3-Ethylamino-indole dimers as serotonergic agents useful in the treatment of serotonin-related disorders

Abstract

This application relates to 3-ethylamino-indole dimers of general formula I, processes for their preparation, compositions containing them, and their use in activating intracellular serotonin receptors, and to treating diseases, disorders, or conditions, such as psychoses, psychiatric disorders, and CNS disorders, by activating intracellular or cell surface serotonin receptors.

Description

[Technical Field]

[0001] (Related Applications) This application claims priority to co-pending U.S. Provisional Patent Application No. 63 / 395,499, filed August 5, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present application relates to 3-ethylamino-indole dimers of general formula I for the treatment of various pathologies treated by activation of serotonin receptors, such as psychiatric and neurological disorders, in the fields of psychiatry, neurobiology and pharmacotherapy. [Background technology]

[0003] Mental health disorders, or psychiatric illnesses, refer to a wide range of disorders, including but not limited to depressive disorders, anxiety and panic disorders, schizophrenia, eating disorders, substance misuse disorders, post-traumatic stress disorder, attention-deficit / hyperactivity disorder, and obsessive-compulsive disorder. Many mental health disorders and neurological disorders are affected by alterations, dysfunction, degeneration, and / or damage to the brain's serotonergic system, which may partially explain common endophenotypes and comorbidities in neuropsychiatric and neurological disorders.

[0004] The field of hallucinations neuroscience has recently re-emerged after decades of limited research due to legal restrictions. Hallucinogens (serotonergic hallucinogens) are potent psychoactive substances that alter perception and mood and affect numerous cognitive processes. Today, it is commonly understood that hallucinogens are agonists or partial agonists of the serotonin (5-hydroxytryptamine) 2A (5-HT2A) receptor.

[0005] Psychedelics have both immediate effects and long-lasting effects, including changes in mood and brain function. Long-lasting effects may be due to their unique receptor affinity (which influences neurotransmission through neuromodulator systems, which regulate brain activity, i.e., neuroplasticity and promote cell survival), providing neuroprotection and modulating the brain's neuroimmune system. The mechanisms underlying these long-term neuromodulator changes may be related to epigenetic modifications, changes in gene expression, and modulation of pre- and postsynaptic receptor density. These previously understudied psychedelics may offer the next generation of neurotherapeutics, potentially enabling treatments with a low pharmacological risk profile for treatment-resistant psychiatric and neurological disorders, such as depression, post-traumatic stress disorder, dementia, and addiction.

[0006] Although hallucinogens are generally perceived as dangerous, from a physiological safety perspective, they are one of the safest known classes of central nervous system (CNS) drugs. Preliminary data indicate that administration of hallucinogens to humans results in a unique profile of potential adverse responses that must be appropriately addressed to maximize efficacy and safety. Primary safety concerns are primarily psychological rather than physiological in nature. Physical effects vary, but are relatively minor, even at potent psychoactive doses. When administered in a controlled environment, psilocybin has often been reported to produce a transient, delayed headache with dose-related increases in incidence, duration, and severity [Johnson et al., Drug Alcohol Depend (2012) 123(1-3):132-140]. Repeated administration of hallucinogens has been found to result in the very rapid development of tolerance known as tachyphylaxis, a phenomenon thought to be partially mediated by 5-HT2A receptors. Indeed, several studies have shown that rapid tolerance to hallucinogens correlates with downregulation of 5-HT2A receptors. For example, daily administration of LSD selectively reduced 5-HT2 receptor density in the rat brain [Buckholtz et al., Eur. J. Pharmacol. 1990, 109:421-425. 1985; Buckholtz et al., Life Sci. 1985, 42:2439-2445].

[0007] Classical and dissociative hallucinogens are known to have rapid-onset antidepressant and anti-addictive effects unlike any currently available treatment. Randomized, controlled clinical trials have confirmed the antidepressant and anxiolytic effects of classical hallucinogens in humans.

[0008] Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) has the chemical formula C 12 H 17N2O4P, a tryptamine-based prodrug, is one of the major psychoactive components of the Shibiratake mushroom. It was first isolated from the Shibiratake mushroom by Hofmann in 1957 and later synthesized by him in 1958 [Passie et al. Addict Biol., 2002, 7(4):357-364] and was used in psychiatric and psychological research and psychotherapy from the early to mid-1960s until its scheduling as a controlled drug in the United States in the 1970s and in Germany in the 1980s [Passie 2005; Passie et al. Addict Biol., 2002, 7(4):357-364]. Research into the effects of psilocybin resumed in the mid-1990s, and it is now the preferred compound for use in studying the effects of serotonergic hallucinogens [Carter et al. J. Cogn. Neurosci., 2005 17(10):1497-1508; Gouzoulis-Mayfrank et al. Neuropsychopharmacology 1999, 20(6):565-581; Hasler et al. Psychopharmacology (Berl) 2004, 172(2):145-156], likely due to its shorter duration of action and less notorious nature compared to LSD. Like other members of this class, psilocybin induces sometimes profound changes in perception, cognition, and affect, including emotional lability.

[0009] In humans and other mammals, psilocybin is converted to its active metabolite, psilocin, or parent compound, 4-hydroxy-N,N-dimethyltryptamine. Psilocybin likely partially or completely produces most of psilocybin's subjective and physiological effects in humans and nonhuman animals. Recent studies of psilocybin in humans have confirmed its 5-HT2A activity via the parent psilocybin, providing some support for the possibility of indirect effects on dopamine through 5-HT2A activity and activity at other serotonin receptors. Indeed, the most consistent finding regarding the involvement of other receptors in the actions of hallucinogens is the 5-HT1A receptor. This is particularly true for tryptamines and LSD, which generally have significant affinity and functional capacity for this receptor. 5-HT1A receptors colocalize with 5-HT2A receptors on cortical pyramidal cells [Martin-Ruiz et al. J Neurosci. 2001, 21(24):9856-986], and the two receptor types are known to have opposing functional effects [Araneda et al. Neuroscience 1991, 40(2):399-412].

[0010] Although the precise role of the 5-HT2A receptor and other 5-HT2 receptor family members in the amygdala is not fully understood, it is clear that the 5-HT2A receptor plays a key role in emotional responses and is an important target to consider in the actions of 5-HT2A agonist hallucinogens. Indeed, the majority of known 5-HT2A agonists produce hallucinogenic effects in humans, and rodents generalize from one 5-HT2A agonist to another, such as from psilocybin to LSD [Aghajanian et al., Eur J Pharmacol., 1999, 367(2-3):197-206; Nichols et al., J Neurochem., 2004, 90(3):576-584]. Psilocybin has a stronger affinity for human 5-HT2A receptors than for rat receptors, and psilocybin has a lower K(i) than LSD for both 5-HT2A and 5-HT2C receptors. Furthermore, results from a series of drug discrimination tests in rats found that 5-HT2A antagonists, but not 5-HT1A antagonists, prevented rats from recognizing psilocybin [Winter et al., Pharmacol Biochem Behav., 2007, 87(4):472-480]. Daily doses of LSD and psilocybin decrease 5-HT2 receptor density in the rat brain.

[0011] Today, psilocybin is one of the most widely used hallucinogens in human research due to its relative safety, moderately long duration of activity, and good absorption in subjects. It has shown varying degrees of success in treating neurotic disorders, alcoholism, depression associated with major depressive disorder, treatment-resistant depression, and even terminal cancer patients, obsessive-compulsive disorder, addiction, anxiety, post-traumatic stress disorder, and cluster headaches, suggesting that psilocybin still has strong research and therapeutic potential.

[0012] Recent developments include several double-blind, placebo-controlled, phase 2 trials of psilocybin-assisted psychotherapy in patients with treatment-resistant depression, major depressive disorder, and cancer-related psychosocial distress, demonstrating unprecedented positive relief of anxiety and depression. Two recent small pilot trials of psilocybin-assisted psychotherapy also demonstrated positive benefits in the treatment of both alcoholism and nicotine dependence. Recently, blood oxygen level-dependent functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) have been used for in vivo brain imaging in humans after hallucinogen administration, and results indicate that intravenously administered psilocybin and LSD produced a decrease in oscillatory power in regions of the brain's default mode network [Nichols DE. Pharmacol Rev., 2016, 68(2):264-355].

[0013] Preliminary studies using positron emission tomography (PET) have shown that in healthy participants, psilocybin ingestion (15 or 20 mg orally) increased absolute glucose metabolic rates in the frontal cortex and, to a lesser extent, in other cortical regions and in the striatum and limbic subcortical structures, suggesting that some of psilocybin's key behavioral effects involve the frontal cortex [Gouzoulis-Mayfrank et al., Neuropsychopharmacology, 1999, 20(6):565-581; Vollenweider et al., Brain Res. Bull. 2001, 56(5):495-507]. Although 5-HT2A agonism is widely recognized as the primary action of classical hallucinogens, psilocybin has lower affinity for a wide range of other pre- and postsynaptic serotonin and dopamine receptors, as well as the serotonin reuptake transporter [Tyls et al., Eur. Neuropsychopharmacol., 2014, 24(3):342-356]. Psilocybin activates 5-HT1A receptors, which may contribute to its antidepressant / anxiety effects.

[0014] Depression and anxiety are two of the most common mental disorders worldwide. Depression is a multifaceted condition characterized by mood disturbances and other symptoms, such as episodes of anhedonia, psychomotor symptoms, guilt, attention deficits, and suicidal ideation, all of which can vary in severity. Similarly, anxiety disorders are a collection of etiologically complex disorders characterized by intense psychosocial distress and other symptoms depending on the subtype. Anxiety associated with life-threatening illnesses is the only anxiety subtype that has been studied from the perspective of hallucinogen-assisted therapy. Pharmacological and psychosocial interventions are commonly used to manage this type of anxiety, but their efficacy is mixed and limited, such that they often fail to provide sufficient emotional relief. Recent interest in the use of hallucinogen-assisted therapy may represent a promising alternative for patients with depression and anxiety ineffectively managed by conventional methods.

[0015] Generally, the hallucinogen treatment model involves administering an orally active drug to induce a mystical experience lasting approximately 4–9 hours, depending on the hallucinogen [Halberstadt, Behav Brain Res., 2015, 277:99–120; Nichols, Pharmacol Rev., 2016, 68(2):264–355]. This allows participants to confront and integrate difficult emotions and situations, leading to lasting antidepressant and anxiolytic effects. Classic hallucinogens such as psilocybin and LSD are being investigated as potential candidates. One study using classic hallucinogens for the treatment of depression and anxiety associated with life-threatening illness found that, in a supportive environment, psilocybin and LSD consistently produced significant and sustained antidepressant and anxiolytic effects.

[0016] Psychedelic treatments are generally well tolerated, with few, if any, lasting side effects. Their primary therapeutic effects are mediated biochemically through serotonin receptor agonism and psychologically by eliciting meaningful psychospiritual experiences that contribute to mental flexibility. Given the limited success of current treatments for anxiety and mood disorders and the high morbidity associated with these conditions, psychedelics have the potential to alleviate symptoms in patients who are inadequately managed by conventional methods.

[0017] Furthermore, emerging clinical research and evidence suggests that psychedelic-assisted therapy may also show promise as an alternative treatment for refractory substance use disorders and mental health conditions, and therefore may be an important tool in crisis situations where existing approaches have had limited success [dos Santos et al., Ther Adv Psychopharmacol., 2016, 6(3):193-213]. Similarly encouraging, findings from a recent pilot study of psilocybin-assisted therapy for tobacco use disorder demonstrated an 80% abstinence rate at 6-month follow-up and a 67% abstinence rate at 12-month follow-up [Johnson et al., https: / / www.ncbi.nlm.nih.gov / pubmed / 27441452J Drug Alcohol Abuse, 2017, 43(1):55-60; Johnson et al., Psychopharmacol. 2014, 28(11):983-992]; these rates are significantly higher than those documented in any smoking cessation literature. Notably, the mystical-type experiences produced by psilocybin sessions were significantly correlated with positive treatment outcomes. These results are consistent with a growing body of evidence from recent clinical trials supporting the efficacy of psilocybin-assisted therapy for treatment-resistant depression and end-of-life anxiety [Carhart-Harris et al. Neuropsychopharmacology, 2017, 42(11):2105-2113]. Research on the potential benefits of psychedelic-assisted therapy for opioid use disorder (OUD) is beginning to emerge, and evidence is accumulating to support the need to advance this line of research. Available evidence from a previous randomized clinical trial suggests a promising role for treating OUD: higher rates of drug withdrawal were observed at long-term follow-up in participants receiving high-dose LSD- and ketamine-assisted therapy for heroin dependence compared with controls.Recently, a large-scale US population study of 44,000 individuals found that hallucinogen use, as defined by DSM-IV criteria, was associated with a 40% lower risk of next-year opioid abuse and a 27% lower risk of next-year opioid dependence [Pisano et al., J Psychopharmacol., 2017, 31(5):606-613]. Similarly, a protective moderating effect of hallucinogen use was found in the relationship between prescription opioid use and suicide risk among marginalized women [Argento et al., J Psychopharmacol., 2018, 32(12):1385-1391]. Despite these promising preliminary findings for classic hallucinogens, further research is warranted to determine how hallucinogens may improve opioid crisis response. Meanwhile, growing evidence of the safety and efficacy of psilocybin for psychiatric and substance use disorders should help motivate further clinical research into its use as a novel intervention for OUD.

[0018] Sleep disorders are common among depressed patients, with over 80% complaining of poor sleep quality. Regular doses of hallucinogens can also improve sleep problems. These sleep symptoms often do not resolve with first-line treatment, carrying a greater risk of relapse and recurrence. Interestingly, sleep problems often precede other depressive symptoms, and subjective sleep quality worsens before the onset of a depressive episode. Two other studies evaluating electroencephalographic (EEG) brain activity during sleep have shown that hallucinogens, such as LSD, positively affect sleep patterns. A single dose of hallucinogens has been shown to reset the circadian clock underlying the sleep / wake cycle, thereby enhancing cognitive-emotional processes in depressed individuals and, in turn, promoting feelings of well-being and improving mood in healthy individuals [Kuypers, Medical Hypotheses, 2019, 125:21-24].

[0019] A systematic meta-analysis of clinical trials from 1960 to 2018 that used psychedelics to treat patients with serious or terminal illnesses and related psychiatric disorders found that psychedelic therapy (mostly LSD-based) may improve cancer-related depression, anxiety, and fear of death. Four randomized controlled clinical trials published between 2011 and 2016, most of which involved psilocybin, demonstrated that psychedelic-assisted therapy can produce rapid, robust, and sustained improvements in cancer-related psychological and existential distress [Ross S, Int Rev Psychiatry, 2018, 30(4):317-330]. Many patients facing cancer or other life-threatening illnesses experience significant existential distress related to a loss of meaning or purpose in life, which can be associated with hopelessness, demoralization, helplessness, perceived burdensomeness, and a desire for an earlier death. These characteristics are also often central to clinically significant anxiety and depression, which can substantially reduce the quality of life in this patient population. Alleviating these core features of existential distress should be among the central goals of palliative care. Accordingly, several manualized psychotherapies for cancer-related existential distress, focusing on dignity and meaning, have been developed in recent years. However, there are currently no pharmacological interventions for existential distress itself, and available pharmacological treatments for depressive symptoms in cancer patients have not demonstrated superiority over placebo. There remains a need for additional effective treatments for these conditions [Rosenbaum et al., Curr. Oncol., 2019, 26(4):225-226].

[0020] Recently, there has been growing interest in a new administration paradigm for hallucinogens such as psilocybin and LSD, colloquially referred to as microdosing.In this paradigm, a sub-perceptual dose of serotonergic hallucinogens, approximately 10% or less of the total dose, is taken on a more consistent basis, such as once a day, once every two days, once every three days, or similar permutations.This administration paradigm is not only consistent with the current standards of pharmacological care, but may also be particularly beneficial for some pathologies, such as Alzheimer's disease, other neurodegenerative diseases, attention deficit disorder, attention deficit hyperactivity disorder, and some patient groups, such as elderly patients, young patients, and patients who are afraid of or opposed to hallucinogen-assisted therapy.Furthermore, this approach may be particularly suitable for managing cognitive impairment and preventing neurodegeneration. For example, subpopulations of attentive and less motivated rats showed improved performance on a five-choice reaction time task and a progressive ratio task after subthreshold psilocybin doses that elicited the classic wet dog shake behavioral response associated with hallucinogenic doses (Blumstock et al., WO2020 / 157569 A1). Similarly, treating patients with hallucinogenic doses of 5-HT2A agonists was associated with increased BDNF and activation of the mTOR pathway, which is thought to promote neuroplasticity and may serve as a molecular target for treating dementia and other neurodegenerative disorders (Ly et al., Cell Rep., 2018, 23(11):3170-3182).Additionally, several groups have demonstrated that low, non-hallucinogenic, and non-psychotropic doses of 5-HT2A agonists also exhibit similar neuroprotective, neuroplasticity-enhancing (neuroplastogenic) and neuroinflammation-reducing effects, which may be beneficial for both neurodegenerative and neurodevelopmental disorders, as well as chronic disorders (Manfredi et al., WO2020 / 181194; Flanagan et al., Int. Rev. Psychiatry, 2018, 13:1-13; Nichols et al., 2016, Psychedelics as medicines; an emerging new paradigm). Such repeated low-dose paradigms may prove useful for extending the utility of these compounds to additional indications and health applications.

[0021] Psychosis is often referred to as an abnormal mental state characterized by hallucinatory experiences, delusional thoughts, and disordered thoughts. This state is further accompanied by social-cognitive dysfunction, inappropriate emotional expression, and bizarre behavior. In most cases, psychosis manifests as a subset of psychiatric disorders, particularly schizophrenia. It corresponds to the most aggressive phase of the illness. The first symptom of psychosis in a patient is called first-episode psychosis. It reflects a critical transition toward chronic disease establishment, i.e., it is presumed to be mediated by progressive abnormalities in structure and function observed in diagnosed patients. [ACS Chem. Neurosci., 2018, 9, 2241-2251]. There is scant evidence to support the suggestion that regularly administered small, non-hallucinogenic doses (microdosing) of hallucinogens can reduce the symptoms of schizophrenia and psychosis. Summary of the Invention

[0022] The present application provides compounds of formula I: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: Q is P(O)OR 9 , C1-C4 alkylene-P(O)OR 9 -C1-C6 alkylene, C(O), SO2, C(O)Q'C(O), C(O)OQ'OC(O) and C(O)NR 9 'Q'NR 9 'C(O) is selected from; R 1 is H, C1-C3 alkyl, C(O)R 10 , CO2R 10 , C(O)N(R 10 )(R 11 ), S(O)R 10 and SO2R 10 Selected from; R 2 , R 3 , R 3 ', R 4 and R 4 ' is independently selected from H and C1-C6 alkyl; R 5 and R 5 ' is independently selected from H and C1-C6 alkyl; or R 5 and R 5 ' together with the nitrogen atom therebetween form a 3-7 membered heterocyclic ring which may optionally contain 1-2 additional ring heteromoieties selected from O, S, S(O), SO2, N and NC1-C6 alkyl; R 6 , R 7 and R 8 are independently H, halo, CN, OR 12 , N(R 12 )(R 13 ), SR 12 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, CO2R 12 , C(O)N(R 12 )(R 13 ), S(O)R 12 , SO2R 12, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl, and O, S, S(O), SO2, N, and NR 14 wherein said C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl, and C3-C7 heterocycloalkyl are selected from CN, OR 15 , N(R 15 )(R 16 ) and SR 15 wherein said C3-C7 cycloalkyl and C3-C7 heterocycloalkyl may each be further substituted with one or more substituents independently selected from halo, COR 17 , C(O)N(R 17 )(R 18 ), SO2R 17 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, and O, S, S(O), SO2, N, and NR 19 and optionally substituted with one or more substituents selected from C3-C6 heterocycloalkyl containing 1-2 hetero moieties selected from: Q' is a direct bond, C1 to C 20 Alkylene, C1-C 20 Haloalkylene, C2-C 20 Alkenylene, C2-C 20 Haloalkenylene, C2-C 20 Alkynylene, C2-C 20 Haloalkynylene, C3-C7 cycloalkylene, and O, S, S(O), SO2, N, and NR 20 C3-C7 heterocycloalkylene containing 1 to 2 hetero moieties selected from the group consisting of 20 Alkylene, C2-C 20 Haloalkylene, C2-C6 alkenylene, C2-C 20Haloalkenylene, C3-C7 cycloalkylene, and C3-C7 heterocycloalkylene are substituted with CN, OR 21 , N(R 21 )(R 22 ), and S.R. 21 and / or C1-C6 alkyl, or C 2~6 together with the alkylene, are disubstituted at the same carbon atom to form a C3-C7 cycloalkyl ring, wherein said C3-C7 cycloalkylene and C3-C7 heterocycloalkylene are each optionally further substituted with one or more substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, provided that Q is C(O)OQ'OC(O) or C(O)NR 9 'Q'NR 9 'If C(O), then Q' is not a direct bond; R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are each independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C6 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C6 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C6 alkylenearyl, and substituted or unsubstituted C1-C6 alkyleneheteroaryl; R 9 ' is independently selected from H and C1-C6 alkyl; wherein all available hydrogen atoms may be optionally substituted with fluorine or chlorine atoms, and / or all available atoms may be optionally substituted with alternative isotopes thereof].

[0023] In a further embodiment, the compounds of the present application are used as pharmaceuticals. Thus, the present application also includes compounds of the present application for use as pharmaceuticals.

[0024] The present application also includes a method of treating psychosis or psychotic symptoms, comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need of treatment.

[0025] The present application also includes a method of treating a psychiatric disorder, comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need of treatment.

[0026] The present application additionally provides processes for preparing the compounds of the present application, the general and specific processes being explained in more detail below and in the examples that follow.

[0027] Other features and advantages of the present application will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while showing embodiments of the present application, are given by way of example only, and the scope of the claims is not limited by these embodiments, but should be accorded the broadest interpretation consistent with the entire description. DETAILED DESCRIPTION OF THE INVENTION

[0028] I. Definition Unless otherwise stated, the definitions and embodiments set forth in this and other sections are intended to be applicable to all embodiments and aspects of this application and are appropriately described herein as understood by one of ordinary skill in the art.

[0029] The terms "compound(s) of the present application" or "compound(s) of the present application," and the like, as used herein, refer to compounds of Formula I (including Formulas IA, IB, IC, ID, IE, and IF, which are within the scope of Formula I), including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, and all stereoisomers and positional isomers.

[0030] The terms "composition(s) of the present application" or "composition(s) of the present application" and the like, as used herein, refer to a composition, e.g., a pharmaceutical composition, comprising one or more compounds of the present application.

[0031] The term "and / or," as used herein, refers to the presence or use of the listed items, either individually or in combination. In effect, the term means that "at least one" or "one or more" of the listed items are used or present. With respect to pharmaceutically acceptable salts and / or solvates thereof, the term "and / or" means that the compounds of the present application are present as individual salts and solvates, as well as in combinations, e.g., salts of solvates of the compounds of the present application.

[0032] As used in this application, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, an embodiment including "a compound" should be understood to present aspects with one compound, or two or more additional compounds.

[0033] As used in this application and in the claims, the words "comprising" (and any form of comprising, e.g., "comprise" and "comprises"), "having" (and any form of having, e.g., "have" and "has"), "including" (and any form of including, e.g., "include" and "includes" or "containing" (and any form of containing, e.g., "contain" and "contains") are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0034] The term "consisting of" and its derivatives, as used herein, is intended to be a qualifying term specifying the presence of stated features, elements, components, groups, integers and / or steps, and excluding the presence of other unstated features, elements, components, groups, integers and / or steps.

[0035] The term "consisting essentially of," as used herein, is intended to identify the presence of the stated features, elements, components, groups, integers, and / or steps, and that which does not materially affect the basic property(ies) and novel property(ies) of those features, elements, components, groups, integers, and / or steps.

[0036] In embodiments that include an "additional" or "second" component, e.g., an additional or second compound, the second component, as used herein, is chemically distinct from the other or first component. A "third" component is different from the other, first, or second component, and further listed or "additional" components are similarly distinct.

[0037] The term "suitable," as used herein, means that the selection of a particular compound or conditions will depend on the specific synthetic operation being performed, the properties of the molecule(s) being altered, and / or the specific use of the compound, but such selection would be well within the skill of one of ordinary skill in the art. All process / method steps described herein are carried out under conditions sufficient to provide the indicated product. One of ordinary skill in the art will understand that all reaction conditions, such as reaction solvent, reaction time, reaction temperature, reaction pressure, ratio of reactants, and whether the reaction should be carried out under anhydrous conditions or an inert atmosphere, can be varied to optimize production of the desired product, and this is within the skill of one of ordinary skill in the art.

[0038] The terms "about," "substantially," and "approximately," as used herein, refer to a reasonable amount of deviation from the modified word that does not significantly change the end result. These terms of degree should be interpreted as including a deviation of at least ±5% of the modified word, unless the deviation would negate the meaning of the modified word or the context would suggest otherwise to one of ordinary skill in the art.

[0039] This description makes reference to numerous chemical terms and abbreviations used by those of ordinary skill in the art. Nonetheless, definitions of selected words are provided for clarity and consistency.

[0040] The term "solvate" as used herein means a compound or a salt and / or prodrug of a compound, wherein suitable solvent molecules are incorporated into the crystal lattice.

[0041] The term "prodrug," as used herein, means a compound or a salt of a compound that is converted into an active drug after administration.

[0042] The term "alkyl," as used herein, whether used alone or as part of another group, refers to a straight or branched chain saturated alkyl group. The possible number of carbon atoms in the referenced alkyl group is indicated by the prefix "C n1-n2 ". Thus, for example, the term "C 1~6 "Alkyl" (or "C1-C6 alkyl") means an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0043] The term "alkenyl," whether used alone or as part of another group, refers to a straight or branched, saturated alkylene group, i.e., a saturated carbon chain containing two substituents at either end. The possible number of carbon atoms in the referenced alkylene group is indicated by the prefix "C n1-n2 For example, the term C 2~6 Alkylene means an alkylene group having 2, 3, 4, 5 or 6 carbon atoms.

[0044] The term "alkynyl," as used herein, whether used alone or as part of another group, means a straight or branched chain unsaturated alkynyl group containing at least one triple bond. The possible number of carbon atoms in the referenced alkyl group is indicated by the prefix "C n1-n2 For example, the term "C 2~6 "Alkynyl" means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms.

[0045] The term "alkoxy" as used herein, alone or in combination, includes an alkyl group bound to an atom which is bound to an oxygen.

[0046] The term "cycloalkyl," as used herein, whether used alone or as part of another group, refers to a saturated carbocyclic group containing from 3 to 6 carbon atoms and one or more rings. The possible number of carbon atoms in a referenced cycloalkyl group is determined by the numerical prefix "Cn1-n2 For example, the term C 3~10 Cycloalkyl means a cycloalkyl group having 3, 4, 5 or 6 carbon atoms.

[0047] The term "heterocycloalkyl," as used herein, whether used alone or as part of another group, refers to a cyclic group containing at least one non-aromatic ring containing 3 to 6 atoms, one or more of which are heteromoieties selected from O, S, S(O), SO, and N, and the remaining atoms are C. Heterocycloalkyl groups are either saturated or unsaturated (i.e., contain one or more double bonds). Heterocycloalkyl groups are denoted by the prefix C. n1-n2 or "n1-n2", this prefix refers to the number of carbon atoms in the corresponding carbocyclic group in which one or more, preferably 1 to 4, of the ring atoms are replaced by a hetero moiety selected from O, S, S(O), SO2, and N, and the remaining atoms are C.

[0048] The term "aryl," as used herein, whether used alone or as part of another group, refers to a carbocyclic group containing at least one aromatic ring and containing 6 to 20 carbon atoms.

[0049] The term "heteroaryl," as used herein, whether used alone or as part of another group, refers to a cyclic group containing at least one heteroaromatic ring containing 5 to 6 atoms, of which one or more atoms are heteroatoms selected from O, S, and N, and the remaining atoms are C. A heteroaryl group is denoted by the prefix C. n1~n2 When included, this prefix refers to the number of carbon atoms in the corresponding carbocyclic group, where one or more, preferably 1 to 4, of the ring atoms are replaced by a heteroatom as defined above.

[0050] All cyclic groups, including aryl, heteroaryl, heterocycloalkyl, and cycloalkyl groups, contain one ring or more than one ring (i.e., are polycyclic). When a cyclic group contains more than one ring, the rings may be fused, bridged, spirofused, or joined by bonds.

[0051] The term "benzofused," as used herein, refers to a polycyclic group in which a benzene ring is fused to another ring.

[0052] A first ring is "fused" to a second ring means that the first ring and the second ring share two adjacent atoms between them.

[0053] A first ring is "bridged" to a second ring means that the first ring and the second ring share two non-adjacent atoms between them.

[0054] A first ring is "spirofused" to a second ring means that the first ring and the second ring share one atom between them.

[0055] The term "halogen" (or "halo"), whether used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo, and iodo.

[0056] The term "haloalkyl," as used herein, refers to an alkyl group, as defined above, in which one or more available hydrogen atoms has been replaced with a halogen. Thus, for example, "C 1~6 "Haloalkyl" refers to a C1 to C6 straight or branched chain alkyl group as defined above having one or more halogen substituents.

[0057] As used herein, the term "haloalkenyl" refers to an alkenyl group, as defined above, in which one or more available hydrogen atoms has been replaced by a halogen. Thus, for example, "C 1~6"Haloalkenyl" (or "C1-C6 haloalkenyl") refers to a C1-C6 straight or branched chain alkenyl group, as defined above, having one or more halogen substituents.

[0058] As used herein, the term "haloalkynyl" refers to an alkynyl group, as defined above, in which one or more available hydrogen atoms has been replaced by a halogen. Thus, for example, "C 1~6 "Haloalkynyl" (or "C1-C6 haloalkynyl") refers to a C1-C6 straight or branched chain alkynyl group, as defined above, having one or more halogen substituents.

[0059] The term "deuteroalkyl," as used herein, refers to an alkyl group, as defined above, in which one or more available hydrogen atoms have been replaced with deuterium. Thus, for example, "C 1~6 "Deuteroalkyl" refers to a C1-C6 straight or branched chain alkyl group as defined above having one or more deuterium substituents.

[0060] The suffix "ene" at the end of a group (e.g., "alkylene" or "alkenylene") means that the group is divalent, i.e., it is attached to two variables, one at each end of the group.

[0061] The term "optionally substituted," as used herein, means that the group in question is either unsubstituted or substituted, and the terms "optionally substituted" and "unsubstituted or substituted" are used interchangeably herein.

[0062] As used herein, the term "substituted" means that one or more hydrogen atoms of the group are substituted or replaced with a substituent independently selected from halo, C1-C4 alkyl, OC1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 haloalkyl, CN, OH, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)(C1-C4 alkyl), SC1-C4 alkyl, S(O)C1-C4 alkyl, SO2C1-C4 alkyl, CO2H, CO2C1-C4 alkyl, C(O)NH2, C(O)NHC1-C4 alkyl, C(O)N(C1-C4 alkyl)(C1-C4 alkyl), and C3-C6 cycloalkyl and 3- to 6-membered heterocyclic rings, including ring heteromoieties selected from O, S, S(O), SO2, N, NH, and NC1-C4 alkyl.

[0063] The term "available" as in "available hydrogen atom" or "available atom" refers to an atom known by those skilled in the art to be replaceable with a substituent.

[0064] As used herein, the term "one or more" includes a single item selected from the list and mixtures of two or more items selected from the list.

[0065] The term "alternate isotopes thereof," as used herein, refers to isotopes of an element other than the most common isotope occurring in nature.

[0066] In the compounds of general formula I, and their pharmaceutically acceptable salts and / or solvates, atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. The present disclosure is intended to include all appropriate isotopic variations of the compounds of general formula I, and their pharmaceutically acceptable salts and / or solvates. For example, protium ( 1 H), deuterium ( 2 H) and tritium (3 Protium is the predominant hydrogen isotope found in nature.

[0067] The term "compound" refers to the compound, and in some embodiments, to any hydrates or solvates thereof, to the extent they are stable. A hydrate is a compound complexed with water, and a solvate is a compound complexed with a solvent, which may be an organic or inorganic solvent. A "stable" compound is one that can be prepared and isolated, and whose structure and properties remain essentially unchanged or essentially unchanged for a period of time sufficient to use the compound for the purposes described herein (e.g., administering a therapeutic agent to a subject). The compounds of the present application are limited to stable compounds encompassed by general formula I, or pharmaceutically acceptable salts and / or solvates thereof.

[0068] The term "pharmaceutically acceptable" refers to compatible with the treatment of a subject.

[0069] The term "pharmaceutically acceptable carrier" refers to a non-toxic solvent, dispersant, excipient, adjuvant or other material that is mixed with an active ingredient to enable the formulation of a pharmaceutical composition, i.e., a dosage form that can be administered to a subject.

[0070] The term "pharmaceutically acceptable salt" means either an acid addition salt or a base addition salt which is appropriate or compatible with the treatment of a subject.

[0071] Acid addition salts suitable or compatible for the treatment of a subject are any non-toxic organic or inorganic acid addition salts of any basic compounds.

[0072] A base addition salt that is suitable or compatible for the treatment of a subject is any non-toxic organic or inorganic base addition salt of any acidic compound.

[0073] The term "protecting group" or "PG" as used herein refers to a chemical moiety that protects or masks a reactive site of a molecule, preventing side reactions at that reactive site while a different site of the molecule is manipulated or reacted. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remainder of the molecule. The selection of an appropriate protecting group can be made by one skilled in the art. Many conventional protecting groups are known in the art and are described, for example, in "Protective Groups in Organic Chemistry" McOmie, JFW Ed., Plenum Press, 1973, in Greene, TW and Wuts, PGM, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3rd Edition, 1999, and Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0074] The term "subject," as used herein, includes all members of the animal kingdom, including mammals, and suitably refers to humans. Thus, the methods of the present application are applicable to both human therapy and veterinary uses.

[0075] The terms "treating" or "treatment," as used herein and as well understood in the art, refer to an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in disease extent, stabilized (i.e., not worsening) disease, preventing disease spread, delay or slowing of disease progression, amelioration or palliation of the disease state, reduction in disease recurrence, and remission (partial or complete remission), which may or may not be detectable. "Treating" and "treatment" can also mean prolonging survival compared to expected survival in the absence of treatment. "Treating" and "treatment," as used herein, also include prophylactic treatment. For example, a subject with early-stage cancer can be treated to prevent progression, or a subject in remission can be treated with a compound or composition of the present application to prevent recurrence. The method of treatment involves administering to the subject a therapeutically effective amount of one or more compounds of the present application, which may consist of a single dose or may include a series of multiple doses, as appropriate.

[0076] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of one or more compounds of the present application that is effective at dosages and for periods of time necessary to achieve a desired result. For example, in the context of treating a disease, disorder, or condition mediated or treated by agonism or activation of serotonergic receptors and downstream second messengers, an effective amount is, for example, an amount that improves activation compared to the activation when one or more compounds are not administered.

[0077] "Palliating" a disease, disorder, or condition means reducing the severity and / or undesirable clinical symptoms of the disease, disorder, or condition and / or slowing or prolonging the course of progression compared to not treating the disorder.

[0078] The term "administered," as used herein, means administering a therapeutically effective amount of one or more compounds or compositions of the present application to a cell, tissue, organ, or subject.

[0079] The terms "prevention" or "prophylaxis," or synonyms thereof, as used herein, refer to reducing the risk or likelihood that a patient will acquire a disease, disorder, or condition, or develop symptoms associated with a disease, disorder, or condition.

[0080] "Disease, disorder, or condition," as used herein, refers to a disease, disorder, or condition that is treated or treatable by activation of a serotonin receptor (e.g., 5-HT2A, particularly using a serotonin receptor agonist (e.g., one or more compounds of the present application described herein)).

[0081] The term "treating a disease, disorder, or condition by activating serotonin receptors," as used herein, means that the disease, disorder, or condition to be treated is directly or indirectly affected, modulated, and / or has some biological basis that includes (particularly increases) serotonergic activity. These diseases preferably respond when the serotonergic activity associated with the disease, disorder, or condition is agonized by one or more compounds or compositions of the present application.

[0082] The term "activation" as used herein includes agonism, partial agonism, and positive allosteric modulation of serotonin receptors.

[0083] The terms "5-HT1A" and "5-HT2A," as used herein, refer to the 5-HT2A and 5-HT2A receptor subtypes of the 5-HT2 serotonin receptor.

[0084] The term "therapeutic agent," as used herein, refers to any drug or active agent that has a pharmacological effect when administered to a subject.

[0085] II. Compounds Applicant has developed and prepared novel ethylamine indole dimer compounds. In some embodiments, the dimer compounds are metabolized in vivo to provide active metabolites. For example, in some embodiments, exemplary dimer compounds I-24 and I-37 are metabolized in vivo to provide the active metabolites psilocin and compound 7, respectively, as described herein.

[0086] The present application provides compounds of formula I: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: Q is P(O)OR 9 , C1-C4 alkylene-P(O)OR 9 -C1-C6 alkylene, C(O), SO2, C(O)Q'C(O), C(O)OQ'OC(O) and C(O)NR 9 'Q'NR 9 'C(O) is selected from; R 1 is H, C1-C3 alkyl, C(O)R 10 , CO2R 10 , C(O)N(R 10 )(R 11 ), S(O)R 10 and SO2R 10 Selected from; R 2 , R 3 , R 3 ', R 4 and R 4 ' is independently selected from H and C1-C6 alkyl; R 5 and R 5 ' is independently selected from H and C1-C6 alkyl; or R 5 and R 5' together with the nitrogen atom therebetween form a 3-7 membered heterocyclic ring which may optionally contain 1-2 additional ring heteromoieties selected from O, S, S(O), SO2, N and NC1-C6 alkyl; R 6 , R 7 and R 8 are independently H, halo, CN, OR 12 , N(R 12 )(R 13 ), SR 12 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, CO2R 12 , C(O)N(R 12 )(R 13 ), S(O)R 12 , SO2R 12 , C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl, and O, S, S(O), SO2, N, and NR 14 wherein said C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl and C3-C7 heterocycloalkyl are selected from CN, OR 15 , N(R 15 )(R 16 ) and SR 15 wherein said C3-C7 cycloalkyl and C3-C7 heterocycloalkyl may each be further substituted with one or more substituents independently selected from halo, COR 17 , C(O)N(R 17 )(R 18 ), SO2R 17 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, and O, S, S(O), SO2, N, and NR 19 and optionally substituted with one or more substituents selected from C3-C6 heterocycloalkyl containing 1-2 hetero moieties selected from: Q' is a direct bond, C1 to C 20 Alkylene, C1-C 20 Haloalkylene, C2-C 20 Alkenylene, C2-C 20 Haloalkenylene, C2-C 20 Alkynylene, C2-C 20 Haloalkynylene, C3-C7 cycloalkylene, and O, S, S(O), SO2, N, and NR 20 C3-C7 heterocycloalkylene containing 1 to 2 hetero moieties selected from the group consisting of 20 Alkylene, C2-C 20 Haloalkylene, C2-C6 alkenylene, C2-C 20 Haloalkenylene, C3-C7 cycloalkylene, and C3-C7 heterocycloalkylene are substituted with CN, OR 21 , N(R 21 )(R 22 ), and S.R. 21 and / or C1-C6 alkyl, or C 2~6 Together with the alkylene, they are disubstituted at the same carbon atom to form a C3-C7 cycloalkyl ring, wherein said C3-C7 cycloalkylene and C3-C7 heterocycloalkylene are each optionally further substituted with one or more substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, provided that Q is C(O)OQ'OC(O) or C(O)NR 9 'Q'NR 9 'If C(O), then Q' is not a direct bond; R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22are each independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C6 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C6 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C6 alkylenearyl, and substituted or unsubstituted C1-C6 alkyleneheteroaryl; R 9 ' is independently selected from H and C1-C6 alkyl; wherein all available hydrogen atoms may be optionally substituted with fluorine or chlorine atoms, and / or all available atoms may be optionally substituted with alternative isotopes thereof].

[0087] The present application provides compounds of formula I: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: Q is P(O)OR 9 , C1-C4 alkylene-P(O)OR 9 -selected from C1-C6 alkylene, C(O), SO2 and C(O)Q'C(O); R 1 is H, C1-C3 alkyl, C(O)R 10 , CO2R 10 , C(O)N(R 10 )(R 11 ), S(O)R 10 and SO2R 10 Selected from; R 2 , R 3 , R 3 ', R 4 and R 4 ' is independently selected from H and C1-C6 alkyl; R 5 and R 5 ' is independently selected from H and C1-C6 alkyl; or R 5 and R 5 ' together with the nitrogen atom therebetween form a 3-7 membered heterocyclic ring which may optionally contain 1-2 additional ring heteromoieties selected from O, S, S(O), SO2, N and NC1-C6 alkyl; R 6 , R 7 and R 8 are independently H, halo, CN, OR 12 , N(R 12 )(R 13 ), SR 12 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, CO2R 12 , C(O)N(R 12 )(R 13 ), S(O)R 12 , SO2R 12 , C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl, and O, S, S(O), SO2, N, and NR 14 wherein said C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl and C3-C7 heterocycloalkyl are selected from CN, OR 15 , N(R 15 )(R 16 ) and SR 15 wherein said C3-C7 cycloalkyl and C3-C7 heterocycloalkyl may each be further substituted with one or more substituents independently selected from halo, COR 17 , C(O)N(R 17 )(R 18 ), SO2R 17, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, and O, S, S(O), SO2, N, and NR 19 and optionally substituted with one or more substituents selected from C3-C6 heterocycloalkyl containing 1 to 2 hetero moieties selected from Q' is a direct bond, C1 to C 20 Alkylene, C1-C 20 Haloalkylene, C2-C 20 Alkenylene, C2-C 20 Haloalkenylene, C2-C 20 Alkynylene, C2-C 20 Haloalkynylene, C3-C7 cycloalkylene, and O, S, S(O), SO2, N, and NR 20 C3-C7 heterocycloalkylene containing 1 to 2 hetero moieties selected from the group consisting of 20 Alkylene, C2-C 20 Haloalkylene, C2-C6 alkenylene, C2-C 20 Haloalkenylene, C3-C7 cycloalkylene, and C3-C7 heterocycloalkylene are substituted with CN, OR 21 , N(R 21 )(R 22 ), and S.R. 21 and / or C1-C6 alkyl, or C 2~6 together with alkylene, disubstituted at the same carbon atom to form a C3-C7 cycloalkyl ring, wherein said C3-C7 cycloalkylene and C3-C7 heterocycloalkylene each may be further optionally substituted with one or more substituents selected from C1-C3 alkyl and C1-C3 haloalkyl; R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R18 , R 19 , R 20 , R 21 and R 22 are each independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C6 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C6 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C6 alkylenearyl, and substituted or unsubstituted C1-C6 alkyleneheteroaryl; wherein all available hydrogen atoms may be optionally substituted with fluorine or chlorine atoms, and / or all available atoms may be optionally substituted with alternative isotopes thereof].

[0088] In some embodiments, all available hydrogen atoms may be optionally replaced with their alternative isotopes. In some embodiments, the alternative isotope of hydrogen is deuterium. Thus, in some embodiments, the compounds of the present application are isotopically enriched with deuterium.

[0089] In some embodiments, R 1 is H, C1-C3 alkyl, C(O)R 10 , CO2R 10 and C(O)N(R 10 )(R 11 ), wherein all available hydrogen atoms may be optionally replaced with fluorine or chlorine atoms, and / or all available atoms may be optionally replaced with alternative isotopes thereof. In some embodiments, R 1 is H, C1-C3 alkyl, C(O)R 10 and CO2R 10wherein all available hydrogen atoms may be optionally replaced with fluorine or chlorine atoms and / or all available atoms may be optionally replaced with alternative isotopes thereof. 1 is selected from H, CH and CHCH, where any available hydrogen atom may be optionally replaced with a fluorine or chlorine atom and / or any available atom may be optionally replaced with an alternative isotope thereof. 1 is selected from H, CH, CHCH, where any available hydrogen atom may be independently replaced with a fluorine atom or a deuterium atom as appropriate. 1 is independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CF2H, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. 1 is selected from H, D, CH3 and CD3. In some embodiments, R 1 are H, CH3, CH2CH3, C(O)R 10 and CO2R 10 wherein all available hydrogen atoms may be optionally replaced with fluorine or chlorine atoms and / or all available atoms may be optionally replaced with alternative isotopes thereof. 1 is selected from H, CH, and CHCH, where any available hydrogen atom may be independently replaced with a fluorine atom or a deuterium atom as appropriate. 1 is selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CFH2, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. 1 is selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CF2H, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 1 is selected from H and D. In some embodiments, R1 is H. In some embodiments, R 1 is S(O)R 10 and SO2R 10 wherein all available hydrogen atoms may be optionally replaced by fluorine or chlorine atoms, and / or all available atoms may be optionally replaced by alternative isotopes thereof.

[0090] In some embodiments, R 2 , R 3 , R 3 ', R 4 and R 4 is independently selected from hydrogen and C1-C4 alkyl, where any available hydrogen atom may be optionally replaced with a fluorine or chlorine atom, and / or any available atom may be optionally replaced with an alternative isotope thereof. In some embodiments, R 2 , R 3 , R 3 ', R 4 and R 4 is independently selected from H, CH, CHCH, CH(CH) and C(CH), where any available hydrogen atom may be optionally replaced by a fluorine or chlorine atom and / or any available atom may be optionally replaced by an alternative isotope thereof.

[0091] In some embodiments, R 2 is selected from hydrogen, CH, CHCH, CH(CH) and C(CH), where any available hydrogen atom may be independently replaced with a fluorine atom or a deuterium atom as appropriate. 2 is selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CFH2, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 2 is selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CF2H, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R2 is selected from H, D, F, CH3, CF3, CH2CH3, CD2CD3, CF2CF3, CH(CH3)2, CD(CD3)2, CF(CF3)2, C(CD3)3, C(CF3)3, and C(CH3)3. In some embodiments, R 2 is selected from H and D. In some embodiments, R 2 is H.

[0092] In some embodiments, R 3 , R 3 ', R 4 and R 4 is independently selected from H, CH, CHCH, CH(CH), and C(CH), where any available hydrogen atom may be optionally replaced with a fluorine or chlorine atom, and / or any available hydrogen atom may be optionally replaced with a deuterium atom. In some embodiments, R 3 , R 3 ', R 4 and R 4 is independently selected from H, CH, CHCH, CH(CH) and C(CH), where any available hydrogen atom may be independently replaced with a fluorine atom or a deuterium atom as appropriate. 3 , R 3 ', R 4 and R 4 At least one of ' is D or R 3 , R 3 ', R 4 and R 4 At least one of R ' contains D. In some embodiments, 3 , R 3 ', R 4 and R 4 R' is independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CF2H, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 3 , R 3 ', R 4 and R 4R' is independently selected from H, D, F, CH, CDH, CDH, and CD. In some embodiments, R 3 , R 3 ', R 4 and R 4 In some embodiments, R ' is independently selected from H, D, F, CH3, and CD3. 3 , R 3 ', R 4 and R 4 is independently selected from H, D, and F. In some embodiments, R 3 , R 3 ', R 4 and R 4 At least one of R ' is F. In some embodiments, 3 , R 3 ', R 4 and R 4 In some embodiments, R 3 , R 3 ', R 4 and R 4 In some embodiments, R 3 , R 3 ', R 4 and R 4 At least one of R ' is H. In some embodiments, 3 , R 3 ', R 4 and R 4 In some embodiments, R 3 , R 3 ', R 4 and R 4 At least two of R' are D. In some embodiments, 3 and R 4 are both D and R 3 ' and R 4 In some embodiments, R 3 and R 4 are both H and R 3 ' and R 4 ' are both D.

[0093] In some embodiments, R 5 and R 5 is independently selected from H and C1-C4 alkyl, where any available hydrogen atom may be optionally replaced with a fluorine or chlorine atom, and / or any available atom may be optionally replaced with an alternative isotope thereof. In some embodiments, R 5 and R 5 is independently selected from H and C1-C4 alkyl, where all available hydrogen atoms may be optionally replaced with fluorine or chlorine atoms, and / or all available hydrogen atoms may be optionally replaced with deuterium. In some embodiments, R 5 and R 5 is independently selected from hydrogen, CH, CHCH, CH(CH), and C(CH), where any available hydrogen atom may be optionally substituted with a fluorine or chlorine atom, and / or any available hydrogen atom may be optionally substituted with a deuterium atom. In some embodiments, R 5 and R 5 R' is independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CFH2, CH2CH3, CH2CH2D, CH2CD2H, CD2CD3, CD(CD3)2, and CH(CH3)2. In some embodiments, R 5 and R 5 R' is independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CF2H, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 5 and R 5 ' is independently selected from H, D, CH, CD, CHCH, and CH(CH). In some embodiments, R 5 and R 5 ' is independently selected from H, D, CH3 and CD3. In some embodiments, R 5 and R 5 ' is independently selected from H and D. In some embodiments, R 5 and R 5In some embodiments, R 5 is CD3. In some embodiments, R 5 and R 5 In some embodiments, R 5 and R 5 In some embodiments, R 5 and R 5 In some embodiments, R 5 and R 5 In some embodiments, R 5 and R 5 In some embodiments, R 5 and R 5 One of the groups is CH3 or CD3, and R 5 and R 5 The other of R' is H or D. In some embodiments, R 5 and R 5 ' is CH2CH3 and CH(CH3)2, and R 5 and R 5 The other of ' is H, CH3 or CD3.

[0094] In some embodiments, R 5 and R 5 ' together with the nitrogen atom therebetween form a 3-7 membered heterocyclic ring which may optionally contain 1-2 additional ring heteromoieties selected from O, S, S(O), SO, N, and NC-C alkyl, wherein all available hydrogen atoms may be optionally replaced by halogen atoms and / or all available atoms may be optionally replaced by alternative isotopes thereof. In some embodiments, R 5 and R 5 ', together with the nitrogen atom between them, form O, S, S(O), SO2, N and NC 1~4alkyl, wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by an isotope thereof. 5 and R 5 ' together with the nitrogen atom between them form an azetidinyl, diazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiozolidinyl, piperidinyl, diazinanyl (e.g., piperazinyl), morpholinyl, or azepanyl ring, in which any available hydrogen atom may be optionally replaced by a halogen atom and / or any available atom may be optionally replaced by its corresponding isotope. In some embodiments, R 5 and R 5 ' together with the nitrogen atom between them form pyrrolidinyl, piperidinyl, morpholinyl, or diazinanyl, in which any available hydrogen atom may be optionally replaced by a halogen atom and / or any available atom may be optionally replaced by its alternative isotope. In some embodiments, R 5 and R 5 ' together with the nitrogen atom between them form pyrrolidinyl, piperidinyl, morpholinyl, or diazinanyl, in which all available hydrogen atoms may be optionally replaced with fluorine and / or chlorine atoms, and / or all available hydrogen atoms may be optionally replaced with deuterium. In some embodiments, R 5 and R 5 ' together with the nitrogen atom between them form pyrrolidinyl, piperidinyl, morpholinyl, or diazinanyl, where all available hydrogens may be optionally replaced with deuterium. In some embodiments, R 5 and R 5 ' together with the nitrogen atom between them form pyrrolidinyl, piperidinyl or morpholinyl, where all available hydrogens may be optionally replaced with deuterium.

[0095] In some embodiments, R 6 , R 7 and R 8 are independently H, halo, CN, OR 12 , N(R 12 )(R 13 ), SR 12 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 12 , C(O)N(R 12 )(R 13 ), S(O)R 12 , SO2R 12 , C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl, and O, S, S(O), SO2, N, and NR 14 and C3-C7 heterocycloalkyl containing 1 to 2 hetero moieties selected from, wherein said C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl and C3-C7 heterocycloalkyl are selected from CN, OR 15 , N(R 15 )(R 16 ) and SR 15 wherein the C-C cycloalkyl and C-C heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halo, COR 17 , C(O)N(R 17 )(R 18 ), SO2R 17 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, and O, S, S(O), SO2, N, and NR 19 wherein any available hydrogen atom may be optionally replaced by a fluorine or chlorine atom, and / or any available atom may be optionally replaced by an alternative isotope thereof.

[0096] In some embodiments, R 6 , R 7 and R 8 are independently H, halo, CN, OR 12 , N(R 12 )(R 13 ), SR 12 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 12 , C(O)N(R 12 )(R 13 ), S(O)R 12 , SO2R 12 , C2-C6 alkenyl, C2-C6 alkynyl and C2-C6 haloalkynyl, wherein said C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl and C2-C6 haloalkynyl groups are selected from CN, OR 15 , N(R 15 )(R 16 ) and SR 15 wherein all available hydrogen atoms may be optionally replaced with fluorine or chlorine atoms, and / or all available atoms may be optionally replaced with alternative isotopes thereof. 6 , R 7 and R 8 are independently H, F, Cl, Br, CN, OR 12 , N(R 12 )(R 13 ), SR 12 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 12 , C(O)N(R 12 )(R 13 ), S(O)R 12 , SO2R 12 , C2-C6 alkenyl, C2-C6 alkynyl and C2-C6 haloalkynyl, wherein said C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl and C2-C6 haloalkynyl groups are selected from CN, OR15 , N(R 15 )(R 16 ) and SR 15 wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with alternative isotopes thereof. 6 , R 7 and R 8 are independently H, F, Cl, Br, CN, OR 12 , N(R 12 )(R 13 ), SR 12 , CH3, CH2CH3, CH(CH3)2, C(CH3)3, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 12 , S(O)R 12 , SO2R 12 , C(O)N(R 12 )(R 13 ), C2-C6 alkenyl and C2-C6 alkynyl, wherein said C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl and C2-C6 alkynyl groups are selected from CN, OR 15 , N(R 15 )(R 15 )2 and SR 15 wherein all available hydrogen atoms may be optionally substituted with fluorine or chlorine atoms, and / or all available atoms may be optionally substituted with alternative isotopes thereof. 6 , R 7 and R 8 are independently H, F, Cl, Br, CN, OR 12 , N(R 12 )(R 13 ), SR 12 , CH3, CH2CH3, CH(CH3)2, C(CH3)3, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 12 , S(O)R 12 , SO2R 12and C2-C6 alkenyl, wherein any available hydrogen atom may be optionally replaced with a fluorine or chlorine atom and / or any available atom may be optionally replaced with an alternative isotope thereof. 6 , R 7 and R 8 are independently selected from hydrogen, F, Cl, Br, and CN. In some embodiments, R 6 , R 7 and R 8 is independently selected from H, D, F, Cl, Br, and CN. In some embodiments, R 6 , R 7 and R 8 is independently selected from H and D. In some embodiments, R 6 , R 7 and R 8 are all H. In some embodiments, R 6 , R 7 and R 8 are all D. In some embodiments, R 7 is selected from H, D, F, Cl, Br and CN, and R 6 and R 8 is selected from hydrogen and deuterium. 7 is selected from H, D, F and CN, and R 6 and R 8 is selected from H and D. In some embodiments, R 7 is selected from H, F and CN, and R 6 and R 8 is selected from H and D. In some embodiments, R 7 is selected from hydrogen, F and CN, and R 6 and R 8 are both H.

[0097] In some embodiments, R 6 , R 7 and R 8is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein any available hydrogen atom may be optionally replaced with a fluorine or chlorine atom, and / or any available atom may be optionally replaced with an alternative isotope thereof.

[0098] In some embodiments, R 6 , R 7 and R 8 In some embodiments, the C3-C7 heterocycloalkyl in R is independently a saturated or unsaturated heterocycle. 6 , R 7 and R 8 In some embodiments, the C3-C7 heterocycloalkyl is independently a saturated or unsaturated bridged bicyclic heterocycle. In some embodiments, the saturated or unsaturated bridged bicyclic heterocycle is independently selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl, and oxobicycloheptanenyl, wherein all available hydrogen atoms are optionally replaced with fluorine or chlorine atoms and / or all available atoms are optionally replaced with their corresponding isotopes.

[0099] In some embodiments, R 6 , R 7 and R 8C3-C7 heterocycloalkyl in the formula (I) is independently aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxathiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furanyl, and azaniyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, and diazepanyl, wherein all available hydrogen atoms may be optionally replaced by fluorine or chlorine atoms, and / or all available atoms may be optionally replaced by their corresponding isotopes.

[0100] In some embodiments, Q is P(O)OR 9 , C1-C2 alkylene-P(O)OR 9 -C1-C2 alkylene, C(O), SO2, C(O)Q'C(O), C(O)OQ'OC(O) and C(O)NR 9 'Q'NR 9 'C(O), where any available hydrogen atom may be optionally replaced by a fluorine or chlorine atom, and / or any available atom may be optionally replaced by an alternative isotope thereof. In some embodiments, Q is selected from a direct bond, P(O)OR 9 , C1-C2 alkylene-P(O)OR 9 and -C1-C2 alkylene, C(O), SO2, and C(O)(Q')C(O), where any available hydrogen atom may be optionally replaced with a fluorine or chlorine atom and / or any available atom may be optionally replaced with an alternative isotope thereof. In some embodiments, Q is selected from P(O)OR 9 and C1-C2 alkylene-P(O)OR 9In some embodiments, Q is selected from C1-C2 alkylene-P(O)OR 9 In some embodiments, Q is -C1-C2 alkylene, where any available hydrogen atom may be optionally replaced with a fluorine or chlorine atom, and / or any available atom may be optionally replaced with an alternative isotope thereof. 9 -CH2, where any available hydrogen atom may be optionally replaced by a fluorine or chlorine atom and / or any available atom may be optionally replaced by an alternative isotope thereof. In some embodiments, Q is selected from C(O), C(O)Q'C(O), C(O)OQ'OC(O), and C(O)NR 9 'Q'NR 9 In some embodiments, Q is selected from C(O), C(O)(Q' ... 9 'Q'NR 9 'C(O). In some embodiments, QSO2.

[0101] In some embodiments, Q' is C1-C 10 Alkylene, C2-C 10 Alkenylene and C-C 10 alkynylene, wherein the C1 to C 10 Alkylene, C2-C 10 Alkenylene and C-C 10 Alkynylene is CN, OR 21, N(R 21 )(R 22 ), and S.R. 21 and / or C 1~6 With alkyl or C 2~6 Together with the alkylene, they are disubstituted at the same carbon atom to form a C3-C7 cycloalkyl ring, wherein said C3-C7 cycloalkyl may be further optionally substituted with substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, and wherein all available hydrogen atoms may be optionally replaced with fluorine or chlorine atoms and / or all available atoms may be optionally replaced with alternative isotopes thereof. In some embodiments, Q' is OR 21 and N(R 21 )(R 22 and / or C 1~6 With alkyl or C 2~6 Together with the alkylene, Q' is disubstituted at the same carbon atom to form a C3-C7 cycloalkyl ring, wherein said C3-C7 cycloalkyl ring is optionally further substituted with substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, wherein all available hydrogen atoms are optionally replaced with fluorine or chlorine atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, Q' is selected from C1-C4 alkylene and C2-C4 alkenylene, wherein all available hydrogen atoms are optionally replaced with fluorine or chlorine atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, Q' is selected from CH2, CH2CH2, CH2CH2CH2, and CH=CH.

[0102] In some embodiments, when Q is C(O)Q'C(O), Q' is a direct bond. In some embodiments, Q' is a direct bond.

[0103] In some embodiments, Q' is selected from the group consisting of C3-C7 cycloalkylene, as well as O, S, S(O), SO2, N, and NR 20 and C3-C7 heterocycloalkylene containing 1 to 2 hetero moieties selected from the group consisting of CN, OR 21 , N(R 21 )(R 22 ), SR 21 , optionally substituted with 1 to 3 substituents independently selected from C1-C3 alkyl and C1-C3 haloalkyl. In some embodiments, the C3-C7 cycloalkyl in Q' is selected from cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene, where any available hydrogen atoms may be optionally replaced with fluorine or chlorine atoms and / or any available atoms may be optionally replaced with alternative isotopes thereof.

[0104] In some embodiments, the C3-C7 heterocycloalkyl in Q' is selected from saturated or unsaturated heterocycles. In some embodiments, Q' is selected from aziridinylene, oxiranylene, thiiranylene, oxaziridinylene, dioxiranylene, azetidinylene, oxetanylene, titanylene, diazetidinylene, dioxetanylene, dithietanylene, tetrahydrofuranylene, tetrahydrothiophenylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, isoxathiolidinylene, thiazolidinylene, isothiazolidinylene, dioxolanylene, dithiolanylene, piperidinylene, triazolylene, furazanylene, and selected from oxadiazolylene, thiadiazolylene, oxazolylene, thiazolylene, tetrazolylene, tetrazolylene, tetrahydropyranylene, diazinanylene (e.g., piperazinylene), morpholinylene, thiomorpholinylene, dioxanylene, dithianylene, azepanylene, oxepanylene, thiepanylene, and diazepanylene, wherein all available hydrogen atoms may be optionally replaced by fluorine or chlorine atoms and / or all available atoms may be optionally replaced by their alternative isotopes.

[0105] In some embodiments, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22are each independently selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C4 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C4 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C4 alkylene aryl, and substituted or unsubstituted C1-C4 alkylene heteroaryl, wherein any available hydrogen atoms may be optionally replaced by fluorine or chlorine atoms, and / or any available atoms may be optionally replaced by alternative isotopes thereof.

[0106] In some embodiments, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22 are each independently selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0107] In some embodiments, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R19 , R 20 , R 21 , and R 22 The C3-C7 cycloalkyl in each is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein any available hydrogen atom may be optionally replaced with a fluorine or chlorine atom, and / or any available atom may be optionally replaced with an alternative isotope thereof.

[0108] In some embodiments, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22 The C3-C7 heterocycloalkyl in each is independently selected from saturated or unsaturated heterocycles. 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22C3-C7 heterocycloalkyl in each of the above is independently aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, titanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxathiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, or furazanyl. , oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, and diazepanyl, wherein all available hydrogen atoms may be optionally replaced by fluorine or chlorine atoms, and / or all available atoms may be optionally replaced by their corresponding isotopes.

[0109] In some embodiments, R 9 and R 10 wherein the C3-C7 heterocycloalkyl is independently selected from saturated or unsaturated bridged bicyclic heterocycles. In some embodiments, the saturated or unsaturated bridged bicyclic heterocycles are independently selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl, and oxobicycloheptanenyl, wherein all available hydrogen atoms are optionally replaced with fluorine or chlorine atoms and / or all available atoms are optionally replaced with their corresponding isotopes.

[0110] In some embodiments, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R21 , and R 22 Heteroaryl in each of the above is independently selected from the group consisting of azepinyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxa and thienyl, wherein any available hydrogen atom may be optionally substituted with a fluorine or chlorine atom, and / or any available atom may be optionally substituted with an alternative isotope thereof.

[0111] In some embodiments, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22are each independently selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and substituted or unsubstituted C1-C4 haloalkyl, where any available hydrogen atom may be optionally replaced with a fluorine or chlorine atom, and / or any available atom may be optionally replaced with its corresponding isotope. 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are each independently selected from H, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C4 haloalkyl, where any available hydrogen atom may be optionally replaced with a fluorine or chlorine atom, and / or any available atom may be optionally replaced with an alternative isotope thereof. In some embodiments, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are each independently selected from H, C1-C4 alkyl, and C2-C6 alkenyl, where any available hydrogen atom may be optionally replaced with a fluorine or chlorine atom, and / or any available atom may be optionally replaced with an alternative isotope thereof. In some embodiments, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15, R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are each independently selected from H and C1-C4 alkyl, where any available hydrogen atom may be independently replaced with a fluorine atom or a deuterium atom as appropriate. 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are each independently selected from H, D, CH, CD, H, CDH, CD, CF, CHF, CF, H, CHCH, D, CHCD, H, CHCH, and CDCD. 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are each independently selected from H, D, CH3 and CD3.

[0112] In some embodiments, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R22 are each independently selected from substituted or unsubstituted C1-C4 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C4 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C4 alkylene aryl, and substituted or unsubstituted C1-C4 alkylene heteroaryl, where any available hydrogen atom may be optionally replaced with a fluorine or chlorine atom and / or any available atom may be optionally replaced with an alternative isotope thereof. 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are each independently selected from substituted or unsubstituted C1-C4 alkylenearyl and substituted or unsubstituted C1-C4 alkyleneheteroaryl, where any available hydrogen atom may be optionally replaced with a fluorine or chlorine atom and / or any available atom may be optionally replaced with its corresponding isotope. 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are each independently a substituted or unsubstituted C1-C4 alkylenearyl, where any available hydrogen atoms may be optionally replaced with fluorine or chlorine atoms, and / or any available atoms may be optionally replaced with alternative isotopes thereof. In some embodiments, R 9 , R 10 , R 11 , R 12 , R13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 are each independently substituted or unsubstituted CHaryl, where any available hydrogen atom may be optionally replaced with a fluorine or chlorine atom, and / or any available atom may be optionally replaced with an alternative isotope thereof. In some embodiments, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22 are each independently substituted or unsubstituted CH2 phenyl.

[0113] R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22 is substituted, in some embodiments, the substituents are each independently selected from one or more of Br, Cl, F, COH, COCH, C(O)NH, C(O)N(CH), C(O)NHCH, SOCH, C-C alkyl, C-C fluoroalkyl, C-C alkenyl, C-C fluoroalkenyl, C-C alkynyl, C-C fluoroalkynyl, C-C cycloalkyl, and 3-6 membered heterocyclic rings containing 1-2 ring heteromoieties selected from O, S, S(O), SO, N, NH, and NCH.9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22 The above substituents are independently selected from 1 to 3 of Br, Cl, F, C1-C4 alkyl, C1-C4 fluoroalkyl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, C2-C6 alkynyl, and C2-C6 fluoroalkynyl. 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22 The above substituents are independently selected from one or two of Br, Cl, F, CH3, and CF3.

[0114] In some embodiments, R 9 is selected from H and C1-C4 alkyl, where any available hydrogen atom may be optionally replaced with a fluorine or chlorine atom, and / or any available atom may be optionally replaced with an alternative isotope thereof. In some embodiments, R 9 is selected from H and C1-C4 alkyl, where all available hydrogen atoms may be optionally replaced with fluorine or chlorine atoms, and / or all available hydrogen atoms may be optionally replaced with deuterium. In some embodiments, R 9R' is selected from hydrogen, CH, CHCH, CH(CH) and C(CH), where all available hydrogen atoms may be optionally substituted with fluorine or chlorine atoms, and / or all available hydrogen atoms may be optionally substituted with deuterium. In some embodiments, R 9 R' is selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CFH2, CH2CH3, CH2CH2D, CH2CD2H, CD2CD3, CD(CD3)2, and CH(CH3)2. In some embodiments, R 9 In some embodiments, R' is selected from H, D, CH, CD, CHCH, and CH(CH). 9 In some embodiments, R' is selected from H, D, CH3, and CD3. 9 In some embodiments, R ′ is selected from H and D. 9 In some embodiments, R' is selected from CH3 and CD3. 9 In some embodiments, R' is CD3. 9 ' is H.

[0115] In some embodiments, Q is P(O)(OH) and the compound of Formula I has Formula IA: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, wherein R 1 , R 2 , R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ', R 6 , R 7 and R 8 is as defined in Formula I.

[0116] In some embodiments, Q is CH2P(O)(OH)CH2 and the compound of Formula IB: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, wherein R 1 , R 2 , R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ', R 6 , R 7 and R 8 is as defined in Formula I.

[0117] In some embodiments, Q is C(O)-Q'-C(O) and the compound of Formula I has the formula IC: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, wherein R 1 , R 2 , R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ', R 6 , R 7 , R 8 and Q′ is as defined in Formula I.

[0118] In some embodiments, Q is SO2 and the compound of Formula I has Formula ID: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, wherein R 1 , R 2 , R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ', R 6 , R 7 and R8 is as defined in Formula I.

[0119] In some embodiments, Q is C(O)OQ'OC(O) and the compound of Formula I has the formula IE: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, wherein R 1 , R 2 , R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ', R 6 , R 7 , R 8 and Q′ is as defined in Formula I.

[0120] In some embodiments, Q is C(O)NR 9 'Q'NR 9 'C(O), and the compound of formula I has the formula IF: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, wherein R 1 , R 2 , R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ', R 6 , R 7 , R 8 , R 9 ' and Q' are as defined in Formula I.

[0121] In some embodiments, the compound of Formula I is selected from the compounds listed in Table 1 below, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9]

[0122] In some embodiments, the compound of Formula I is selected from one or more compounds listed in Table 1 or pharmaceutically acceptable salts, solvates and / or prodrugs thereof. In some embodiments, the compound of Formula I is selected from the compounds listed in Table 1 or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, and combinations thereof.

[0123] In some embodiments, the compound of Formula I is cleaved in vivo to provide an active metabolite. Thus, in some embodiments, the present application includes the compound of Formula I and its metabolites. In some embodiments, the present application includes the compound of Formula I or a pharmaceutically acceptable salt, solvate, metabolite, and / or prodrug thereof.

[0124] In some embodiments, the active metabolite has Formula II: [ka] is a compound of [In the formula, R 1 , R 2 , R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ', R 6 , R 7 and R 8 is as defined above for Formula I and its embodiments].

[0125] In some embodiments, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt.The selection of an appropriate salt can be performed by those skilled in the art.Suitable salts include acid addition salts, for example, can be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid (e.g., hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid). Additionally, acids generally considered suitable for forming pharmaceutically useful salts from pharmaceutical basic compounds are discussed, for example, in P. Stahl et al., Camille G. (ed.) and Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley VCH; S. Berge et al., Journal of Pharmaceutical Sciences 1977 66(1)1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (website of the U.S. Food and Drug Administration, Washington, D.C.).

[0126] Acid addition salts suitable for or compatible with the treatment of subjects are any non-toxic organic or inorganic acid addition salts for any basic compound.Basic compounds that form acid addition salts include, for example, compounds containing amino groups.Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acid metal salts, such as sodium hydrogen phosphate and potassium hydrogen sulfate.Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids. Examples of such organic acids include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In some embodiments, exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, cinnamate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate ("mesylate"), naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), and the like. In some embodiments, mono- or di-acid salts are formed, and such salts exist in either hydrate, solvate, or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base forms. The criteria for selecting an appropriate salt will be well known to those skilled in the art. Other pharmaceutically unacceptable salts, such as, but not limited to, oxalates, may be used, for example, in the isolation of compounds of the present application for experimental use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0127] The base addition salt suitable for or compatible with the treatment of the subject is any non-toxic organic or inorganic base addition salt of any acidic compound.A compound that forms a base addition salt includes, for example, a compound containing a carbonyl group.Exemplary inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide, and ammonia.Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.Selecting an appropriate salt may be useful, for example, to prevent the ester functional group of another part of the compound, if present, from being hydrolyzed.The criteria for selecting an appropriate salt will be well known to those skilled in the art.In some embodiments, representative basic salts also include ammonium salts, alkali metal salts (e.g., sodium, lithium, and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), salts containing organic bases (e.g., organic amines) (e.g., dicyclohexylamine, butylamine, choline), and salts containing amino acids (e.g., arginine, lysine). Groups containing a basic nitrogen may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfate), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl bromide and phenethyl bromide), and the like.Compounds having an acidic moiety can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands, such as quaternized ammonium salts. Also, when an acid (—COOH) or alcohol group is present, pharmaceutically acceptable esters can be used to modify the solubility or hydrolysis characteristics of the compound.

[0128] All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of this application, and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of this application. Furthermore, when a compound of this application contains both a basic moiety (e.g., but not limited to, an aliphatic primary, secondary, tertiary, or cyclic amine, an aromatic amine, or a heteroaryl amine, pyridine, or imidazole) and an acidic moiety (e.g., but not limited to, a tetrazole or a carboxylic acid), zwitterions ("internal salts") may be formed and are included within the scope of the term "salt(s)" as used herein. It is understood that some compounds of this application may exist in the form of zwitterions, having both an anionic and a cationic center in the same compound and having a net neutral charge. Such zwitterions are included within the scope of this application.

[0129] Solvates of the compounds of the present application include, for example, those formed using pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvates are called hydrates) and ethanol. Suitable solvents are physiologically acceptable at the dosage administered.

[0130] Prodrugs of the compounds of the present application include, for example, conventional esters formed with available hydroxy, thiol, amino, or carboxyl groups. Some common esters that have been utilized as prodrugs include phenyl esters, aliphatic (C1-C6) esters, and the like. 24) esters, acyloxymethyl esters, carbamates and amino acid esters.

[0131] It is understood and appreciated that in some embodiments, the compounds of the present application may have at least one chiral center and, therefore, may exist as enantiomers and / or diastereomers. All such isomers and mixtures thereof, in all proportions, are encompassed within the scope of the present application. While the stereochemistry of a compound may be as shown in a given compound listed herein, it should be further understood that such compounds may contain a certain amount (e.g., less than 20%, preferably less than 10%, more preferably less than 5%) of compounds of the present application having an alternative stereochemistry. All optical isomers, as separated, pure, or partially pure optical isomers, or racemic mixtures thereof, are intended to be encompassed within the scope of the present application.

[0132] In some embodiments, the compounds of the present application may also include tautomeric forms, such as keto-enol tautomers. The tautomeric forms may be in equilibrium or may be sterically locked into one form by appropriate substitution. Any tautomeric forms that the compounds form, as well as mixtures thereof, are intended to be included within the scope of the present application.

[0133] The compounds of the present application may further exist in various amorphous and polymorphic forms, and any amorphous form, polymorph, or mixture thereof is contemplated and is within the scope of the present application.

[0134] The compounds of the present application may further be radiolabeled, and therefore all radiolabeled forms of the compounds of the present application are included within the scope of the present application. The compounds of the present application also include compounds having one or more radioactive atoms incorporated into their structure.

[0135] III. Composition The compounds of the present application are suitably formulated into compositions using one or more carriers in a conventional manner. Accordingly, the present application also includes compositions comprising one or more compounds of the present application and a carrier. The compounds of the present application are suitably formulated into pharmaceutical compositions for administration to a subject in a biologically compatible form suitable for in vivo administration. Accordingly, the compounds of the present application further include pharmaceutical compositions comprising one or more compounds of the present application and a pharmaceutically acceptable carrier. In an embodiment of the present application, the pharmaceutical composition is used in the treatment of any disease, disorder, or condition described herein.

[0136] The compounds of the present application may be administered to a subject in various forms depending on the route of administration selected, as will be understood by those skilled in the art. For example, the compounds of the present application may be administered orally, by inhalation, parenterally, bucally, sublingually, by insufflation, epidurally, nasally, rectally, intravaginally, by patch, pump, minipump, topically, or transdermally, and the pharmaceutical composition may be formulated accordingly. In some embodiments, the compounds may be administered by pump for periodic or continuous delivery. Conventional procedures and ingredients for selecting and preparing suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000-20 edition) and the United States Pharmacopeia: National Formulary, 1999 (USP 24 NF19).

[0137] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, and includes, for example, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary (e.g., using an aerosol), intrathecal, rectal, and topical (including use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0138] In some embodiments, the compounds of the present application are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or enclosed in a hard or soft shell gelatin capsule, or compressed into tablets, or taken directly with food at mealtimes. In some embodiments, the compounds are incorporated with excipients and used in the form of orally ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions. In the case of tablets, carriers used include lactose, corn starch, sodium citrate, and phosphate salts. Pharmaceutically acceptable excipients include binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), or solvents (e.g., medium-chain triglycerides, ethanol, water). In embodiments, tablets are coated by methods well known in the art. For tablets, capsules, caplets, pellets, or granules for oral administration, pH-sensitive enteric coatings, such as Eudragits™, designed to control the release of active ingredients, may be used as appropriate. Oral dosage forms also include modified release, such as immediate-release and timed-release formulations. Examples of modified release formulations include, for example, sustained release (SR), extended release (ER, XR, or XL), time-release or timed release, controlled release (CR), or continuous release (CR or Contin), used in the form of, for example, coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, agglomerated particles (e.g., as molecular sieve-type particles), or fine hollow permeable fiber bundles, or chopped hollow permeable fibers collected or held together in a fibrous packet.The time-release composition is formulated, for example, as a liposome, or in which the active compound is protected with a differentially degradable coating, for example, by microencapsulation, multilayer coating, etc. Liposomal delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. In some embodiments, liposomes are formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. For oral administration in capsule form, useful carriers, solvents, or diluents include lactose, medium-chain triglycerides, ethanol, and dried corn starch.

[0139] In some embodiments, liquid preparations for oral administration may take the form of, for example, solutions, syrups, or suspensions, or may be suitably provided as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compounds of the present application are suitably suspended or dissolved in an oil phase combined with an emulsifying and / or suspending agent. If desired, several sweetening and / or flavoring and / or coloring agents may be added. Such liquid preparations for oral administration are prepared by conventional means using pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., medium-chain triglycerides, almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0140] For example, it is possible to lyophilize the compounds of the present application and use the resulting lyophilizates for the preparation of injectable products.

[0141] In some embodiments, the compounds of the present application are administered parenterally. For example, solutions of the compounds of the present application are prepared in water, appropriately mixed with a surfactant such as hydroxypropyl cellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof (with or without alcohol), and in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. Those skilled in the art will know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the present application are usually prepared, and the pH of the solution is appropriately adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to make the preparation isotonic. For ophthalmic administration, ointments or instillable liquids are delivered, for example, by ophthalmic delivery systems (e.g., applicators or eyedroppers) known in the art. In some embodiments, such compositions comprise a mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose, or polyvinyl alcohol, a preservative such as sorbic acid, EDTA, or benzyl chromium chloride, and a conventional amount of diluent or carrier. For pulmonary administration, the diluent or carrier will be selected to be appropriate to allow for the formation of an aerosol.

[0142] In some embodiments, the compounds of the present application are formulated for parenteral administration by injection, including the use of conventional catheterization techniques or infusion. Formulations for injection are provided, for example, in unit dosage forms (e.g., in ampoules or multi-dose containers, with an added preservative). In some embodiments, the compositions take the form of a sterile suspension, solution, or emulsion in an oily or aqueous vehicle, and contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. In all cases, they must be sterile and fluid to the extent that they are easily syringable. Alternatively, the compounds of the present application are preferably in sterile powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0143] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels, and powders. For intranasal or inhalation administration, the compounds of the present application are conveniently delivered in the form of a solution, dry powder formulation, or suspension from a pump spray container that is squeezed or pumped onto the patient, or as an aerosol spray from a pressurized container or nebulizer. Aerosol formulations generally comprise a solution or fine suspension of an active compound in a physiologically acceptable aqueous or non-aqueous solvent, and are typically provided in a single or multiple doses in a sterile sealed container (e.g., in the form of a cartridge or refill for use with a spray device). Alternatively, the sealed container may be a single-dose device, such as a single-dose nasal inhaler, or an aerosol dispenser equipped with a metered-dose valve that is intended to be discarded after use. When the dosage form includes an aerosol dispenser, it will contain a propellant, such as a compressed gas, e.g., compressed air, or an organic propellant, e.g., a fluorochlorohydrocarbon. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or other suitable gases. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator are formulated containing, for example, a powder mix of the compound of the present application and a suitable powder base, such as lactose or starch. The aerosol dosage form can also take the form of a pump-atomizer.

[0144] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, in which the compounds of the present application are formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0145] Suppository formulations of the compounds of the present application are useful for vaginal, urethral and rectal administration.Such suppositories will generally be composed of a mixture of materials that are solid at room temperature but melt at body temperature.Materials commonly used to make such vehicles include, but are not limited to, cocoa oil (also known as cocoa butter), glycerin gelatin, other glycerides, hydrogenated vegetable oils, and mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.For further description of suppository dosage forms, see, for example, Remington's Pharmaceutical Sciences, 16th edition, Mack Publishing, Easton, PA, 1980, pp. 1530-1533.

[0146] In some embodiments, the compounds of the present application are conjugated to soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, the compounds of the present application are conjugated to crosslinked or amphiphilic block copolymers of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylic acids, and hydrogels.

[0147] The compounds of the present application are particularly suitable for administration with nanocarrier systems such as liposomes, micelles, nanoparticles, nanoemulsions, lipid nanosystems, etc. (See, e.g., Bhat, M. et al. Chem. And Phys. Of Lipids, 2021, 236, 105053.) Accordingly, the present application includes compositions comprising one or more compounds of the present application and one or more components of a nanocarrier system.

[0148] Although the compounds of the present application, including their pharmaceutically acceptable salts and / or solvates, are suitably used per se, they will generally be administered in the form of a pharmaceutical composition in which one or more compounds of the present application (active ingredients) are combined with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will contain from about 0.05% to about 99% by weight, or from about 0.10% to about 70% by weight, of the active ingredient(s) and from about 1% to about 99.95% by weight, or from about 30% to about 99.90% by weight of the pharmaceutically acceptable carrier (all weight percentages based on the total weight of the composition).

[0149] In some embodiments, the compounds of the present application, including their pharmaceutically acceptable salts and / or solvates, are used in and administered in compositions containing additional therapeutic agents. Thus, the present application also includes pharmaceutical compositions comprising one or more compounds of the present application, or pharmaceutically acceptable salts and / or solvates thereof, and additional therapeutic agents, and optionally one or more pharmaceutically acceptable excipients. In some embodiments, the additional therapeutic agent is another known agent useful for treating diseases, disorders, or conditions by activating serotonin receptors, such as those listed in the methods and uses section below. In some embodiments, the additional therapeutic agent is a psychoactive agent.

[0150] In the above, the term "a compound" also includes embodiments in which more than one compound is referenced.

[0151] IV. Methods and Uses of the Present Application The compounds of the present application are useful for treating diseases, disorders, or conditions by activating serotonin receptors. Therefore, the compounds of the present application are useful as pharmaceuticals. Therefore, the present application also includes the compounds of the present application for use as pharmaceuticals.

[0152] The present application also includes a method of treating a disease, disorder, or condition treated by activation of a serotonin receptor, the method comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof, i.e., a subject having said disease, disorder, or condition.

[0153] The present application also includes the use of one or more compounds of the present application for treating a disease, disorder, or condition that is treated by activation of a serotonin receptor, as well as the use of one or more compounds of the present application for preparing a medicament for treating a disease, disorder, or condition that is treated by activation of a serotonin receptor. The present application further includes one or more compounds of the present application for use in treating a disease, disorder, or condition that is treated by activation of a serotonin receptor.

[0154] In some embodiments, the serotonin receptor is 5-HT2A. Accordingly, the present application includes a method for activating 5-HT2A in a cell (of a biological sample or a patient), the method comprising administering an effective amount of one or more compounds of the present application to the cell. The present application also includes the use of one or more compounds of the present application to activate 5-HT2A in a cell, as well as the use of one or more compounds of the present application to prepare a medicament for activating 5-HT2A in a cell. The present application further includes one or more compounds of the present application for use in activating 5-HT2A in a cell. In some embodiments, the method for activating 5-HT2A is a method within a cell or on the cell surface.

[0155] The present application also includes a method for treating a disease, disorder, or condition that is treated by activation of 5-HT2A, comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof, i.e., a subject having said disease, disorder, or condition. The present application also includes the use of one or more compounds of the present application for treating a disease, disorder, or condition that is treated by activation of 5-HT2A, as well as the use of one or more compounds of the present application for preparing a medicament for treating a disease, disorder, or condition that is treated by activation of 5-HT2A. The present application further includes one or more compounds of the present application for use in treating a disease, disorder, or condition that is treated by activation of 5-HT2A.

[0156] In some embodiments, the compounds of the present application are useful for preventing, treating, and / or reducing the severity of psychiatric disorders and / or conditions in a subject that are treated by activating 5-HT2A. Thus, in some embodiments, the disease, disorder, or condition that is treated by activating serotonin receptors is a psychiatric disorder. Thus, the present application also includes a method for treating a psychiatric disorder, the method comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need of treatment. The present application also includes the use of one or more compounds of the present application for treating a psychiatric disorder, as well as the use of one or more compounds of the present application for preparing a medicament for treating a psychiatric disorder. The present application further includes one or more compounds of the present application for use in treating a psychiatric disorder.

[0157] In some embodiments, the psychiatric disorder is selected from: anxiety disorders, such as generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobias; depression, such as hopelessness, loss of pleasure, fatigue, and suicidal ideation; mood disorders, such as depression, bipolar disorder, cancer-related depression, anxiety, and cyclothymic disorder; psychotic disorders, such as hallucinations, delusions, schizophrenia; impulse control disorders and addictive disorders, such as pyromania (fire-setting), kleptomania (stealing), and compulsive gambling; alcoholism; drug dependence, such as opioid dependence; personality disorders, such as antisocial behavior. Personality disorders, obsessive-compulsive personality disorder and paranoid personality disorder; obsessive-compulsive disorder (OCD), e.g., thoughts or fears that cause the subject to perform some ritualistic or daily activity; post-traumatic stress disorder (PTSD); stress response syndromes (formerly called adjustment disorders); dissociative disorders (formerly called multiple personality disorder, or "split personality," and depersonalization disorder); functional disorders; sexual and gender disorders, e.g., sexual dysfunction, gender identity disorder and paraphilia; somatoform disorders (formerly known as psychosomatic or somatic symptom disorders); and combinations of these.

[0158] In some embodiments, diseases, disorders, or conditions treated by activation of serotonin receptors include: cognitive dysfunction; ischemic stroke; neurodegeneration; refractory substance use disorders; sleep disorders; pain, e.g., social pain, acute pain, cancer pain, chronic pain, breakthrough pain, bone pain, soft tissue pain, neuralgia, referred pain, phantom limb pain, neuropathic pain, cluster headaches, and migraines; obesity and eating disorders; epilepsy and seizure disorders; neuronal cell death; excitotoxic cell death; or combinations thereof.

[0159] In some embodiments, the psychiatric disorder is selected from hallucinations and delusions, and combinations thereof.

[0160] In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, and chronoceptive hallucinations, and combinations thereof.

[0161] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is psychosis or a psychotic condition. Accordingly, the present application also includes a method of treating psychosis or a psychotic condition, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application.

[0162] The present application also includes the use of one or more compounds of the present application for treating psychosis or psychotic symptoms, as well as the use of one or more compounds of the present application for preparing a medicament for treating psychosis or psychotic symptoms. The present application further includes one or more compounds of the present application for use in treating psychosis or psychotic symptoms.

[0163] In some embodiments, administering a therapeutically effective amount of a compound of the present application to the subject in need of treatment does not worsen psychosis or psychotic symptoms (such as, but not limited to, hallucinations and delusions). In some embodiments, administering a therapeutically effective amount of a compound of the present application to the subject in need of treatment ameliorates psychosis or psychotic symptoms (such as, but not limited to, hallucinations and delusions). In some embodiments, administering a therapeutically effective amount of a compound of the present application to the subject in need of treatment ameliorates psychosis or psychotic symptoms.

[0164] In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a disease, disorder, or condition of the central nervous system (CNS) and / or a neurological disease, disorder, or condition. Accordingly, the present application also includes a method for treating a disease, disorder, or condition of the CNS and / or a neurological disease, disorder, or condition treated by activating serotonin receptors, comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof (i.e., a subject having a disease, disorder, or condition of the central nervous system (CNS) and / or a neurological disease, disorder, or condition). The present application also includes the use of one or more compounds of the present application to treat a disease, disorder, or condition of the CNS and / or a neurological disease, disorder, or condition treated by activating serotonin receptors, as well as the use of one or more compounds of the present application to prepare a medicament for treating a disease, disorder, or condition of the CNS and / or a neurological disease, disorder, or condition treated by activating serotonin receptors. The present application further includes one or more compounds of the present application for use in the treatment of a disease, disorder or condition of the CNS and / or a neurological disease, disorder or condition that is treated by activation of a serotonin receptor.

[0165] In some embodiments, the CNS disease, disorder or condition and / or neurological disease, disorder or condition is selected from neurological diseases, including neurodevelopmental and neurodegenerative diseases, such as Alzheimer's disease; presenile dementia; senile dementia; vascular dementia; dementia with Lewy bodies; cognitive impairment, Parkinson's disease and Parkinson's disease-related disorders, such as Parkinsonism, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disorders; Fragile X syndrome; Angelman syndrome; genetic disorders. These conditions include ataxia; neuro-otological and oculomotor disorders; retinal neurodegenerative diseases; amyotrophic lateral sclerosis; tardive dyskinesia; hyperkinetic disorder; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette's syndrome; schizophrenia; autism spectrum disorder; tuberous sclerosis; Rett's syndrome; cerebral palsy; eating disorders, such as reward system disorders including anorexia nervosa ("AN") and bulimia nervosa ("BN"); and binge eating disorder ("BED"), trichotillomania, excoriation disorder, nail biting; migraine; fibromyalgia; and peripheral neuropathies of any etiology, and combinations thereof.

[0166] In some embodiments, the subject is a mammal. In other embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. Thus, the compounds, methods, and uses of the present application are directed to diseases, disorders, and conditions in both human and veterinary medicine.

[0167] In some embodiments, a "subject in need thereof" is a subject having a disease, disorder, or condition to be treated.

[0168] In some embodiments, the compounds of the present application are useful for treating behavioral problems in subjects that are cats or dogs.

[0169] Thus, in some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is problem behavior in a cat or dog subject. Thus, the present application also includes a method for treating problem behavior, comprising administering a therapeutically effective amount of one or more compounds of the present application to a non-human subject in need thereof (i.e., a subject with problem behavior). The present application also includes the use of one or more compounds of the present application to treat problem behavior in a non-human subject, as well as the use of one or more compounds of the present application to prepare a medicament for treating problem behavior in a non-human subject. The present application further includes one or more compounds of the present application for use in treating problem behavior in a non-human subject.

[0170] In some embodiments, the problem behavior is selected from, but not limited to, anxiety, fear, stress, sleep disorders, cognitive impairment, aggression, excessive fussing, scratching, biting, and combinations thereof.

[0171] In some embodiments, the non-human subject is a dog. In some embodiments, the non-human subject is a cat.

[0172] The present application also includes a method for treating a disease, disorder, or condition by activating serotonin receptors, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application in combination with other known agents useful for treating the disease, disorder, or condition by activating serotonin receptors. The present application also includes the use of one or more compounds of the present application in combination with other known agents useful for treating the disease, disorder, or condition by activating serotonin receptors to treat a disease, disorder, or condition that is treated by activating serotonin receptors, as well as the use of one or more compounds of the present application in combination with other known agents useful for treating the disease, disorder, or condition by activating serotonin receptors to prepare a medicament for treating a disease, disorder, or condition that is treated by activating serotonin receptors. The present application further includes one or more compounds of the present application for use in combination with other known agents useful for treating the disease, disorder, or condition by activating serotonin receptors in the treatment of a disease, disorder, or condition by activating serotonin receptors.

[0173] In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a psychiatric disorder. In some embodiments, the psychiatric disorder is selected from hallucinations and delusions, and combinations thereof. In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a disorder of the central nervous system (CNS). In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is psychosis or a psychotic symptom. In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is problematic behavior in non-human subjects.

[0174] In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a psychiatric disorder, and one or more compounds of the present application are administered in combination with one or more additional treatments for the psychiatric disorder.In some embodiments, the additional treatment for the psychiatric disorder is selected from antipsychotic drugs, including typical and atypical antipsychotic drugs; antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs) (e.g., bupropion), and GABAA receptor allosteric modulators (including but not limited to inhibitory pregnane neurosteroids, such as zuranolone and brexanolone); antianxiety drugs, including benzodiazepines such as alprazolam; mood stabilizers such as lithium, and anticonvulsants such as carbamazepine, dipalproex (valproic acid), lamotrigine, gabapentin and topiramate. In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a psychiatric disorder, and one or more compounds of the present application are administered in combination with one or more additional treatments for the psychiatric disorder. In some embodiments, the additional treatment for the psychiatric disorder is selected from antipsychotic drugs, including typical and atypical antipsychotic drugs; antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) (e.g., bupropion); antianxiety drugs, including benzodiazepines such as alprazolam; mood stabilizers, such as lithium, and anticonvulsants, such as carbamazepine, dipalproex (valproic acid), lamotrigine, gabapentin and topiramate.

[0175] In some embodiments, the disease, disorder or condition that is treated by activating serotonin receptor is selected from attention deficit hyperactivity disorder and attention deficit disorder, and combinations thereof.In some embodiments, the disease, disorder or condition that is treated by activating serotonin receptor is selected from attention deficit hyperactivity disorder and / or attention deficit disorder, and combinations thereof, and one or more compounds of the present application are administered in combination with one or more additional treatments for attention deficit hyperactivity disorder and / or attention deficit disorder, and combinations thereof.In some embodiments, the one or more additional treatments for attention deficit hyperactivity disorder and / or attention deficit disorder, and combinations thereof are selected from methylphenidate, atomoxetine and amphetamine, and combinations thereof.

[0176] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is dementia or Alzheimer's disease, and one or more compounds of the present application are administered in combination with one or more additional treatments for dementia or Alzheimer's disease. In some embodiments, the additional treatments for dementia and Alzheimer's disease are selected from an acetylcholinesterase inhibitor, an NMDA antagonist, a muscarinic agonist, a muscarinic antagonist, and a nicotinic agonist.

[0177] In some embodiments, the acetylcholinesterase inhibitor is selected from donepezil, galantamine, rivastigmine, and phenserine, and combinations thereof.

[0178] In some embodiments, the NMDA antagonist is selected from MK-801, ketamine, phencyclidine, and memantine, and combinations thereof.

[0179] In some embodiments, the nicotinic agonist is nicotine, nicotinic acid, a nicotinic alpha 7 agonist, or an alpha 2 beta 4 agonist, or a combination thereof.

[0180] In some embodiments, the muscarinic agonist is a muscarinic M1 agonist or a muscarinic M4 agonist, or a combination thereof.

[0181] In some embodiments, the muscarinic antagonist is a muscarinic M2 antagonist.

[0182] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is psychosis or a psychotic condition, and one or more compounds of the present application are administered in combination with one or more additional treatments for the psychosis or psychotic condition. In some embodiments, the additional treatment for the psychosis or psychotic condition is selected from a typical antipsychotic and an atypical antipsychotic.

[0183] In some embodiments, the typical antipsychotic is acepromazine, acetophenazine, benperidol, bromperidol, butaperazine, carphenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, dixyrazine, droperidol, fluanisone, flupenthixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, lenperone, loxapine, mesoridazine, methytepin, molindone, mope The active ingredient is selected from the group consisting of thiazol-3, thiazol-4, thiazol-5, thiazol-6, thiazol-7, thiazol-8, thiazol-9, thiazol-10, thiazol-11, thiazol-12, thiazol-13, thiazol-14, thiazol-15, thiazol-16, thiazol-17, thiazol-18, thiazol-19, thiazol-20, thiazol-21, thiazol-22, thiazol-23, thiazol-24, thiazol-25, thiazol-26, thiazol-27, thiazol-28, thiazol-29, thiazol-30, thiazol-31, thiazol-32, thiazol-33, thiazol-34, thiazol-35, thiazol-36, thiazol-37, thiazol-38, thiazol-40, thiazol-41, thiazol-42, thiazol-43, thiazol-44, thiazol-45, thiazol-46, thiazol-47, thiazol-48, thiazol-49, thiazol-50, thiazol-51, thiazol-52, thiazol-53, thiazol-54, thiazol-55, thiazol-56, thiazol-57, thiazol-58, thiazol-59, thiaz

[0184] In some embodiments, the atypical antipsychotic is selected from amoxapine, amisulpride, aripiprazole, asenapine, blonanserin, brexpiprazole, cariprazine, carpipramine, clocapramine, chlorothepine, clotiapine, clozapine, iloperidone, levosulpiride, lurasidone, melperone, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpiride, sultopride, tiapride, veralipride, ziprasidone, and zotepine, and combinations thereof.

[0185] In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a psychiatric disorder, and one or more compounds of the present application are administered in combination with one or more additional treatments for the psychiatric disorder. In some embodiments, the additional treatment for the psychiatric disorder is selected from a typical antipsychotic and an atypical antipsychotic.

[0186] In some embodiments, an effective amount varies depending on factors such as the disease state, age, sex, and / or weight of the subject or species. In some embodiments, the amount of a given compound, or the amount of a compound that corresponds to an effective amount, will vary depending on factors such as the given agent(s) or compound(s), pharmaceutical formulation, route of administration, condition, type of disease or disorder, identity of the subject being treated, etc., but can nevertheless be routinely determined by one of ordinary skill in the art.

[0187] In some embodiments, the compound of the present application is administered once, twice, three times, or four times per year. In some embodiments, the compound of the present application is administered at least once per week. However, in other embodiments, the compound is administered to a subject from about once per two weeks, three weeks, or month. In other embodiments, the compound is administered from about once per week to about once per day. In other embodiments, the compound is administered 1, 2, 3, 4, 5, or 6 times per day. The length of treatment depends on various factors, such as the severity of the disease, disorder, or condition, the age of the subject, the concentration and / or activity of the compound of the present application, and / or a combination thereof. It will also be understood that the effective dosage of the compound used for treatment may increase or decrease during a particular treatment regimen. Dosage variations will occur and be evident using standard diagnostic assays known in the art. In some cases, long-term administration is necessary. For example, the compound is administered to a subject in an amount and for a duration sufficient to treat the subject.

[0188] In some embodiments, the compounds of the present application are administered at a hallucinogenic or psychotomimetic dose, taken in conjunction with psychotherapy or therapy, and may be administered once, twice, three times, or four times per year. However, in some embodiments, the compounds are administered to a subject at a dose that is not hallucinogenic or psychotomimetic, once per day, once every two days, once per three days, once per week, once every two weeks, once per month, once every two months, or once per three months.

[0189] The compounds of the present application may be used alone or in combination with other known agents (e.g., compounds of the present application) that are useful for treating diseases, disorders, or conditions by activating serotonin receptors. When used in combination with other known agents that are useful for treating diseases, disorders, or conditions by activating serotonin receptors, it is an embodiment for the compounds of the present application to be administered simultaneously with those agents. As used herein, "co-administration" of two substances to a subject means providing the two substances, respectively, so that both are active in the individual at the same time. The exact details of administration depend on the pharmacokinetics of the two substances in the presence of each other, but may include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of the other, if the pharmacokinetics are suitable. Designing an appropriate dosing regimen is a routine task for those skilled in the art. In certain embodiments, the two substances are administered substantially simultaneously, i.e., within a few minutes of each other, or in a single composition containing both substances. It is a further embodiment of the present application that the combination of drugs is administered to a subject non-simultaneously. In some embodiments, the compounds of the present application are administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or are administered together in a single unit dosage form. Thus, the present application provides a single unit dosage form comprising one or more compounds of the present application, an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0190] The dosage of the compounds of the present application varies depending on many factors, including the pharmacokinetic properties of the compound, the mode of administration, the age, health, and weight of the recipient, the nature and severity of symptoms, the frequency of treatment and type of concurrent treatment (if any), and the clearance rate of the compound in the treated subject. Those skilled in the art can determine appropriate dosages based on the above factors. In some embodiments, one or more compounds of the present application are initially administered at an appropriate dosage, and the dosage is adjusted as needed depending on the clinical response. Dosages are generally selected to maintain serum levels of one or more compounds of the present application between about 0.01 μg / cc and about 1000 μg / cc, or between about 0.1 μg / cc and about 100 μg / cc. Typically, oral dosages of one or more compounds of the present application range from about 10 μg / day to about 1000 mg / day, preferably about 10 μg / day to about 500 mg / day, and more preferably about 10 μg / day to about 200 mg / day for adults. For parenteral administration, a typical dose would be about 0.0001 mg / kg to about 10 mg / kg, about 0.0001 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, or about 0.0001 mg / kg to about 0.01 mg / kg. For oral administration, a typical dose would be about 0.001 μg / kg to about 10 mg / kg, about 0.1 μg / kg to about 10 mg / kg, about 0.01 μg / kg to about 1 mg / kg, or about 0.1 μg / kg to about 1 mg / kg. For administration in suppository form, a typical dose would be about 0.1 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. In some embodiments of the present application, the compositions are formulated for oral administration, and the one or more compounds are preferably in tablet form, with each tablet containing 0.1, 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the active ingredient (one or more compounds of the present application).In some embodiments of the present application, one or more compounds of the present application are administered in a dose once daily, once weekly, or once monthly, or the total daily dose is divided into two, three, or four doses per day.

[0191] In some embodiments, the compounds of the present application are used or administered in an effective amount, including administering a dose or dosage regimen that lacks clinically meaningful hallucinogenic / psychotometic effects. In some embodiments, the compounds of the present application are used or administered in an effective amount, including administering a dose or dosage regimen that provides a clinical effect manifested by a human plasma psilocin Cmax of 4 ng / mL or less and / or a human 5-HT2A human CNS receptor occupancy of 40% or less, or a clinical effect similar to a clinical effect manifested by a human plasma psilocin Cmax of 1 ng / mL or less and / or a human 5-HT2A human CNS receptor occupancy of 30% or less. In some embodiments, the compounds of the present application are used or administered in an effective amount, including administering a dose or dosage regimen that provides a clinical effect similar to a clinical effect manifested by a human plasma psilocin Tmax of greater than 60 minutes, greater than 120 minutes, or greater than 180 minutes.

[0192] For clarity, in the above, the term "a compound" includes embodiments in which more than one compound is referenced. Similarly, the term "compounds of the present application" includes embodiments in which only one compound is referenced.

[0193] V. Compound Preparation The compounds of the present application can be prepared by a variety of synthetic processes. The selection of certain structural features and / or substituents may influence the selection of one process over another. The selection of a particular process for preparing a given compound of the present application is within the skill of one of ordinary skill in the art. Some starting materials for preparing the compounds of the present application are available from commercial chemical sources or may be extracted from cells, plants, animals, or fungi. Other starting materials are readily prepared from available precursors using simple transformations well known in the art, for example, as described below. In the following schemes illustrating some embodiments of methods for preparing the compounds of the present application, all variables are as defined in Formula I unless otherwise specified.

[0194] In some embodiments of the present application, the compounds of the present application are generally prepared according to the processes shown in Schemes I-V.

[0195] In some embodiments, Q is P(O)OR 9 and R 9 Compounds of formula (I) where is H are prepared as shown in Scheme I. That is, a compound of formula A is reacted with a phosphorylating agent, such as phosphoryl chloride, in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane, to provide a compound of formula I. [ka]

[0196] In some embodiments, as shown in Scheme I, compounds of Formula I are provided using reaction conditions found, for example, in CN102382135 (Faming Zhuanli Shenqing) and Mondal et al, Tetrahedron Letters, 58(25), 2460-2464; 2017.

[0197] In some embodiments, Q is C1-C6 alkylene-P(O)OR 9 -C1-C6 alkylene, and R 9Compounds of formula (I), wherein is H, are prepared as shown in Scheme II, namely, reacting a compound of formula A with a compound of formula B in the presence of a suitable base, such as a sodium base, in a suitable solvent, such as dimethylformamide, at a suitable temperature, such as about 140° C., to provide a compound of formula I. [ka]

[0198] In some embodiments, as shown in Scheme II, compounds of Formula I are provided using reaction conditions found, for example, in Mukhametzyanova et al., Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, Issue: 2, Pages: 373-80, 1969.

[0199] In some embodiments, compounds of Formula I, where Q is C(O)Q'C(O), are prepared as shown in Scheme III: a compound of Formula A is reacted with a compound of Formula C in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane, at a suitable temperature, such as from about 0°C to about room temperature (e.g., from about 18°C to about 25°C), to provide a compound of Formula I. [ka]

[0200] In some embodiments, as shown in Scheme III, compounds of Formula I are provided using reaction conditions found, for example, in Derosa J. et al., Journal of the American Chemical Society, 2021 Volume 143, Issue 25, pp 9303-9307.

[0201] In some embodiments, Q is C(O)OQ'OC(O) or C(O)NR 9 'Q'NR 9Compounds of formula I that are 'C(O) are prepared as shown in Scheme III, except using the appropriate compound of formula C.

[0202] In some embodiments, compounds of formula I where Q is C(O) are prepared as shown in Scheme IV: a compound of formula A is reacted with a compound of formula D (a triphosphene) in the presence of a suitable base, such as triethylamine and sodium hydroxide, in a suitable solvent, such as dichloromethane and HO, at a suitable temperature, such as with heating (e.g., above about 25° C.), to provide a compound of formula I. [ka]

[0203] In some embodiments, as shown in Scheme IV, compounds of Formula I are provided using reaction conditions found, for example, in Guangzhou Huagong, 39(14), 81-82; 201.

[0204] In some embodiments, compounds of Formula (I) where Q is SO2 are prepared as shown in Scheme V. That is, a compound of Formula A is reacted with N,N'-sulfuryldiimidazole E1 in the presence of a suitable base, such as cesium carbonate, in a suitable solvent, such as tetrahydrofuran, at a suitable temperature, such as from about reflux to about room temperature (e.g., from about 70°C to about 25°C), to provide a compound of Formula I, and / or sulfuryl chloride E2 is used to provide a compound of Formula I. [ka]

[0205] In some embodiments, as shown in Scheme V, compounds of Formula I are provided using reaction conditions found, for example, in Guan, Bing-Tao et al., Organic Letters, 12(2), 396-399; 2010 and / or Younker, Jarod M., Journal of Organic Chemistry, 69(26), 9043-9048; 2004.

[0206] In some embodiments, compounds of formula A are prepared using known methods, for example, using the synthetic procedures found in WO2021 / 155468A1 (Mindset Pharma Inc.).

[0207] Those skilled in the art will appreciate that, using known chemistry, further substituent modifications can be performed on the intermediate and final compounds in the above schemes to provide alternatives to the compounds of the present application.

[0208] Salts of the compounds of the present application may be formed by methods known to those skilled in the art, such as by reacting a compound of the present application with an amount (e.g., equivalent) of an acid or base in a medium (e.g., a medium in which the salt precipitates) or in an aqueous medium, followed by lyophilization.

[0209] The formation of solvates varies depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in an appropriate solvent and isolating the solvate by cooling or using an anti-solvent. The solvate is typically dried or azeotroped under ambient conditions. Selection of appropriate conditions for forming a particular solvate can be made by one of ordinary skill in the art. Examples of suitable solvents are ethanol, water, etc. When water is the solvent, the molecule is referred to as a "hydrate." The formation of solvates of the compounds of the present application varies depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in an appropriate solvent and isolating the solvate by cooling or using an anti-solvent. The solvate is typically dried or azeotroped under ambient conditions. Selection of appropriate conditions for forming a particular solvate can be made by one of ordinary skill in the art.

[0210] Isotopically enriched compounds of the present application and pharmaceutically acceptable salts, solvates and / or prodrugs thereof can be prepared without undue experimentation by conventional methods well known to those skilled in the art, or by processes analogous to those described in the schemes and examples herein, using appropriate isotopically enriched reagents and / or intermediates.

[0211] It should be understood that throughout the processes described herein, suitable protecting groups are added, and subsequently removed, where appropriate, to the various reactants and intermediates in a manner readily understood by those of skill in the art. Conventional procedures for using such protecting groups, as well as examples of suitable protecting groups, are described, for example, in "Protective Groups in Organic Synthesis," T.W. Green, P.G.M. Buts, Wiley-Interscience, New York, (1999). It should also be understood that the conversion of groups or substituents to other groups or substituents by chemical manipulation may be performed on any intermediate or final product along the synthetic route to the final product, and that the types of transformations possible are limited only by the inherent incompatibility of other functionality possessed by the molecule at that stage with the conditions or reagents used in said transformation. Such inherent incompatibilities, and how to circumvent them by performing appropriate transformations and synthetic steps in a suitable order, will be readily understood by those of skill in the art. While examples of transformations are given herein, it should be understood that the described transformations are not limited to only the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are provided in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations" by R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions can be found in organic chemistry textbooks, such as "Advanced Organic Chemistry", March, 4th Edition, McGraw Hill (1992) or "Organic Synthesis", Smith, McGraw Hill, (1994).

[0212] Nucleophilic substitution reaction conditions include any known method for a reaction in which a nucleophile displaces a leaving group to form a bond, and may be used to prepare the intermediates and products shown in the schemes above or to prepare compounds of the present application. In some embodiments, such conditions include combining the reagents in a suitable solvent in the presence of a base.

[0213] Techniques for purifying intermediates and final products include, for example, normal and reverse phase chromatography using columns or spinning plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, and will be readily understood by those skilled in the art. [Example]

[0214] The following non-limiting examples are illustrative of the present application.

[0215] A. Synthesis Protocol General Procedure All starting materials used herein are either commercially available or have been previously described in the literature. 1 H and 13 C NMR spectra were recorded on either a Bruker 300, Bruker DPX 400 or Varian + 400 spectrometer, respectively. 1 The H NMR was operated at 300 MHz, 400 MHz, and 400 MHz, with TMS or residual solvent signals used as internal reference; the solvent was deuterated chloroform unless otherwise noted. All chemical shifts reported are in ppm on the delta scale; where fine splitting of signals occurs in the recording, they are designated, for example, s: singlet, br s: broad singlet, d: doublet, t: triplet, q: quatlet, m: multiplet. Unless otherwise noted, in the tables below: 1 1 H NMR data was obtained at 400 MHz using CDCl 3 as the solvent.

[0216] Product purification is performed using Chem Elut Extraction Columns (Varian, cat#1219-8002), Mega BE-SI (Bond Elut Silica) SPE Columns (Varian, cat#12256018; 12256026; 12256034), or by flash chromatography in silica-packed glass columns.

[0217] Synthesis of exemplary compounds of the present application Example 1: Bis(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)glutarate (I-24) [ka] Synthesis of 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (2): A solution of 4-(benzyloxy)-1H-indole (3.77 g, 16.88 mmol) in anhydrous ether (100 mL) was treated dropwise with oxalyl chloride (1.43 mL, 16.88 mmol) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 3 h. The reaction was cooled to 0 °C and treated with dimethylamine solution (42.2 mL, 84.41 mmol, 2 M solution in THF) for 5 min. The reaction was allowed to warm to room temperature and stirred overnight (18 h). The reaction was quenched with water (100 mL) and the product was extracted into ethyl acetate (2 × 100 mL). The combined ethyl acetate layers were washed with brine (50 mL) and dried (NaSO). The solvent was evaporated and the crude product was purified by flash silica gel column chromatography (MeOH:CH 2 Cl 2 , 2:98) to give the title compound 2 (3.7 g, 68%) as a light brown solid. 1H NMR (CDCl3): δ 10.14 (s,1H),7.56-7.53 (m,3H),7.41-7.29 (m,3H),7.05 (t,1H,J = 6.0 Hz),6.90 (d,1H,J = 6.0 Hz),6.65 (d,1H,J = 6.0 Hz),5.26 (s,2H),2.97 (s,3H),2.92 (s,3H); ESI-MS (m / z,%): 345 (M+Na),323 (MH + ,100).

[0218] Synthesis of 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethylethan-1-amine (3): A suspension of lithium aluminum hydride (3.32 g, 87.60 mmol) in anhydrous THF (50 mL) was treated with 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (3.53 g, 10.95 mmol) in anhydrous THF (50 mL) at 0° C. for 10 minutes. The reaction was allowed to warm to room temperature and refluxed for an additional 16 hours. The reaction was cooled to 0° C. and quenched by the sequential addition of water (3.3 mL), 2N NaOH solution (3.3 mL), and water (3.3 mL). The reaction was allowed to warm to room temperature and stirred for 30 minutes. The solid was filtered and washed with THF (2×50 mL). The combined THF layers were evaporated and the crude product was purified by silica gel column chromatography (2M NH3 / MeOH:CH2Cl2, 5:95) to give the title compound 3 (2.85 g, 88.5%) as a tan solid. 1 H NMR (DMSO-d6): δ 10.76 (s,1H),7.55-7.53 (m,2H),7.42-7.39 (m,2H),7.35-7.32 (m,1H),6.99-6.92 (m,3H),6.56-6.51 (m,1H),5.17 (s,2H),2.94-2.90 (m,2H),2.49-2.45 (m,2H),2.06 (s,6H); ESI-MS (m / z,%): 295 (MH + ,100).

[0219] Synthesis of bis(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)glutarate dihydrochloride (I-24): A solution of 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethylethan-1-amine (1.7 g, 5.87 mmol) in MeOH (50 mL) was treated with palladium on carbon (0.6 g, 10% dry basis) and hydrogenated at 40 PSI using a Paar apparatus for 1 hour. The reaction was filtered through a pad of Celite and washed with methanol (2 x 25 mL). The combined methanol layers were evaporated and the crude product was dissolved in anhydrous THF (50 mL). The reaction mixture was treated with EtN (1.93 mL, 13.97 mmol), followed by a solution of glutaroyl chloride (0.35 mL, 2.79 mmol) in anhydrous THF (20 mL) at 0 °C over 10 minutes. The reaction was allowed to warm to room temperature and stirred overnight (16 hours). The reaction was quenched with water (100 mL), and the product was extracted into ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (25 mL) and dried (NaSO). The solvent was evaporated, and the crude product was purified by flash silica gel column chromatography (2 M NH / MeOH:CHCl, 5:95 to 1:9) to afford the title compound I-24 (0.65 g, 46%) as a pale yellow oil, which was converted to the dihydrochloride salt using HCl / ether (2 M). 1 H NMR (HCl salt,DMSO-d6): δ 11.30 (s,2H),10.64 (s,2H),7.31-7.28 (m,4H),7.12-7.05 (m,2H),6.87-6.75 (m,2H),3.41-3.33 (m,4H),3.16-3.12 (m,4H),3.03 (t,4H,J = 6.0 Hz),2.86-2.81 (m,12H),2.14-2.07 (m,2H); ESI-MS (m / z,%): 505 (MH + ,100).

[0220] Example 2: Synthesis of bis(3-(2-(diisopropylamino)ethyl)-1H-indol-4-yl)glutarate dihydrochloride (I-37) [ka] Synthesis of 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-diisopropyl-2-oxoacetamide (5): A solution of 4-(benzyloxy)-1H-indole (10.0 g, 44.78 mmol) in anhydrous THF (150 mL) was treated with oxalyl chloride (3.79 mL, 44.78 mmol) at 0° C. The reaction was allowed to warm to room temperature and stirred for an additional 5 hours. The reaction was cooled to 0° C. and treated with diisopropylamine (19.0 mL, 134.35 mmol) for 5 minutes. The reaction was allowed to warm to room temperature and stirred overnight (16 hours). The reaction was worked up and purified as described for compound 2 to afford the title compound 5 (13.37 g, 79%) as a yellow solid. 1 H NMR (DMSO-d6): δ 12 13 (s,1H),7.88 (s,1H),7.68 (d,1H,J = 6.0 Hz),7.39-7.36 (m,2H),7.30-7.26 (m,1H),7.20-7.12 (m,2H),6.81 (d,1H,J = ESI-MS (m / z,%): 438 (100),401 (M+Na),379 (MH + ).

[0221] Synthesis of N-(2-(4-(benzyloxy)-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine (6): A solution of 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-diisopropyl-2-oxoacetamide (10.0 g, 31.02 mmol) in anhydrous THF (200 mL) was treated with LiAlH (9.4 g, 248.17 mmol) over 15 minutes at 0 °C. The reaction was allowed to warm to room temperature and then stirred overnight (16 hours). The reaction was worked up and purified as described for compound 3 to give the title compound 6 (6.8 g, 74.5%) as a light brown glue. 1H NMR (DMSO-d6): δ 10.75 (s,1H),7.54-7.50 (m,2H),7.41-7.30 (m,3H),6.98-6.89 (m,3H),6.50 (s,1H),5.20 (s,2H),2.93-2.85 (m,4H),2.65-2.60 (m,2H),0.97-0.88 (m,12H); ESI-MS (m / z,%): 351 (MH + ,100).

[0222] Synthesis of bis(3-(2-(diisopropylamino)ethyl)-1H-indol-4-yl)glutarate dihydrochloride (I-37): A solution of N-(2-(4-(benzyloxy)-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine (2.01 g, 5.74 mmol) in MeOH (50 mL) was treated with palladium on carbon (0.5 g, 10% dry basis) and hydrogenated at 40 PSI using a Paar apparatus for 1 hour. The reaction was filtered through a pad of Celite and washed with methanol (2 × 25 mL). The combined methanol layers were evaporated and the resulting crude product was dissolved in anhydrous THF (50 mL). The reaction mixture was treated with EtN (1.44 mL, 10.44 mmol) followed by glutaroyl chloride (0.33 mL, 2.61 mmol) in anhydrous THF (20 mL) at 0 °C over 10 minutes. The reaction was allowed to warm to room temperature and stirred overnight (16 hours). The reaction was worked up and purified as described for compound I-24 to afford the title compound I-37 (0.45 g, 28%) as a pale yellow oil that was converted to the dihydrochloride salt using HCl / ether (2M). 1H NMR (HCl salt,DMSO-d6): δ 11.32 (s,2H),9.73 (s,2H),7.40 (s,2H),7.29 (d,2H,J = 6.0 Hz),7.12-7.06 (m,2H),6.74 (d,2H,J = 6.0 ESI-MS (m / z,%): 617 (MH + ,100).

[0223] The following compounds were prepared in an analogous manner using one or more of the synthetic methods summarized in Schemes I-V and Examples 1 and 2: [Table 10] [Table 11] [Table 12] [Table 13]

[0224] B. Biological Testing Example 3: Human 5-HT2A: Functional FLIPR Assay the purpose: In the agonist mode, we evaluated the potential excitatory effects of compounds targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A). 1 Materials and equipment [Table 14] [Table 15] [Table 16]

[0225] 2. Experimental Method 2.1 Cell culture HTR2A&Gα15-HEK293 cells were cultured in DMEM medium containing 10% dialyzed FBS, 1x penicillin-streptomycin, 100 μg / mL hygromycin B, and 300 μg / mL G418. Cells were subcultured approximately three times a week and maintained at approximately 30% to 90% confluence.

[0226] 2.2 Cell plating 1. Cell culture medium (DMEM medium containing 10% dialyzed FBS and 1× penicillin-streptomycin, 100 μg / mL hygromycin B, and 300 μg / mL G418), TrypLE™ Express, and DPBS were pre-warmed to room temperature.

[0227] 2. For expression induction, 1 μg / ml tetracycline (final concentration) was added to the cell culture medium and incubated at 37°C, 5% (v / v) CO2 for 48 hours before seeding the cells on plates. The cell culture medium was removed from the flasks. The cells were washed with DPBS.

[0228] 3. 2 mL of TrypLE™ Express was added to the flask, gently shaken to mix well, and the cells were incubated at 37° C. for a few minutes.

[0229] 4. The morphological changes of the cells were confirmed under a microscope, and when the majority of the cells had become round, 4 mL of cell culture medium was added to the flask to stop the digestion.

[0230] 5. The cell suspension was transferred to a 15 mL centrifuge tube and then centrifuged at 1,200 rpm for 5 minutes.

[0231] 6. The supernatant was removed and the cell pellet was resuspended in 2 mL of cell culture medium.

[0232] 7. Cell density was counted using a cell counter. Only cells with viability greater than 85% were used in the assay.

[0233] 8. The cells were diluted to 6.67 x 105 / mL using cell culture medium.

[0234] 9. 30 μL / well of the cell suspension was added to a 384-well cell plate (cell density was 20,000 cells / well).

[0235] 10. The cell plates were incubated overnight at 37°C under 5% (v / v) CO2.

[0236] 2.3 Cell handling 1. On the day of the experiment, the culture medium was removed from the cell plates.

[0237] 2. 10 μL of assay buffer (20 mM HEPES in 1×HBSS, pH 7.4) was added to each well of the cell plate.

[0238] 3. 2x dye solution was prepared according to the FLIPR® Calcium 6 Assay Kit manual:

[0239] i. The dye was diluted using assay buffer.

[0240] ii. Probenecid was added to a final concentration of 5 mM.

[0241] iii. Vortex vigorously for 1-2 minutes.

[0242] 4. 10 μL of 2× dye solution was added to each well of the cell plate.

[0243] 5. The cell plate was placed on a plate shaker and shaken at 600 rpm for 2 minutes.

[0244] 6. The plate was incubated at 37°C for 2 hours, followed by an additional 15 minutes at 25°C.

[0245] 2.4 Preparation of 3x Compound 1. Serotonin HCl was prepared at a concentration of 10 mM using DMSO.

[0246] 2. Test compounds were prepared at a concentration of 10 mM using DMSO.

[0247] 3. Compounds were added to a 384-well compound source plate.

[0248] [4. A 3-fold dilution series was prepared using DMSO.

[0249] 5. Using the Echo, 90 nL / well of serially diluted compounds was transferred from the source plate to the 384-well compound plate.

[0250] 6. 30 μL / well of assay buffer (20 mM HEPES / 1×HBSS, pH 7.4) was added to the compound plate.

[0251] 7. The plate was mixed on a plate shaker for 2 minutes.

[0252] 2.5 FLIPR assay 1. After incubating the cells with the dye solution, the cell plate, the compound plate containing 3x compounds and the FLIPR chip were subjected to FLIPR.

[0253] 2. 10 μL of 3× compound was transferred from the compound plate to the cell plate by FLIPR.

[0254] 3. The plate was read at 1 second intervals for 160 seconds to obtain agonist mode data.

[0255] 3. Data analysis 1. Normalized fluorescence readings (RFU) were calculated as follows, where Fmax and Fmin represent the maximum and minimum values of calcium signal within a given time period: RFU=Fmax-Fmin

[0256] 2. Calculate the EC by fitting the RFU to the logarithm of the compound concentration using XLfit. 50 was calculated.

[0257] II. Results and Discussion Exemplary dimeric compounds of the present application (I-24 and I-37) and their respective metabolites, psilocin and 7: [ka] The results of potential competitive binding of compounds targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A) are summarized in Table 2. The results of exemplary compounds of the present application are shown in the IC 50 is presented as. [Table 17]

[0258] Exemplary compounds of Formula I were evaluated using a radioligand binding assay for the human 5-HT2A receptor. EC 50 Concentrations (nM) are shown in Table 2. This assay confirms that exemplary compounds or metabolites of the present application are effective ligands for the target human 5-HT2A receptor.

[0259] Example 4: Human 5-HT2A: Radioligand Binding Assay: the purpose The purpose of this study was to evaluate the binding of exemplary compounds of Formula I to the 5-hydroxytryptamine receptor 2A (5-HT2A). 1 Materials and equipment [Table 18] [Table 19]

[0260] 2. Experimental Method 1. Assay buffer was prepared according to the table below. [Table 20]

[0261] 2. Eight doses of reference and test compounds were prepared by 5-fold serial dilutions starting from the required stock solution of 10 mM with 100% (v / v) DMSO.

[0262] 3. UniFilter-96 GF / B plates were pretreated:

[0263] 50 μl / well of 0.5% (v / v) PEI was added to a UniFilter-96 GF / C plate, which was sealed and incubated at 4° C. for 3 hours.

[0264] ii. After incubation, the plates were washed three times with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0265] 4. Assay plates were prepared:

[0266] i. Cell membranes were diluted in assay buffer and added to a 96-well round-bottom plate at 330 μl / well to reach a concentration of 20 μg / well.

[0267] ii. Eight concentrations of reference or test compounds were prepared and added at 110 μl / well to a 96 deep-well round-bottom plate.

[0268] iii. [3H]-Ketanserin was diluted in assay buffer to 5 nM (5x final concentration) and added at 110 μl / well to a 96 deep well round bottom plate.

[0269] 5. The plate was centrifuged at 1000 rpm for 30 seconds, then agitated at 600 rpm for 5 minutes at room temperature.

[0270] 6. The plate was sealed and incubated at 27°C for 90 minutes.

[0271] 7. The incubation was terminated by vacuum filtration onto GF / B filter plates, followed by four washes with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0272] 8. The plates were dried at 37°C for 45 minutes.

[0273] 9. The filter plate was sealed and 40 μl / well of scintillation cocktail was added.

[0274] 10. Microbeta 2 The plates were read using a microplate counter.

[0275] 3. Data analysis 1. For reference and test compounds, the results were expressed as % inhibition using the normalization formula: N = 100-100 × (U-C2) / (C1-C2), where U is the unknown value, C1 is the mean value of the high control, and C2 is the mean value of the low control.

[0276] 2. Use XLfit to fit the Hill equation with % inhibition as a function of compound concentration to obtain the IC 50 It was decided that:

[0277] Results and Discussion Exemplary prodrug compounds of the present application are I-24 and I-37, and their respective metabolites psilocin and formula (7): [ka] The results of the potential competitive binding of compounds targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A) are summarized in Table 3. The results of exemplary compounds of the present application are shown in Table 3. 50 is presented as. [Table 21]

[0278] II. Results and Discussion Exemplary compounds of Formula I were evaluated using a radioligand binding assay for the human 5-HT2A receptor. IC 50 Concentrations (nM) are shown in Table 3. This assay confirms that the precursor parent compounds of the present application or their respective metabolites are effective ligands for the target human 5-HT2A receptor.

[0279] Example 5: Human 5-HT1A: Functional FLIPR Assay 1 purpose In the agonist mode, the potential excitatory effects of compounds targeting the 5-hydroxytryptamine receptor 1A were evaluated. 2 Materials and equipment [Table 22] [Table 23] [Table 24]

[0280] 3 Experimental Method 3.1 Cell culture HTR1A&Gα15-CHO cells were cultured in DMEM / F12 medium containing 10% dialyzed FBS, 1x penicillin-streptomycin, and 600 μg / mL hygromycin B. Cells were subcultured approximately three times a week and maintained at approximately 30% to 90% confluence.

[0281] 3.2 Cell plating 1. Cell culture medium (DMEM / F12 medium containing 10% dialyzed FBS, 1× penicillin-streptomycin, and 600 μg / mL hygromycin B), TrypLE™ Express, and DPBS were pre-warmed to room temperature.

[0282] 2. The cell culture medium was removed from the flask. The cells were washed with DPBS.

[0283] 3. 1 mL of TrypLE™ Express was added to the flask and mixed well by gently shaking, after which the cells were incubated at 37°C for a few minutes.

[0284] 4. The morphological changes of the cells were confirmed under a microscope, and when the majority of the cells had become round, the digestion was stopped by adding 2 mL of cell culture medium.

[0285] 5. The cell suspension was transferred to a 15 mL centrifuge tube and then centrifuged at 1,200 rpm for 5 minutes.

[0286] 6. The supernatant was removed and the cell pellet was resuspended in 2 mL of cell culture medium.

[0287] 7. Cell density was counted using a cell counter. Only cells with viability above 85% were used in the assay.

[0288] 8. The cells were diluted to 4 x 105 / mL using cell culture medium.

[0289] 9. 30 μL / well of the cell suspension was added to a 384-well cell plate (cell density was 12,000 cells / well).

[0290] 10. The cell plates were incubated overnight at 37°C under 5% (v / v) CO2.

[0291] 3.3 Cell handling 1. On the day of the experiment, the culture medium was removed from the cell plates.

[0292] 2. 10 μL of assay buffer (20 mM HEPES in 1×HBSS, pH 7.4) was added to each well of the cell plate.

[0293] 3. Prepare 2x dye solution according to the FLIPR® Calcium 6 Assay Kit product instructions:

[0294] i. The dye was diluted in assay buffer.

[0295] ii. Probenecid was added to a final concentration of 5 mM.

[0296] iii. Vortex vigorously for 1-2 minutes and adjust the pH to 7.4.

[0297] 4. 10 μL of 2× dye solution was added to each well of the cell plate.

[0298] 5. The cell plate was placed on a plate shaker and then shaken at 600 rpm for 2 minutes.

[0299] 6. The plate was incubated at 37°C for 2 hours, followed by an additional 15 minutes at 25°C.

[0300] 3.4 Preparation of 3x Compound 1. Serotonin was prepared at a concentration of 10 mM using DMSO, and serially diluted 3-fold using DMSO.

[0301] 2. Test compounds were prepared to 10 mM using DMSO and serially diluted 3-fold using DMSO.

[0302] 3. Compounds were added to a 384-well compound source plate.

[0303] 4. Using the Echo, 90 nL / well of serially diluted compounds was transferred from the source plate to the 384-well compound plate.

[0304] 5. 30 μL / well of assay buffer was added to the compound plate.

[0305] 6. The plate was mixed on a plate shaker for 2 minutes.

[0306] 3.5 FLIPR assay 1. After incubating the cells with the dye solution, the cell plate, the compound plate containing 3x compound and the FLIPR chip were subjected to FLIPR.

[0307] 2. 10 μL of 3× compound was transferred from the compound plate to the cell plate by FLIPR.

[0308] 3. The plate was read at 1 second intervals for 160 seconds to obtain agonist mode data.

[0309] 4. Data analysis 1. The normalized fluorescence reading (RFU) was calculated as follows: where Fmax and Fmin represent the maximum and minimum values of calcium signal within a given time period. RFU=Fmax-Fmin

[0310] 2. EC 50 was calculated by fitting the RFU to the logarithm of the compound concentration to the Hill equation using XLfit.

[0311] II. Results and Discussion Exemplary prodrug compounds of the present application are I-24 and I-37, and their respective metabolites psilocin and formula (7): [ka] The competitive binding potential results of compounds targeting the human 5-hydroxytryptamine receptor 1A (5-HT1A) are summarized in Table 4. The results for exemplary compounds of the present application are shown in Table 4. 50 is presented as. [Table 25]

[0312] Exemplary compounds of Formula I were evaluated using a functional FLIPR assay against the human 5-HT1A receptor. EC 50 The concentrations (nM) are shown in Table 4. This assay confirms that the compounds or metabolites of the present application have moderate functional activity at the target human 5-HT1A receptor.

[0313] Example 6: Human 5-HT1A: Radioligand Binding Assay: 1 purpose The purpose of this study was to evaluate the binding ability of test compounds to the 5-hydroxytryptamine receptor 1A. 2 Materials and equipment [Table 26] [Table 27]

[0314] 3 Experimental Method 1. Assay buffer was prepared according to the table below. [Table 28]

[0315] 1. Eight doses of reference and test compounds were prepared by 5-fold serial dilutions starting from a 10 mM stock solution with 100% (v / v) DMSO.

[0316] 2. UniFilter-96 GF / B plates were pretreated:

[0317] 50 μl / well of 0.5% (v / v) PEI was added to a UniFilter-96 GF / B plate, which was then sealed and incubated at 4° C. for 3 hours.

[0318] ii. After incubation, the plates were washed three times with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0319] 3. Assay plates were prepared:

[0320] i. Cell membranes were diluted in assay buffer and 100 μl / well was added to a 96-well round-bottom plate to give a concentration of 20 μg / well.

[0321] ii. Eight concentrations of reference or test compounds were prepared and 50 μl / well was added to a 96 deep-well round-bottom plate.

[0322] iii. [3H]-8-hydroxy-DPAT was diluted to 2 nM (4x final concentration) in assay buffer and 50 μl / well was added to a 96-well round-bottom plate.

[0323] 4. The plate was centrifuged at 1000 rpm for 30 seconds, then agitated at 600 rpm at room temperature.

[0324] 5. The plate was sealed and incubated at 27°C for 90 minutes.

[0325] 6. The incubation was stopped by vacuum filtration onto GF / B filter plates, followed by four washes with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0326] 7. The plates were dried at 37°C for 45 minutes.

[0327] 8. The filter plate was sealed and 40 μl / well of scintillation cocktail was added.

[0328] 9. Microbeta 2 Plates were read using a microplate counter.

[0329] 4. Data analysis 1. For reference and test compounds, results were expressed as % inhibition using the normalization formula: N=100-100×(U-C2) / (C1-C2), where U is the unknown, C1 is the mean value of the high control, and C2 is the mean value of the low control.

[0330] 2. Using XLfit, calculate the IC by fitting the Hill equation as % inhibition versus bound compound concentration. 50 It was decided that:

[0331] Results and Discussion Exemplary prodrug compounds of the present application are I-24 and I-37, and their respective metabolites psilocin and formula (7): [ka] The competitive binding potential results of compounds targeting the human 5-hydroxytryptamine receptor (5-HT1A) are summarized in Table 5. The results for exemplary compounds of the present application are shown in Table 5. 50 is presented as. [Table 29]

[0332] II. Results and Discussion Exemplary compounds of Formula I and their metabolites were evaluated using a radioligand binding assay for the human 5-HT1A receptor. IC 50 Concentrations (nM) are shown in Table 5. This assay confirms that the precursor parent compounds of the present application or their respective metabolites are effective ligands of the target human 5-HT1A receptor.

[0333] Example 7: Human, rat and mouse liver microsome stability the purpose The purpose of this study was to estimate the in vitro metabolic stability of exemplary compounds I-24 and I-37 in pooled liver microsomes from humans, male rats, and male mice. To estimate stability in pooled liver microsomes from humans, male rats, and male mice, the concentration of the parent compound in the reaction system was assessed by LC-MS / MS. The in vitro intrinsic clearance of the test compounds was also determined.

[0334] protocol A master solution containing phosphate buffer, ultrapure water, MgCl2 solution, and liver microsomes was made in an "incubation plate" according to Table 6. The mixture was pre-warmed in a 37°C water bath for 5 minutes. [Table 30]

[0335] To each well, 40 μL of 10 mM NADPH solution was added. The final concentration of NADPH was 1 mM. A negative control sample was prepared by replacing NADPH with 40 μL of ultrapure water. Samples were prepared in duplicate. One negative control was prepared.

[0336] Reactions were initiated by adding 4 μL of 200 μM of an exemplary test compound of the present application or a control compound to each master solution for a final concentration of 2 μM. The test was performed in duplicate.

[0337] At 0, 15, 30, 45, and 60 minutes, 50 μL aliquots were removed from the reaction mixture. The reaction mixture was stopped by adding four volumes of cold methanol containing IS (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol, and 2 μM ketoprofen). The samples were centrifuged at 3,220 g for 40 minutes. A 90 μL aliquot of the supernatant was mixed with 90 μL of ultrapure water and then used for LC-MS / MS analysis.

[0338] LC / MS analysis of all samples in this study was performed using a Shimadzu liquid chromatographic separation system equipped with a degasser DGU-20A5R, a solvent delivery unit LC-30AD, a system controller SIL-30AC, a column oven CTO-30A, and a CTC analytical HTC PAL system. Mass spectrometry was performed using a Triple Quad™ 5500 instrument.

[0339] All calculations were performed using Microsoft Excel. Peak area ratios of test compounds relative to internal standards (listed in the table below) were determined from extracted ion chromatograms.

[0340] All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The slope value k was determined by linear regression of the curve of the natural logarithm of the percentage of parent drug remaining versus incubation time.

[0341] The in vitro half-life (in vitro t) was determined from the slope value: In vitro 1 / 2 =-(0.693 / k)

[0342] Conversion of in vitro t (min) to in vitro intrinsic clearance (in vitro CLint, μL / min / mg protein) was performed using the following formula (mean of duplicate determinations):

number

[0343] For exemplary compounds of the present application or control compounds that showed an initial rapid elimination followed by a slower elimination, only time points within the initial rate range were included in the calculations.

[0344] Results and Discussion Human, rat, and mouse liver microsomes contain various drug-metabolizing enzymes and are commonly used to support in vitro ADME (absorption, distribution, metabolism, and excretion) studies. These microsomes are used to examine potential first-pass metabolic byproducts of orally administered drugs. Exemplary compounds of the present application were evaluated for their stability in human, rat, and mouse liver microsomes. In the liver microsomes of the three species, human, rat, and mouse, the majority of the exemplary compounds of the present application were recovered within 60 minutes, indicating that the compounds were not rapidly eliminated (see Table 7 for exemplary compounds of Formula I). [Table 31] [Table 32]

[0345] Consideration The results showed that the exemplary compounds (I-24 and I-37) were rapidly metabolized.

[0346] Example 8: Human, rat, mouse and dog: plasma stability 1. Preparation of Stock Solutions

[0347] Stock solutions of test compounds were prepared in DMSO and diluted to a final concentration of 200 μM. 1 mM working solutions of lovastatin and propantheline were prepared in DMSO and acetonitrile, respectively. Lovastatin was used as a positive control for plasma stability assays in rats and dogs. Propantheline was used as a positive control in plasma stability assays in humans, mice, and monkeys.

[0348] 2. Plasma Stability Procedure

[0349] 2.5 μL of 200 μM or 1 mM test compound or control compound solution was mixed with 497.5 μL of plasma to give a final concentration of 1 μM or 5 μM. The final concentration of organic solvent was 0.5%. Assays were performed in duplicate.

[0350] b. The reaction samples were incubated in a water bath at 37°C at approximately 60 rpm.

[0351] c. 50 μL aliquots were removed from the reaction samples at 0, 30, 60, 120, 180, and 240 min. The reactions were stopped by adding 7 volumes of cold acetonitrile containing internal standards (IS: 100 nM alprazolam, 200 nM imipramine, 200 nM labetalol, and 2 μM ketoprofen).

[0352] d. All samples were vortexed for 2 minutes, followed by centrifugation at 3,220 g for 30 minutes to precipitate proteins. 100 μL of the supernatant was transferred to a new plate. The supernatant was diluted with ultrapure water according to the LC-MS signal response and peak shape.

[0353] 3. Sample Analysis

[0354] The samples were analyzed by LC-MS / MS. LC system: Shimadzu MS analysis: Triple Quad™ 6500+ with ESI interface manufactured by AB Inc. (Canada) Column temperature: 40℃ Column: Xselect® Hss T3 2.5μ (2.1 x 30 mm) with pre-guard column Mobile phase: water containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B) [Table 33]

[0355] 4. Data Analysis

[0356] All calculations were performed using Microsoft Excel. The percentage of parent compound remaining at each time point was estimated by determining peak area ratios from extracted ion chromatograms. [Table 34]

[0357] Example 9: Intestinal mucosal permeability of exemplary compounds of the present application and their metabolites using Caco-2 cell monolayers 1. Preparation for cell seeding 1. Caco-2 cell culture medium was prepared consisting of Dulbecco's Modified Eagle's Medium (DMEM) containing high glucose and L-glutamine, supplemented with 10% FBS, 1x penicillin-streptomycin mixture, and 1x non-essential amino acids (NEAA).

[0358] 2. 50 μL of culture medium was added to each well of the Transwell insert. The Transwell insert was removed from the reservoir and 25 mL of culture medium was added.

[0359] 3. Incubate at 37°C under 5% CO2 for 1 hour. The plate is now ready for cell seeding.

[0360] 4. Cells were cultured in T-75 flasks in a cell culture incubator set at 37°C, 5% CO2, and 95% relative humidity. Cells were allowed to reach 80-90% confluence before detachment and splitting.

[0361] 5. Cultured cells were rinsed in a T-75 flask with 5 mL of PBS. The PBS was aspirated, and 1.5 mL of trypsin / EDTA was added. The cells were incubated at 37°C for approximately 5-10 minutes or until the cells detached and released. The trypsin / EDTA was inactivated by adding an excess amount of serum-containing medium.

[0362] 6. The cell suspension was transferred to a conical tube and centrifuged at 120 xg for 10 minutes to pellet the cells.

[0363] 7. Resuspend the cells in seeding medium at a density of 6.86 x 105 cells / mL. This cell concentration is 2.40 x 105 cells / cm 2 It can be used to sow seeds in

[0364] 2. Seeding and Feeding Caco-2 Cells into Transwell Plates 1. 50 μL of the above cell suspension was added to each well of the previously prepared Transwell plate.

[0365] 2. The plates were incubated for 14-18 days, with medium changes every two days, starting 48 hours after initial plating.

[0366] 3. The procedure for medium change was as follows: The plate was removed from the incubator and placed in the hood. The medium was aspirated from the reservoir and each Transwell insert. 75 μL of culture medium was added to each well of the Transwell insert, and 25 mL of culture medium was added to the reservoir tray. The plate was returned to the incubator.

[0367] 3. Assessment of cell monolayer integrity 1. When day 14 Caco-2 cultures have reached confluence and differentiated, they are ready for use in transport studies.

[0368] 2. The medium was removed from the reservoir and Transwell insert.

[0369] 3. 75 μL of pre-warmed culture medium was added to each Transwell insert and 25 mL reservoir tray.

[0370] 4. Electrical resistance across the monolayer was measured using an automated tissue electrical resistance measurement system (World Precision Instruments, Sarasota, FL).

[0371] 5. The electrical resistance was recorded for each well.

[0372] 6. After all wells were measured, the plate was returned to the incubator.

[0373] 7. The TEER of each well was calculated using the following formula. The TEER value of each well was 230 Ω cm 2 must be exceeded. TEER measurement value (Ω) × membrane area (cm 2 ) = TEER value (Ω cm 2 )

[0374] 4. Performing drug transport assays 1. The Caco-2 plate was removed from the incubator. The monolayer was then washed with two volume changes of pre-warmed HBSS (10 mM HEPES, pH 7.4). The plate was then incubated at 37°C for 30 minutes.

[0375] 2. 1 mM stock solutions of control and test compound(s) were prepared in DMSO and diluted with HBSS (10 mM HEPES, pH 7.4) to a final concentration of 5 μM. The final concentration of DMSO in the incubation system was 0.5%. Digoxin, prazosin, and propranolol were used as control compounds in this assay.

[0376] 3. After 30 minutes of pre-incubation, the HBSS (10 mM HEPES, pH 7.4) was removed.

[0377] 4. Drug transport rate from the apical to the basolateral direction was measured. 75 μL of control and test compounds were added to the Transwell insert (apical compartment). The wells of the receiver plate (basolateral compartment) were filled with 235 μL of HBSS (10 mM HEPES, pH 7.4).

[0378] 5. The rate of drug transport from the basolateral to the apical direction was determined. 235 μL of control compound and test compound(s) were added to the wells of the receiver plate (basolateral compartment). The Transwell insert (apical compartment) was filled with 75 μL of HBSS (10 mM HEPES, pH 7.4).

[0379] 6. Time point 0 samples were prepared by transferring 50 μL of working solution to a well of a 96-deep well plate, followed by the addition of 200 μL of cold methanol containing the appropriate internal standards (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 200 nM diclofenac).

[0380] 7. Incubate at 37°C for 2 hours.

[0381] 8. At the end of the transport period, 50 μL of sample was removed from the donor and receiver sides and transferred to a new plate. The reaction was then terminated by adding 200 μL of cold methanol containing internal standards (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 200 nM diclofenac). The mixture was vortexed for 5 minutes. The sample was centrifuged at 3,220 g for 40 minutes. A 100 μL aliquot of the supernatant was mixed with 100 μL of ultrapure water for LC-MS / MS analysis. All incubations were performed in duplicate.

[0382] 9. The solution from the Transwell was discarded. 100 μL of Lucifer Yellow solution (100 μM / HBSS) was added to each well of the Transwell insert, and 300 μL of HBSS was added to each well of the receiver. Incubated at 37°C for 30 minutes. 80 μL was removed from each apical and basolateral well and transferred to a solid black plate. The plate was read on a Tecan Infinite™ M200 (excitation / emission wavelengths 485 nM / 530 nM).

[0383] Results and Discussion Regarding psilocin (a metabolite of I-24), app (A→B) and P app The values for (B → A) are 24.57 and 18.71 cm / sec × 10, respectively. -6 and the corresponding efflux ratio was 0.76. Permeability results for psilocin and exemplary compounds of the present application in Caco-2 cell monolayers are shown in Table 10.

[0384] The results indicate that the metabolites of the exemplary dimeric compounds of Formula I have highly membrane permeable compounds and are unlikely to be substrates for efflux transporters. [Table 35] [Table 36]

[0385] Although the present application has been described with reference to examples, it should be understood that the scope of the claims is not limited to the embodiments set forth in the examples, but should be accorded the broadest interpretation consistent with the entire description.

[0386] All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entireties, and the disclosures of these publications are incorporated by reference in their entireties into this application in order to more fully describe the state of the art that is known to those skilled in the art as of the date of the application described and claimed herein.

Claims

1. Formula I: 【Chemical 1】 or a pharmaceutically acceptable salt, solvate and / or prodrug thereof [In the formula: Q is P(O)OR ９ , C １ ~C ４ Alkylene-P(O)OR ９ -C １ ~C ６ Alkylene, C(O), SO ２ C(O)Q'C(O), C(O)OQ'OC(O) and C(O)NR ９ 'Q'NR ９ 'C(O); R １ is H, C １ ~C ３ Alkyl, C(O)R １０ , CO ２ R １０ , C(O)N(R １０ ) (R １１ ), S(O)R １０ and S.O. ２ R １０ Selected from: R ２ , R ３ , R ３ ', R ４ and R ４ ' are independently H and C １ ~C ６ alkyl; R ５ and R ５ ' are independently H and C １ ~C ６ alkyl; or R ５ and R ５ ', together with the nitrogen atom between them, form O, S, S(O), SO ２ , N and NC １ ~C ６ forming a 3- to 7-membered heterocyclic ring optionally containing 1-2 additional ring heteromoieties selected from alkyl; R ６ , R ７ and R ８ are independently H, halo, CN, OR １２ , N(R １２ ) (R １３ ), S.R. １２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ２ ~C ６ Haloalkenyl, CO ２ R １２ , C(O)N(R １２ ) (R １３ ), S(O)R １２ , S.O. ２ R １２ , C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ２ ~C ６ Haloalkynyl, C ３ ~C ７ Cycloalkyl, as well as O, S, S(O), SO ２ , N and NR １４ C containing 1 to 2 hetero moieties selected from ３ ~C ７ heterocycloalkyl, wherein said C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Haloalkenyl, C ２ ~C ６ Alkynyl, C ２ ~C ６ Haloalkynyl, C ３ ~C ７ Cycloalkyl and C ３ ~C ７ Heterocycloalkyl is CN, OR １５ , N(R １５ ) (R １６ ) and S.R. １５ and optionally substituted with one or more substituents independently selected from ３ ~C ７ Cycloalkyl and C ３ ~C ７ Each heterocycloalkyl may further include halo, CO ２ R １７ , C(O)N(R １７ ) (R １８ ), SO ２ R １７ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Haloalkenyl, C ２ ~C ６ Alkynyl, C ２ ~C ６ Haloalkynyl, C ３ ~C ６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, and NR １９ C containing 1 to 2 hetero moieties selected from ３ ~C ６ heterocycloalkyl; Q' is a direct bond, C １ ~C ２０ Alkylene, C １ ~C ２０ Haloalkylene, C ２ ~C ２０ Alkenylene, C ２ ~C ２０ Haloalkenylene, C ２ ~C ２０ Alkynylene, C ２ ~C ２０ Haloalkynylene, C ３ ~C ７ Cycloalkylene, as well as O, S, S(O), SO ２ , N, and NR ２０ C containing 1 to 2 hetero moieties selected from ３ ~C ７ heterocycloalkylene, wherein said C １ ~C ２０ Alkylene, C ２ ~C ２０ Haloalkylene, C ２ ~C ６ Alkenylene, C ２ ~C ２０ Haloalkenylene, C ３ ~C ７ Cycloalkylene, and C ３ ~C ７ Heterocycloalkylene is CN, OR ２１ , N(R ２１ ) (R ２２ ), and S.R. ２１ and / or C １ ~C ６ With alkyl or C ２～６ With alkylene, disubstituted on the same carbon atom, C ３ ~C ７ Forms a cycloalkyl ring, wherein said C ３ ~C ７ Cycloalkylene and C ３ ~C ７ Each heterocycloalkylene further includes C １ ~C ３ Alkyl and C １ ~C ３ haloalkyl, provided that Q is C(O)OQ'OC(O) or C(O)NR ９ 'Q'NR ９ When 'C(O), Q' is not a direct bond; R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ and R ２２ are each independently H, substituted or unsubstituted C １ ~C ６ Alkyl, substituted or unsubstituted C ２ ~C ６ Alkenyl, substituted or unsubstituted C ２ ~C ６ Alkynyl, substituted or unsubstituted C １ ~C ６ Haloalkyl, substituted or unsubstituted C ３ ~C ７ Cycloalkyl, substituted or unsubstituted C ３ ~C ７ Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C １ ~C ６ Alkylene C ３ ~C ７ Cycloalkyl, substituted or unsubstituted C １ ~C ６ Alkylene C ３ ~C ７ Heterocycloalkyl, substituted or unsubstituted C １ ~C ６ Alkylenearyl, and substituted or unsubstituted C １ ~C ６ alkyleneheteroaryl; R ９ ' is H and C １ ~C ６ alkyl; wherein all available hydrogen atoms may be optionally substituted with fluorine or chlorine atoms, and / or all available atoms may be optionally substituted with alternative isotopes thereof.

2. R １ But H, C １ ~C ３ Alkyl, C(O)R １０ , CO ２ R １０ and C(O)N(R １０ ) (R １１ ) wherein all available hydrogen atoms may be optionally replaced with fluorine or chlorine atoms and / or all available atoms may be optionally replaced with alternative isotopes thereof.

3. R １ But H, CH ３ and C.H. ２ CH ３ wherein all available hydrogen atoms may be optionally replaced by fluorine or chlorine atoms and / or all available atoms may be optionally replaced by alternative isotopes thereof.

4. R １ But H, D, F, CH ３ , CDs ２ H, CDH ２ , CDs ３ , C.F. ３ , CHF ２ , C.F.H. ２ , C.H. ２ CH ３ , C.H. ２ CH ２ D, CH ２ CD ２ H and CD ２ CD ３ 4. The compound of claim 3, independently selected from:

5. R １ But H, D, CH ３ and CDs ３ 5. The compound of claim 4, selected from:

6. R ２ , R ３ , R ３ ', R ４ and R ４ ' is independent, H, CH ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ and C(CH ３ ) ３ wherein all available hydrogen atoms may be optionally replaced by fluorine or chlorine atoms, and / or all available atoms may be optionally replaced by alternative isotopes thereof.

7. R ２ But H, D, F, CH ３ , CDs ２ H, CDH ２ , CDs ３ , C.F. ３ , CHF ２ , C.F. ２ H, CH ２ CH ３ , C.H. ２ CH ２ D, CH ２ CD ２ H and CD ２ CD ３ 7. The compound of claim 6, selected from:

8. R ２ The compound of claim 7 , wherein is selected from H and D.

9. R ３ , R ３ ', R ４ and R ４ ' is independent, H, D, F, CH ３ , CDs ２ H, CDH ２ , CDs ３ , C.F. ３ , CHF ２ , C.F.H. ２ , C.H. ２ CH ３ , C.H. ２ CH ２ D, CH ２ CD ２ H and CD ２ CD ３ The compound according to any one of claims 6 to 8, selected from:

10. R ３ , R ３ ', R ４ and R ４ ' is independent, H, D, F, CH ３ , and C.D. ３ 10. The compound of claim 9 selected from:

11. R ５ and R ５ ' is independent, H, D, F, CH ３ , CDs ２ H, CDH ２ , CDs ３ , C.F. ３ , CHF ２ , C.F.H. ２ , C.H. ２ CH ３ , C.H. ２ CH ２ D, CH ２ CD ２ H, CD ２ CD ３ , CD (CD ３ ) ２ and CH(CH ３ ) ２ The compound according to any one of claims 1 to 10, selected from:

12. R ５ and R ５ 12. The compound of claim 11, wherein ' together with the nitrogen atom between them form pyrrolidinyl, piperidinyl, morpholinyl, or diazinanyl, and all available hydrogens may optionally be replaced with deuterium.

13. R ６ , R ７ and R ８ are independently H, F, Cl, Br, CN, OR １２ , N(R １２ ) (R １３ ), S.R. １２ , C １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C ２ ~C ６ Haloalkenyl, CO ２ R １２ , C(O)N(R １２ ) (R １３ ), S(O)R １２ , S.O. ２ R １２ , C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl and C ２ ~C ６ haloalkynyl, wherein said C １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Haloalkenyl, C ２ ~C ６ Alkynyl and C ２ ~C ６ The haloalkynyl group is CN, OR １５ , N(R １５ ) (R １６ ) and S.R. １５ wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with alternative isotopes thereof.

14. R ６ , R ７ and R ８ is independently selected from H, D, F, Cl, Br and CN.

15. Q is P(O)OR ９ and C １ ~C ２ Alkylene-P(O)OR ９ -C １ ~C ２ 15. The compound of any one of claims 1 to 14, wherein the compound is selected from alkylene, wherein all available hydrogen atoms may be optionally replaced by fluorine or chlorine atoms, and / or all available atoms may be optionally replaced by alternative isotopes thereof.

16. Q is CH ２ -P(O)OR ９ -CH ２ 16. The compound of claim 15, wherein all available hydrogen atoms may be optionally substituted with fluorine or chlorine atoms and / or all available atoms may be optionally substituted with alternative isotopes thereof.

17. Q is C(O), C(O)Q'C(O), C(O)OQ'OC(O) and C(O)NR ９ 'Q'NR ９ 15. A compound according to any one of claims 1 to 14, wherein the compound is selected from: C(O), wherein all available hydrogen atoms may be optionally replaced by fluorine or chlorine atoms, and / or all available atoms may be optionally replaced by alternative isotopes thereof.

18. Q' is C １ ~C １０ Alkylene, C ２ ~C １０ Alkenylene and C ２ ~C １０ alkynylene, wherein C １ ~C １０ Alkylene, C ２ ~C １０ Alkenylene and C ２ ~C １０ Alkynylene is CN, OR ２１ , N(R ２１ ) (R ２２ ), and S.R. ２１ and / or C １ ~C ６ With alkyl or C ２～６ With alkylene, disubstituted on the same carbon atom, C ３ ~C ７ Forms a cycloalkyl ring, ３ ~C ７ The cycloalkyl may further be C １ ~C ３ Alkyl and C １ ~C ３ 18. The compound of claim 17, wherein the compound is optionally substituted with substituents selected from haloalkyl, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or wherein all available atoms are optionally substituted with alternative isotopes thereof.

19. Q' is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl and C ２ ~C ６ alkynyl, wherein C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl and C ２ ~C ６ Alkynyl is OR ２１ and N(R ２１ ) (R ２２ and / or C １ ~C ６ With alkyl or C ２～６ With alkylene, disubstituted on the same carbon atom, C ３ ~C ７ Forms a cycloalkyl ring, ３ ~C ７ The cycloalkyl ring may further comprise C １ ~C ３ Alkyl and C １ ~C ３ 19. The compound of claim 18, wherein all available hydrogen atoms are optionally substituted with substituents selected from haloalkyl, all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with alternative isotopes thereof.

20. Q' is C １ ~C ４ Alkylene and C ２ ~C ４ 20. The compound of claim 19, wherein the compound is selected from alkenylene, wherein all available hydrogen atoms may be optionally replaced with fluorine or chlorine atoms, and / or all available atoms may be optionally replaced with alternative isotopes thereof.

21. 18. The compound of claim 17, wherein Q' is a direct bond.

22. R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , and R ２２ are each independently H, substituted or unsubstituted C １ ~C ４ Alkyl, substituted or unsubstituted C ２ ~C ６ Alkenyl, substituted or unsubstituted C ２ ~C ６ Alkynyl, substituted or unsubstituted C １ ~C ４ Haloalkyl, substituted or unsubstituted C ３ ~C ７ The compound of any one of claims 1 to 21, wherein the compound is selected from cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

23. R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , and R ２２ are each independently H, substituted or unsubstituted C １ ~C ４ Alkyl, substituted or unsubstituted C ２ ~C ６ Alkenyl, substituted or unsubstituted C ２ ~C ６ Alkynyl, and substituted or unsubstituted C １ ~C ４ 23. The compound of claim 22, wherein the compound is selected from haloalkyl, wherein all available hydrogen atoms may be optionally replaced with fluorine or chlorine atoms, and / or all available atoms may be optionally replaced with alternative isotopes thereof.

24. R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ and R ２２ are independently H, D, CH ３ , CDs ２ H, CDH ２ , CDs ３ , C.F. ３ , CHF ２ , C.F. ２ H, CH ２ CH ２ D, CH ２ CD ２ H, CH ２ CH ３ and CDs ２ CD ３ 24. The compound of claim 23, selected from:

25. R ９ ', H and C １ ~C ４ 25. The compound of any one of claims 1 to 24, wherein the alkyl is selected from alkyl, wherein all available hydrogen atoms may optionally be replaced by fluorine or chlorine atoms, and / or wherein all available hydrogen atoms may optionally be replaced by deuterium.

26. The compound of claim 1 selected from the following table: 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

27. 27. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 26, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, and a pharmaceutically acceptable carrier.

28. 27. A method of treating a disease, disorder or condition treated by activation of a serotonin receptor, comprising administering to a subject having said disease, disorder or condition a therapeutically effective amount of one or more compounds of any one of claims 1 to 26, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof.

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