3-ethylamino-indole dimers as serotonergic agents for treatment of diseases associated therewith

Abstract

The present application relates to 3-ethylamino-indole dimers of general formula I, processes for their preparation, compositions comprising said dimers and their use to activate serotonin receptors in cells, and to the treatment of diseases, disorders or conditions by activation of serotonin receptors in or on cells. The diseases, disorders, or conditions include, for example, psychosis, mental disorders, and CNS disorders. # imgabs0 #

Description

[0001] Related Applications

[0002] This application claims priority to co-pending U.S. Provisional Patent Application No. 63 / 395,499, filed Aug. 5, 2022, the content of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention relates to 3-ethylamino-indole dimers of general formula I for the treatment of different disorders in the fields of psychiatry, neurobiology and pharmacotherapy, which are treated by activation of serotonin receptors, such as mental and neurological disorders. Background Art

[0004] Mental health disorders or mental illnesses refer to a wide range of conditions, including but not limited to depression, anxiety and panic disorders, schizophrenia, eating disorders, substance use disorders, post-traumatic stress disorder, attention deficit / hyperactivity disorder, and obsessive-compulsive disorder. Many mental health disorders as well as neurological disorders are affected by alterations, dysfunctions, degeneration, and / or damage to the serotonergic system of the brain, which can partially explain the endophenotypes and comorbidities common in neuropsychiatric and neurological diseases.

[0005] Due to the legal status of psychedelics, the field of psychedelic neuroscience has seen a renaissance after decades of restricted research. Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect many cognitive processes. There is now a consensus that psychedelics are agonists or partial agonists of the serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor.

[0006] Psychedelics have rapid-onset and persistent effects long after their acute effects, including changes in mood and brain function. The long-term effects may be the result of their unique receptor affinity, which affects neurotransmission (i.e., neuroplasticity) via neuromodulatory systems that regulate brain activity, and promotes cell survival, has neuroprotective effects, and modulates the brain's neuroimmune system. The mechanisms leading to these long-term neuromodulatory changes may be related to epigenetic modifications, changes in gene expression, and regulation of presynaptic and postsynaptic receptor density. These previously understudied psychedelic drugs may potentially provide the next generation of neurological therapies, where refractory mental and neurological disorders (e.g., depression, post-traumatic stress disorder, dementia, and addiction) may become treatable by reducing the pharmacological risk profile.

[0007] Despite the widespread perception that psychedelic drugs are dangerous, they are one of the safest classes of CNS drugs known in terms of physical safety. Preliminary data suggest that the administration of psychedelics in humans produces effects with unique characteristics and potential adverse reactions that need to be appropriately addressed to maximize safety. Essentially, the major safety concerns are largely psychological rather than physical. Somatic effects vary but are relatively insignificant, even at doses that elicit strong psychological effects. Psilocybin has been frequently reported to cause transient delayed headaches when administered in a controlled environment, with the incidence, duration, and severity increasing in a dose-dependent manner [Johnson et al., Drug Alcohol Depend (2012) 123(1-3):132–140]. It has been found that repeated administration of psychedelics leads to a very rapid development of tolerance (termed tachyphylaxis), a phenomenon thought to be mediated in part by 5-HT2A receptors. In fact, several studies have shown that tachyphylaxis to psychedelics is associated with downregulation of 5-HT2A receptors. For example, daily administration of LSD selectively decreases the density of 5-HT2 receptors in the brains of rats [Buckholtz et al., Eur. J. Pharmacol. 1990, 109:421–425.1985; Buckholtz et al., Life Sci. 1985, 42:2439–2445].

[0008] Unlike any currently available treatments, classical and dissociative psychedelics are known to have rapid-acting antidepressant and anti-addiction effects. Randomized clinical controlled studies have confirmed the antidepressant and anti-anxiety effects of classical psychedelics in humans.

[0009] Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) has the chemical formula C 12 H 17N2O4P。Psilocybin is a tryptamine-based prodrug and one of the main psychoactive components in psilocybin mushrooms. Psilocybin was first isolated from psilocybin mushrooms 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 psychiatry, psychological research, and psychotherapy during the early to mid-1960s until it was classified as a controlled drug in the United States in 1970 and in Germany in the 1980s [Passie 2005; Passie et al. Addict Biol., 2002, 7(4):357-364]. Research on the effects of psilocybin resumed in the mid-1990s, and currently it is the preferred compound for studies on serotonergic hallucinogenic effects [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], probably because it has a shorter duration of action and suffers less stigma than LSD. Like other members of this class, psilocybin sometimes causes large changes in perception, cognition, and mood, including mood lability.

[0010] In humans and other mammals, psilocybin is converted to the active metabolite psilocin, or 4-hydroxy-N,N-dimethyltryptamine parent compound. Psilocin may partially or fully produce most of the subjective and physiological effects of psilocybin in humans and non-human animals. Recently, research on human psilocybin has confirmed the 5HT2A activity of psilocybin via the parent psilocin and provided some support for an indirect effect on dopamine via 5-HT2A activity and possible activity at other serotonin receptors. In fact, the most consistent finding for the involvement of other receptors in hallucinogenic effects is the 5-HT1A receptor. This is especially true for tryptamines and LSD, which generally have significant affinity and functional potency for this receptor. The 5-HT1A receptor is known to be co-localized with the 5-HT2A receptor on cortical pyramidal cells [Martín-Ruiz et al. J Neurosci. 2001, 21(24):9856–986], where the two receptor types have opposing functional effects [Araneda et al. Neuroscience 1991, 40(2):399–412].

[0011] Although the exact role of the 5-HT2A receptor and other 5-HT2 receptor family members with respect to the amygdala is not clear, it is evident that the 5-HT2A receptor plays an important role in emotional responses and is an important target to be considered in the action of 5-HT2A agonist hallucinogens. In fact, most known 5-HT2A agonists produce hallucinogenic effects in humans and rodents (extrapolating from one 5-HT2A agonist to other agonists), such as between psilocybin and 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 higher affinity for the human 5-HT2A receptor than for the rat receptor, and its K(i) for both the 5-HT2A and 5-HT2C receptors is lower than that of LSD. In addition, from the results of a series of rat drug discrimination studies, it was found that 5-HT2A antagonists (but not 5-HT1A antagonists) prevent rats from recognizing psilocybin [Winter et al., Pharmacol Biochem Behav., 2007, 87(4):472-480]. Daily doses of LSD and psilocybin decreased the density of 5-HT2 receptors in the rat brain.

[0012] Today, due to its relative safety, moderately long duration of activity, and good absorbability, psilocybin is one of the most widely used hallucinogens in human studies. Because recent studies have shown varying degrees of success of psilocybin in neurotic disorders, alcoholism, depression associated with major depressive disorder, treatment-resistant depression, and patients with advanced cancer, obsessive-compulsive disorder, addiction, anxiety disorders, post-traumatic stress disorder, and even cluster headache, it still has strong research and therapeutic potential.

[0013] Recent advances include several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with treatment-resistant depression, major depressive disorder, and cancer-related psychological distress, which have shown unprecedented positive remission of anxiety and depression. Two recent small pilot studies of psilocybin-assisted psychotherapy have also shown positive benefits in the treatment of alcohol and nicotine addiction. Recently, blood oxygenation level-dependent functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) have been used for in vivo brain imaging in humans after administration of hallucinogens, and the results have shown that intravenously administered psilocybin and LSD decrease the oscillatory power in regions of the brain's default mode network [Nichols DE. Pharmacol Rev., 2016, 68(2):264–355].

[0014] Preliminary studies using positron emission tomography (PET) have shown that in healthy participants, psilocybin ingestion (oral 15 or 20 mg) increased the absolute metabolic rate of glucose in the frontal lobe and, to a lesser extent, in other cortical regions, the striatum, and limbic subcortical structures, suggesting that some of the key behavioral effects of psilocybin 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 5HT2A agonism is widely considered the primary action of classical hallucinogens, psilocybin has low affinity for many other presynaptic 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 / anxiolytic effects.

[0015] Depression and anxiety are two of the most common mental disorders in the world. Depression is a multi-faceted disorder characterized by episodes of mood disturbance accompanied by other symptoms such as anhedonia, psychomotor symptoms, feelings of guilt, attention deficits, and suicidal tendencies, all of which can vary in severity. Similarly, anxiety disorders are a group of conditions with complex etiologies, characterized by intense psychological distress and other symptoms depending on the subtype. Anxiety disorders associated with life-threatening illnesses are the only subtype of anxiety disorder that has been studied in the context of psychedelic-assisted therapy. Pharmacological and psychosocial interventions are commonly used to manage this type of anxiety disorder, but their efficacy is mixed and limited, such that they often do not provide satisfactory mood relief. The recent interest in using psychedelic-assisted therapy may represent a promising alternative for patients with depression and anxiety disorders who are unresponsive to conventional methods of control.

[0016] Typically, the psychedelic treatment model involves the administration of orally active drugs to induce a mystical experience lasting approximately 4 - 9 h (depending on the psychedelic) [Halberstadt, Behav Brain Res., 2015, 277:99 - 120; Nichols, Pharmacol Rev., 2016, 68(2):264 - 355]. This enables participants to resolve and integrate difficult feelings and situations, resulting in lasting antidepressant and anti - anxiety effects. Classical psychedelics, such as psilocybin and LSD, are being investigated as potential candidates. In a study of treating depression and anxiety associated with life - threatening diseases with classical hallucinogens, it was found that psilocybin and LSD consistently produced significant and sustained antidepressant and anti - anxiety effects in a supportive environment.

[0017] Psychedelic treatments are generally well - tolerated with few, if any, persistent side effects. Regarding their mechanism of action, they modulate their primary therapeutic effects biochemically via serotonin receptor agonism and psychologically by producing meaningful psycho - spiritual experiences that contribute to psychological flexibility. Given the limited success rates of current treatments for anxiety disorders and mood disorders and considering the high prevalence associated with these conditions, psychedelics have the potential to provide symptom relief for patients who cannot be adequately controlled by conventional methods.

[0018] Further emerging clinical studies and evidence suggest that psychedelic-assisted therapies also show potential as alternative treatments for treatment-resistant substance use disorders and mental health conditions and may thus be important tools in a crisis where existing methods have had limited success [dos Santos et al., Ther Adv Psychopharmacol., 2016, 6(3):193-213]. Equally encouraging are the results of a recent pilot study of psilocybin-assisted therapy for tobacco use disorder, showing abstinence rates of 80% at six-month follow-up and 67% at 12-month follow-up [Johnson et al. https: / / www.ncbi.nlm.nih.gov / pubmed / 27441452 J Drug Alcohol Abuse, 2017, 43(1):55-60; Johnson et al., Psychopharmacol. 2014, 28(11):983-992]; such rates are considered higher than any rates documented in the smoking cessation literature. Notably, the mystical-type experiences generated by psilocybin sessions were significantly associated with positive treatment outcomes. These results are consistent with emerging evidence from recent clinical trials that support the effectiveness 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) has begun to emerge, and growing evidence supports the need to pursue this line of research. Available evidence from early randomized clinical trials suggests a promising role for the treatment of OUD: higher abstinence rates were observed in participants receiving high-dose LSD and ketamine-assisted therapy for heroin addiction compared to control groups at long-term follow-up. Recently, a large US population study of 44,000 individuals found that, as defined by DSM-IV criteria, the use of psychedelics was associated with a 40% reduction in the risk of opioid abuse and a 27% reduction in the risk of opioid dependence in the following year [Pisano et al., J Psychopharmacol., 2017, 31(5):606-613]. Similarly, among marginalized women, the use of psychedelics was found to have a protective moderating effect on the relationship between prescription opioid use and suicide risk [Argento et al., J Psychopharmacol., 2018, 32(12):1385-1391]. Although these preliminary findings regarding classical psychedelics are promising, further research is needed to determine how psychedelics can improve the opioid crisis response.Concurrently, the growing body of evidence on the safety and efficacy of psilocybin for the treatment of mental and substance use disorders should help to drive further clinical research on its use as a novel intervention for OUD.

[0019] Conventional doses of psychedelics have also improved sleep disorders, which are very common in patients with depression, with over 80% of patients complaining of poor sleep quality. Sleep symptoms are usually not resolved by first-line treatments and are associated with a greater risk of relapse and recurrence. Intriguingly, sleep problems often precede other depressive symptoms, and subjective sleep quality deteriorates before recurrent depressive episodes. Two other studies assessing electroencephalogram (EEG) brain activity during sleep have shown that psychedelics (such as LSD) have a positive effect on sleep patterns. It further suggests that a single dose of psychedelic causes a reset of the circadian clock based on the sleep / wake cycle, thereby enhancing cognitive-emotional processes in patients with depression and also improving well-being and mood in healthy individuals [Kuypers, Medical Hypotheses, 2019, 125:21–24].

[0020] In a systematic meta-analysis of clinical trials from 1960 to 2018 that examined the therapeutic use of psychedelic treatments in patients with severe or advanced illness and related psychiatric disorders, it was found that psychedelic therapy (primarily with LSD) could improve cancer-related depression, anxiety, and fear of death. Four randomized controlled clinical trials published between 2011 and 2016, primarily using psilocybin treatment, demonstrated that psychedelic-assisted therapy could rapidly, robustly, and sustainably improve 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 the loss of meaning or purpose in life, which can be associated with despair, demoralization, a sense of powerlessness, feeling burdened, and a desire to hasten death. These features are also typically at the core of clinically significant anxiety and depression, and they can greatly reduce the quality of life in this patient population. Alleviating these core features of existential distress should be a central goal in palliative care. Therefore, several manualized psychotherapies that target cancer-related existential distress and emphasize dignity and meaning creation 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 shown superiority over placebo. Additional effective treatments for these conditions are still needed [Rosenbaum et al., Curr. Oncol., 2019, 26(4):225–226].

[0021] Recently, there has been increasing interest in a new dosing paradigm of microdosing of psychedelic drugs (such as psilocybin and LSD). In this paradigm, sub-perceptual doses of serotonergic hallucinogens, which are approximately 10% or less of the full dose, are taken once daily, every other day, or every three days or the same permutation on a more consistent basis. This dosing paradigm is not only more in line with current standards of pharmacological care, but may also be particularly beneficial for certain disorders (such as Alzheimer's disease, other neurodegenerative diseases, attention deficit disorder, attention deficit hyperactivity disorder) and for certain patient groups (such as the elderly, adolescents, and patients who are afraid or opposed to psychedelic-assisted therapy). In addition, this approach may be particularly suitable for managing cognitive deficits and preventing neurodegeneration. For example, at psilocybin doses below the threshold that elicits the classic wet dog shake behavioral response associated with hallucinogenic doses, a subset of low-attention and low-motivation rats showed improved performance on 5-choice serial reaction time and progressive ratio tasks (Blumstock et al., WO 2020 / 157569 A1). Similarly, treating patients with hallucinogenic doses of 5-HT2A agonists is associated with increased activation of the BDNF and mTOR pathways, which are thought to promote neuroplasticity and are hypothesized as molecular targets for treating dementia and other neurodegenerative disorders (Ly et al., Cell Rep., 2018, 23(11):3170-3182). Additionally, some groups have demonstrated that low-dose, non-hallucinogenic, and non-psychotomimetic doses of 5-HT2A agonists also show similar neuroprotective effects and increased neuroplasticity effects (neuroplasticity agents) and reduced neuroinflammation, which may be beneficial for neurodegenerative diseases, neurodevelopmental diseases, and chronic conditions (Manfredi et al., WO 2020 / 181194, Flanagan et al., Int. Rev. Psychiatry, 2018, 13:1-13; Nichols et al., 2016, Psychedelics as medicines; an emerging new paradigm). This repeated, lower-dose paradigm may extend the utility of these compounds to additional indications and may prove useful for health applications.

[0022] Psychosis generally refers to an abnormal mental state characterized by hallucinatory experiences, delusional thinking, and thought disorder. Additionally, this state is accompanied by social cognitive impairment, inappropriate emotional expression, and bizarre behavior. Most commonly, psychosis develops as part of a mental disorder, in which it represents a component of schizophrenia. It corresponds to the most fully developed stage of the disease. The initial manifestation of psychosis in a patient is called first-episode psychosis. It reflects a critical transitional stage towards the chronic establishment of the disease, which is presumably mediated by progressive structural and functional abnormalities that occur in diagnosed patients. [ACS Chem. Neurosci., 2018, 9, 2241 - 2251]. Anecdotal evidence suggests that regular administration of low, non-hallucinogenic (microdose) doses of psychedelic agents can alleviate the symptoms of schizophrenia and psychosis. Summary of the Invention

[0023] The present invention encompasses compounds of formula I:

[0024]

[0025] or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof,

[0026] wherein:

[0027] Q is selected from P(O)OR 9 、C1 - C4 alkylene - P(O)OR 9 -C1 - C6 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);

[0028] R 1 is selected from H, C1 - C3 alkyl, C(O)R 10 、CO2R 10 、C(O)N(R 10 )(R 11 )、S(O)R 10 and SO2R 10 ;

[0029] R 2 、R 3 、R 3' 、R 4 and R 4' are independently selected from H and C1 - C6 alkyl;

[0030] R 5 and R 5' are independently selected from H and C1 - C6 alkyl, or

[0031] R5 and R 5' together with the nitrogen atom between them form a 3- to 7-membered heterocycle, which optionally contains 1 to 2 additional heterocyclic moieties of a ring selected from O, S, S(O), SO2, N, and NC 1-6 alkyl;

[0032] R 6 , R 7 and R 8 are independently selected from 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 C3-C7 heterocycloalkyl containing 1 to 2 heterocyclic moieties selected from O, S, S(O), SO2, N, and NR 14 , wherein the 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 optionally substituted by one or more substituents independently selected from CN, OR 15 , N(R 15 )(R 16 ), and SR 15 , and wherein the C3-C7 cycloalkyl and C3-C7 heterocycloalkyl are each further optionally substituted by one or more substituents selected from halo, CO2R 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 C3-C6 heterocycloalkyl containing 1 to 2 heterocyclic moieties selected from O, S, S(O), SO2, N, and NR 19 ;

[0033] Q' is selected from a direct bond, C1-C 20 alkylene, C1-C 20 haloalkylene, C2-C 20 alkenylene, C2-C 20 haloalkenylene, C2-C 20Alkynylene, C2-C 20 Halogenated alkynylene, C3-C7 cycloalkyl and C3-C7 heterocycloalkyl containing 1 to 2 hetero moieties selected from O, S, S(O), SO2, N and NR 20 wherein the C1-C 20 Alkylene, C2-C 20 Halogenated alkylene, C2-C6 alkenylene, C2-C 20 Halogenated alkenylene, C3-C7 cycloalkyl and C3-C7 heterocycloalkyl are optionally substituted by one or more substituents independently selected from CN, OR 21 , N(R 21 )(R 22 ) and SR 21 , and / or disubstituted on the same carbon atom by C 1-6 alkyl or by C 2-6 alkylene to form a C3-C7 cycloalkyl ring, and wherein the C3-C7 cycloalkyl and C3-C7 heterocycloalkyl are each further optionally substituted by one or more substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, provided that when Q is C(O)OQ'OC(O) or C(O)NR 9' Q'NR 9' C(O), then Q' is not a straight bond;

[0034] Each 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 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 alkylene aryl and substituted or unsubstituted C1-C6 alkylene heteroaryl; and

[0035] R 9' is independently selected from H and C1-C6 alkyl;

[0036] wherein all available hydrogen atoms are optionally substituted by fluorine or chlorine atoms, and / or all available atoms are optionally substituted by their alternative isotopes.

[0037] In a further embodiment, the compounds of the invention are used as medicaments. Accordingly, the invention also encompasses the compounds of the invention for use as medicaments.

[0038] The invention also encompasses a method of treating a psychotic disorder or psychotic symptoms, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the invention.

[0039] The invention also encompasses a method of treating a mental disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the invention.

[0040] The invention further provides a process for preparing the compounds of the invention. General and specific methods will be discussed in more detail below and illustrated in the following examples.

[0041] From the following detailed description, other features and advantages of the invention will become apparent. However, it should be understood that the detailed description and the specific examples, while indicating embodiments of the invention, are given by way of illustration only, and the scope of the claims should not be limited by these embodiments, but should be given the broadest interpretation consistent with the whole of this specification. DETAILED DESCRIPTION

[0042] I. DEFINITIONS

[0043] Unless otherwise indicated, the definitions and embodiments described in this section and other sections are intended to apply to all embodiments and aspects of the invention described herein, as will be understood by those skilled in the art.

[0044] As used herein, the term "compounds of the invention" or "compounds of the present invention", etc. refers to compounds of formula I (including formulae IA, IB, IC, ID, IE and IF falling within the scope of formula I), and includes their pharmaceutically acceptable salts, solvates and / or prodrugs as well as all stereoisomers and regioisomers.

[0045] As used herein, the term "compounds of the invention" or "compounds of the present invention", etc. refers to a composition comprising one or more compounds of the invention, such as a pharmaceutical composition.

[0046] As used herein, the term "and / or" means that the listed items are present or used individually or in combination. In fact, this term means the use or presence of "at least one" or "one or more" of the listed items. The term "and / or" with respect to its pharmaceutically acceptable salts and / or solvates means that the compounds of the invention are present in the form of the individual salts and solvates as well as in combinations such as, for example, a salt or a solvate of a compound of the invention.

[0047] As used in the present invention, the singular forms "a / an" and "the" include plural referents unless the context clearly indicates otherwise. For example, an embodiment that includes "a compound" is to be understood as representing certain aspects with one compound or two or more additional compounds.

[0048] As used in the present invention and in the claims, the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "include" and "includes") or "containing" (and any form of containing, such as "contain" and "contains") are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0049] As used herein, the term "consisting of" and its derivatives are closed terms that specify the presence of the stated features, elements, components, groups, wholes, and / or steps and also exclude the presence of other unstated features, elements, components, groups, wholes, and / or steps.

[0050] As used herein, the term "consisting essentially of" is intended to specify the presence of the stated features, elements, components, groups, wholes, and / or steps, as well as those that do not materially affect the basic and novel features of these features, elements, components, groups, wholes, and / or steps.

[0051] In embodiments that include an "additional" or "second" component (such as an additional or second compound), the second component, as used herein, is chemically different from the other components or the first component. The "third" component is different from the other components, and the first component, the second component, and the other recited components or "additional" groups are similarly different.

[0052] As used herein, the term "suitable" means that the selection of a particular compound or condition will depend on the particular synthetic operation to be performed, the identity of the molecule to be transformed, and / or the particular use of the compound, but the selection is entirely within the skill of one of ordinary skill in the art. All process / method steps described herein will be carried out under conditions sufficient to provide the indicated product. One of ordinary skill in the art will understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio, and whether the reaction should be carried out under anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product, and doing so is within the skill of one of ordinary skill in the art.

[0053] As used herein, the terms "about", "substantially", and "approximate" mean a reasonable deviation of the modified term such that the final result is not significantly changed. These degree terms should be construed to include at least a ±5% deviation of the modified term, provided that such deviation does not negate the meaning of the term it modifies, or unless the context otherwise indicates to one of ordinary skill in the art.

[0054] This specification refers to many chemical terms and abbreviations used by one of ordinary skill in the art. However, for clarity and consistency, definitions of selected terms are provided.

[0055] As used herein, the term "solvate" means a compound, or a salt and / or prodrug of a compound, in which molecules of a suitable solvent are incorporated into the lattice.

[0056] As used herein, the term "prodrug" means a compound or a salt of a compound that is converted to an active drug upon administration.

[0057] As used herein, whether used alone or as part of another group, the term "alkyl" means a straight-chain or branched-chain saturated alkyl group. The possible number of carbon atoms in the alkyl group mentioned is indicated by the prefix "C n1-n2 ". Thus, for example, the term "C 1-6 alkyl" (or "C 1-6 alkyl") means an alkyl group having 1, 2, 3, 4, or 5 carbon atoms.

[0058] Whether used alone or as part of another group, the term "alkenyl" means a straight-chain or branched-chain saturated alkenylene group, i.e., a saturated carbon chain having substituents at both ends. The possible number of carbon atoms in the alkenylene group mentioned is indicated by the prefix "C n1-n2 ". For example, the term C 2-6 alkenylene means an alkenylene group having 2, 3, 4, 5, or 6 carbon atoms.

[0059] As used herein, whether used alone or as part of another group, the term "alkynyl" means a straight or branched chain unsaturated alkynyl group containing at least one triple bond. The possible number of carbon atoms in the alkyl group mentioned is represented 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.

[0060] As used herein, the term "alkoxy", when used alone or in combination herein, includes an alkyl group attached to an oxygen linking atom.

[0061] As used herein, whether used alone or as part of another group, the term "cycloalkyl" means a saturated carbocyclic group containing 3 to 6 carbon atoms and one or more rings. The possible number of carbon atoms in the cycloalkyl group mentioned is represented by the numerical prefix "C n1-n2 ". For example, the term C 3-10 cycloalkyl means a cycloalkyl group having 3, 4, 5 or 6 carbon atoms.

[0062] As used herein, whether used alone or as part of another group, the term "heterocycloalkyl" refers to a cyclic group containing at least one non-aromatic ring (containing 3 to 6 atoms), wherein one or more atoms are hetero moieties selected from O, S, S(O), SO2 and N, and the remaining atoms are C. Heterocycloalkyl is saturated or unsaturated (i.e., contains one or more double bonds). When heterocycloalkyl contains the prefix C n1-n2 or "n1-n2", this prefix represents the number of carbon atoms in the corresponding carbocyclic group, wherein one or more, suitably 1-4 ring atoms are replaced by heteroatoms selected from O, S, S(O), SO2 and N, and the remaining atoms are C.

[0063] As used herein, whether used alone or as part of another group, the term "aryl" means a carbocyclic group containing at least one aromatic ring and containing 6 to 20 carbon atoms.

[0064] As used herein, whether used alone or as part of another group, the term "heteroaryl" means a cyclic group containing at least one heteroaromatic ring (containing 5-6 atoms), wherein one or more atoms are heteroatoms selected from O, S and N, and the remaining atoms are C. When heteroaryl contains the prefix C n1-n2 , this prefix represents the number of carbon atoms in the corresponding carbocyclic group, wherein one or more, suitably 1-4 ring atoms are replaced by heteroatoms as defined above.

[0065] All cyclic groups, including aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, contain one or more rings (i.e., polycyclic). When a cyclic group contains more than one ring, the rings can be fused, bridged, spiro-fused, or linked by bonds.

[0066] As used herein, the term "benzo-fused" refers to a polycyclic group in which a benzene ring is fused to another ring.

[0067] "Fused" of a first ring to a second ring means that the first and second rings share two adjacent atoms therebetween.

[0068] "Bridged" of a first ring to a second ring means that the first and second rings share two non-adjacent atoms therebetween.

[0069] "Spiro-fused" of a first ring to a second ring means that the first and second rings share one atom therebetween.

[0070] Whether used alone or as part of another group, the term "halogen" (or "halo") refers to a halogen atom and includes fluorine, chlorine, bromine, and iodine.

[0071] As used herein, the term "haloalkyl" refers to an alkyl group as defined above, wherein one or more available hydrogen atoms are replaced by 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.

[0072] As used herein, the term "haloalkenyl" refers to an alkenyl group as defined above, wherein one or more available hydrogen atoms are replaced by a halogen. Thus, for example, "C 1-6 haloalkenyl" (or "C1-C6 haloalkenyl") refers to a C1 to C6 straight or branched chain alkenyl group as defined above having one or more halogen substituents.

[0073] As used herein, the term "haloalkynyl" refers to an alkynyl group as defined above, wherein one or more available hydrogen atoms are replaced by a halogen. Thus, for example, "C 1-6 haloalkynyl" (or "C1-C6 haloalkynyl") refers to a C1 to C6 straight or branched chain alkynyl group as defined above having one or more halogen substituents.

[0074] As used herein, the term "deuterated alkyl" refers to an alkyl group as defined above, wherein one or more available hydrogen atoms are replaced by deuterium. Thus, for example, "C 1-6 deuterated alkyl" refers to a C1 to C6 straight or branched chain alkyl group as defined above having one or more deuterium substituents.

[0075] The suffix “ene” at the end of a group (such as “alkylene” or “alkenylene”) means that the group is divalent, i.e., it is bonded to two variables, each at a different end of the group.

[0076] As used herein, the term “optionally substituted” means that the subject group is unsubstituted or substituted, and the terms “optionally substituted” and “unsubstituted or substituted” are used interchangeably herein.

[0077] The term “substituted” herein means that one or more hydrogen atoms in the group are replaced or substituted by substituents independently selected from the following: 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), C3-C6 cycloalkyl, and 3- to 6-membered heterocycles containing 1 to 2 ring hetero moieties selected from O, S, S(O), SO2, N, NH, and NC1-C4 alkyl.

[0078] In “available hydrogen atoms” or “available atoms”, the term “available” means an atom known to those skilled in the art to be capable of being replaced by a substituent.

[0079] As used herein, the term “one or more” items includes a single item selected from the list and mixtures of two or more items selected from the list.

[0080] As used herein, the term “its alternative isotope” means an isotope of an element other than the most abundant isotope found in nature.

[0081] In the compounds of formula I and their pharmaceutically acceptable salts and / or solvates, atoms may exhibit their natural isotope abundances, or one or more atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is intended to include all suitable isotopic variants of the compounds of formula I and their pharmaceutically acceptable salts and / or solvates. For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H). Protium is the major hydrogen isotope found in nature.

[0082] The term "compound" refers to the compound, and in certain embodiments, within the range in which they are stable, refers to any hydrate or solvate thereof. A hydrate is a compound complexed with water, and a solvate is a compound complexed with a solvent, which can be an organic or inorganic solvent. A "stable" compound is a compound that can be prepared and isolated, and whose structure and properties remain or can be caused to remain substantially unchanged over a period of time sufficient to permit the use of the compound for the purposes described herein (e.g., therapeutic administration to a subject). The compounds of the present invention are limited to stable compounds encompassed by General Formula I, or pharmaceutically acceptable salts and / or solvates thereof.

[0083] The term "pharmaceutically acceptable" means compatible with the treatment of a subject.

[0084] The term "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant or other substance that is mixed with an active ingredient to permit the formation of a pharmaceutical composition (i.e., a dosage form capable of being administered to a subject).

[0085] The term "pharmaceutically acceptable salt" means an acid addition salt or a base addition salt that is suitable for or compatible with the treatment of a subject.

[0086] An acid addition salt that is suitable for or compatible with the treatment of a subject is any non-toxic organic or inorganic acid addition salt of any basic compound.

[0087] A base addition salt that is suitable for or compatible with the treatment of a subject is any non-toxic organic or inorganic base addition salt of any acidic compound.

[0088] As used herein, the terms "protecting group" or "PG" and the like refer to chemical moieties that protect or mask reactive portions of a molecule to prevent side reactions in those reactive portions of the molecule while manipulating different portions of the molecule or causing it to react. After the operation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portion of the molecule. One of ordinary skill in the art can select a suitable protecting group. Many conventional protecting groups are known in the art, such as those described in "Protective Groups in Organic Chemistry", McOmie, J.F.W., ed., Plenum Press, 1973; Greene, T.W. and Wuts, P.G.M., "Protective Groups in Organic Synthesis", John Wiley & Sons, 3rd ed., 1999; and Kocienski, P. Protecting Groups, 3rd ed., 2003, Georg Thieme Verlag (The Americas).

[0089] As used herein, the term "subject" includes all members of the animal kingdom, including mammals, and, where appropriate, refers to humans. Accordingly, the methods of the present invention are applicable to human therapy and veterinary applications.

[0090] As used herein and as is well known in the art, the terms "treating" or "treatment" mean a method of obtaining a beneficial or desired result (including a clinical result). Beneficial or desired clinical results include, but are not limited to, alleviating or ameliorating one or more symptoms or disorders, reducing the severity of a disease, stabilizing (i.e., not worsening) a disease state, preventing the spread of a disease, delaying or slowing the progression of a disease, alleviating or mitigating a disease state, reducing disease recurrence, and remission (whether partial or complete), whether detectable or undetectable. "Treating" and "treatment" can also mean prolonging survival as compared to expected survival without receiving treatment. As used herein, "treating" and "treatment" 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 invention to prevent recurrence. Methods of treatment include administering to a subject a therapeutically effective amount of one or more compounds of the present invention, and optionally consisting of a single administration, or alternatively including a series of administrations.

[0091] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of one or more compounds of the present invention that is effective within the dosage and time required to achieve the desired result. For example, in the context of treating a disease, disorder or condition mediated or treated by agonizing or activating serotonergic receptors and downstream second messengers, an effective amount is, for example, an amount that increases such activation as compared to activation in the absence of administration of one or more compounds.

[0092] "Mitigating" a disease, disorder or condition means that the severity and / or the time course of progression of the adverse clinical manifestations of the disease, disorder or condition are reduced and / or slowed or extended as compared to not treating the condition.

[0093] As used herein, the term "administering" means administering a therapeutically effective amount of one or more compounds or compositions of the present invention to a cell, tissue, organ or subject.

[0094] As used herein, the terms "prevention" or "prophylaxis" or synonyms thereof refer to reducing the risk or probability that a patient will develop a disease, disorder or condition or exhibit symptoms associated with a disease, disorder or condition.

[0095] As used herein, "disease, disorder or condition" refers to a disease, disorder or condition that can be treated or is treatable by activating a serotonin receptor, such as 5-HT 2A , in particular by using a serotonin receptor agonist, such as one or more of the compounds of the present invention described herein.

[0096] As used herein, the term "treating a disease, disorder or condition by activating a serotonin receptor" means that the disease, disorder or condition to be treated is directly or indirectly affected, regulated and / or has certain biological bases, including serotonergic activity, in particular an increase in serotonergic activity. When the serotonergic activity associated with the disease, disorder or condition is agonized by one or more compounds or compositions of the present invention, these diseases respond well.

[0097] As used herein, the term "activation" includes agonist, partial agonist and positive allosteric modulation of serotonin receptors.

[0098] As used herein, the term "5-HT 1A " and "5-HT 2A " mean the 5-HT 2A and 5-HT 2A receptor subtypes of the 5-HT2 serotonin receptor.

[0099] As used herein, the term "therapeutic agent" refers to any drug or active agent that has a pharmacological effect when administered to a subject.

[0100] II. Compounds

[0101] The inventors have 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, the 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.

[0102] The present invention includes compounds of formula I:

[0103]

[0104] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0105] wherein:

[0106] Q is selected from 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'NR9’ C(O);

[0107] R 1 selected from H, C1-C3 alkyl, C(O)R 10 , CO2R 10 , C(O)N(R 10 )(R 11 ), S(O)R 10 and SO2R 10 ;

[0108] R 2 , R 3 , R 3' , R 4 and R 4' are independently selected from H and C1-C6 alkyl;

[0109] R 5 and R 5' are independently selected from H and C1-C6 alkyl, or

[0110] R 5 and R 5' together with the nitrogen atom between them form a 3- to 7-membered heterocycle, which optionally contains 1 to 2 additional heterocyclic moieties selected from O, S, S(O), SO2, N, and NC 1-6 alkyl;

[0111] R 6 , R 7 and R 8 are independently selected from 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 C3-C7 heterocycloalkyl containing 1 to 2 heterocyclic moieties selected from O, S, S(O), SO2, N, and NR 14 , wherein the 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 optionally substituted with one or more independently selected from CN, OR 15 , N(R 15 )(R 16 ) and SR15 is substituted with substituents, and wherein each of said C3-C7 cycloalkyl and C3-C7 heterocycloalkyl is further optionally substituted with one or more substituents independently selected from halo, CO2R 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 C3-C6 heterocycloalkyl containing 1 to 2 hetero moieties independently selected from O, S, S(O), SO2, N and NR 19 ;

[0112] Q' is selected from a direct bond, C1-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 C3-C7 heterocycloalkylene containing 1 to 2 hetero moieties independently selected from O, S, S(O), SO2, N and NR 20 , wherein said C1-C 20 alkylene, C2-C 20 haloalkylene, C2-C6 alkenylene, C2-C 20 haloalkenylene, C3-C7 cycloalkylene and C3-C7 heterocycloalkylene are optionally substituted with one or more substituents independently selected from CN, OR 21 , N(R 21 )(R 22 ) and SR 21 , and / or disubstituted on the same carbon atom with C 1-6 alkyl or with C 2-6 alkylene to form a C3-C7 cycloalkyl ring, and wherein each of said C3-C7 cycloalkylene and C3-C7 heterocycloalkylene is further optionally substituted with one or more substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, provided that when Q is C(O)OQ'OC(O) or C(O)NR 9’ Q'NR 9’ C(O), then Q' is not a direct bond;

[0113] Each R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are 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 alkylene aryl, and substituted or unsubstituted C1-C6 alkylene heteroaryl; and

[0114] R 9' is independently selected from H and C1-C6 alkyl;

[0115] wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes.

[0116] The present invention includes compounds of formula I:

[0117]

[0118] or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof,

[0119] wherein:

[0120] Q is selected from P(O)OR 9 , C1-C4 alkylene-P(O)OR 9 -C1-C6 alkylene, C(O), SO2, and C(O)Q'C(O);

[0121] R 1 is selected from H, C1-C3 alkyl, C(O)R 10 , CO2R 10 , C(O)N(R 10 )(R 11 ), S(O)R 10 and SO2R 10 ;

[0122] R 2 、R 3 、R 3' 、R 4 and R 4' are independently selected from H and C1-C6 alkyl;

[0123] R 5 and R 5' are independently selected from H and C1-C6 alkyl, or

[0124] R 5 and R 5' together with the nitrogen atom between them form a 3- to 7-membered heterocycle, which optionally contains 1 to 2 additional heteroatoms selected from O, S, S(O), SO2, N, and NC 1-6 alkyl of the additional ring;

[0125] R 6 , R 7 and R 8 are independently selected from 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 C3-C7 heterocycloalkyl containing 1 to 2 heteroatoms selected from O, S, S(O), SO2, N, and NR 14 wherein the 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 optionally substituted by one or more substituents independently selected from CN, OR 15 , N(R 15 )(R 16 ), and SR 15 , and wherein the C3-C7 cycloalkyl and C3-C7 heterocycloalkyl are each further optionally substituted by one or more substituents selected from halo, CO2R 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 C3-C6 heterocycloalkyl containing 1 to 2 heteroatoms selected from O, S, S(O), SO2, N, and NR 19 of the additional ring;

[0126] Q' is selected from a direct bond, C1-C20 Alkylene, C1-C 20 Halogenated alkylene, C2-C 20 Alkenylene, C2-C 20 Halogenated alkenylene, C2-C 20 Alkynylene, C2-C 20 Halogenated alkynylene, C3-C7 cycloalkylene and C3-C7 heterocycloalkylene containing 1 to 2 hetero moieties selected from O, S, S(O), SO2, N and NR 20 wherein said C1-C 20 alkylene, C2-C 20 halogenated alkylene, C2-C6 alkenylene, C2-C 20 halogenated alkenylene, C3-C7 cycloalkylene and C3-C7 heterocycloalkylene are optionally substituted by one or more substituents independently selected from CN, OR 21 、N(R 21 )(R 22 ) and SR 21 and / or disubstituted on the same carbon atom by C 1-6 alkyl or by C 2-6 alkylene to form a C3-C7 cycloalkyl ring, and wherein said C3-C7 cycloalkylene and C3-C7 heterocycloalkylene are each further optionally substituted by one or more substituents selected from C1-C3 alkyl and C1-C3 haloalkyl; and

[0127] each 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 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 alkylene aryl and substituted or unsubstituted C1-C6 alkylene heteroaryl;

[0128] wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes.

[0129] In some embodiments, all available hydrogen atoms are optionally substituted with their alternative isotopes. In some embodiments, the alternative isotope of hydrogen is deuterium. Thus, in some embodiments, the compounds of the invention are isotopically enriched in deuterium.

[0130] In some embodiments, R 1 is selected from H, C1-C3 alkyl, C(O)R 10 , CO2R 10 and C(O)N(R 10 )(R 11 ), wherein all available hydrogen atoms are optionally substituted with fluorine atoms or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, R 1 is selected from H, C1-C3 alkyl, C(O)R 10 and CO2R 10 , wherein all available hydrogen atoms are optionally substituted with fluorine atoms or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, R 1 is selected from H, CH3, and CH2CH3, wherein all available hydrogen atoms are optionally substituted with fluorine atoms or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, R 1 is selected from H, CH3, CH2CH3, wherein all available hydrogen atoms are optionally and independently substituted with fluorine atoms or deuterium atoms. In some embodiments, R 1 is independently 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, D, CH3, and CD3. In some embodiments, R 1 is selected from H, CH3, CH2CH3, C(O)R 10 and CO2R 10 , wherein all available hydrogen atoms are optionally substituted with fluorine atoms or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, R 1 is selected from H, CH3, and CH2CH3, wherein all available hydrogen atoms are optionally and independently substituted with fluorine atoms or deuterium atoms. In some embodiments, R 1Selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CFH2, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 1 Selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CF2H, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD 3。 In some embodiments, R 1 Selected from H and D. In some embodiments, R 1 is H. In some embodiments, R 1 Selected from S(O)R 10 and SO2R 10 wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes.

[0131] In some embodiments, R 2 、R 3 、R 3' 、R 4 and R 4' are independently selected from hydrogen and C1-C4 alkyl, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, R 2 、R 3 、R 3' 、R 4 and R 4' are independently selected from H, CH3, CH2CH3, CH(CH3)2, and C(CH3)3, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes.

[0132] In some embodiments, R 2 is selected from hydrogen, CH3, CH2CH3, CH(CH3)2, and C(CH3)3, wherein all available hydrogen atoms are optionally and independently substituted with fluorine or deuterium atoms. In some embodiments, R 2 Selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CFH2, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 2 Selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CF2H, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 2Selected 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.

[0133] In some embodiments, R 3 , R 3' , R 4 , and R 4' are independently selected from H, CH3, CH2CH3, CH(CH3)2, and C(CH3)3, where all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available hydrogen atoms are optionally substituted with deuterium. In some embodiments, R 3 , R 3' , R 4 , and R 4' are independently selected from H, CH3, CH2CH3, CH(CH3)2, and C(CH3)3, where all available hydrogen atoms are optionally and independently replaced with fluorine or deuterium atoms. In some embodiments, at least one of R 3 , R 3' , R 4 , and R 4' is D, or at least one of R 3 , R 3' , R 4 , and R 4' contains D. In some embodiments, R 3 , R 3' , R 4 , and R 4' are independently selected from H, D, F, CH3, CD2H, CDH2, CD 3、 CF3, CHF2, CF2H, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 3 , R 3' , R 4 , and R 4' are independently selected from H, D, F, CH3, CD2H, CDH2, and CD3. In some embodiments, R 3 , R 3' , R 4 , and R 4' are independently selected from H, D, F, CH3, and CD3. In some embodiments, R 3 , R 3' , R 4 , and R 4'Independently selected from H, D, and F. In some embodiments, R 3 , R 3' , R 4 , and R 4' are at least one of F. In some embodiments, R 3 , R 3' , R 4 , and R 4' are all H. In some embodiments, R 3 , R 3' , R 4 , and R 4' are all F. In some embodiments, R 3 , R 3' , R 4 , and R 4' are at least one of H. In some embodiments, R 3 , R 3' , R 4 , and R 4' are all D. In some embodiments, R 3 , R 3' , R 4 , and R 4' are at least two of D. In some embodiments, R 3 and R 4 are both D and R 3' and R 4' are both H. In some embodiments, R 3 and R 4 are both H and R 3' and R 4' are both D.

[0134] In some embodiments, R 5 and R 5' are independently selected from H and C1-C4 alkyl, where all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, R 5 and R 5' are independently selected from H and C1-C4 alkyl, where all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available hydrogen atoms are optionally substituted with deuterium. In some embodiments, R 5 and R 5' are independently selected from hydrogen, CH3, CH2CH3, CH(CH3)2, and C(CH3)3, where all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available hydrogen atoms are optionally substituted with deuterium. In some embodiments, R 5 and R 5'Independently selected from H, D, F, CH3, CD2H, CDH2, CD 3、 CF3, CHF2, CFH2, CH2CH3, CH2CH2D, CH2CD2H, CD2CD3, CD(CD3)2, and CH(CH3)2. In some embodiments, R 5 and R 5' are 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' are independently selected from H, D, CH3, CD3, CH2CH3, and CH(CH3)2. In some embodiments, R 5 and R 5' are independently selected from H, D, CH3, and CD3. In some embodiments, R 5 and R 5' are independently selected from H and D. In some embodiments, R 5 and R 5' are independently selected from CH3 and CD3. In some embodiments, R 5 is CD3. In some embodiments, R 5 and R 5' are both CH3. In some embodiments, R 5 and R 5' are both CD3. In some embodiments, R 5 and R 5' are both CH(CH3)2. In some embodiments, R 5 and R 5' are both CH2CH3. In some embodiments, R 5 and R 5' are both H. In some embodiments, one of R 5 and R 5' is CH3 or CD3 and the other of R 5 and R 5' is H or D. In some embodiments, one of R 5 and R 5' is CH2CH3 and CH(CH3)2 and the other of R 5 and R 5' is H, CH3, or CD3.

[0135] In some embodiments, R 5 and R 5' together with the nitrogen atom between them form a 3- to 7-membered heterocycle, which optionally contains 1 to 2 members selected from O, S, S(O), SO2, N, and NC1-6 An additional cyclic hetero moiety of an alkyl group, wherein all available hydrogen atoms are optionally substituted with halogen atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, R 5 and R 5' together with the nitrogen atom therebetween form a 4- to 7-membered heterocycle, which optionally contains 1 to 2 members selected from O, S, S(O), SO2, N, and NC 1-4 An additional cyclic hetero moiety of an alkyl group, wherein all available hydrogen atoms are optionally substituted with halogen atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, R 5 and R 5' together with the nitrogen atom therebetween form an azetidinyl, diazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, diazinyl (e.g., piperazinyl), morpholinyl, or azepanyl ring, wherein all available hydrogen atoms are optionally substituted with halogen atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, R 5 and R 5' together with the nitrogen atom therebetween form a pyrrolidinyl, piperidinyl, morpholinyl, or diazinyl group, wherein all available hydrogen atoms are optionally substituted with halogen atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, R 5 and R 5' together with the nitrogen atom therebetween form a pyrrolidinyl, piperidinyl, morpholinyl, or diazinyl group, wherein all available hydrogen atoms are optionally substituted with fluorine and / or chlorine atoms, and / or all available hydrogen atoms are optionally substituted with deuterium. In some embodiments, R 5 and R 5' together with the nitrogen atom therebetween form a pyrrolidinyl, piperidinyl, morpholinyl, or diazinyl group, wherein all available hydrogen is optionally substituted with deuterium. In some embodiments, R 5 and R 5' together with the nitrogen atom therebetween form a pyrrolidinyl, piperidinyl, or morpholinyl group, wherein all available hydrogen is optionally substituted with deuterium.

[0136] In some embodiments, R 6 , R 7 and R 8 are independently selected from 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(R12 )(R 13 )、S(O)R 12 、SO2R 12 、C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl and C3-C7 heterocycloalkyl containing 1 to 2 hetero moieties selected from O, S, S(O), SO2, N and NR 14 , wherein the 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 optionally substituted by one or more substituents independently selected from CN, OR 15 , N(R 15 )(R 16 ) and SR 15 , and wherein the C3-C7 cycloalkyl and C3-C7 heterocycloalkyl are each further optionally substituted by one or more substituents selected from halo, CO2R 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 C3-C6 heterocycloalkyl containing 1 to 2 hetero moieties selected from O, S, S(O), SO2, N and NR 19 ; wherein all available hydrogen atoms are optionally substituted by fluorine or chlorine atoms, and / or all available atoms are optionally substituted by their alternative isotopes.

[0137] In some embodiments, R 6 , R 7 and R 8 are independently selected from 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 the C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl and C2-C6 haloalkynyl groups are optionally substituted by one or more substituents independently selected from CN, OR 15, N(R 15 )(R 16 ) and SR 15 are substituted with substituents, and all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, R 6 , R 7 and R 8 are independently selected from 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 the C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl and C2-C6 haloalkynyl groups are optionally substituted with one to three substituents independently selected from CN, OR 15 , 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 their alternative isotopes. In some embodiments, R 6 , R 7 and R 8 are independently selected from 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 the C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl and C2-C6 alkynyl groups are optionally substituted with one or two substituents independently selected from CN, OR 15 , N(R 15 )(R 15 )2 and SR15 is substituted with substituents, where all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, R 6 , R 7 and R 8 are independently selected from 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 and C2-C6 alkenyl, where all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, R 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 are independently selected from H, D, F, Cl, Br and CN. In some embodiments, R 6 , R 7 and R 8 are 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 are selected from hydrogen and deuterium. In some embodiments, R 7 is selected from H, D, F and CN and R 6 and R 8 are selected from H and D. In some embodiments, R 7 is selected from H, F and CN and R 6 and R 8 are 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.

[0138] In some embodiments, R6 , R 7 and R 8 The C3-C7 cycloalkyl groups in are independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, where all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes.

[0139] In some embodiments, the C3-C7 heterocycloalkyl groups in R 6 , R 7 and R 8 are independently saturated or unsaturated heterocycles. In some embodiments, the C3-C7 heterocycloalkyl groups in R 6 , R 7 and R 8 are independently saturated or unsaturated bridged bicyclic heterocycles. In some embodiments, the saturated or unsaturated bridged bicyclic heterocycles are independently selected from azabicyclohexyl, diazabicycloheptyl, oxabicyclohexyl, oxabicycloheptyl, and oxabicycloheptenyl, where all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes.

[0140] In some embodiments, the C3-C7 heterocycloalkyl groups in R 6 , R 7 and R 8 are independently selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxathiolanyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, diazinyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, and diazepanyl, where all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes.

[0141] In some embodiments, Q is selected from 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), wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, Q is selected from a direct bond, P(O)OR 9 、C1-C2 alkylene-P(O)OR 9 -C1-C2 alkylene, C(O), SO2 and C(O)(Q')C(O), wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, Q is selected from P(O)OR 9 and C1-C2 alkylene-P(O)OR 9 -C1-C2 alkylene. In some embodiments, Q is C1-C2 alkylene-P(O)OR 9 -C1-C2 alkylene, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, Q is CH2-P(O)OR 9 -CH2, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. 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’ C(O), wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, Q is selected from a direct bond, C(O) and C(O)(Q’)C(O), wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, Q is a direct bond. In some embodiments, Q is C(O). In some embodiments, Q is C(O)(Q')C(O). In some embodiments, Q is C(O)OQ'OC(O). In some embodiments, Q is C(O)NR 9' Q'NR 9' C(O). In some embodiments, Q is SO2.

[0142] In some embodiments, Q′ is selected from C1-C 10 alkylene, C2-C 10 alkenylene and C2-C 10 alkynylene, wherein the C1-C 10 alkylene, C2-C 10 alkenylene and C2-C 10 alkynylene are optionally substituted with one to three groups independently selected from CN, OR 21 、N(R21 )(R 22 ) and SR 21 is substituted with substituents of, and / or on the same carbon atom is disubstituted with C 1-6 alkyl or is disubstituted with C 2-6 alkylene to form a C3-C7 cycloalkyl ring, wherein the C3-C7 cycloalkyl is further optionally substituted with substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, Q′ is selected from C1-C6 alkylene, C2-C6 alkenylene, and C2-C6 alkynylene, which are optionally substituted with one or two substituents independently selected from OR 21 and N(R 21 )(R 22 ) and / or on the same carbon atom is disubstituted with C 1-6 alkyl or is disubstituted with C 2-6 alkylene to form a C3-C7 cycloalkyl ring, wherein the C3-C7 cycloalkyl ring is further optionally substituted with substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, Q′ is selected from C1-C4 alkylene and C2-C4 alkenylene, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, Q′ is selected from CH2, CH2CH2, CH2CH2CH2, and CH═CH.

[0143] In some embodiments, when Q is C(O)Q′C(O), Q′ is a straight bond. In some embodiments, Q′ is a straight bond.

[0144] In some embodiments, Q′ is selected from C3-C7 subcycloalkyl and C3-C7 subheterocycloalkyl containing 1 to 2 hetero moieties selected from O, S, S(O), SO2, N, and NR 20 , wherein the C3-C7 subcycloalkyl and C3-C7 subheterocycloalkyl are optionally substituted with one to three substituents independently selected from CN, OR 21 , N(R 21 )(R 22 ), SR 21 , C1-C3 alkyl, and C1-C3 haloalkyl. In some embodiments, the C3-C7 cycloalkyl in Q' is selected from cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes.

[0145] In some embodiments, the C3-C7 heterocycloalkyl in Q′ is selected from saturated or unsaturated heterocycles. In some embodiments, Q′ is selected from aziridinyl, oxiranyl, thiiranyl, oxiridino, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, diazinyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, and diazepanyl, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes.

[0146] In some embodiments, each 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 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 all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes.

[0147] In some embodiments, each R 9 、R 10 、R 11 、R 12 、R 13 、R14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are 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.

[0148] In some embodiments, each 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 in C3-C7 cycloalkyl is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes.

[0149] In some embodiments, each 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 in C3-C7 heterocycloalkyl is independently selected from saturated or unsaturated heterocycles. In some embodiments, each 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 the group is independently selected from aziridine, oxirane, thiirane, oxaziridine, dioxirane, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxathianyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl , piperidinyl, triazolyl, 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 are optionally replaced by fluorine or chlorine atoms, and / or all available atoms are optionally replaced by alternative isotopes thereof.

[0150] In some embodiments, R 9 and R 10 The C3-C7 heterocycloalkyl in is independently selected from saturated or unsaturated bridged bicyclic heterocycles. In some embodiments, saturated or unsaturated bridged bicyclic heterocycles are independently selected from azabicyclohexyl, diazabicycloheptyl, oxobicyclohexyl, oxobicycloheptyl and oxobicycloheptenyl, wherein all available hydrogen atoms are optionally substituted by fluorine or chlorine atoms, and / or all available atoms are optionally substituted by alternative isotopes thereof.

[0151] In some embodiments, each 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 22The heteroaryl groups are independently selected from azepinyl, benzisoxazolyl, benzofuranyl, chromenyl, chromanyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrochromanyl, dihydrochromanyl sulfone, 1,3-dioxolanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-azepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuranyl, thienothienyl, triazolyl and thienyl, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes.

[0152] In some embodiments, each 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 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, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, each 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 22Independently selected from H, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C4 haloalkyl, where all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, each 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 R 22 Independently selected from H, C1-C4 alkyl, and C2-C6 alkenyl, where all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, each 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 R 22 Independently selected from H and C1-C4 alkyl, where all available hydrogen atoms are optionally and independently substituted with fluorine atoms or deuterium atoms. In some embodiments, each 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 R 22 Independently selected from H, D, CH3, CD2H, CDH2, CD 3、 CF3, CHF2, CF2H, CH2CH2D, CH2CD2H, CH2CH3, and CD2CD3. In some embodiments, each R 9 R 10 R 11 R12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently selected from H, D, CH3, and CD3.

[0153] In some embodiments, each 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 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, substituted or unsubstituted C1-C4 alkylene heteroaryl, wherein all available hydrogen atoms are optionally replaced by fluorine or chlorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, each 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 selected from substituted or unsubstituted C1-C4 alkylene aryl and substituted or unsubstituted C1-C4 alkylene heteroaryl, wherein all available hydrogen atoms are optionally replaced by fluorine or chlorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, each R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently a substituted or unsubstituted C1-C4 alkylene aryl, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, each 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 a substituted or unsubstituted CH2 aryl, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, each 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 a substituted or unsubstituted CH2 phenyl.

[0154] In some embodiments, when 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 22When substituted, the substituents are independently selected from Br, Cl, F, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, SO2CH3, C1-C4 alkyl, C1-C4 fluoroalkyl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, C2-C6 alkynyl, C2-C6 fluoroalkynyl, C3-C6 cycloalkyl, and one or more of 3- to 6-membered heterocycles containing 1 to 2 ring hetero moieties selected from O, S, S(O), SO2, N, NH, and NCH3. 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 substituents on are independently selected from one or three of Br, Cl, F, C1-C4 alkyl, C1-C4 fluoroalkyl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, C2-C6 alkynyl, and C2-C6 fluoroalkynyl. 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 substituents on are independently selected from one or two of Br, Cl, F, CH3, and CF3.

[0155] In some embodiments, R 9' is selected from H and C1-C4 alkyl, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes. In some embodiments, R 9' is selected from H and C1-C4 alkyl, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available hydrogen atoms are optionally substituted with deuterium. In some embodiments, R 9'Selected from hydrogen, CH3, CH2CH3, CH(CH3)2, and C(CH3)3, wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available hydrogen atoms are optionally substituted with deuterium. In some embodiments, R 9' is selected from H, D, F, CH3, CD2H, CDH2, CD 3、 CF3, CHF2, CFH2, CH2CH3, CH2CH2D, CH2CD2H, CD2CD3, CD(CD3)2, and CH(CH3)2. In some embodiments, R 9' is selected from H, D, CH3, CD3, CH2CH3, and CH(CH3)2. In some embodiments, R 9' is selected from H, D, CH3, and CD3. In some embodiments, R 9' is selected from H and D. In some embodiments, R 9' is selected from CH3 and CD3. In some embodiments, R 9' is CD3. In some embodiments, R 9' is H.

[0156] In some embodiments, Q is P(O)(OH) and the compound of formula I is a compound of formula IA:

[0157]

[0158] or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof,

[0159] wherein R 1 , R 2 , R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 7 , and R 8 are as defined in formula I. In some embodiments, Q is CH2P(O)(OH)CH2 and the compound of formula I is a compound of formula IB:

[0160]

[0161] or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof,

[0162] wherein R 1 , R 2 , R 3 , R 3' , R 4 , R 4' , R5 , R 5' , R 6 , R 7 and R 8 are as defined in Formula I. In some embodiments, Q is C(O)-Q'-C(O) and the compound of Formula I is a compound of Formula IC:

[0163]

[0164] or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof,

[0165] 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' are as defined in Formula I. In some embodiments, Q is SO2 and the compound of Formula I is a compound of Formula ID:

[0166]

[0167]

[0168] or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof,

[0169] wherein R 1 , R 2 , R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 6 , R 7 and R 8 are as defined in Formula I. In some embodiments, Q is C(O)OQ′OC(O) and the compound of Formula I is a compound of Formula IE:

[0170]

[0171] or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof,

[0172] 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' are as defined in Formula I.

[0173] In some embodiments, Q is C(O)NR 9’ Q′NR 9’ C(O) and the compound of Formula I is a compound of Formula IF:

[0174]

[0175] or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof,

[0176] 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.

[0177] 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:

[0178] Table 1:

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189] In some embodiments, the compound of Formula I is selected from one or more of the compounds listed in Table 1 or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof. In some embodiments, the compound of Formula I is selected from the compounds listed in Table 1 or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof and combinations thereof.

[0190] In some embodiments, the compound of Formula I decomposes in vivo to provide an active metabolite. Accordingly, in some embodiments, the present invention includes the compound of Formula I and its metabolites. In some embodiments, the present invention includes the compound of Formula I or a pharmaceutically acceptable salt, solvate, metabolite, and / or prodrug thereof.

[0191] In some embodiments, the active metabolite is a compound of Formula II:

[0192]

[0193] wherein R 1 、R 2 、R 3 、R 3' 、R 4 、R 4' 、R 5 、R 5' 、R 6 、R 7 and R 8 are as defined above for Formula I, including its embodiments.

[0194] In some embodiments, the pharmaceutically acceptable salts are acid addition salts or base addition salts. A person skilled in the art can select a suitable salt. Suitable salts include acid addition salts, which can be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or benzoic acid. In addition, acids generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical 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 (Food & Drug Administration, Washington, D.C. on their website).

[0195] Acid addition salts suitable for or compatible with the treatment of a subject are any non-toxic organic or inorganic acid addition salts of any basic compound. Basic compounds that form acid addition salts include, for example, compounds containing an amino group. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acidic 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 are, 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 also include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, mesylate (methanesulfonate), naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate (also known as toluenesulfonate), etc. In some embodiments, mono- or di-acid salts are formed, and such salts exist in hydrated, solvated, or substantially anhydrous forms. Generally, acid addition salts are more soluble in water and various hydrophilic organic solvents and typically exhibit higher melting points compared to their free base forms. The criteria for selecting suitable salts are known to those skilled in the art. Other non-pharmaceutically acceptable salts may be used, for example but not limited to oxalates, for example for isolating the compounds of the present invention for laboratory applications or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0196] Base addition salts suitable for or compatible with the treatment of a subject are any non-toxic organic or inorganic base addition salts of any acidic compound. Acidic compounds that form basic addition salts include, for example, compounds containing a carboxylic acid group. Exemplary inorganic bases that form suitable salts include hydroxides of lithium, sodium, potassium, calcium, magnesium, or barium, and ammonia. Exemplary organic bases that form suitable salts include aliphatic, cycloaliphatic, or aromatic organic amines, such as isopropylamine, methylamine, trimethylamine, methylpyridine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. It may be useful to select a suitable salt, for example, such that an ester functional group elsewhere in the compound, if any, is not hydrolyzed. The criteria for selecting a suitable salt are known to those skilled in the art. In some embodiments, exemplary basic salts also include ammonium salts, alkali metal salts (such as sodium salts, lithium salts, and potassium salts), alkaline earth metal salts (such as calcium salts and magnesium salts), salts formed with organic bases (such as organic amines) (such as dicyclohexylamine, abutilonamine, choline), and salts formed with amino acids (such as arginine, lysine, etc.). Basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl halides (such as methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (such as dimethyl, diethyl, and dibutyl sulfates), long-chain halides (such as decyl, lauryl, and stearyl chlorides, bromides, and iodides), aralkyl halides (such as benzyl and phenethyl bromides), etc. Compounds carrying an acidic moiety can be mixed with a suitable pharmaceutically acceptable salt to provide, for example, alkali metal salts (such as sodium salts or potassium salts), alkaline earth metal salts (such as calcium salts or magnesium salts), and salts formed with suitable organic ligands (such as quaternary ammonium salts). In addition, in the presence of an acid (-COOH) or alcohol group, pharmaceutically acceptable esters can be used to modify the solubility or hydrolysis characteristics of the compound.

[0197] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the present invention, and all acid salts and base salts are considered equivalent to the free form of the corresponding compound for the purposes of the present invention. In addition, when a compound of the present invention contains both a basic moiety, such as but not limited to aliphatic primary, secondary, or tertiary amines or cyclic amines, aromatic amines, or heteroaryl amines, pyridine, or imidazole, and an acidic moiety, such as but not limited to tetrazole or carboxylic acid, zwitterions ("inner salts") can be formed and are included in the term "salt" as used herein. It should be understood that certain compounds of the present invention can exist in zwitterionic form, having anionic and cationic centers and a net neutral charge within the same compound. Such zwitterions are included in the present invention.

[0198] Solvates of the compounds of the present invention include, for example, solvates made with pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvate is called a hydrate) and ethanol. Suitable solvents are physiologically tolerable at the administered dose.

[0199] Prodrugs of the compounds of the present invention include, for example, conventional esters formed with available hydroxyl, thiol, amino, or carboxyl groups. Some common esters that have been used as prodrugs are phenyl esters, aliphatic (C1-C 24 ) esters, acyloxymethyl esters, carbamates, and amino acid esters.

[0200] It should be understood and appreciated that in some embodiments, the compounds of the present invention can have at least one chiral center and thus can exist as enantiomers and / or diastereoisomers. It should be understood that all such isomers and mixtures of any ratio thereof are included within the scope of the present invention. It should also be understood that although the stereochemistry of the compound can be as shown for any given compound listed herein, such compounds can also contain a certain amount (e.g., less than 20%, suitably less than 10%, more suitably less than 5%) of the compounds of the present invention having alternative stereochemistry. Any optical isomers, such as isolated, pure, or partially purified optical isomers or their racemic mixtures, are expected to be included within the scope of the present invention.

[0201] In some embodiments, the compounds of the present invention can also include tautomeric forms, such as keto-enol tautomers, etc. Through appropriate substitution, the tautomers can be in equilibrium or sterically locked into one form. Any tautomeric forms formed by the compound and their mixtures are expected to be included within the scope of the present invention.

[0202] The compounds of the present invention can also exist in various amorphous and polymorphic forms, and any amorphous form, polymorph, or mixture thereof is expected to be included within the scope of the present invention.

[0203] The compounds of the present invention can be further radiolabeled, and thus all radiolabeled forms of the compounds of the present invention are included within the scope of the present invention. The compounds of the present invention also include those compounds that incorporate one or more radioactive atoms in their structure.

[0204] III. Compositions

[0205] Using one or more carriers, the compounds of the present invention are suitably formulated into compositions in a conventional manner. Accordingly, the present invention also includes a composition comprising one or more compounds of the present invention and a carrier. The compounds of the present invention are suitable for formulation into pharmaceutical compositions for administration to a subject in a biocompatible form suitable for in vivo administration. Accordingly, the present invention also includes a pharmaceutical composition comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier. In embodiments of the present invention, the pharmaceutical composition is for the treatment of any disease, disorder or condition described herein.

[0206] As will be understood by those skilled in the art, the compounds of the present invention are administered to a subject in a variety of forms depending on the selected route of administration. For example, the compounds of the present invention are administered orally, by inhalation, parenterally, buccally, sublingually, insufflated, epidurally, intranasally, rectally, vaginally, by patch, pump, micropump, topically or transdermally, and the pharmaceutical compositions are formulated accordingly. In some embodiments, administration is 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 - 20th edition) and The National Formulary (USP 24NF19), published in 1999.

[0207] Parenteral administration includes systemic routes of administration other than the gastrointestinal (GI) tract and includes, for example, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transcutaneous, intranasal, intrapulmonary (e.g., by use of an aerosol), intrathecal, rectal and topical (including use of a patch or other transdermal delivery device) modes of administration. Parenteral administration can be carried out by continuous infusion over a selected period of time.

[0208] In some embodiments, the compounds of the invention are administered orally, e.g., with an inert diluent or an assimilable edible carrier, or encapsulated in a hard or soft shell gelatin capsule, or compressed into tablets, or directly incorporated into the food of the diet. In some embodiments, the compounds are mixed with excipients and used in the form of ingestible tablets, lozenges, troches, capsules, caplets, pills, granules, lozenges, chewing gums, powders, syrups, elixirs, wafers, aqueous solutions, and suspensions. In the case of tablets, carriers used include lactose, corn starch, sodium citrate, and phosphates. 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, the tablets are coated by methods well known in the art. For tablets, capsules, caplets, pills, or granules for oral administration, pH-sensitive enteric coatings such as Eudragits designed to control the release of the active ingredient may be optionally used. TM Oral dosage forms also include modified-release formulations, 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), timed-release, controlled-release (CR), or continuous-release (CR or Contin), e.g., used in the form of coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, agglomerated particles (e.g., molecular sieve-type particles), or fine hollow permeable fiber bundles or chopped hollow permeable fibers, agglomerated or held in a fiber pack. Timed-release compositions are formulated, for example, as liposomes or compositions in which the active compound is protected by different degradable coatings (e.g., by microencapsulation, multilayer coating, etc.). Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. In some embodiments, the liposomes are formed from a variety of 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 dry corn starch.

[0209] In some embodiments, liquid formulations for oral administration take the form of, for example, solutions, syrups or suspensions, or they are suitable to be present as dry products for reconstitution with water or other suitable vehicle before use. When orally administering water suspensions and / or emulsions, the compounds of the present invention are suitably suspended or dissolved in an oil phase combined with an emulsifier and / or a suspending agent. If desired, certain sweetening agents and / or flavoring agents and / or coloring agents may be added. Such liquid formulations for oral administration are prepared by conventional methods with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or gum arabic); non-aqueous vehicles (e.g., medium-chain triglycerides, almond oil, oily esters or ethanol); and preservatives (e.g., methyl p-hydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0210] The compounds of the present invention may also be lyophilized and the obtained lyophilizates may be used, for example, for the preparation of injectable products.

[0211] In some embodiments, the compounds of the present invention are administered parenterally. For example, a solution of the compounds of the present invention is prepared in water and suitably mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycol, DMSO and their mixtures with or without alcohol and in oils. Under ordinary storage and use conditions, these formulations contain preservatives to prevent microbial growth. Those skilled in the art know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the present invention are generally prepared and the pH of the solution is suitably adjusted and buffered. For intravenous injection, the total concentration of the solute should be controlled to make the formulation isotonic. For ocular administration, for example, an ointment or a droppable liquid is delivered through an ocular delivery system known in the art such as an applicator or an eye dropper. In some embodiments, such compositions include muco-mimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzalkonium chloride, and conventional amounts of diluents or carriers. For pulmonary administration, diluents or carriers are selected to be suitable for forming an aerosol.

[0212] In some embodiments, the compounds of the present invention are formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Injectable preparations are present, for example, in unit dosage forms, such as in ampoules or multi-dose containers, and are added with preservatives. In some embodiments, the composition takes the form of a sterile suspension, solution or emulsion in an oily or aqueous vehicle, and contains formulating agents such as suspending agents, stabilizers and / or dispersing agents. In all cases, the dosage form must be sterile and must be a fluid that is easy to inject. Alternatively, the compounds of the present invention are suitably in the form of sterile powders for reconstitution with a suitable vehicle (such as sterile pyrogen-free water) before use.

[0213] In some embodiments, the compositions for intranasal administration are conveniently formulated as aerosols, drops, gels and powders. For intranasal or inhalational administration, the compounds of the present invention are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container squeezed or pumped by the patient, or as an aerosol spray from a pressurized container or nebulizer. Aerosol formulations generally contain a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent, and are usually present in a sealed container in sterile form in single-dose or multi-dose, the container being, for example, in the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container is an integral dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser fitted with a metering valve, which 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 such as compressed air or an organic propellant such as a chlorofluorocarbon. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluorohydrocarbon, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is appropriately determined by a valve that provides a metered amount of delivery. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound. Capsules and cartridges (such as made of gelatin) for inhalers or insufflators are formulated, for example, to contain a powder mixture of the compounds of the present invention and a suitable powder matrix such as lactose or starch. The aerosol dosage form may also take the form of a pump nebulizer.

[0214] Compositions suitable for buccal or sublingual administration include tablets, lozenges and troches, in which the compounds of the present invention are formulated with carriers such as sugar, gum arabic, tragacanth or gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing conventional suppository bases such as cocoa butter.

[0215] The suppository form of the compounds of the present invention can be used for vaginal, urethral, and rectal administration. Such suppositories are typically composed of a mixture of substances that are solid at room temperature but melt at body temperature. Substances commonly used to produce such vehicles include, but are not limited to, cocoa butter (also known as theobroma oil), glycerogelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and polyethylene glycol fatty acid esters. See, for example, for further discussion of suppository dosage forms, Remington’s Pharmaceutical Sciences, 16th Edition, Mack Publishing, Easton, PA, 1980, pages 1530-1533.

[0216] In some embodiments, the compounds of the present invention are conjugated with a soluble polymer as a targeted drug carrier. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymers, poly(hydroxypropyl methacrylamide)-phenol, poly(hydroxyethylasparagine)-phenol, or poly(ethylene oxide)-polylysine substituted with palmitoyl residues. In addition, in some embodiments, the compounds of the present invention are conjugated with a class of biodegradable polymers that can be used to achieve controlled release of the drug, such polymers as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly(ε-caprolactone), polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0217] The compounds of the present invention are particularly suitable for administration together with air in a nanocarrier system, such as liposomes, micelles, nanoparticles, nanoemulsions, lipid nanosystems, etc. (see, for example, Bhat, M. et al. Chem. and Phys. of Lipids, 2021, 236, 105053). Accordingly, the present invention includes a composition comprising one or more compounds of the present invention and one or more components of a nanocarrier system.

[0218] The compounds of the present invention, including their pharmaceutically acceptable salts and / or solvates, are suitable for use alone, but are generally administered in the form of a pharmaceutical composition in which one or more compounds of the present invention (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 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 being based on the total composition.

[0219] In some embodiments, the compounds of the invention, including their pharmaceutically acceptable salts and / or solvates, are used or administered in the form of a composition comprising an additional therapeutic agent. Accordingly, the invention also encompasses a pharmaceutical composition comprising one or more compounds of the invention or their pharmaceutically acceptable salts and / or solvates and an additional therapeutic agent, and optionally one or more pharmaceutically acceptable excipients. In some embodiments, the additional therapeutic agent is another agent known to be useful for treating a disease, disorder or condition 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 drug.

[0220] As used above, the term "compound" also encompasses embodiments in which one or more compounds are recited.

[0221] IV. Methods and Uses of the Invention

[0222] The compounds of the invention are useful for treating a disease, disorder or condition by activating serotonin receptors. Accordingly, the compounds of the invention can be used as medicaments. Accordingly, the invention also encompasses the compounds of the invention for use as medicaments.

[0223] The invention also encompasses a method of treating a disease, disorder or condition treatable by activating serotonin receptors, the method comprising administering to a subject in need thereof (i.e., a subject suffering from the disease, disorder or condition) a therapeutically effective amount of one or more compounds of the invention.

[0224] The invention also encompasses the use of one or more compounds of the invention for treating a disease, disorder or condition treatable by activating serotonin receptors, and the use of one or more compounds of the invention for the manufacture of a medicament for treating a disease, disorder or condition treatable by activating serotonin receptors. The invention also encompasses one or more compounds of the invention for treating a disease, disorder or condition treatable by activating serotonin receptors.

[0225] In some embodiments, the serotonin receptor is 5-HT 2A . Accordingly, the invention encompasses a method for activating 5-HT 2A in a biological sample or in cells in a patient, the method comprising administering to the cells an effective amount of one or more compounds of the present application. The invention also encompasses the use of one or more compounds of the present application for activating 5-HT 2A in cells, and the use of one or more compounds of the invention for the manufacture of a medicament for activating 5-HT 2A in cells. The invention also encompasses one or more compounds of the invention for activating 5-HT 2A in cells. In some embodiments, for activating 5-HT2A The method is carried out in or on cells.

[0226] The present invention also includes a method for treating a disease, disorder or affliction that is treated by activating 5-HT 2A The method includes administering a therapeutically effective amount of one or more compounds of the present invention to a subject in need thereof (i.e., a subject suffering from the disease, disorder or affliction). The present invention also includes the use of one or more compounds of the present invention for treating a disease, disorder or affliction that is treated by activating 5-HT 2A and the use of one or more compounds of the present invention for preparing a medicament for treating a disease, disorder or affliction that is treated by activating 5-HT 2A The present invention also includes one or more compounds of the present application for treating a disease, disorder or affliction that is treated by activating 5-HT 2A The disease, disorder or affliction is treated by activating 5-HT.

[0227] In some embodiments, the compounds of the present invention can be used to prevent, treat and / or alleviate the severity of mental disease conditions and / or afflictions in a subject that are treated by activating 5-HT 2A Therefore, in some embodiments, the disease, disorder or affliction that is treated by activating a serotonin receptor is a mental disease. Accordingly, the present invention also includes a method for treating a mental disease, which includes administering a therapeutically effective amount of one or more compounds of the present invention to a subject in need thereof. The present invention also includes the use of one or more compounds of the present invention for treating a mental disease, and the use of one or more compounds of the present invention for preparing a medicament for treating a mental disease. The present invention also includes one or more compounds of the present application for treating a mental disease.

[0228] In some embodiments, the mental diseases are selected from anxiety disorders such as generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia; depressive disorders such as despair, loss of pleasure, fatigue, and suicidal thoughts; mood disorders such as major depressive disorder, bipolar disorder, cancer-related depression, anxiety disorder, and cyclothymic disorder; psychotic disorders such as hallucinations, delusions, schizophrenia; impulse control and addiction disorders such as pyromania (fire-setting), kleptomania (stealing), and compulsive gambling; alcohol addiction; drug addiction such as opioid addiction; personality disorders such as antisocial personality disorder, obsessive-compulsive personality disorder, and paranoid personality disorder; obsessive-compulsive disorder (OCD) such as thoughts or fears that cause a subject to perform certain rituals or life habits; post-traumatic stress disorder (PTSD); stress response syndrome (formerly called adjustment disorder); dissociative disorders, formerly called multiple personality disorder, or "split personality", and depersonalization disorder; factitious disorder; sexual and gender disorders such as sexual dysfunction, gender identity disorder, and paraphilia; somatic symptom disorders, formerly called psychosomatic disorders or somatoform disorders; and combinations thereof.

[0229] In some embodiments, the diseases, conditions, or disorders treatable by activating serotonin receptors include cognitive impairment; ischemia, including stroke; neurodegeneration; refractory substance use disorder; sleep disorder; pain such as social pain, acute pain, cancer pain, chronic pain, breakthrough pain, bone pain, soft tissue pain, neuralgia, referred pain, phantom limb pain, neuropathic pain, cluster headache, and migraine; obesity and eating disorders; epilepsy and spastic disorders; neuronal cell death; excitotoxic cell death; or combinations thereof.

[0230] In some embodiments, the mental diseases are selected from hallucinations and delusions and combinations thereof.

[0231] In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, vestibular hallucinations, nociceptive hallucinations, thermoceptive hallucinations, and time perception hallucinations and combinations thereof.

[0232] In some embodiments, the diseases, conditions, or disorders treatable by activating serotonin receptors are psychosis or psychotic symptoms. Accordingly, the present invention also includes a method for treating psychosis or psychotic symptoms, which comprises administering to a subject in need a therapeutically effective amount of one or more compounds of the present invention.

[0233] The present invention also includes the use of one or more compounds of the present invention for treating psychosis or psychotic symptoms, and the use of one or more compounds of the present invention for preparing a medicament for treating psychosis or psychotic symptoms. The present invention also includes one or more compounds of the present invention for treating psychosis or psychotic symptoms.

[0234] In some embodiments, administering a therapeutically effective amount of a compound of the invention to a subject in need thereof does not result in the exacerbation of 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 invention to a subject in need thereof results in the improvement of 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 invention to the subject in need thereof results in the improvement of psychosis or psychotic symptoms.

[0235] In some embodiments, the diseases, disorders or conditions treatable by activating serotonin receptors are central nervous system (CNS) diseases, disorders or conditions and / or neurological diseases, disorders or conditions. Accordingly, the present invention also includes a method of treating a CNS disease, disorder or condition and / or a neurological disease, disorder or condition treatable by activating serotonin receptors, the method comprising administering to a subject in need thereof (i.e., a subject suffering from a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition) a therapeutically effective amount of one or more compounds of the invention. The present invention also includes the use of one or more compounds of the invention for treating a CNS disease, disorder or condition and / or a neurological disease, disorder or condition treatable by activating serotonin receptors, and the use of one or more compounds of the invention for the manufacture of a medicament for treating a CNS disease, disorder or condition and / or a neurological disease, disorder or condition treatable by activating serotonin receptors. The present invention also includes one or more compounds of the invention for treating a CNS disease, disorder or condition and / or a neurological disease, disorder or condition treatable by activating serotonin receptors.

[0236] In some embodiments, the CNS disease, disorder, or condition and / or the neurological disease, disorder, or condition are selected from neurological diseases, including neurodevelopmental diseases and neurodegenerative diseases, such as Alzheimer's disease; presenile dementia; senile dementia; vascular dementia; Lewy body dementia; cognitive impairment, Parkinson's disease, and Parkinson's related diseases, such as Parkinson's dementia, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial diseases; fragile X syndrome; Angelman syndrome; hereditary ataxia; neuro-otological and oculomotor disorders; retinal neurodegenerative diseases; amyotrophic lateral sclerosis; tardive dyskinesia; hyperkinesis; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette syndrome; schizophrenia; autism spectrum disorder; tuberous sclerosis; Rett syndrome; cerebral palsy; reward system disorders, including eating disorders, such as anorexia nervosa ("AN") and bulimia nervosa ("BN"); and binge eating disorder ("BED"), trichotillomania, dermatophytosis, nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology, and combinations thereof.

[0237] In some embodiments, the subject is a mammal. In another embodiment, the subject is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a canine. In some embodiments, the subject is a feline. Thus, the compounds, methods, and uses of the present invention are directed to human and veterinary diseases, disorders, and conditions.

[0238] In some embodiments, a "subject in need" is a subject suffering from a disease, disorder, or condition to be treated.

[0239] In some embodiments, the compounds of the present invention can be used to treat behavioral problems in feline or canine subjects.

[0240] Thus, in some embodiments, the disease, disorder, or condition treated by activating a serotonin receptor is a behavioral problem in a feline or canine subject. Accordingly, the present invention also includes a method of treating a behavioral problem, the method comprising administering to a non-human subject in need (i.e., a non-human subject having a behavioral problem) a therapeutically effective amount of one or more compounds of the present invention. The present invention also includes the use of one or more compounds of the present invention for treating a behavioral problem in a non-human subject, and the use of one or more compounds of the present invention for preparing a medicament for treating a behavioral problem in a non-human subject. The present invention also includes one or more compounds of the present invention for treating a behavioral problem in a non-human subject.

[0241] In some embodiments, the behavioral problems are selected from, but not limited to, anxiety, fear, stress, sleep disorders, cognitive dysfunction, aggressive behavior, excessive noise making, scratching, biting, and combinations thereof.

[0242] In some embodiments, the non-human subject is a canine. In some embodiments, the non-human subject is a feline.

[0243] The present invention also includes a method of treating a disease, disorder, or condition by activating a serotonin receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a combination of one or more compounds of the present invention and another agent known to be used for treating a disease, disorder, or condition by activating a serotonin receptor. The present invention also includes the use of a combination of one or more compounds of the present invention and another agent known to be useful for treating a disease, disorder, or condition treatable by activating a serotonin receptor for treating a disease, disorder, or condition by activating a serotonin receptor, and the use of a combination of one or more compounds of the present invention and another agent known to be useful for treating a disease, disorder, or condition treatable by activating a serotonin receptor for preparing a medicament for treating a disease, disorder, or condition treatable by activating a serotonin receptor. The present invention also includes a combination of one or more compounds of the present invention and another agent known to be useful for treating a disease, disorder, or condition treatable by activating a serotonin receptor for treating a disease, disorder, or condition by activating a serotonin receptor.

[0244] In some embodiments, the disease, disorder, or condition treatable by activating a serotonin receptor is a mental disease. In some embodiments, the mental disease is selected from hallucinations and delusions and combinations thereof. In some embodiments, the disease, disorder, or condition treatable by activating a serotonin receptor is a central nervous system (CNS) disorder. In some embodiments, the disease, disorder, or condition treatable by activating a serotonin receptor is a psychosis or psychotic symptom. In some embodiments, the disease, disorder, or condition treatable by activating a serotonin receptor is a behavioral problem in a non-human subject.

[0245] In some embodiments, the disease, disorder, or condition treatable by activating a serotonin receptor is a mental disease, and a combination of one or more compounds of the present invention and one or more additional treatments for mental diseases is administered. In some embodiments, the additional treatments for mental diseases are selected from antipsychotics, including typical antipsychotics and atypical antipsychotics; antidepressants, including selective serotonin reuptake inhibitors (SSRI) and selective norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants, monoamine oxidase inhibitors (MAOI) (such as bupropion), GABA AAllosteric modulators of a receptor, including but not limited to inhibitory pregnane neurosteroids such as zuranolone and brexanolone; anxiolytic drugs, including benzodiazepines such as alprazolam; mood stabilizers such as lithium and antiepileptic drugs such as carbamazepine, divalproex sodium (valproic acid), lamotrigine, gabapentin, and topiramate. In some embodiments, the disease, disorder, or condition treated by activating a serotonin receptor is a mental disorder, and one or more compounds of the invention are administered in combination with one or more additional treatments for mental disorders. In some embodiments, the additional treatments for mental disorders are selected from antipsychotics, including typical and atypical antipsychotics; antidepressants, including selective serotonin reuptake inhibitors (SSRI) and selective norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants, and monoamine oxidase inhibitors (MAOI) (e.g., bupropion); anxiolytic drugs, including benzodiazepines such as alprazolam; mood stabilizers such as lithium and antiepileptic drugs such as carbamazepine, divalproex sodium (valproic acid), lamotrigine, gabapentin, and topiramate.

[0246] In some embodiments, the disease, disorder, or condition treated by activating a serotonin receptor is selected from attention deficit hyperactivity disorder and attention deficit disorder and combinations thereof. In some embodiments, the disease, disorder, or condition treated by activating a serotonin receptor is attention deficit hyperactivity disorder and / or attention deficit disorder and combinations thereof, and one or more compounds of the invention 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 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.

[0247] In some embodiments, the disease, disorder, or condition treated by activating a serotonin receptor is dementia or Alzheimer's disease, and one or more compounds of the invention 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 acetylcholinesterase inhibitors, NMDA antagonists, and muscarinic agonists and antagonists, and nicotinic agonists.

[0248] In some embodiments, the acetylcholinesterase inhibitors are selected from donepezil, galantamine, rivastigmine, and physostigmine and combinations thereof.

[0249] In some embodiments, the NMDA antagonists are selected from MK-801, ketamine, phencyclidine, and memantine and combinations thereof.

[0250] In some embodiments, the nicotinic agonist is nicotine, niacin, a nicotinic α7 agonist, or an α2β4 agonist, or a combination thereof.

[0251] In some embodiments, the muscarinic agonist is a muscarinic M1 agonist or a muscarinic M4 agonist, or a combination thereof.

[0252] In some embodiments, the muscarinic antagonist is a muscarinic M2 antagonist.

[0253] In some embodiments, the disease, disorder, or condition treated by activating a serotonin receptor is a psychosis or psychotic symptom, and one or more compounds of the invention are administered in combination with one or more additional treatments for the psychosis or psychotic symptom. In some embodiments, the additional treatment for the psychosis or psychotic symptom is selected from typical antipsychotics and atypical antipsychotics.

[0254] In some embodiments, typical antipsychotic drugs are selected from acepromazine, acetophenazine, benperidol, bromperidol, butaperazine, carfenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, dixyrazine, droperidol, fluanisone, flupentixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, lenperone, loxapine, mesoridazine, metitepine, molindone, moperone, oxypertine, oxyprotepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, piperacetazine, pipotiazine, prochlorperazine, promazine, prothipendyl, spiperone, sulforidazine, thiopropazate, thioproperazine, thioridazine, thiothixene, timiperone, trifluoperazine, trifluperidol, triflupromazine, and zuclopenthixol and combinations thereof.

[0255] In some embodiments, the atypical antipsychotic drug is selected from amoxapine, amisulpride, aripiprazole, asenapine, blonanserin, brexpiprazole, cariprazine, carpipramine, clocapramine, clorotepine, 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.

[0256] In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a mental disorder, and one or more compounds of the invention are administered in combination with one or more additional treatments for mental disorders. In some embodiments, the additional treatment for mental disorders is selected from typical antipsychotic drugs and atypical antipsychotic drugs.

[0257] In some embodiments, the 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 one or more given compounds corresponding to the effective amount will vary depending on a variety of factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the disorder, the type of disease or condition, the identity of the subject to be treated, etc., but can still be routinely determined by those skilled in the art.

[0258] In some embodiments, the compounds of the invention are administered once, twice, three times, or four times per year. In some embodiments, the compounds of the invention are administered at least once per week. However, in another embodiment, the compounds are administered to a subject at a frequency of about once every two weeks, three weeks, or one month. In another embodiment, the compounds are administered from once a week to once a day. In another embodiment, the compounds are administered 1, 2, 3, 4, 5, or 6 times per day. The length of the treatment period depends on a variety of factors such as the severity of the disease, disorder, or condition, the age of the subject, the concentration and / or activity of the compounds of the invention, and / or combinations thereof. It should also be understood that the effective dose of the compound used for treatment can be increased or decreased during the course of a particular treatment regimen. Dose variations may occur and become apparent by standard diagnostic assays known in the art. In certain cases, long-term administration is required. For example, the compound is administered to a subject in an amount and for a duration sufficient to treat the subject.

[0259] In some embodiments, the compounds of the invention are administered in hallucinogenic or psychotomimetic doses and taken in combination with psychotherapy or therapy, and can be done once, twice, three times, or four times a year. However, in some embodiments, the compounds are administered to a subject at non-hallucinogenic or non-psychotomimetic doses once a day, once every two days, once every 3 days, once a week, once every two weeks, once a month, once every two months, or once every three months.

[0260] The compounds of the invention are used alone or in combination with another agent known to be useful for treating a disease, disorder, or condition by activating serotonin receptors (e.g., a compound of the invention). When used in combination with another agent known to be useful for treating a disease, disorder, or condition by activating serotonin receptors, one embodiment is to administer the compounds of the invention simultaneously with those agents. As used herein, "administering" two substances to a subject means providing each of the two substances such that they are both active in the individual at the same time. The exact details of administration will depend on the pharmacokinetics of the two substances in the presence of each other and can include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of administering the other substance if the pharmacokinetics are appropriate. The design of a suitable dosing regimen is routine for those skilled in the art. In a particular embodiment, the two substances will be administered substantially simultaneously, i.e., within a few minutes of each other, or in a single composition containing both substances. Another embodiment of the invention is to administer the combination of agents to a subject in a non-simultaneous manner. In some embodiments, the compounds of the invention are administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together in a single unit dosage form. Accordingly, the invention provides a single unit dosage form comprising one or more compounds of the invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0261] The dosage of the compounds of the present invention varies depending on a number of factors, such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of treatment and the type of concurrent treatment (if any), and the clearance rate of the compound in the subject to be treated. A person skilled in the art can determine a suitable dosage based on the above factors. In some embodiments, one or more compounds of the present invention are initially administered at a suitable dosage, which is adjusted as needed based on the clinical response. The dosage is typically selected to maintain a serum level of one or more compounds of the present invention of from about 0.01 μg / cc to about 1000 μg / cc or from about 0.1 μg / cc to about 100 μg / cc. As a representative example, for an adult, the oral dosage of one or more compounds of the present invention will be in the range of from about 10 μg / day to about 1000 mg / day, suitably from about 10 μg / day to about 500 mg / day, more suitably from about 10 μg / day to about 200 mg / day. For parenteral administration, representative amounts are from about 0.0001 mg / kg to about 10 mg / kg, from about 0.0001 mg / kg to about 1 mg / kg, from about 0.01 mg / kg to about 0.1 mg / kg, or from about 0.0001 mg / kg to about 0.01 mg / kg. For oral administration, representative amounts are from about 0.001 μg / kg to about 10 mg / kg, from about 0.1 μg / kg to about 10 mg / kg, from about 0.01 μg / kg to about 1 mg / kg, or from about 0.1 μg / kg to about 1 mg / kg. For administration in the form of a suppository, representative amounts are from about 0.1 mg / kg to about 10 mg / kg or from about 0.1 mg / kg to about 1 mg / kg. In some embodiments of the present invention, the composition is formulated for oral administration and one or more compounds are suitably in the form of tablets, 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 invention). In some embodiments of the present invention, one or more compounds of the present invention are administered at a daily, weekly or monthly dosage, or the total daily dosage is divided into two, three or four sub-dosages.

[0262] In some embodiments, the compounds of the invention are used or administered in an effective amount, including administering a dose or dosing regimen that has no clinically significant hallucinogenic / psychomimetic effects. In some embodiments, the compounds of the invention are used or administered in an effective amount, which includes administering a dose or dosing regimen that provides a clinical effect similar to the clinical effect exhibited by a psilocybin Cmax in human plasma of 4 ng / mL or less and / or a 5-HT 2A clinical effect exhibited by a human CNS receptor occupancy of 40% or less or a psilocybin Cmax in human plasma of 1 ng / mL or less and / or a 5-HT 2A clinical effect exhibited by a human CNS receptor occupancy of 30% or less. In some embodiments, the compounds of the invention are used or administered in an effective amount, including administering a dose or dosing regimen that provides a clinical effect similar to the clinical effect exhibited when the psilocybin Tmax in human plasma exceeds 60 minutes, exceeds 120 minutes, or exceeds 180 minutes.

[0263] For clarity, in the foregoing, the term "compound" also includes embodiments that refer to one or more compounds. Similarly, the term "compounds of the invention" also includes embodiments in which only one compound is referred to.

[0264] V. Preparation of Compounds

[0265] The compounds of the invention can be prepared by a variety of synthetic methods. The choice of specific structural features and / or substituents may influence the choice of one method over another. The choice of a particular method for preparing a given compound of the present application is within the knowledge of those skilled in the art. Some of the starting materials for preparing the compounds of the invention are available from commercial chemical sources or can be extracted from cells, plants, animals, or fungi. Other starting materials can be readily prepared from available precursors using direct transformations well known in the art, as described below. In the schemes showing some embodiments of the methods for preparing the compounds of the invention below, all variables are as defined in formula I, unless otherwise specified.

[0266] In some embodiments of the invention, the compounds of the invention are generally prepared according to the methods described in Schemes I-V.

[0267] In some embodiments, the compound of formula I is prepared as shown in Scheme I, where Q is P(O)OR 9 and R 9 is H. Thus, in the presence of a suitable base such as triethylamine and in a suitable solvent such as dichloromethane, the compound of formula A is reacted with a phosphorylating agent such as phosphoryl chloride to obtain the compound of formula I.

[0268]

[0269] In some embodiments, as shown in Scheme I, reaction conditions such as those found in CN 102382135 (Faming Zhuanli Shenqing) and Mondal et al., Tetrahedron Letters, 58(25), 2460 - 2464; 2017 are used to provide the compound of formula I.

[0270] In some embodiments, the compound of formula I is prepared as shown in Scheme II, where Q is C1 - C6 alkylene - P(O)OR 9 -C1 - C6 alkylene and R 9 is H. Thus, 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, the compound of formula A is reacted with the compound of formula B to obtain the compound of formula I.

[0271]

[0272] In some embodiments, as shown in Scheme II, reaction conditions such as those found in Mukhametzyanova et al., Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, issue 2, pp. 373 - 80, 1969 are used to provide the compound of formula I.

[0273] In some embodiments, the compound of formula I is prepared as shown in Scheme III, where Q is C(O)Q'C(O). Thus, in the presence of a suitable base such as triethylamine, in a suitable solvent such as dichloromethane, at a suitable temperature such as about 0 °C to about room temperature (e.g., about 18 °C to about 25 °C), the compound of formula A is reacted with the compound of formula C to obtain the compound of formula I.

[0274]

[0275]

[0276] In some embodiments, as shown in Scheme III, reaction conditions such as those found in Derosa J. et al., Journal of the American Chemical Society, 2021, volume 143, issue 25, pp. 9303 - 9307 are used to provide the compound of formula I.

[0277] In some embodiments, the compound of formula I is prepared as shown in Scheme III, where Q is C(O)OQ'OC(O) or C(O)NR 9’ Q'NR 9’C(O), except that a suitable Compound of Formula C is used.

[0278] In some embodiments, the Compound of Formula I is prepared as shown in Scheme IV, where Q is C(O). Thus, in the presence of a suitable base such as triethylamine and sodium hydroxide, in a suitable solvent such as dichloromethane and H2O, and at a suitable temperature such as under heating (e.g., greater than about 25 °C), the Compound of Formula A is reacted with the Compound of Formula D (triphosphole) to obtain the Compound of Formula I.

[0279]

[0280] In some embodiments, as shown in Scheme IV, reaction conditions found, for example, in Guangzhou Huagong, 39(14), 81 - 82; 201 are used to provide the Compound of Formula I.

[0281] In some embodiments, the Compound of Formula I is prepared as shown in Scheme V, where Q is SO2. Thus, in the presence of a suitable base such as cesium carbonate, in a suitable solvent such as tetrahydrofuran, and at a suitable temperature such as from about reflux to about room temperature (e.g., about 70 °C to about 25 °C), the Compound of Formula A is reacted with N,N'-sulfonyldiimidazole E1 and / or using sulfonyl chloride E2 to obtain the Compound of Formula I.

[0282]

[0283] In some embodiments, as shown in Scheme V, 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 are used to provide the Compound of Formula I.

[0284] In some embodiments, the Compound of Formula A is prepared using known methods, for example, using the synthetic procedures found in WO2021 / 155468A1 (Mindset Pharma Inc.).

[0285] Those skilled in the art will understand that known chemistry can be used to further manipulate the substituents of the intermediates and final compounds in the above - mentioned schemes to provide alternative compounds of the present invention.

[0286] The salts of the compounds of the present invention can be formed by methods known to those of ordinary skill in the art, for example, by reacting the compounds of the present invention with a certain amount of acid or base (such as an equivalent amount of acid or base) in a medium (such as a medium in which the salt precipitates) or in an aqueous medium, and then lyophilizing.

[0287] The formation of solvates will vary depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in a suitable solvent and separating the solvate by cooling or using an anti-solvent. Solvates are typically dried under ambient conditions or azeotropically. Those skilled in the art can select suitable conditions for forming a particular solvate. 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 invention will vary depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in a suitable solvent and separating the solvate by cooling or using an anti-solvent. Solvates are typically dried under ambient conditions or azeotropically. Those skilled in the art can select suitable conditions for forming a particular solvate.

[0288] The isotopically enriched compounds of the present invention and their pharmaceutically acceptable salts, solvates, and / or prodrugs can be prepared by conventional techniques well known to those skilled in the art or by methods similar to those described in the schemes and examples herein, using suitable isotopically enriched reagents and / or intermediates, without undue experimentation.

[0289] Throughout the processes described herein, it is to be understood that, where appropriate, suitable protecting groups will be added to the various reactants and intermediates in a manner readily understandable to one of ordinary skill in the art and subsequently removed therefrom. Conventional procedures for using such protecting groups and examples of suitable protecting groups are described, for example, in “Protective Groups in Organic Synthesis”, T.W. Green, P.G.M. Wuts, Wiley-Interscience, New York, (1999). It is also to be understood that the conversion of one group or substituent into another by chemical manipulation can be carried out on any intermediate or final product in the synthetic pathway towards the final product, where the possible types of conversions are limited only by the inherent incompatibility of the other functional groups carried by the molecule at that stage with the conditions or reagents used in the conversion. Such inherent incompatibilities and methods for overcoming them by carrying out appropriate conversions and synthetic steps in a suitable order are readily understandable to one of ordinary skill in the art. Examples of conversions are given herein, and it is to be understood that the conversions described are not limited to the general groups or substituents used as examples of conversions. References and descriptions of other suitable conversions are given in “Comprehensive Organic Transformations – A Guide to Functional Group Preparations” R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in organic chemistry textbooks, such as “Advanced Organic Chemistry”, March, 4th Edition McGraw Hill (1992) or “Organic Synthesis”, Smith, McGraw Hill, (1994).

[0290] Nucleophilic substitution reaction conditions include any known reaction methods for causing a nucleophile to displace a leaving group to form a bond that is compatible with the intermediates and products shown in the above schemes or that can be used to prepare the compounds of the present invention. In some embodiments, such conditions include combining the reactants in a suitable solvent in the presence of a base.

[0291] Techniques for purifying intermediates and final products include, for example, normal and reverse phase chromatography on columns or rotating plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, which are readily understandable to one of ordinary skill in the art.

[0292] Examples

[0293] The following non-limiting examples illustrate the present invention.

[0294] A. Synthetic Scheme

[0295] General method

[0296] All starting materials used in this article are commercially available or have been described in the literature. 1 H and 13 1H and 13C NMR spectra were recorded on a Bruker 300, Bruker DPX 400 or Varian +400 spectrometer, which operates at 1 1H NMR at 300, 400 and 400 MHz respectively, using TMS or the residual solvent signal as an internal reference, in deuterochloroform as the solvent, unless otherwise stated. All reported chemical shifts are in ppm on the δ scale, and the fine splitting of the signals appearing in the record is usually indicated as, for example, s: singlet, br s: broad singlet, d: doublet, t: triplet, q: quartet, m: multiplet. Unless otherwise stated, in the following table, 1 1H NMR data were obtained at 400 MHz using CDCl3 as the solvent.

[0297] The products were purified using a Chem Elut extraction column (Varian, catalog number 1219 - 8002), a Mega BE - SI (Bond Elut Silica) SPE column (Varian, catalog numbers 12256018; 12256026; 12256034) or by flash chromatography in a glass column packed with silica.

[0298] Synthesis of exemplary compounds of the present invention

[0299] Example 1: Bis(3-(2-(dimethylamino)ethyl)-1H - indol - 4 - yl) pentanedioate (I - 24)

[0300]

[0301] Synthesis of 2-(4-(benzyloxy)-1H - indol - 3 - yl)-N,N - dimethyl - 2 - oxoacetamide (2):

[0302] A solution of 4-(benzyloxy)-1H-indole (3.77 g, 16.88 mmol) in anhydrous diethyl ether (100 mL) was treated dropwise with oxalyl chloride (1.43 mL, 16.88 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was cooled to 0 °C over a 5 min period and treated with dimethylamine solution (42.2 mL, 84.41 mmol, 2 M solution in THF). The reaction mixture was warmed to room temperature and stirred overnight (18 h). The reaction mixture was quenched with water (100 mL) and the product was extracted into ethyl acetate (2 x 100 mL). The combined ethyl acetate layers were washed with brine (50 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by flash column chromatography on silica gel (MeOH:CH2Cl2, 2:98) to afford the title compound 2 (3.7 g, 68%) as a light brown solid. 1 H 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).

[0303] Synthesis of 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethylethan-1-amine (3):

[0304] 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 over a 10 min period. The reaction mixture was warmed to room temperature and then refluxed for 16 h. The reaction mixture was cooled to 0 °C and quenched by the sequential addition of water (3.3 mL), 2 N NaOH solution (3.3 mL) and water (3.3 mL). The reaction mixture was warmed to room temperature and stirred for 30 min. The solid was filtered off and washed with THF (2 x 50 mL). The combined THF layers were evaporated and the crude product was purified by column chromatography on silica gel (MeOH:CH2Cl2 containing 2 M NH3, 5:95) to afford the title compound 3 (2.85 g, 88.5%) as a brown solid. 11H 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).

[0305] Synthesis of bis(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) glutarate dihydrochloride (I-24):

[0306] 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 for 1 h using a Paar apparatus. The reaction mixture was filtered through a Celite pad 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 Et3N (1.93 mL, 13.97 mmol), followed by treatment with a solution of glutaroyl chloride (0.35 mL, 2.79 mmol) in anhydrous THF (20 mL) at 0 °C over a 10 min period. The reaction mixture was warmed to room temperature and stirred overnight (16 h). The reaction mixture was quenched with water (100 mL) and the product was extracted into ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (25 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by flash column chromatography on silica gel (MeOH:CH2Cl2 containing 2M NH3, 5:95 to 1:9) to give the title compound I-24 as a pale yellow oil (0.65 g, 46%), which was converted to the dihydrochloride using a solution of 2M HCl in ether. 1 1H 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).

[0307] Example 2: Synthesis of bis(3-(2-(diisopropylamino)ethyl)-1H-indol-4-yl)pentanedioate dihydrochloride (I-37)

[0308]

[0309] Synthesis of 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-diisopropyl-2-oxoacetamide (5):

[0310] 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 mixture was warmed to room temperature and stirred for an additional 5 h. The reaction mixture was cooled to 0 °C over a 5 min period and treated with diisopropylamine (19.0 mL, 134.35 mmol). The reaction mixture was warmed to room temperature and stirred overnight (16 h). The reaction mixture was worked up and purified as described for compound 2 to afford the title compound 5 as a yellow solid (13.37 g, 79%). 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 = 6.0 Hz), 5.26 (s, 2H), 3.84 - 3.77 (m, 1H), 3.63 - 3.57 (m, 1H), 1.46 (d, 6H, J = 6.0 Hz), 1.11 (d, 6H, J = 6.0 Hz); ESI-MS (m / z, %): 438 (100), 401 (M+Na), 379 (MH + )

[0311] Synthesis of N-(2-(4-(benzyloxy)-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine (6):

[0312] 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 LiAlH4 (9.4 g, 248.17 mmol) at 0 °C over a 15 min period. The reaction mixture was warmed to room temperature and then refluxed overnight (16 h). The reaction mixture was worked up and purified as described for compound 3 to afford the title compound 6 as a light brown gum (6.8 g, 74.5%). 11H 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).

[0313] Synthesis of bis(3-(2-(diisopropylamino)ethyl)-1H-indol-4-yl) glutarate dihydrochloride (I-37):

[0314] 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 for 1 h using a Paar apparatus. The reaction mixture was filtered through a Celite pad and washed with methanol (2 x 25 mL). The combined methanol layers were evaporated and the crude product 7 obtained was dissolved in anhydrous THF (50 mL). The reaction mixture was treated with Et3N (1.44 mL, 10.44 mmol) and subsequently with a solution of glutaroyl chloride (0.33 mL, 2.61 mmol) in anhydrous THF (20 mL) at 0 °C over a 10 min period. The reaction mixture was warmed to room temperature and stirred overnight (16 h). The reaction mixture was worked up and purified as described for compound I-24 to give the title compound I-37 (0.45 g, 28%) as a pale yellow oil, which was converted to the dihydrochloride using a solution of 2M HCl in diethyl ether. 1 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 Hz), 3.73 - 3.65 (m, 4H), 3.40 - 3.36 (m, 4H), 3.23 - 3.18 (m, 4H), 3.11 - 3.07 (m, 4H), 2.07 - 1.99 (m, 2H), 1.42 - 1.33 (m, 24H); ESI-MS (m / z, %): 617 (MH + , 100).

[0315] The following compounds were prepared in a similar manner using one or more of the synthetic methods outlined in Schemes I to V and Examples 1 and 2:

[0316]

[0317]

[0318]

[0319]

[0320] B. Biological Test

[0321] Example 3: Human 5-HT2A: Functional FLIPR Assay

[0322] Objective:

[0323] Evaluate the potential excitatory effect of a compound targeting the human serotonin receptor 2A (5-HT2A) in agonist mode 1. Materials and Instruments Used

[0324] 1.1 Cell Line

[0325]

[0326] 1.2 Materials

[0327]

[0328] 1.3 Instruments and Consumables Used

[0329]

[0330]

[0331] 2 Experimental Methods

[0332] 2.1 Cell Culture

[0333] Culture HTR2A&Gα15-HEK293 cells in DMEM medium containing 10% dialyzed FBS, 1× penicillin-streptomycin, 100 μg / mL hygromycin B, and 300 μg / mL G418. Passage the cells approximately three times a week, maintaining a confluence of approximately 30% to approximately 90%.

[0334] 2.2 Cell Seeding

[0335] 1. Pre-warm the cell culture medium (DMEM medium containing 10% dialyzed FBS, 1× penicillin-streptomycin, 100 μg / mL hygromycin B, and 300 μg / mL G418), TrypLE TM Express, and DPBS to room temperature.

[0336] 2. Induction: Add 1 μg / ml tetracycline (final concentration) to the cell culture medium and incubate for 48 hours before inoculating the cells into the plate at 37 °C and 5% (v / v) CO2. Remove the cell culture medium from the flask. Wash the cells with DPBS.

[0337] 3. Add 2 mL TrypLE TM Express to the flask, mix well by gentle shaking, and incubate the cells at 37 °C for a few minutes.

[0338] 4. Observe the morphological changes of the cells under the microscope, and when most of the cells become round, stop the digestion by adding 4 mL of cell culture medium to the flask.

[0339] 5. Transfer the cell suspension to a 15 mL centrifuge tube and then centrifuge at 1200 rpm for 5 minutes.

[0340] 6. Remove the supernatant. Resuspend the cell pellet in 2 mL of cell culture medium.

[0341] 7. Calculate the cell density using a cell counter. Only use cells with a viability > 85% for the assay.

[0342] 8. Dilute the cells with cell culture medium to 6.67×10 5 / mL.

[0343] 9. Add 30 μL / well of the cell suspension to a 384-well cell plate (cell density of 20,000 cells / well).

[0344] 10. Incubate the cell plate overnight at 37 °C and 5% (v / v) CO2.

[0345] 2.3 Cell treatment

[0346] 1. On the day of the experiment, remove the medium from the cell plate.

[0347] 2. Add 10 μL of assay buffer (20 mM HEPES in 1×HBSS, pH 7.4) to each well of the cell plate.

[0348] 3. Prepare a 2-fold dye solution according to the instructions of the Calcium 6 assay kit:

[0349] i. Dilute the dye with assay buffer.

[0350] ii. Add probenecid to a final concentration of 5 mM.

[0351] iii. Vortex vigorously for 1 - 2 minutes.

[0352] 4. Add 10 μL of 2-fold dye solution to each well of the cell plate.

[0353] 5. Place the cell plate on a plate shaker and shake at 600 rpm for 2 minutes.

[0354] 6. Incubate the plate at 37 °C for 2 hours, followed by an additional 15-minute incubation at 25 °C.

[0355] 2.4 Preparation of 3× compound

[0356] 1. Prepare serotonin HCl in DMSO at a concentration of 10 mM.

[0357] 2. Prepare the test compound in DMSO at a concentration of 10 mM.

[0358] 3. Add the compound to the 384-well compound source plate.

[0359] 4. Perform a 3-fold serial dilution with DMSO.

[0360] 5. Transfer 90 nL / well of the serially diluted compound from the source plate to the 384-well compound plate using Echo.

[0361] 6. Add 30 μL / well of the assay buffer (1× HBSS solution with 20 mM HEPES, pH 7.4) to the compound plate.

[0362] 7. Mix on a plate shaker for 2 minutes.

[0363] 2.5 FLIPR assay

[0364] 1. After incubating the cells with the dye solution, place the cell plate, the compound plate containing 3× compound, and the FLIPR tips in the FLIPR.

[0365] 2. Transfer 10 μL of 3× compound from the compound plate to the cell plate via FLIPR.

[0366] 3. Read the plate at 1-second intervals for 160 seconds to obtain agonist mode data.

[0367] 3 Data analysis

[0368] 1. The normalized fluorescence readings (RFU) are calculated as follows, where Fmax and Fmin represent the maximum and minimum calcium signals within a defined time window:

[0369] RFU = Fmax – Fmin

[0370] 2. Using XLfit, calculate the EC by fitting the logarithm of the compound concentration to the RFU with the Hill equation 50 .

[0371] II. Results and Discussion

[0372] The results of the potential competitive binding properties of exemplary dimeric compounds (I-24 and I-37) of the present invention and their corresponding metabolites (psilocin and 7, ) targeting human serotonin receptor 2A (5-HT2A) are summarized in Table 2. The results of the exemplary compounds of the present invention are shown as IC 50 as shown.

[0373] Table 2: Effects of Exemplary Compounds of Formula I on Human 5-HT2A Receptor Using FLIPR Functional Assay

[0374]

[0375] (1) Curve fitting of activation (%) at 10 mM vs. RFU

[0376] (2) Not detected

[0377] The exemplary compounds of Formula I were evaluated using a radioligand binding assay for the human 5-HT2A receptor. The EC50 (nM) concentrations are shown in Table 2. This assay confirmed that the exemplary compounds or metabolites of the present invention are effective ligands for the target human 5-HT2A receptor.

[0378] Example 4: Human 5-HT2A: Radioligand Binding Assay:

[0379] Objective

[0380] The objective of this study was to evaluate the binding properties of exemplary compounds of Formula I to serotonin receptor 2A (5-HT2A).

[0381] 1 Materials and Instruments Used

[0382] 1.1 Reagents

[0383]

[0384]

[0385] 1.2 Instruments and Consumables Used

[0386]

[0387] 2 Experimental Methods

[0388] 1. Prepare the assay buffer according to the following table.

[0389]

[0390] Adjust the pH to 7.4 and then perform a 0.2 μM sterile filtration.

[0391] 2. As needed, starting from a 10 mM stock solution, prepare 8 doses of the reference and test compounds by 5-fold serial dilutions with 100% (v / v) DMSO.

[0392] 3. Pretreat the UniFilter-96 GF / B plate:

[0393] i. Add 50 μl / well of 0.5% (v / v) PEI to the UniFilter-96 GF / C plate. Seal the plate and incubate at 4 °C for 3 hours.

[0394] ii. After incubation, wash the plate 3 times with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0395] 4. Prepare the assay plate:

[0396] i. Dilute the cell membrane with the assay buffer and add 330 μl / well to a 96-well round-bottom deep well plate to achieve a concentration of 20 μg / well.

[0397] ii. Prepare 8 concentrations of the reference or test compound and add 110 μl / well to the 96-well round-bottom deep well plate.

[0398] iii. Dilute [3H]-ketanserin with the assay buffer to 5 nM (5X final concentration) and add 110 μl / well to the 96-well round-bottom deep well plate.

[0399] 5. Centrifuge the plate at 1000 rpm for 30 seconds and then stir at 600 rpm for 5 minutes at room temperature.

[0400] 6. Seal the plate and incubate at 27 °C for 90 min.

[0401] 7. Stop the incubation by vacuum filtration through the GF / B filter plate and then wash 4 times with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0402] 8. Dry the plate at 37 °C for 45 min.

[0403] 9. Seal the filter plate and add 40 μl / well of the scintillation mixture.

[0404] 10. Read the plate using a Microbeta 2 microplate counter.

[0405] 3 Data analysis

[0406] 1. For reference and test compounds, the results were expressed as % inhibition using the normalization equation: N = 100 - 100×(U - C2) / (C1 - C2), where U is the unknown value, C1 is the high control mean, and C2 is the low control mean.

[0407] 2. IC 50 was determined by fitting the percent inhibition as a function of compound concentration to the Hill equation using XLfit.

[0408] Results and Discussion

[0409] The results of the potential competitive binding properties of the exemplary prodrug compounds I-24 and I-37 of the present invention and their corresponding metabolites psilocin and (7) targeting the human serotonin receptor 2A (5-HT2A) are summarized in Table 3. The results of the exemplary compounds of the present invention are as shown by the IC 50 as shown.

[0410] Table 3: Effects of Exemplary Compounds of Formula I on the Human 5-HT2A Receptor Using Radioligand Binding Assay

[0411] II.

[0412] Results and Discussion

[0413] Exemplary compounds of Formula I were evaluated using a radioligand binding assay for the human 5-HT2A receptor. The IC 50 (nM) concentrations are shown in Table 3. This assay confirmed that the precursor parent compounds of the present invention or their corresponding metabolites are effective ligands for the target human 5-HT2A receptor.

[0414] Example 5: Human 5-HT1A: Functional FLIPR Assay

[0415] 1 Objective

[0416] The potential excitatory effects of the compounds targeting the serotonin receptor 1A in agonist mode were evaluated.

[0417] 2 Materials and Instruments Used

[0418] 2.1 Cell Line

[0419]

[0420] 2.2 Materials

[0421]

[0422] 2.3 Instruments and Consumables Used

[0423]

[0424]

[0425] 3 Experimental methods

[0426] 3.1 Cell culture

[0427] The HTR1A&Gα15-CHO cells were cultured in DMEM / F12 medium containing 10% dialyzed FBS, 1× penicillin-streptomycin, and 600 μg / mL hygromycin B. The cells were passaged approximately three times a week and maintained at a confluence of approximately 30% to approximately 90%.

[0428] 3.2 Cell seeding

[0429] 1. Pre-warm the cell culture medium (DMEM / F12 medium containing 10% dialyzed FBS, 1× penicillin-streptomycin, and 600 μg / mL hygromycin B), TrypLE TM Express, and DPBS to room temperature.

[0430] 2. Remove the cell culture medium from the flask. Wash the cells with DPBS.

[0431] 3. Add 1 mL of TrypLE TM Express to the flask, mix well by gentle shaking, and then incubate the cells at 37 °C for a few minutes.

[0432] 4. Observe the morphological changes of the cells under a microscope, and when most cells become round, stop the digestion by adding 2 mL of cell culture medium to the flask.

[0433] 5. Transfer the cell suspension to a 15 mL centrifuge tube and then centrifuge at 1200 rpm for 5 minutes.

[0434] 6. Remove the supernatant. Resuspend the cell pellet in 2 mL of cell culture medium.

[0435] 7. Use a cell counter to calculate the cell density. Only cells with a viability > 85% were used for the assay.

[0436] 8. Dilute the cells with cell culture medium to 4×10 5 / mL.

[0437] 9. Add 30 μL / well of the cell suspension to a 384-well cell plate (cell density of 12000 cells / well).

[0438] 10. Incubate the cell plate overnight at 37 °C, 5% (v / v) CO2.

[0439] 3.3 Cell treatment

[0440] 1. On the day of the experiment, remove the culture medium from the cell plate.

[0441] 2. Add 10 μL of assay buffer (20 mM HEPES, in 1× HBSS, pH 7.4) to each well of the cell plate.

[0442] 3. Prepare a 2× dye solution according to the manufacturer's instructions of the Calcium 6 Assay Kit:

[0443] i. Dilute the dye with assay buffer.

[0444] ii. Add probenecid to a final concentration of 5 mM.

[0445] iii. Vortex vigorously for 1 - 2 minutes and adjust the pH to 7.4.

[0446] 4. Add 10 μL of 2× dye solution to each well of the cell plate.

[0447] 5. Place the cell plate on a plate shaker and then shake at 600 rpm for 2 minutes.

[0448] 6. Incubate the plate at 37 °C for 2 hours and then at 25 °C for an additional 15 minutes.

[0449] 3.4 Preparation of 3× Compounds.

[0450] 1. Prepare serotonin at a concentration of 10 mM with DMSO and perform 3-fold serial dilutions with DMSO.

[0451] 2. Prepare the test compound at a concentration of 10 mM with DMSO and perform 3-fold serial dilutions with DMSO.

[0452] 3. Add the compounds to a 384-well compound source plate.

[0453] 4. Transfer 90 nL / well of the serial diluted compounds from the source plate to a 384-well compound plate using an Echo.

[0454] 5. Add 30 μL / well of assay buffer to the compound plate.

[0455] 6. Mix on a plate shaker for 2 minutes.

[0456] 3.5 FLIPR Assay

[0457] 1. After incubating the cells with the dye solution, place the cell plate, the compound plate containing 3× compounds, and the FLIPR tips in the FLIPR.

[0458] 2. Transfer 10 μL of 3-fold compound from the compound plate to the cell plate via FLIPR.

[0459] 3. Read the plate at 1-second intervals for 160 seconds to obtain agonist mode data.

[0460] 4 Data analysis

[0461] 1. The normalized fluorescence reading (RFU) is calculated as follows, where Fmax and Fmin represent the maximum and minimum values of the calcium signal within the defined time window:

[0462] RFU = Fmax – Fmin

[0463] 2. Use XLfit to calculate the EC by fitting the logarithm of the compound concentration against RFU with the Hill equation 50 .

[0464] II. Results and discussion

[0465] The results of the potential competitive binding properties of the exemplary prodrug compounds I-24 and I-37 of the present invention and their corresponding metabolites psilocin and (7) targeting human serotonin receptor 1A (5-HT1A) are summarized in Table 4. The results of the exemplary compounds of the present invention are shown as IC 50 as shown.

[0466] Table 4: Effects of exemplary compounds of formula I on the human 5-HT1A receptor using FLIPR functional assay

[0467]

[0468] (1) Curve fitting of activation (%) at 10 mM against RFU

[0469] (2) Not detected

[0470] The exemplary compounds of formula I were evaluated using a functional FLIPR assay for the human 5-HT1A receptor. The EC50 (nM) concentrations are shown in Table 4. This assay confirmed that the compounds or metabolites of the present invention have moderate functional activity at the target human 5-HT1A receptor.

[0471] Example 6: Human 5-HT1A: Radioactive ligand binding assay:

[0472] 1 Objective

[0473] The objective of this study was to evaluate the binding properties of the test compounds to serotonin receptor 1A.

[0474] 2 Materials and instruments used

[0475] 2.1 Reagents

[0476]

[0477]

[0478] 2.2 Instruments and Consumables Used

[0479]

[0480] 3 Experimental Methods

[0481] 1. Prepare the assay buffer according to the following table.

[0482]

[0483] Adjust the pH to 7.4 and then perform 0.2 μM sterile filtration.

[0484] 1. Prepare 8 doses of reference and test compounds by 5-fold serial dilution with 100% (v / v) DMSO starting from a 10 mM stock solution as needed.

[0485] 2. Pretreat the UniFilter-96 GF / B plate:

[0486] i. Add 50 μl / well of 0.5% (v / v) PEI to the UniFilter-96 GF / B plate. Seal the plate and incubate at 4 °C for 3 hours.

[0487] ii. After incubation, wash the plate 3 times with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0488] 3. Prepare the assay plate:

[0489] i. Dilute the cell membrane with the assay buffer and add 100 μl / well to a 96-well round-bottom plate to achieve a concentration of 20 μg / well.

[0490] ii. Prepare 8 concentrations of reference or test compounds and add 50 μl / well to a 96-well round-bottom deep-well plate.

[0491] iii. Dilute [3H]-8-hydroxy-DPAT with the assay buffer to 2 nM (4X final concentration) and add 50 μl / well to a 96-well round-bottom plate.

[0492] 4. Centrifuge the plate at 1000 rpm for 30 seconds and then stir at 600 rpm for 5 minutes at room temperature.

[0493] 5. Seal the plate and incubate the plate at 27 °C for 90 min.

[0494] 6. Stop the incubation by vacuum filtering on a GF / B filter plate, and then wash 4 times with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0495] 7. Dry the plate at 37 °C for 45 min.

[0496] 8. Seal the filter plate and add 40 μl / well of scintillation mixture.

[0497] 9. Read the plate by using a Microbeta 2 microplate counter.

[0498] 4 Data analysis

[0499] 1. For reference and test compounds, express the results as % inhibition using the normalization equation: N = 100 - 100×(U - C2) / (C1 - C2), where U is the unknown value, C1 is the high control mean, and C2 is the low control mean.

[0500] 2. IC 50 is determined by fitting the percent inhibition as a function of compound concentration to the Hill equation using XLfit.

[0501] Results and discussion

[0502] The results of the potential competitive binding properties of exemplary prodrug compounds I-24 and I-37 of the present invention and their corresponding metabolites psilocin and (7) targeting the human serotonin receptor (5-HT1A) are summarized in Table 5. The results of the exemplary compounds of the present invention are as shown by the IC 50 presented.

[0503] Table 5: Effects of exemplary compounds of formula I on the human 5-HT1A receptor using a radioligand binding assay

[0504]

[0505]

[0506] II. Results and discussion

[0507] The exemplary compounds of formula I and their metabolites were evaluated using a radioligand binding assay for the human 5-HT1A receptor. The IC 50 (nM) concentrations are shown in Table 5. This assay confirmed that the precursor parent compounds of the present invention or their corresponding metabolites are effective ligands for the target human 5-HT1A receptor.

[0508] Example 7: Human, rat, and mouse liver microsomal stability

[0509] Objective

[0510] The objective of this study was to evaluate the in vitro metabolic stability of the exemplary compounds I-24 and I-37 in pooled human, male rat, and male mouse liver microsomes. The concentration of the parent compound in the reaction system was evaluated by LC-MS / MS for assessing the stability in pooled human, male rat, and male mouse liver microsomes. The in vitro intrinsic clearance of the test compounds was also determined.

[0511] Protocol

[0512] Prepare the stock solution in an “incubation plate” containing phosphate buffer, ultrapure H2O, MgCl2 solution, and liver microsomes according to Table 6. Preheat the mixture in a 37 °C water bath for 5 minutes.

[0513] Table 6: Preparation of Stock Solution

[0514]

[0515] Add 40 μL of 10 mM NADPH solution to each well. The final concentration of NADPH was 1 mM. Prepare the negative control sample by replacing NADPH with 40 μL of ultrapure H2O. Samples were prepared in duplicate. The negative control was prepared as a single portion.

[0516] At the start of the reaction, add 4 μL of 200 μM of the exemplary test compound or control compound of the present invention to each stock solution to obtain a final concentration of 2 μM. This study was conducted in duplicate.

[0517] Withdraw 50 μL aliquots from the reaction solution at 0, 15, 30, 45, and 60 minutes. Terminate the reaction solution by adding 4 volumes of cold methanol and IS (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol, and 2 μM ketoprofen). Centrifuge the samples at 3220 g for 40 minutes. Mix an aliquot of 90 μL of the supernatant with 90 μL of ultrapure H2O and then use for LC-MS / MS analysis.

[0518] Perform LC / MS analysis on all samples of this study using a Shimadzu liquid chromatography separation system equipped with a degasser DGU-20A5R; a solvent delivery device LC-30AD; a system controller SIL-30AC; a column oven CTO-30A; a CTC analysis HTC PAL system. Perform mass spectrometry using a Triple QuadTM 5500 instrument.

[0519] All calculations were performed using Microsoft Excel. The peak area ratio of the test compound to the internal standard (listed in the table below) was determined from the extracted ion chromatogram.

[0520] All calculations were performed using Microsoft Excel. The peak areas were determined from the extracted ion chromatograms. The slope value k was determined by linear regression of the natural logarithm of the percentage of the parent drug remaining versus the incubation time.

[0521] The in vitro half-life (in vitro t1 / 2) was determined from the slope value as follows:

[0522] In vitro t 1 / 2 = -(0.693 / k)

[0523] The in vitro t1 / 2 (in minutes) was converted to the in vitro intrinsic clearance (in vitro CLint, in μL / min / mg protein) using the following equation (average of two determinations):

[0524]

[0525] For the exemplary compounds of the present invention or control compounds that showed an initial rapid disappearance followed by a slow disappearance, only the time points within the initial rate were included in the calculations.

[0526] Results and Discussion

[0527] Human, rat, and mouse liver microsomes contain multiple drug-metabolizing enzymes and are commonly used to support in vitro ADME (absorption, distribution, metabolism, and excretion) studies. These microsomes were used to examine the potential first-pass metabolic by-products of orally administered drugs. The stability of the exemplary compounds of the present invention in human, rat, and mouse liver microsomes was evaluated. In the liver microsomes of three species, human, rat, and mouse, most of the exemplary compounds of the present invention were recovered within a 60-minute period, indicating that these compounds were not rapidly cleared (see the exemplary compounds of Formula I in Table 7).

[0528] Table 7: Metabolic Stability of Exemplary Dimer Compounds of Formula I (I-24 and I-37), Control Compounds Diclofenac and Psilocybin in Humans, Rats, and Mice with NADPH

[0529]

[0530] * If the remaining % at 30 minutes was less than 1%, then CL int and t 1 / 2 were reported as ">307.01" and "<4.51", respectively.

[0531] Table 8: Metabolic Stability of Exemplary Dimer Compounds of Formula I (I-24 and I-37), Control Compounds Diclofenac and Psilocybin in Human, Rat, and Mouse Liver Microsomes

[0532]

[0533] (1) Not tested

[0534] Discussion:

[0535] The results demonstrated that the exemplary compounds (I-24 and I-37) were rapidly metabolized.

[0536] Example 8: Human, rat, mouse, and dog: Plasma stability

[0537] 1. Preparation of stock solutions

[0538] Stock solutions of the test compounds were prepared in DMSO and diluted to a final concentration of 200 μM. Working solutions of 1 mM lovastatin and propantheline were prepared in DMSO and acetonitrile, respectively. Lovastatin was used as a positive control for the plasma stability determination in rats and dogs. Propantheline was used as a positive control in the plasma stability determination in humans, mice, and monkeys.

[0539] 2. Plasma stability procedure

[0540] a. 2.5 μL of a 200 μM or 1 mM test compound or control compound solution was spiked into 497.5 μL of plasma to achieve a final concentration of 1 μM or 5 μM. The final concentration of the organic solvent was 0.5%. The assay was performed in duplicate.

[0541] b. The reaction samples were incubated in a water bath at approximately 60 rpm at 37 °C.

[0542] c. 50 μL aliquots were removed from the reaction samples at 0, 30, 60, 120, 180, and 240 minutes. The reaction was terminated by adding 7 volumes of cold acetonitrile containing internal standards (IS: 100 nM alprazolam, 200 nM imipramine, 200 nM labetalol, and 2 μM ketoprofen).

[0543] d. All samples were vortexed for 2 minutes and then centrifuged at 3220 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.

[0544] 3. Sample analysis

[0545] The samples were analyzed by LC-MS / MS.

[0546] · LC system: Shimadzu

[0547] · MS analysis: Triple QuadTM 6500+ with ESI interface from AB Inc (Canada)

[0548] · Column temperature: 40 °C

[0549] · Column: Used in combination with a guard column Hss T3 2.5μ (2.1×30mm)

[0550] · Mobile phase: Aqueous solution of 0.1% formic acid (A) and acetonitrile solution of 0.1% formic acid (B)

[0551]

[0552] 4. Data analysis

[0553] All calculations were performed using Microsoft Excel. The remaining percentage of the parent compound at each time point was estimated by determining the peak area ratio from the extracted ion chromatogram.

[0554] Table 9. Stability results of exemplary compounds in plasma of different species

[0555]

[0556] 1. If no peak is detected at 30 min, then T 1 / 2 is reported as "N.A."

[0557] 2. For compounds showing initial rapid disappearance followed by slow disappearance, only time points within the initial rate were included in the calculation.

[0558] Example 9: Intestinal mucosal permeability of exemplary compounds of the present invention and their metabolites using Caco-2 cell monolayers

[0559] 1. Cell seeding preparation

[0560] 1. Prepare Caco-2 cell medium, which consists of Dulbecco's Modified Eagle Medium (DMEM) containing high glucose and L-glutamine supplemented with 10% FBS, 1× penicillin-streptomycin mixture, and 1× non-essential amino acids (NEAA).

[0561] 2. Add 50 μL of medium to each well of the Transwell insert. Remove the Transwell insert from the storage bottle and add 25 mL of medium.

[0562] 3. Incubate at 37 °C, 5% CO2 for 1 hour. The plate is ready for cell seeding.

[0563] 4. Culture the cells in a T-75 flask in a cell culture incubator set at 37 °C, 5% CO2, 95% relative humidity. Allow the cells to reach 80%-90% confluence before splitting and subculturing.

[0564] 5. Rinse the cultured cells in a T-75 flask with 5 mL of PBS. Aspirate and add 1.5 mL of trypsin / EDTA and incubate at 37 °C for approximately 5 to 10 minutes, or until the cells detach and float. Inactivate the trypsin / EDTA by adding an excess of serum-containing medium.

[0565] 6. Transfer the cell suspension to a conical tube and pellet the cells by centrifugation at 120 × g for 10 minutes.

[0566] 7. Resuspend the cells in the seeding medium at a density of 6.86×10 5 cells / mL. This cell concentration can be used to seed 2.40×10 5 cells / cm 2 .

[0567] 2. Seeding and Culturing of Caco-2 Cells in Transwell Plates

[0568] 1. Add 50 μL of the above cell suspension to each well of a pre-prepared Transwell plate.

[0569] 2. Incubate the plate for 14 - 18 days. The medium is changed every other day, starting as early as within 48 hours after initial seeding.

[0570] 3. The procedure for medium change is as follows. Remove the plate from the incubator and place it in the fume hood. Aspirate the medium from the storage bottle and each Transwell insert. Add 75 μL of medium to each well of the Transwell insert and 25 mL of medium to the storage tray. Return the plate to the incubator.

[0571] 3. Assessment of Cell Monolayer Integrity

[0572] 1. When the 14-day-old Caco-2 cultured cells reach confluence and differentiation, they are ready for transport studies.

[0573] 2. Remove the medium from the storage bottle and the Transwell insert.

[0574] 3. Add 75 μL of pre-warmed medium to each transwell insert and 25 mL to the storage tray.

[0575] 4. Measure the resistance across the monolayer using an automated tissue resistance measurement system (World Precision Instruments, Sarasota, FL).

[0576] 5. Record the resistance of each well.

[0577] 6. Once all the wells have been measured, return the plate to the incubator.

[0578] 7. The TEER of each well is calculated by the following equation. The TEER value of each well should be greater than 230 ohms·cm 2 .

[0579] TEER measurement value (ohms) × membrane area (cm 2 ) = TEER value (ohm·cm 2 )

[0580] 4. Perform drug transport assay

[0581] 1. Remove the Caco-2 plate from the incubator. Then, wash the monolayer and perform two volume exchanges with pre-warmed HBSS (10 mM HEPES, pH 7.4). Then incubate the plate at 37 °C for 30 minutes.

[0582] 2. Prepare 1 mM stock solutions of the control compound and test compound in DMSO and dilute with HBSS (10 mM HEPES, pH 7.4) to achieve a final concentration of 5 μM. The final concentration of DMSO in the incubation system is 0.5%. Digoxin, prazosin, and propranolol are used as control compounds in this assay.

[0583] 3. After pre-incubation for 30 minutes, remove the HBSS (10 mM HEPES, pH 7.4).

[0584] 4. Incubate the drug transport rate in the apical-to-basolateral direction. Add 75 μL of the control compound and test compound to the Transwell insert (apical chamber). Fill the wells in the receptor plate (basolateral chamber) with 235 μL of HBSS (10 mM HEPES, pH 7.4).

[0585] 5. Measure the drug transport rate in the basolateral-to-apical direction. Add 235 μL of the control compound and test compound to the wells in the receptor plate (basolateral chamber). Fill the Transwell insert (apical chamber) with 75 μL of HBSS (10 mM HEPES, pH 7.4).

[0586] 6. Prepare 0-time samples by transferring 50 μL of the working solution to the wells of a 96-deep well plate, followed by adding 200 μL of cold methanol containing the appropriate internal standards (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 200 nM diclofenac).

[0587] 7. Incubate at 37 °C for 2 hours.

[0588] 8. At the end of the transit period, 50 μL of samples were taken from both the donor and acceptor sides and transferred to a new plate. Then, 200 μL of cold methanol containing internal standards (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 200 nM diclofenac) was added to terminate the reaction. The samples were vortexed for 5 minutes. The samples were centrifuged at 3220 g for 40 minutes. An aliquot of 100 μL of the supernatant was mixed with 100 μL of ultrapure water for LC-MS / MS analysis. All incubations were performed in duplicate.

[0589] 9. Discard the solution in the transwell plate. Add 100 μL of Lucifer Yellow solution (100 μM in HBSS) to each well of the transwell insert, and add 300 μL of HBSS to each well of the acceptor. Incubate at 37 °C for 30 minutes. Take 80 μL from each well on the apical side and basolateral side to a solid black plate. Read the plate with a Tecan Infinite TM M 200 (excitation / emission wavelength 485 nM / 530 nM).

[0590] Results and Discussion

[0591] The P app(A→B) and P app(B→A) values of psilocin (a metabolite of I-24) were 24.57 and 18.71 cm / s × 10 -6 , corresponding to an efflux ratio of 0.76. The permeability results of psilocin and exemplary compounds applied in the Caco-2 cell monolayer are shown in Table 10.

[0592] The results showed that the dimeric compounds of the exemplary Formula I metabolites were highly permeable compounds and were unlikely to be substrates of efflux transporters.

[0593] Table 10: Permeability results of representative compounds of Formula I and their metabolites in the Caco-2 cell monolayer (mean, n = 2)

[0594]

[0595]

[0596] *Values represent the mean of n = 3

[0597] **Not tested

[0598] Table 11: Assessment of Caco-2 cell monolayer integrity

[0599]

[0600] *Values represent the mean of n = 3

[0601] Although the present invention has been described with reference to embodiments, it should be understood that the scope of the claims should not be limited by the embodiments set forth in the description, but should be given the broadest interpretation consistent with the overall description.

[0602] All patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety. The disclosures of these publications are incorporated into the present invention by reference to more fully describe the prior art known to those skilled in the art as of the filing date of the application described and claimed herein.

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, wherein: Q is selected from 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); R 1 selected from H, C1-C3 alkyl, C(O)R 10 , CO2R 10 , C(O)N(R 10 )(R 11 ), S(O)R 10 and SO2R 10 ; R 2 、R 3 、R 3 ', R 4 and R 4 ' are independently selected from H and C1-C6 alkyl; R 5 and R 5 ' are independently selected from H and C1-C6 alkyl, or R 5 and R 5 ' together with the nitrogen atom therebetween form a 3- to 7-membered heterocycle which optionally contains 1 to 2 additional heteroatoms selected from O, S, S(O), SO2, N and NC 1-6 alkyl of the heterocyclic moiety of the additional ring; R 6 , R 7 and R 8 are independently selected from 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 1 to 2 selected from O, S, S(O), SO2, N and NR 14 wherein the 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 optionally substituted by one or more independently selected from CN, OR 15 、N(R 15 )(R 16 ) and SR 15 wherein the C3-C7 cycloalkyl and C3-C7 heterocycloalkyl are each further optionally substituted by one or more selected from halo, CO2R 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 1 to 2 selected from O, S, S(O), SO2, N and NR 19 The hetero portion of the C3-C6 heterocycloalkyl group is substituted; Q' is selected from a straight chain, C1-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 C3-C7 heterocycloalkylene containing 1 to 2 hetero moieties selected from O, S, S(O), SO2, N and NR 20 wherein said C1-C 20 alkylene, C2-C 20 haloalkylene, C2-C6 alkenylene, C2-C 20 haloalkenylene, C3-C7 cycloalkylene and C3-C7 heterocycloalkylene are optionally substituted by one or more substituents independently selected from CN, OR 21 , N(R 21 )(R 22 ) and SR 21 , and / or are disubstituted on the same carbon atom by C 1-6 alkyl or by C 2-6 alkylene to form a C3-C7 cycloalkyl ring, and wherein said C3-C7 cycloalkylene and C3-C7 heterocycloalkylene are each further optionally substituted by one or more substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, provided that when Q is C(O)OQ'OC(O) or C(O)NR 9’ Q'NR 9’ C(O), then Q' is not a straight chain; Each 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 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 alkylene aryl and substituted or unsubstituted C1-C6 alkylene heteroaryl; and R 9 'selected from H and C1-C6 alkyl; wherein all available hydrogen atoms are optionally substituted by fluorine or chlorine atoms, and / or all available atoms are optionally substituted by their alternative isotopes.

2. The compound according to claim 1, wherein R 1 is selected from H, C1-C3 alkyl, C(O)R 10 , CO2R 10 and C(O)N(R 10 )(R 11 ), wherein all available hydrogen atoms are optionally substituted with a fluorine atom or a chlorine atom, and / or all available atoms are optionally substituted with their alternative isotopes.

3. The compound according to claim 2, wherein R 1 is selected from H, CH3, and CH2CH3, where all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes.

4. The compound according to claim 3, wherein R 1 is independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CFH2, CH2CH3, CH2CH2D, CH2CD2H and CD2CD3.

5. The compound according to claim 4, wherein R 1 is selected from H, D, CH3 and CD3.

6. The compound according to any one of claims 1 to 5, wherein R 2 , R 3 , R 3 ', R 4 and R 4 ' are independently selected from H, CH3, CH2CH3, CH(CH3)2 and C(CH3)3, wherein all available hydrogen atoms are optionally substituted by fluorine atoms or chlorine atoms, and / or all available atoms are optionally substituted by their alternative isotopes.

7. The compound according to claim 6, wherein R 2 is selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CF2H, CH2CH3, CH2CH2D, CH2CD2H and CD2CD3.

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

9. A compound according to any one of claims 6 to 8, wherein R 3 , R 3 ', R 4 and R 4 ' are independently selected from H, D, F, CH3, CD2H, CDH2, CD 3、 CF3, CHF2, CFH2, CH2CH3, CH2CH2D, CH2CD2H and CD2CD 3。 10. The compound according to claim 9, wherein R 3 , R 3 ', R 4 and R 4 ' are independently selected from H, D, F, CH3 and CD3.

11. The compound according to any one of claims 1 to 10, wherein R 5 and R 5 ' are independently selected from H, D, F, CH3, CD2H, CDH2, CD 3、 CF3, CHF2, CFH2, CH2CH3, CH2CH2D, CH2CD2H, CD2CD3, CD(CD3)2 and CH(CH3)2.

12. The compound according to claim 11, wherein R 5 and R 5 ' together with the nitrogen atom between them form pyrrolidinyl, piperidinyl, morpholinyl or diazinylalkyl, wherein all available hydrogens are optionally substituted with deuterium.

13. A compound according to any one of claims 1 to 12, wherein R 6 , R 7 and R 8 are independently selected from 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 the C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl and C2-C6 haloalkynyl groups are optionally substituted with 1 to 3 substituents independently selected from CN, OR 15 , 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 their alternative isotopes.

14. The compound according to claim 13, wherein R 6 , R 7 and R 8 are independently selected from H, D, F, Cl, Br and CN.

15. A compound according to any one of claims 1 to 14, wherein Q is selected from P(O)OR 9 and C1-C2 alkylene-P(O)OR 9 -C1-C2 alkylene, wherein all available hydrogen atoms are optionally substituted by fluorine or chlorine atoms, and / or all available atoms are optionally substituted by their alternative isotopes.

16. The compound according to claim 15, wherein Q is CH2-P(O)OR 9 -CH2, wherein all available hydrogen atoms are optionally substituted by fluorine or chlorine atoms, and / or all available atoms are optionally substituted by their alternative isotopes.

17. A compound according to any one of claims 1 to 14, wherein Q is selected from C(O), C(O)Q'C(O), C(O)OQ'OC(O) and C(O)NR 9’ Q'NR 9’ C(O), wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, and / or all available atoms are optionally substituted with their alternative isotopes.

18. The compound according to claim 17, wherein Q′ is selected from C1-C 10 alkylene, C2-C 10 alkenylene and C2-C 10 alkynylene, wherein the C1-C 10 alkylene, C2-C 10 alkenylene and C2-C 10 alkynylene are optionally substituted by 1 to 3 substituents independently selected from CN, OR 21 , N(R 21 )(R 22 ) and SR 21 , and / or are disubstituted on the same carbon atom by C 1-6 alkyl or by C 2-6 alkylene to form a C3-C7 cycloalkyl ring, wherein the C3-C7 cycloalkyl is further optionally substituted by substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, wherein all available hydrogen atoms are optionally substituted by fluorine or chlorine atoms, and / or all available atoms are optionally substituted by their alternative isotopes.

19. The compound according to claim 18, wherein Q′ is selected from C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, which are optionally substituted by one or two substituents independently selected from OR 21 and N(R 21 )(R 22 ), and / or are disubstituted on the same carbon atom by C 1-6 alkyl or by C 2-6 alkylene to form a C3-C7 cycloalkyl ring, wherein the C3-C7 cycloalkyl ring is further optionally substituted by substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, wherein all available hydrogen atoms are optionally substituted by fluorine or chlorine atoms, and / or all available atoms are optionally substituted by their alternative isotopes.

20. The compound according to claim 19, wherein Q′ is selected from C1-C4 alkylene and C2-C4 alkenylene, wherein all available hydrogen atoms are optionally substituted by fluorine or chlorine atoms, and / or all available atoms are optionally substituted by their alternative isotopes.

21. The compound according to claim 17, wherein Q′ is a direct bond.

22. The compound according to any one of claims 1 to 21, wherein each 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 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.

23. The compound according to claim 22, wherein each 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 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, wherein all available hydrogen atoms are optionally replaced by fluorine or chlorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

24. The compound according to claim 23, wherein each 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 independently selected from H, D, CH3, CD2H, CDH2, CD 3、 CF3, CHF2, CF2H, CH2CH2D, CH2CD2H, CH2CH3 and CD2CD3.

25. A compound according to any one of claims 1 to 24, wherein R 9 ' is selected from H and C1-C4 alkyl, wherein all available hydrogen atoms are optionally substituted with a fluorine atom or a chlorine atom, and / or all available hydrogen atoms are optionally substituted with deuterium.

26. The compound according to claim 1, selected from: or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

27. A pharmaceutical composition comprising one or more compounds as claimed in any one of claims 1 to 26 or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, and a pharmaceutically acceptable carrier.

28. A method of treating a disease, disorder, or condition treatable by activating a serotonin receptor, comprising administering to a subject suffering from said disease, disorder, or condition a therapeutically effective amount of one or more compounds as claimed in any one of claims 1 to 26 or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

Images