only when the patient inhales. Mist can be generated, for example, by passing airflow through a Venturi tube in the nebulizer bowl or cup. A Venturi tube is a system for speeding up fluid flow by compressing the fluid into a cone-shaped tube. At this limit, the fluid must increase its velocity, thereby reducing its pressure and creating a partial vacuum. Once the fluid leaves 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, generating a stream of atomized droplets that then flow to the mouthpiece. As the airflow increases, particle size decreases and output increases. Due to droplets and solvent saturating the emitted gas, jet nebulizers can cool the drug solution in the nebulizer and increase the solute concentration in the residual volume. Baffles in the nebulizer bowl or cup can be affected by larger particles, retaining them and returning them to the solution in the nebulizer bowl or cup for reparticle re-atomization. Air entrainment through the nebulizer bowl as the subject inhales can increase the amount of mist produced during inspiration. Mist generation is more likely with a narrower particle size distribution, but the smaller the particle size used, the longer the nebulization time.

[0382] A commonly used unit of measure for droplet size is the mass median diameter (MMD), which is defined as the average droplet diameter by mass. This unit may also be referred to as the mass mean aerodynamic diameter, or MMAD. The MMD droplet size of a jet nebulizer can be about 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 greater (or any range between about 1.0 and 10.0 μm), which can be smaller than that of an ultrasonic nebulizer.

[0383] Ultrasonic nebulizers generate mist using the vibration of a piezoelectric crystal, which converts an alternating current into high-frequency (about 1 to about 3 MHz) acoustic energy. The solution is broken down into droplets on a surface, and the resulting mist is either drawn from the device by the patient's inhalation or pushed 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 with ultrasonic nebulizers than with jet nebulizers. The MMD droplet size of ultrasonic nebulizers can be about 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 greater (or any range between about 2.0 and 10.0 μm). Ultrasonic nebulizers can produce a high density mist having droplets of about 100, 150, 200, 250, 300 μm / L or more.

[0384] Mesh nebulizer devices 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, vibrating a precisely drilled mesh in contact with the drug solution to generate 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 nebulized, and the vibration forces the liquid through the holes, generating a mist of small droplets. Passive mesh nebulizers generate mist using a transducer horn that induces passive vibrations in a perforated plate with tapered holes. Examples of active mesh nebulizers include the Aeroneb® (Aerogen, Galway, Ireland) and the eFlow® (PARI, Starnberg, Germany), while the Microair NE-U22® (Omron, Bannockburn, IL) is a passive mesh nebulizer. Mesh nebulizers are precise and customizable. By changing the pore size of the mesh, the device can be adjusted for use with drug solutions of different viscosities, resulting in different output rates. Using this nebulization method can offer several advantages. Because droplet size can be determined by the size of the holes in the mesh (which can be customized for the application), droplet size can be extremely precise. Nebulizer meshes can be manufactured using methods such as electrodeposition, electroplating, and laser cutting to generate liquid particles in a gas within the respirable range. The mesh can be made from a metal alloy. Metals used in mesh manufacturing can include platinum, palladium, nickel, and stainless steel. The droplet size is approximately twice the size of the mesh holes. Thus, the mesh holes can be about 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 about 0.1 and 5.0 μm). Mesh generation in mesh nebulizers can also vary based on the shape of the mesh, the material from which the mesh is made, and the method by which the mesh is generated.In other words, different meshes can produce different sizes of droplets suspended in the gas. Generally, the MMD droplet size of a mesh nebulizer can be about 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 micrometers or more (or any value between about 1.0 and 7.0 micrometers).

[0385] Furthermore, droplet size can be programmable. In particular, geometric changes can be made to the nebulizer to provide a specific desired droplet size. Furthermore, droplet size can be controlled independently of droplet velocity. The volume of nebulized 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. Mesh nebulizers can be powered either electrically or by batteries.

[0386] The rate of mist output in standing cloud mL per minute (for any nebulization method described herein) can 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 about 0.1 and 0.9 mL / min), and the residual volume of any type of nebulizer reservoir can be in the range of about 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 about 0.01 and 2.0 mL). Precise droplet size control can be advantageous because droplet size can be directly correlated to kinetic drug release (KDR). Precise control of KDR can be achieved by precise control of droplet size. The compounds herein can be delivered via mist using any method with an MMD droplet size of about 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 greater (or any range between about 0.5 and 10.0 μm).

[0387] In some embodiments, the compounds of Formulae (I)-(V) can be delivered via a continuous positive airway pressure (CPAP) or other pressure-assisted breathing device. Pressure-assisted breathing devices push a continuous column of compressed air or other gas at a fixed, specified pressure against the face and nose of a patient wearing a mask or nose cap. As the patient's glottis opens to inhale, pressure is transmitted across the airway, helping to open it. As the patient exhales, pressure from the contracting lungs and chest wall pushes air against the continuous pressure until the two pressures equalize. At the end of exhalation, the air pressure within the airway equals the external air pressure of the machine, thereby "supporting" the airway and helping to open it, allowing for better oxygenation and airway maintenance. Pressure-assisted breathing devices can be coupled with a means for introducing mist particles into the gas flow within the breathing circuit and / or a means for ceasing the introduction of mist particles into the breathing circuit when the patient exhales. See, e.g., U.S. Pat. No. 7,267,121.

[0388] In some embodiments, the mist can be delivered by a device such as a metered dose inhaler (MDI) (also referred to as a pressurized metered dose inhaler or pMDI), which generates an organic solvent-droplet mist containing a compound of Formulas (I)-(V) combined with an optionally heated helium-oxygen mixture. In some embodiments, the compound can be delivered via an MDI, which is a metered dose inhaler. The MDI device can include a canister containing a compound of Formulas (I)-(V) and a propellant, a metering valve that dispenses the medication from the canister, an actuator body that receives the canister and forms an opening for oral inhalation, and an actuator stem that receives the medication from the canister and directs it out an opening in the actuator body. A non-limiting example of a metering valve and actuator is the Bespak BK357 valve and actuator (opening d=0.22 mm) by Recipharm. By moving the medication canister relative to the actuator body and actuator stem, the metering valve releases a predetermined amount of medication. In some embodiments, a compound of Formulae (I)-(V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, may be dissolved in a liquid propellant mixture (which may contain a small amount of volatile organic solvent) stored in a pressurized container of an MDI. A "metered dose" is a dose prepackaged in a single-dose inhaler or a dose automatically measured from a reservoir by a multi-dose inhaler in preparation for inhalation. MDI devices may be spacer-assisted. An MDI spacer is a spacer interposed between the MDI and the mouth of the MDI user. The MDI spacer allows a small amount of nebulized dose droplets to settle and mix with air or other gases, thus allowing for more effective delivery of the metered dose into the user's lungs upon inhalation. The MDI spacer helps prevent the user from inhaling a metered dose directly from the MDI, which can travel so fast that droplets of the atomized spray from the MDI hit the back of the user's throat and stick, rather than being inhaled into the user's lungs where the metered dose is designed to be delivered. MDI devices offer the advantage of regular dosing, which can be controlled by the manufacture of the medication.

[0389] Drugs can also be delivered by dry powder inhalers (DPIs). In such DPI devices, the drug itself forms a powder, or the powder can be formed from pharmaceutically acceptable excipients or carriers, and the drug is releasably bound to the surface of the carrier powder so that, upon inhalation, moisture in the lungs releases the drug from the surface and makes it available for systemic absorption. In some embodiments, a compound of Formulas (I)-(V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, is delivered by use of a dry powder inhaler (DPI). Depending on the compound or form used, the drug can be formed into the required powder itself or releasably bound to the surface of the carrier powder. Such carrier powders are known in the art (see, e.g., H. Hamishehkar, et al., "The Role of Carrier in Dry Powder Inhaler," Recent Advances in Novel Drug Carrier Systems, 2012, pp. 39-66).

[0390] DPIs are typically formulated as a powder mixture of coarse carrier particles with an aerodynamic particle diameter of 1 to 5 μm and micronized drug particles (see, e.g., Iida, Kotaro, et al., "Preparation of dry powder inhalation by surface treatment of lactose carrier particles," Chemical and Pharmaceutical Bulletin 51.1 (2003): 1-5). Carrier particles are often used to improve the flowability of drug particles, thus improving dosing accuracy and minimizing dose variability observed with drug formulations alone, while making them easier to handle during manufacturing operations. Carrier particles must possess several characteristics, such as compatibility with the drug substance, physicochemical stability, biocompatibility, and biodegradability, and must be inert, available, and economical. The selection of carrier particles (both content and size) is well within the capabilities of those skilled in the art. Most common carrier particles are made from lactose or other sugars, with α-lactose monohydrate being the most common lactose grade used in such particulate carrier inhalation applications.

[0391] Delivery using helium-oxygen mixtures Systemic delivery of a compound of Formulas (I)-(V) can be achieved via inhalation of an aerosol containing the compound and a carrier gas, such as air, oxygen, helium, a mixture of helium and oxygen (i.e., a heliox mixture), other gases, or other gas mixtures. In some embodiments, the carrier gas can be heated. The method can further include using a device containing a balloon with an oxygen-helium mixture, equipped with a suppressor and a mask connected to each other by a gas or air connection tube, an additional heating element capable of heating the gas mixture to 120°C, a nebulizer with a vibrating porous plate or mesh through which droplets less than 5 microns in size can pass, and a disinfection device.

[0392] In some embodiments, compounds of Formulae (I)-(V) are delivered to the lower respiratory tract, e.g., to lung compartments such as the alveoli, alveolar ducts, and / or bronchioles. From there, the drug can enter the bloodstream and travel to the central nervous system. In some embodiments, inhalation of a mist can deliver compounds of Formulae (I)-(V) to a patient's CNS without passing through the liver. Administration via inhalation can allow gaseous drugs or those dispersed in a liquid or mist to be rapidly delivered to the bloodstream, bypassing first-pass metabolism. First-pass metabolism, also referred to as the "first-pass effect" or "pre-systemic metabolism," describes drugs that enter the liver and undergo extensive biotransformation.

[0393] In some embodiments, the present disclosure provides a therapeutic step in which a compound of Formulas (I)-(V) can be administered to a patient in need thereof by administering via inhalation a mixture of helium and oxygen heated to about 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, or higher (or any range between 50°C and 60°C) and the nebulized compound. In some embodiments, the mist or vapor of the compound can have a particle size of about 0.1 microns to about 10 microns (e.g., about 10, 5, 4, 3, 2, 1, 0.1, or less). In some embodiments, nebulization is performed via a nebulizer, which creates an inhalant that is a mist. In some embodiments, the nebulized compound is propelled along a patient delivery line by the patient's inhalation. In some embodiments, the nebulized compound is propelled along a patient delivery line by the patient's inhalation using a carrier gas. The carrier gas may be, inter alia, air, oxygen, a mixture of oxygen and helium, heated air, heated oxygen, or a mixture of heated helium and oxygen.

[0394] In some embodiments, a pretreatment step can be performed before the treatment step. In some embodiments, the pretreatment step can include first administering a pretreatment inhalation therapy before administering the mist of a compound of Formulas (I)-(V). In some embodiments, the pretreatment inhalation step can include (i) administering a temperature by inhalation at about 90°C, 91°C, 92°C, 93°C, 94°C, 95°C, 96°C, 97°C, 98°C, 99°C, 100°C, 101°C, 102°C, 103°C, 104°C, 105°C, 106°C, 107°C, 108°C, 109°C, 110°C, 111°C, 112°C, 113°C, 114°C, 115°C, 116°C, 117°C, 118°C, 119°C, 120°C, or or higher (or any range between about 90°C and 120°C), but no drug, and then (ii) administering a treatment step in which the air, oxygen, oxygen and helium mixture, heated air, heated oxygen, or heated helium and oxygen mixture is inhaled along with a nebulized compound of Formulas (I)-(V). The heated air, heated oxygen, or heated helium and oxygen mixture, in combination with a nebulized compound of the present disclosure, can be heated to about 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, or higher (or any range between about 50°C and 60°C).

[0395] In some embodiments of the present disclosure, the pre-treatment step (i) and the treatment step (ii) can be repeated 0, 1, 2, 3, 4, 5, or more times. In some embodiments of the present disclosure, steps (i) and (ii) can be repeated 0, 1, 2, 3, 4, 5, or more times, followed by a treatment step, which can be repeated 0, 1, 2, 3, 4, 5, or more times. In some embodiments of the present disclosure, the treatment step can be repeated 0, 1, 2, 3, 4, 5, or more times without a pre-treatment step.

[0396] Treatment with optional pretreatment can be administered once a week, twice a week, once daily, twenty-one times daily, three times daily, or more, a defined number of treatments per treatment course (e.g., 1, 2, 3, or 4 treatments per treatment course), or other treatment schedules described herein.

[0397] A drug delivery protocol may involve inhaling a priming non-drug, hot heliox mixture to effectively preheat the mucosal bed, followed by inhalation of a nebulized compound of the present disclosure, again driven by heated heliox, but at a lower temperature determined by the lower thermal tolerance to wet versus dry inhalation gas flow. As a result, this protocol may be performed in multiple repeated cycles, with target PK and drug exposure controlled by drug concentration, temperature, helium-oxygen mixture flow rate, mixture composition, number and duration of cycles, time of day, and combinations of the above.

[0398] Combination therapy with NMDA receptor antagonists Also, the compounds of formula (I) to (V) or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs thereof (5-HT 2A Also disclosed is a combination pharmacotherapy based on the administration of both a 5-HT receptor agonist (as a 5-HT receptor agonist) and an N-methyl-D-aspartate (NMDA) receptor antagonist. The combination pharmacotherapy may enhance the therapeutic efficacy of 5-HT receptor agonists by reducing or eliminating adverse psychotic effects such as acute hallucinogenic crises (frightening hallucinations) and hallucinogen-induced dissociative effects (out-of-body experiences). 2A and / or may enhance activity and improve patient experience when treating NMDA receptor-related diseases or disorders (e.g., neuropsychiatric diseases or disorders, central nervous system (CNS) disorders, psychological disorders, etc.).

[0399] Non-limiting examples of NMDA receptor antagonists include, but are not limited to, ketamine, nitrous oxide, memantine, amantadine, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), dizocilpine (MK-801), esmethadone, or combinations thereof. In particular, nitrous oxide (NO), commonly known as laughing gas, is a rapid, effective analgesic gas with fast acting effects and few side effects when administered under appropriate medical supervision. Nitrous oxide is also a dissociative inhalant known to induce euphoria during inhalation. Notable effects of nitrous oxide include increased euphoria, elevated pain threshold, and involuntary laughter. Furthermore, unlike ketamine, nitrous oxide is not addictive. For these reasons, the use of nitrous oxide as an NMDA receptor antagonist is preferred.

[0400] In some embodiments, the combination drug therapy involves providing a compound of Formulas (I)-(V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, and an NMDA receptor antagonist in a single dosage form for administration to a patient (e.g., each combined to provide a single aerosol inhaled by the patient, or each combined in a single transdermal patch and delivered transdermally or subcutaneously to the patient). For example, when the NMDA receptor antagonist is nitrous oxide, the compound of Formulas (I)-(V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, may be present in the liquid phase of the aerosol, while the nitrous oxide may be present in the gas phase of the aerosol. Nitrous oxide (or a therapeutic gas mixture containing nitrous oxide) may be used to generate the aerosol or may be used as a carrier gas used to deliver the generated aerosol to the patient. When the generated aerosol is combined with a carrier gas, the carrier gas becomes part of the gas phase of the aerosol; i.e., the liquid phase of the aerosol is entrained / diluted by the carrier gas. In some embodiments, the combination drug therapy involves providing a compound of Formulas (I)-(V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, and an NMDA receptor antagonist as separate dosage forms. For example, a compound of Formulas (I)-(V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, may be provided as an aerosol, preferably a mist, while the NMDA receptor antagonist is provided separately as a therapeutic gas mixture. Alternatively, the compounds of Formulae (I)-(V), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, or prodrugs thereof, may be provided as an injection (e.g., intravenous, intradermal, etc.), bolus, infusion, perfusion, etc., while the NMDA receptor antagonist is provided as a therapeutic gas mixture for inhalation delivery.

[0401] Compounds of formula (I) to (V) (5-HT 2AThe co-action of an NMDA receptor antagonist (as a 5-HT2R agonist) and an NMDA receptor antagonist (e.g., nitrous oxide, ketamine, etc.) can provide multiple benefits. For example, an NMDA receptor antagonist can control and / or reduce the effects of 5-HT2R activation, thereby reducing the risk of overstimulation and the occurrence of adverse psychotic effects such as acute hallucinatory crises. Furthermore, administration of an NMDA receptor antagonist can allow for the use of reduced therapeutic doses of the compounds of For...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, wherein: 【Chemical 1】 During the ceremony, X １ and X ２ are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y １ and Y ２ are independently selected from the group consisting of hydrogen and deuterium; R ２ is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R ４ is hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and —OPO ３ H ２ is selected from the group consisting of R ５ is hydrogen, deuterium, hydroxyl, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, unsubstituted alkoxy, alkoxy substituted with one or more deuterium atoms, unsubstituted alkylthio, alkylthio substituted with one or more deuterium atoms, -OR ｆ , and -SR ｆ is selected from the group consisting of R ６ and R ７ are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R ８ is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R ｆ is selected from the group consisting of R ９ is an unsubstituted alkyl, an alkyl substituted with one or more deuterium atoms, R ｆ , -S(O)R ｆ , and -S(O) ２ R ｆ is selected from the group consisting of Or, alternatively, R ８ and R ９ are optionally joined together with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine; and R ｆ is a fluoroalkyl group, and each R ｆ are independently -(CH ｘ ２ ) ｎ CH ２ F, -(CH ｘ ２ ) ｎ CHF ２ , and -(CH ｘ ２ ) ｎ CF ３ wherein n is 0 to 3; and each H ｘ are independently hydrogen or deuterium, R ５ , R ８ , and R ９ At least one of the groups is a fluoroalkyl group, R ｆ and / or R ８ and R ９ are joined together with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine; and However, (i) X １ , X ２ , Y １ , Y ２ , R ２ , R ４ , R ５ , R ６ , and R ７ is hydrogen, and R ８ is hydrogen or methyl, R ９ is -CH ２ CF ３ rather than (ii) X １ , X ２ , Y １ , Y ２ , R ２ , R ４ , R ５ , R ６ , and R ７ is hydrogen, R ８ and R ９ does not combine with the nitrogen atom to which it is attached to form a 4,4-difluoropiperidinyl group, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof.

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

3. R ２ The compound of claim 1 , wherein is hydrogen.

4. R ４ The compound of claim 1 , wherein is hydrogen.

5. R ４ The compound of claim 1 , wherein is hydroxyl.

6. R ５ is hydrogen, unsubstituted alkoxy, alkoxy substituted with one or more deuterium atoms, unsubstituted alkylthio, alkylthio substituted with one or more deuterium atoms, —OR ｆ , and -SR ｆ 2. The compound of claim 1 selected from the group consisting of:

7. R ５ The compound of claim 1 , wherein is hydrogen.

8. R ５ is an unsubstituted alkoxy, an alkoxy substituted with one or more deuterium atoms, and —OR ｆ 2. The compound of claim 1 selected from the group consisting of:

9. R ５ is an unsubstituted alkylthio, an alkylthio substituted with one or more deuterium atoms, and —SR ｆ 2. The compound of claim 1 selected from the group consisting of:

10. R ５ But, -OR ｆ or -SR ｆ 2. The compound of claim 1, wherein:

11. 11. The compound of claim 10, wherein n is 0.

12. R ６ and R ７ The compound of claim 1 , wherein is hydrogen.

13. R ８ is hydrogen or unsubstituted C １ -C ６ The compound of claim 1 , wherein the aryl group is alkyl.

14. R ８ But, R ｆ 2. The compound of claim 1, wherein:

15. H ｘ 15. The compound of claim 14, wherein is hydrogen and n is 2.

16. R ９ is unsubstituted C １ -C ６ The compound of claim 1 , wherein the aryl group is alkyl.

17. R ９ But, R ｆ 2. The compound of claim 1, wherein:

18. H ｘ 18. The compound of claim 17, wherein is hydrogen and n is 2.

19. R ９ But -S(O)R ｆ or -S(O) ２ R ｆ 2. The compound of claim 1, wherein:

20. 20. The compound of claim 19, wherein n is 0.

21. 【Chemical 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof.

22. 10. The compound of claim 1 having the structure of Formula (II), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof: 【Chemistry 11】 During the ceremony, X １ and X ２ are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y １ and Y ２ are independently selected from the group consisting of hydrogen and deuterium; R ８ is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R ｆ is selected from the group consisting of R ９ is an unsubstituted alkyl, an alkyl substituted with one or more deuterium atoms, R ｆ , -S(O)R ｆ , and -S(O) ２ R ｆ is selected from the group consisting of Or, alternatively, R ８ and R ９ are optionally joined together with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine; and R ｆ is a fluoroalkyl group, and each R ｆ are independently -(CH ｘ ２ ) ｎ CH ２ F, -(CH ｘ ２ ) ｎ CHF ２ , and -(CH ｘ ２ ) ｎ CF ３ wherein n is 0 to 3; and each H ｘ are independently hydrogen or deuterium, R ８ and R ９ At least one of the groups is a fluoroalkyl group, R ｆ or R ８ and R ９ are joined together with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine; and However, (i) X １ , X ２ , Y １ , and Y ２ is hydrogen, and R ８ is hydrogen or methyl, R ９ is -CH ２ CF ３ rather than (ii) X １ , X ２ , Y １ , and Y ２ is hydrogen, R ８ and R ９ does not combine with the nitrogen atom to which it is attached to form a 4,4-difluoropiperidinyl group.

23. X １ , X ２ , Y １ , and Y ２ 23. The compound of claim 22, wherein is hydrogen.

24. R ８ is hydrogen or unsubstituted C １ -C ６ 23. The compound of claim 22, wherein the compound is alkyl.

25. R ８ But, R ｆ 23. The compound of claim 22, wherein:

26. H ｘ 26. The compound of claim 25, wherein is hydrogen and n is 2.

27. R ９ But, R ｆ 23. The compound of claim 22, wherein:

28. H ｘ 28. The compound of claim 27, wherein is hydrogen and n is 2.

29. R ９ But -S(O)R ｆ or -S(O) ２ R ｆ 23. The compound of claim 22, wherein:

30. 30. The compound of claim 29, wherein n is 0.

31. [Catalog 12] 【Chemistry 13】 23. The compound of claim 22, selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof.

32. 10. The compound of claim 1 having the structure of Formula (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof: 【Chemistry 14】 During the ceremony, X １ and X ２ are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y １ and Y ２ are independently selected from the group consisting of hydrogen and deuterium; R ８ is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R ｆ is selected from the group consisting of R ９ is an unsubstituted alkyl, an alkyl substituted with one or more deuterium atoms, R ｆ , -S(O)R ｆ , and -S(O) ２ R ｆ is selected from the group consisting of Or, alternatively, R ８ and R ９ are optionally joined together with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine; and R ｆ is a fluoroalkyl group, and each R ｆ are independently -(CH ｘ ２ ) ｎ CH ２ F, -(CH ｘ ２ ) ｎ CHF ２ , and -(CH ｘ ２ ) ｎ CF ３ wherein n is 0 to 3; and each H ｘ are independently hydrogen or deuterium, R ８ and R ９ At least one of the groups is a fluoroalkyl group, R ｆ or R ８ and R ９ and the nitrogen atom to which they are attached together to form a heterocycloalkyl substituted with at least one fluorine.

33. X １ , X ２ , Y １ , and Y ２ 33. The compound of claim 32, wherein is hydrogen.

34. R ８ is hydrogen or unsubstituted C １ -C ６ 33. The compound of claim 32, which is alkyl.

35. R ８ But, R ｆ 33. The compound of claim 32, wherein:

36. H ｘ 36. The compound of claim 35, wherein is hydrogen and n is 2.

37. R ９ But, R ｆ 33. The compound of claim 32, wherein:

38. H ｘ 38. The compound of claim 37, wherein is hydrogen and n is 2.

39. R ９ But -S(O)R ｆ or -S(O) ２ R ｆ 33. The compound of claim 32, wherein:

40. 40. The compound of claim 39, wherein n is 0.

41. 【Catalog 15】 【Chemistry 16】 【Chemistry 17】 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof.

42. 10. The compound of claim 1 having the structure of Formula (IV), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof: 【Chemistry 18】 During the ceremony, X １ and X ２ are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y １ and Y ２ are independently selected from the group consisting of hydrogen and deuterium; R ５ is an unsubstituted alkoxy, an alkoxy substituted with one or more deuterium atoms, and —OR ｆ is selected from the group consisting of R ８ is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R ｆ is selected from the group consisting of R ９ is an unsubstituted alkyl, an alkyl substituted with one or more deuterium atoms, R ｆ , -S(O)R ｆ , and -S(O) ２ R ｆ is selected from the group consisting of Or, alternatively, R ８ and R ９ are optionally joined together with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine; and R ｆ is a fluoroalkyl group, and each R ｆ are independently -(CH ｘ ２ ) ｎ CH ２ F, -(CH ｘ ２ ) ｎ CHF ２ , and -(CH ｘ ２ ) ｎ CF ３ wherein n is 0 to 3; and each H ｘ are independently hydrogen or deuterium, R ５ , R ８ , and R ９ At least one of the groups is a fluoroalkyl group, R ｆ and / or R ８ and R ９ and the nitrogen atom to which they are attached together to form a heterocycloalkyl substituted with at least one fluorine.

43. X １ , X ２ , Y １ , and Y ２ 43. The compound of claim 42, wherein is hydrogen.

44. R ５ is unsubstituted C １ -C ６ 43. The compound of claim 42, which is an alkoxy group.

45. R ５ But, -OR ｆ 43. The compound of claim 42, wherein:

46. 46. ​​The compound of claim 45, wherein n is 0.

47. R ８ is hydrogen or unsubstituted C １ -C ６ 43. The compound of claim 42, which is alkyl.

48. R ８ But, R ｆ 43. The compound of claim 42, wherein:

49. H ｘ 49. The compound of claim 48, wherein is hydrogen and n is 2.

50. R ９ is unsubstituted C １ -C ６ 43. The compound of claim 42, which is alkyl.

51. R ９ But, R ｆ 43. The compound of claim 42, wherein:

52. H ｘ 52. The compound of claim 51, wherein is hydrogen and n is 2.

53. R ９ But -S(O)R ｆ or -S(O) ２ R ｆ 43. The compound of claim 42, wherein:

54. 54. The compound of claim 53, wherein n is 0.

55. 【Catalog 19】 【Chemistry 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemistry 24】 【Chemistry 25】 【Chemical 26】 【Chemical 27】 ​ 【Chemical Formula 29】 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof.

56. 10. The compound of claim 1 having the structure of Formula (V), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof: 【Chemistry 30】 During the ceremony, X １ and X ２ are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y １ and Y ２ are independently selected from the group consisting of hydrogen and deuterium; R ８ is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R ｆ is selected from the group consisting of R ９ is an unsubstituted alkyl, an alkyl substituted with one or more deuterium atoms, R ｆ , -S(O)R ｆ , and -S(O) ２ R ｆ is selected from the group consisting of Or, alternatively, R ８ and R ９ are optionally joined together with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine; and R ｆ is a fluoroalkyl group, and each R ｆ are independently -(CH ｘ ２ ) ｎ CH ２ F, -(CH ｘ ２ ) ｎ CHF ２ , and -(CH ｘ ２ ) ｎ CF ３ wherein n is 0 to 3; and each H ｘ are independently hydrogen or deuterium, R ８ and R ９ At least one of the groups is a fluoroalkyl group, R ｆ or R ８ and R ９ and the nitrogen atom to which they are attached together to form a heterocycloalkyl substituted with at least one fluorine.

57. X １ , X ２ , Y １ , and Y ２ 57. The compound of claim 56, wherein is hydrogen.

58. R ８ is hydrogen or unsubstituted C １ -C ６ 57. The compound of claim 56, which is alkyl.

59. R ８ But, R ｆ 57. The compound of claim 56, wherein:

60. H ｘ 60. The compound of claim 59, wherein is hydrogen and n is 2.

61. R ９ But, R ｆ 57. The compound of claim 56, wherein:

62. H ｘ 62. The compound of claim 61, wherein is hydrogen and n is 2.

63. R ９ But -S(O)R ｆ or -S(O) ２ R ｆ 57. The compound of claim 56, wherein:

64. 64. The compound of claim 63, wherein n is 0.

65. 【Catalog 31】 【Chemical 32】 【Chemical 33】 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof.

66. a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof, and a pharmaceutically acceptable vehicle, 【Chemical 34】 During the ceremony, X １ and X ２ are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y １ and Y ２ are independently selected from the group consisting of hydrogen and deuterium; R ２ is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R ４ is hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and —OPO ３ H ２ is selected from the group consisting of R ５ is hydrogen, deuterium, hydroxyl, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, unsubstituted alkoxy, alkoxy substituted with one or more deuterium atoms, unsubstituted alkylthio, alkylthio substituted with one or more deuterium atoms, -OR ｆ , and -SR ｆ is selected from the group consisting of R ６ and R ７ are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R ８ is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R ｆ is selected from the group consisting of R ９ is an unsubstituted alkyl, an alkyl substituted with one or more deuterium atoms, R ｆ , -S(O)R ｆ , and -S(O) ２ R ｆ is selected from the group consisting of Or, alternatively, R ８ and R ９ are optionally joined together with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine; and R ｆ is a fluoroalkyl group, and each R ｆ are independently -(CH ｘ ２ ) ｎ CH ２ F, -(CH ｘ ２ ) ｎ CHF ２ , and -(CH ｘ ２ ) ｎ CF ３ wherein n is 0 to 3; and each H ｘ are independently hydrogen or deuterium, R ５ , R ８ , and R ９ At least one of the groups is a fluoroalkyl group, R ｆ and / or R ８ and R ９ are joined together with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine.

67. 67. The pharmaceutical composition of claim 66, adapted for oral administration.

68. 1. A method of treating a subject having a disease or disorder, comprising: administering to a subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof; 【Chemistry 35】 During the ceremony, X １ and X ２ are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y １ and Y ２ are independently selected from the group consisting of hydrogen and deuterium; R ２ is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R ４ is hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and —OPO ３ H ２ is selected from the group consisting of R ５ is hydrogen, deuterium, hydroxyl, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, unsubstituted alkoxy, alkoxy substituted with one or more deuterium atoms, unsubstituted alkylthio, alkylthio substituted with one or more deuterium atoms, -OR ｆ , and -SR ｆ is selected from the group consisting of R ６ and R ７ are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R ８ is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R ｆ is selected from the group consisting of R ９ is an unsubstituted alkyl, an alkyl substituted with one or more deuterium atoms, R ｆ , -S(O)R ｆ , and -S(O) ２ R ｆ is selected from the group consisting of Or, alternatively, R ８ and R ９ are optionally joined together with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine; and R ｆ is a fluoroalkyl group, and each R ｆ are independently -(CH ｘ ２ ) ｎ CH ２ F, -(CH ｘ ２ ) ｎ CHF ２ , and -(CH ｘ ２ ) ｎ CF ３ wherein n is 0 to 3; and each H ｘ are independently hydrogen or deuterium, R ５ , R ８ , and R ９ At least one of the groups is a fluoroalkyl group, R ｆ and / or R ８ and R ９ are joined together with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine.

69. Serotonin 5-HT ２ 1. A method of treating a subject having a receptor-associated disease or disorder, comprising: administering to a subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, or prodrug thereof; 【Chemical 36】 During the ceremony, X １ and X ２ are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y １ and Y ２ are independently selected from the group consisting of hydrogen and deuterium; R ２ is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R ４ is hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and —OPO ３ H ２ is selected from the group consisting of R ５ is hydrogen, deuterium, hydroxyl, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, unsubstituted alkoxy, alkoxy substituted with one or more deuterium atoms, unsubstituted alkylthio, alkylthio substituted with one or more deuterium atoms, -OR ｆ , and -SR ｆ is selected from the group consisting of R ６ and R ７ are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R ８ is hydrogen, unsubstituted alkyl, alkyl substituted with one or more deuterium atoms, and R ｆ is selected from the group consisting of R ９ is an unsubstituted alkyl, an alkyl substituted with one or more deuterium atoms, R ｆ , -S(O)R ｆ , and -S(O) ２ R ｆ is selected from the group consisting of Or, alternatively, R ８ and R ９ are optionally joined together with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine; and R ｆ is a fluoroalkyl group, and each R ｆ are independently -(CH ｘ ２ ) ｎ CH ２ F, -(CH ｘ ２ ) ｎ CHF ２ , and -(CH ｘ ２ ) ｎ CF ３ wherein n is 0 to 3; and each H ｘ are independently hydrogen or deuterium, R ５ , R ８ , and R ９ At least one of the groups is a fluoroalkyl group, R ｆ and / or R ８ and R ９ are joined together with the nitrogen atom to which they are attached to form a heterocycloalkyl substituted with at least one fluorine.

70. 70. The method of claim 69, wherein the disease or disorder is a neuropsychiatric disease or disorder or an inflammatory disease or disorder.

71. 70. The method of claim 69, wherein the disease or disorder is a disorder of the central nervous system (CNS).

72. 72. The method of claim 71, wherein the disorder of the central nervous system (CNS) 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 disorders, eating disorders, Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset dysfluency disorder, severe neurocognitive disorder, mild neurocognitive disorder, suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), chronic fatigue syndrome, Lyme disease, gambling disorder, paraphilic disorder, sexual dysfunction, peripheral neuropathy, and obesity.

73. 72. The method of claim 71, wherein the central nervous system (CNS) disorder is major depressive disorder (MDD).

74. 72. The method of claim 71, wherein the central nervous system (CNS) disorder is treatment-resistant depression (TRD).

75. 72. The method of claim 71, wherein the central nervous system (CNS) disorder is generalized anxiety disorder (GAD).

76. 72. The method of claim 71, wherein the central nervous system (CNS) disorder is social anxiety disorder.

77. 72. The method of claim 71, wherein the central nervous system (CNS) disorder is obsessive-compulsive disorder (OCD).

78. 72. The method of claim 71, wherein the central nervous system (CNS) disorder is cluster headache or migraine.

79. 72. The method of claim 71, wherein the central nervous system (CNS) disorder is a substance use disorder.

80. 80. The method of claim 79, wherein the substance use disorder is alcohol use disorder.

81. 80. The method of claim 79, wherein the substance use disorder is nicotine use disorder.

82. 70. The method of claim 69, wherein the disease or disorder is a disease of the autonomic nervous system (ANS).

83. 70. The method of claim 69, wherein the disease or disorder is a pulmonary disorder.

84. 70. The method of claim 69, wherein the disease or disorder is a cardiovascular disorder.

85. 70. The method of claim 69, wherein the compound is administered orally to the subject.

86. 70. The method of claim 69, wherein the compound is administered to the subject orally.

87. 70. The method of claim 69, wherein the compound is administered to the subject at a hallucinogenic dose of about 0.083 mg / kg to about 5 mg / kg.

88. 88. The method of claim 87, wherein the compound is administered at the hallucinogenic dose no more than once a week over the course of treatment.

89. 70. The method of claim 69, wherein the compound is administered to the subject at a non-hallucinogenic dose of from about 0.00001 mg / kg to less than about 0.083 mg / kg.

90. 90. The method of claim 89, wherein the compound is administered at the non-hallucinogenic dose one or more times daily over the course of treatment.

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