3-pyrrolidine-indole dimers as serotonergic agents for treatment of related disorders

Abstract

The present application relates to 3-cyclamine-indole dimers of general formula (I), to processes for their preparation, to compositions comprising said compounds and to their use in activating serotonin receptors in cells, and to the treatment of diseases, disorders or conditions by activating 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 / 395,534, filed Aug. 5, 2022, the content of which is incorporated herein by reference in its entirety. Technical Field

[0003] This application relates to 3-pyrrolidin-indole dimers of formula (I) for the treatment of various disorders treatable by activation of serotonin receptors, such as mental and neurological disorders, in the fields of psychiatry, neurobiology, and pharmacotherapy. 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] The field of psychedelic neuroscience has recently seen a renaissance after decades of restricted research due to its legal status. Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect many cognitive processes. There is a current consensus that psychedelics are agonists or partial agonists of the serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor.

[0006] Psychedelics have rapid-onset and long-lasting effects long after their acute effects, including changes in mood and brain function. The long-term effects may be due to their unique receptor affinity, which affects neurotransmission (i.e., neuroplasticity) via neuromodulatory systems used to regulate brain activity, 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 pre- and post-synaptic receptor density. These previously understudied psychedelic drugs may potentially provide the next generation of neurological therapies, in which refractory mental and neurological disorders (e.g., depression, post-traumatic stress disorder, dementia, and addiction) may become treatable with attenuated pharmacological risk profiles.

[0007] Despite the widespread perception that psychedelic drugs are dangerous, they are one of the safest known classes of CNS drugs from a physiological safety perspective. Preliminary data suggest that psychedelic administration in humans produces a unique profile of effects and potential adverse reactions that need to be appropriately addressed to maximize safety. The primary safety concerns are primarily psychological rather than physiological in nature. Somatic effects vary but are relatively insignificant, even at doses that induce strong psychological effects. Psilocybin has been frequently reported to cause a transient delayed-onset headache when administered under controlled conditions, the incidence, duration, and severity of which increase in a dose-related manner [Johnson et al., Drug Alcohol Depend (2012) 123(1-3):132–140]. Repeated administration of psychedelics has been found to result in the very rapid development of tolerance known as tachyphylaxis (a phenomenon thought to be mediated in part by the 5-HT2A receptor). In fact, several studies have shown that tachyphylaxis to psychedelics is associated with downregulation of the 5-HT2A receptor. For example, daily LSD administration selectively reduces 5-HT2 receptor density in rat brain [Buckholtz et al., Eur. J. Pharmacol. 1990, 109:421-425. 1985; Buckholtz et al., Life Sci. 1985, 42:2439-2445].

[0008] Classical and dissociative psychedelics are known to have rapid onset of antidepressant and anti-addiction effects, unlike any currently available treatment. Randomized controlled clinical studies have confirmed the antidepressant and antianxiety effects of classical psychedelics in humans.

[0009] Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) has the chemical formula C 12 H 17 N 2 O 4Psilocybin is a tryptamine-based prodrug and one of the main psychoactive constituents of mushrooms of the genus Psilocybe. Psilocybin was first isolated from Psilocybe 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, possibly because psilocybin has a shorter duration of action and is not as notorious as LSD, and it is currently the preferred compound for studies of 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]. Like other members of this class, psilocybin sometimes causes profound 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 produce some or all of the majority of the subjective and physiological effects of psilocybin in humans and non-human animals. Recently, human psilocybin research has confirmed the 5-HT2A activity of psilocybin via parent psilocin and provided some support for the possible indirect effects on dopamine via 5-HT2A activity and the possible activity of other serotonin receptors. In fact, the most consistent finding regarding 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 in 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 consider in the actions of 5-HT2A agonist hallucinogens. In fact, most known 5-HT2A agonists produce hallucinogenic effects in humans and rodents, and the generalization from one 5-HT2A agonist to other agonists, such as 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, the results of a series of rat drug discrimination studies 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 reduce the density of 5-HT2 receptors in the rat brain.

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

[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 reduce 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 (15 mg or 20 mg orally) increased the absolute metabolic rate of glucose in the frontal lobe and, to a lesser extent, in other cortical regions as well as in 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 5-HT2A agonism is widely considered to be the primary action of classical hallucinogens, psilocybin has a 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 the 5-HT1A receptor, 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 and 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 refractory to conventional methods of control.

[0016] Typically, the psychedelic therapy model consists of administering an orally active drug to induce a mystical experience that lasts approximately 4 - 9 h and depends 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 long - lasting antidepressant and anti - anxiety effects. Classic 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 classic hallucinogens, it was found that in a supportive environment, psilocybin and LSD continuously produced significant and sustained antidepressant and anti - anxiety effects.

[0017] Psychedelic therapies 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 generating 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 inadequately controlled by conventional methods.

[0018] Further emerging clinical research and evidence suggest that psychedelic-assisted therapies also show promise as alternative treatments for refractory substance use disorders and mental health conditions and may thus be an important tool in the 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 a cessation rate 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 substantially 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 efficacy of psilocybin-assisted therapy for treatment-resistant depression and end-of-life anxiety [Carhart-Harris et al., Neuropsychopharmacology, 2017, 42(11):2105-2113]. Research on the potential benefits of psychedelic-assisted therapy for opioid use disorder (OUD) is beginning to emerge, and there is growing evidence to support 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 cessation rates were observed among 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 people 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 the use of prescription opioids and suicide risk [Argento et al., J Psychopharmacol., 2018, 32(12):1385-1391]. Despite these promising initial findings for classical psychedelics, further research is needed to determine how psychedelics can improve the opioid crisis.Concurrently, the growing body of evidence regarding the safety and efficacy of psilocybin in treating mental and substance use disorders should help drive further clinical research as a novel intervention for OUD.

[0019] Conventional doses of psychedelics also improve sleep disorders, which are highly prevalent in patients with depression, with over 80% of patients complaining of poor sleep quality. Sleep symptoms are typically 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 prior to 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. Further research has shown that a single dose of psychedelics causes resetting of the biological clock underlying the sleep / wake cycle, thereby enhancing cognitive-emotional processes in depressed populations but also improving well-being and enhancing mood in healthy individuals [Kuypers, Medical Hypotheses, 2019, 125:21-24].

[0020] In a systematic meta-analysis of clinical trials from 1960 - 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 produce rapid, robust, and sustained improvements in cancer-related psychological and existential distress [Ross S, Int Rev Psychiatry, 2018, 30(4):317-330]. Many patients facing cancer or other life-threatening illnesses experience significant existential distress related to loss of meaning or purpose in life, which can be associated with despair, demoralization, 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 substantially reduce the quality of life in this patient population. Alleviating these core features of existential distress should be one of the central goals of palliative care. Thus, several manualized psychotherapies targeting cancer-related existential distress, focusing on dignity and meaning-making, have been developed in recent years. However, there are currently no pharmacological interventions for existential distress per se, 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), commonly known as such. Under this paradigm, sub-perceptual doses of serotonergic hallucinogens, which are approximately 10% or less of the full dose, are administered once daily, every other day, or every three days or in 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 for eliciting the classic wet dog shake behavioral response associated with hallucinogenic doses, a subset of low-attention and low-motivation rats showed improved performance on a 5-choice serial reaction time and progressive ratio task (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 research 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 both neurodegenerative and neurodevelopmental diseases as well as 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 can extend the utility of these compounds to additional indications and may prove useful for healthy applications.

[0022] Psychosis generally refers to an abnormal mental state characterized by hallucinatory experiences, delusional thinking, and disordered thinking. In addition, this state is accompanied by social cognitive impairment, inappropriate emotional expression, and bizarre behavior. Most commonly, psychosis develops as part of a mental disorder, among which it represents a component of schizophrenia. It corresponds to the stage in which the disease is most fully developed. The initial manifestation of a patient's psychosis is called the first episode of psychosis. It reflects a critical transition stage toward 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-dose, non-hallucinogenic (microdoses) of psychedelics can alleviate the symptoms of schizophrenia and psychosis. Summary of the invention

[0023] The present application includes compounds of Formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:

[0024]

[0025] in:

[0026] Q is selected from P(O)OR 9 , C 1 -C 4 Alkylene-P(O)OR 9 -C 1 -C 6 Alkylene, C(O), SO 2 , C(O)Q'C(O), C(O)OQ'OC(O) and C(O)NR 9’ QUR 9’ C(O);

[0027] R 1 Selected from H, C 1 -C 3 Alkyl, C(O)R 10 , CO 2 R 10 、C(O)N(R 10 )(R 11 )、S(O)R 10 and SO 2 R 10 ;

[0028] R 2 , R 3 , R 4 and R 5 Independently selected from H and C 1 -C 6 alkyl;

[0029] R 6 , R 7 and R 8 are independently selected from H, halogen, CN, OR 12 、N(R 12 )(R 13 ), SR 12 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Halogenated olefins, CO 2 R 12 、C(O)N(R 12 )(R 13 )、S(O)R 12 、SO 2 R 12 , C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 2 -C 6 Haloalkynyl, C 3 -C 7 Cycloalkyl and containing 1 to 2 selected from O, S, S(O), SO 2 , N and NR 14 C 3 -C 7 Heterocycloalkyl, wherein the C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Halogenated alkenyl, C 2 -C 6 Alkynyl, C 2 -C 6 Haloalkynyl, C 3 -C 7 Cycloalkyl and C 3 -C 7 Heterocycloalkyl is optionally substituted by one or more independently selected from CN, OR 15 、N(R 15 )(R 16 ) and SR 15 Substituents, and wherein the C 3 -C 7 Cycloalkyl and C 3 -C 7The heterocycloalkyl groups are each further optionally substituted by one or more substituents selected from halogen, CO 2 R 17 、C(O)N(R 17 )(R 18 )、SO 2 R 17 、C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl and C 2 -C 19 heterocycloalkyl containing one or two hetero moieties selected from O, S, S(O), SO 3 、N and NR 6 ;

[0030] Q' is selected from a direct bond, C 1 -C 20 alkylene, C 1 -C 20 haloalkylene, C 2 -C 20 alkenylene, C 2 -C 20 haloalkenylene, C 2 -C 20 alkynylene, C 2 -C 20 haloalkynylene, C 3 -C 7 cycloalkylene and C 2 -C 20 heterocycloalkylene containing one or two hetero moieties selected from O, S, S(O), SO 3 、N and NR 7 wherein the C 1 -C 20 alkylene, C 2 -C 20 haloalkylene, C 2 -C 6 alkenylene, C 2 -C 20 haloalkenylene, C 3 -C 7 cycloalkylene and C 3 -C7 The azacycloalkyl group is optionally substituted by one or more substituents independently selected from CN, OR 21 , N(R 21 )(R 22 ), and SR 21 , and / or is disubstituted on the same carbon atom by C 1-6 alkyl or by C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, and wherein said C 3 -C 7 subcycloalkyl and C 3 -C 7 azacycloalkyl are each further optionally substituted by one or more substituents selected from C 1 -C 3 alkyl and C 1 -C 3 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;

[0031] 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 H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 3 -C 7 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 6 alkylene C 3 -C 7Cycloalkyl, substituted or unsubstituted C 1 -C 6 Alkylene C 3 -C 7 Heterocycloalkyl, substituted or unsubstituted C 1 -C 6 Alkylene aryl and substituted or unsubstituted C 1 -C 6 Alkylene heteroaryl; and

[0032] R 9’ Independently selected from H and C 1 -C 6 Alkyl;

[0033] 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.

[0034] In another embodiment, the compounds of the present application are used as drugs. Accordingly, the present application also includes the compounds of the present application for use as drugs.

[0035] The present application also includes a method for treating a mental 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 present application.

[0036] The present application also includes a method for treating a mental illness, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application.

[0037] The present application further provides a method for preparing the compounds of the present application. General and specific methods will be discussed in more detail below and illustrated in the following examples.

[0038] From the following detailed description, other features and advantages of the present application will become apparent. However, it should be understood that the detailed description and specific examples, while indicating embodiments of the present application, 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 entire specification. Detailed Description

[0039] I. Definitions

[0040] Unless otherwise specified, the definitions and embodiments described in this section and other sections are intended to apply to all embodiments and aspects of the present application described herein, as will be understood by those skilled in the art.

[0041] As used herein, terms such as "compound(s) of the application" or "compound(s) of the present application" refer to compounds of Formula I (including Formulas IA, IB, IC, ID, IE, and IF that fall within the scope of Formula I), and include pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, as well as all stereoisomers and regioisomers.

[0042] As used herein, terms such as "composition(s) of the application" or "composition(s) of the present application" refer to compositions that contain one or more compounds of the application, such as pharmaceutical compositions.

[0043] 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 application are present in the form of individual salts and solvates and in combinations such as salts or solvates of the compounds of the application, for example.

[0044] As used in the present application, the singular forms "a", "an", and "the" include plural referents unless the context clearly indicates otherwise. For example, an embodiment that includes "a compound" should be understood to represent certain aspects with one compound or two or more additional compounds.

[0045] As used in the present application 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 method steps.

[0046] As used herein, the term "consisting" and its derivatives are closed - ended 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.

[0047] 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, and the presence of other features, elements, components, groups, wholes, and / or steps that do not materially affect the basic and novel characteristics of these features, elements, components, groups, wholes, and / or steps.

[0048] In embodiments that include an "additional" or "second" component (such as an additional or second compound), as used herein, the second component 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 other recited components or "additional" groupings are similarly different.

[0049] As used herein, the term "suitable" means that the choice of a particular compound or condition will depend on the particular synthetic operation to be carried out, the identity of the molecule to be transformed, and / or the particular use of the compound, but the choice 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 ratios, 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.

[0050] 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. To the extent that the 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, these degree terms should be construed to include a deviation of at least ±5% of the modified term.

[0051] This specification refers to many chemical terms and abbreviations used by those of ordinary skill in the art. However, for clarity and consistency, definitions of selected terms are provided.

[0052] 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.

[0053] As used herein, the term "prodrug" means a compound or a salt of a compound that is converted to an active drug upon administration.

[0054] 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 -C" 6 alkyl") means an alkyl group having 1, 2, 3, 4, or 5 carbon atoms.

[0055] As used herein, whether used alone or as part of another group, the term "alkenyl" means a straight-chain or branched-chain saturated alkylene group, i.e., a saturated carbon chain having substituents at both ends. The possible number of carbon atoms in the alkylene group mentioned is indicated by the prefix "C" n1-n2 ". For example, the term C" 2-6 alkylene means an alkylene group having 2, 3, 4, 5, or 6 carbon atoms.

[0056] As used herein, whether used alone or as part of another group, the term "alkynyl" means a straight-chain or branched-chain unsaturated alkynyl group containing at least one triple bond. The possible number of carbon atoms in the alkyl group mentioned is indicated by the prefix "C" n1-n2 ". For example, the term C" 2-6 alkynyl means an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms.

[0057] As used herein, the term "alkoxy", when used alone or in combination herein, includes an alkyl group attached to an oxygen linking atom.

[0058] 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 indicated 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.

[0059] 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 and containing 3 to 6 atoms, wherein one or more atoms are hetero moieties selected from O, S, S(O), SO 2 and N, and the remaining atoms are C. The heterocycloalkyl group is saturated or unsaturated (i.e., contains one or more double bonds). When the heterocycloalkyl group contains the prefix C" n1-n2 or "n1 to n2", this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, where one or more, suitably 1 to 4, ring atoms are selected from O, S, S(O), SO 2Substituted with heteroatoms of N, and the remaining atoms are C.

[0060] As used herein, whether used alone or as part of another group, the term "aryl" refers to a carbocyclic group containing at least one aromatic ring and containing 6 to 20 carbon atoms.

[0061] As used herein, whether used alone or as part of another group, the term "heteroaryl" refers to 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 the heteroaryl contains the prefix C n1-n2 then, this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, where one or more, suitably 1 - 4 ring atoms, are replaced by heteroatoms as defined above.

[0062] 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, these rings can be fused, bridged, spiro - fused, or linked by bonds.

[0063] As used herein, the term "benzo - fused" refers to a polycyclic group in which a benzene ring is fused to another ring.

[0064] The first ring being "fused" to the second ring means that the first ring and the second ring share two adjacent atoms therebetween.

[0065] The first ring being "bridged" to the second ring means that the first ring and the second ring share two non - adjacent atoms therebetween.

[0066] The first ring being "spiro - fused" to the second ring means that the first ring and the second ring share one atom therebetween.

[0067] 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.

[0068] As used herein, the term "haloalkyl" refers to an alkyl group as defined above, wherein one or more available hydrogen atoms are replaced by halogen. Thus, for example, "C 1-6 haloalkyl" refers to a C 1 to C 6 linear or branched alkyl having one or more halogen substituents as defined above.

[0069] As used herein, the term "haloalkenyl" refers to an alkenyl group as defined above, wherein one or more available hydrogen atoms are replaced by halogen. Thus, for example, "C 1-6 haloalkenyl" (or "C 1 -C6 "Halogenated alkenyl") means a C as defined above having one or more halogen substituents 1 to C 6 linear or branched alkenyl.

[0070] As used herein, the term "halogenated alkynyl" means an alkynyl as defined above, wherein one or more of the available hydrogen atoms are replaced by a halogen. Thus, for example, "C 1-6 halogenated alkynyl" (or "C 1 -C 6 halogenated alkynyl") means a C as defined above having one or more halogen substituents 1 to C 6 linear or branched alkynyl.

[0071] As used herein, the term "deuterated alkyl" means an alkyl as defined above, wherein one or more of the available hydrogen atoms are replaced by deuterium. Thus, for example, "C 1-6 deuterated alkyl" means a C as defined above having one or more deuterium substituents 1 to C 6 linear or branched alkyl.

[0072] The suffix "(ene)" at the end of a group (e.g., "alkylene" or "alkenylene") means that the group is divalent, i.e., it is bonded to two variables, each variable being at a different end of the group.

[0073] 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.

[0074] 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: halogen, C 1 -C 4 alkyl, OC 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 haloalkyl, CN, OH, NH 2 , NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), SC 1 -C 4 alkyl, S(O)C 1 -C 4 alkyl, SO2 C 1 -C 4 alkyl, CO 2 H, CO 2 C 1 -C 4 alkyl, C(O)NH 2 、C(O)NHC 1 -C 4 alkyl, C(O)N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), C 3 -C 6 cycloalkyl and a 3- to 6-membered heterocycle containing a heterocyclic moiety of 1 to 2 members selected from O, S, S(O), SO 2 、N, NH and NC 1 -C 4 alkyl.

[0075] In "available hydrogen atom" or "available atom", the term "available" means an atom known to those skilled in the art to be replaceable by a substituent.

[0076] As used herein, the term "one or more" items includes a single item selected from the list and a mixture of two or more items selected from the list.

[0077] As used herein, the term "its alternative isotope" means an isotope of an element other than the most abundant isotope found in nature.

[0078] In the compounds of formula I and their pharmaceutically acceptable salts and / or solvates, the atoms may exhibit their natural isotope abundances, or one or more atoms may be artificially enriched with a specific 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. This disclosure is intended to include all suitable isotopic variants of the compounds of formula I and their pharmaceutically acceptable salts and / or solvates. For example, the 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.

[0079] The term "compound" refers to the compound, and in certain embodiments, in terms of its stability, 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 solvent or an inorganic solvent. A "stable" compound is a compound that can be prepared and isolated, and whose structure and properties remain or can cause 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 application are limited to stable compounds covered by general formula (I), or pharmaceutically acceptable salts and / or solvates thereof.

[0080] The term "pharmaceutically acceptable" means compatible with the treatment of a subject.

[0081] The term "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant or other substance that is mixed with the active ingredient to permit the formation of a pharmaceutical composition (i.e., a dosage form capable of being administered to a subject).

[0082] 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.

[0083] An acid addition salt that is suitable for or compatible with the treatment of a subject is any non-toxic organic acid addition salt or inorganic acid addition salt of any basic compound.

[0084] A base addition salt that is suitable for or compatible with the treatment of a subject is any non-toxic organic base addition salt or inorganic base addition salt of any acidic compound.

[0085] As used herein, terms such as "protecting group" or "PG" refer to chemical moieties that protect or mask reactive moieties of a molecule to prevent side reactions in those reactive moieties of the molecule while manipulating different moieties of the molecule or causing it to react. After the manipulation 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 Edition, 1999; and Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0086] As used herein, the term "subject" includes all members of the animal kingdom, including mammals, and preferably refers to humans. Thus, the methods of the present application are applicable to human therapy and veterinary applications.

[0087] As used herein and as is well known in the art, the terms "treating" or "treatment" refer to methods 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 not. "Treating" and "treatment" can also mean prolonging survival as compared to expected survival in the absence of 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 application to prevent recurrence. Methods of treatment include administering to a subject a therapeutically effective amount of one or more compounds of the present application, and optionally consisting of a single administration, or alternatively including a series of administrations.

[0088] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of one or more compounds of the present application 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 activating serotonergic receptors and downstream second messengers, an effective amount is, for example, an amount that increases such activation compared to activation in the absence of administration of one or more compounds.

[0089] "Mitigating" a disease, disorder or condition means that the degree and / or adverse clinical manifestations of the disease, disorder or condition are reduced and / or the time course of progression is slowed or extended compared to not treating the condition.

[0090] As used herein, the term "administer" means administering a therapeutically effective amount of one or more compounds or compositions of the present application to a cell, tissue, organ or subject.

[0091] As used herein, the term "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.

[0092] As used herein, "disease, disorder or condition" refers to a disease, disorder or condition that is treatable or can be treated by activating a serotonin receptor (such as 5-HT2A), particularly using a serotonin receptor agonist (such as one or more compounds of the present application described herein).

[0093] 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, particularly an increase in serotonergic activity. These diseases respond well when the serotonergic activity associated with the disease, disorder or condition is agonized by one or more compounds or compositions of the present application.

[0094] As used herein, the term "activation" includes agonist, partial agonist and positive allosteric modulation of serotonin receptors.

[0095] As used herein, the term "5-HT 1A " and "5-HT 2A " mean 5-HT 2 serotonin receptor 5-HT 2A receptor subtypes and 5-HT 2A receptor subtypes.

[0096] As used herein, the term "therapeutic agent" refers to any drug or active agent that has a pharmacological effect when administered to a subject.

[0097] II. Compounds

[0098] The applicant has developed and prepared novel pyrrolidine - 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 - 13 and I - 122 are metabolized in vivo to provide the active metabolites of compound 10 and compound 13, respectively, as described herein.

[0099] This application includes compounds of formula I or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof:

[0100]

[0101] Wherein:

[0102] Q is selected from P(O)OR 9 , C 1 -C 4 alkylene - P(O)OR 9 -C 1 -C 6 alkylene, C(O), SO 2 , C(O)Q'C(O), C(O)OQ'OC(O) and C(O)NR 9’ Q'NR 9’ C(O);

[0103] R 1 is selected from H, C 1 -C 3 alkyl, C(O)R 10 , CO 2 R 10 , C(O)N(R 10 )(R 11 ), S(O)R 10 and SO 2 R 10 ; y

[0104] R 2 , R 3 , R 4 and R 5 are independently selected from H and C 1 -C 6 alkyl;

[0105] R 6 , R 7 and R 8 are independently selected from H, halogen, CN, OR 12 , N(R 12 )(R 13 ), SR 12 , C1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, CO 2 R 12 , C(O)N(R 12 )(R 13 ), S(O)R 12 , SO 2 R 12 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl and C 2 -C 14 heterocycloalkyl containing one or two hetero moieties selected from O, S, S(O), SO 3 -C 7 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl and C 3 -C 7 heterocycloalkyl is optionally substituted by one or more substituents independently selected from CN, OR 15 , N(R 15 )(R 16 ) and SR 15 ; and wherein the C 3 -C 7 cycloalkyl and C 3 -C 7 heterocycloalkyl are each further optionally substituted by one or more substituents selected from halogen, CO 2 R 17 , C(O)N(R 17 )(R 18 ), SO 2 R 17 , C 1 -C6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Haloalkenyl, C 2 -C 6 Alkynyl, C 2 -C 6 Haloalkynyl, C 3 -C 6 Cycloalkyl and C containing 1 to 2 hetero moieties selected from O, S, S(O), SO 2 , N and NR 19 of C 3 -C 6 substituted by heterocycloalkyl substituents;

[0106] Q' is selected from a direct bond, C 1 -C 20 Alkylene, C 1 -C 20 Haloalkylene, C 2 -C 20 Alkenylene, C 2 -C 20 Haloalkenylene, C 2 -C 20 Alkynylene, C 2 -C 20 Haloalkynylene, C 3 -C 7 Cycloalkylene and C containing 1 to 2 hetero moieties selected from O, S, S(O), SO 2 , N and NR 20 of C 3 -C 7 Heterocycloalkylene, wherein the C 1 -C 20 Alkylene, C 2 -C 20 Haloalkylene, C 2 -C 6 Alkenylene, C 2 -C 20 Haloalkenylene, C 3 -C 7 Cycloalkylene and C 3 -C 7 Heterocycloalkylene is optionally substituted by one or more substituents independently selected from CN, OR 21 , N(R 21 )(R 22 ) and SR 21 and / or on the same carbon atom by C 1-6 alkyl or by C2-6 The alkylene is disubstituted to form a C 3 -C 7 cycloalkyl ring, and wherein the C 3 -C 7 cycloalkylene and C 3 -C 7 heterocycloalkylene are each further optionally substituted by one or more substituents selected from C 1 -C 3 alkyl and C 1 -C 3 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;

[0107] 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 C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 3 -C 7 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 6 alkylene C 3 -C 7 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkylene C 3 -C 7 heterocycloalkyl, substituted or unsubstituted C 1 -C 6 alkylene aryl and substituted or unsubstituted C 1 -C6 Alkylene heteroaryl; and

[0108] R 9’ is independently selected from H and C 1 -C 6 alkyl;

[0109] 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.

[0110] This application includes compounds of formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:

[0111]

[0112] wherein:

[0113] Q is selected from P(O)OR 9 、C 1 -C 4 alkylene-P(O)OR 9 -C 1 -C 6 alkylene, C(O), SO 2 and C(O)Q'C(O);

[0114] R 1 is selected from H, C 1 -C 3 alkyl, C(O)R 10 、CO 2 R 10 、C(O)N(R 10 )(R 11 )、S(O)R 10 and SO 2 R 10 ;

[0115] R 2 、R 3 、R 4 and R 5 are independently selected from H and C 1 -C 6 alkyl;

[0116] R 6 、R 7 and R 8 are independently selected from H, halogen, CN, OR 12 、N(R 12 )(R 13 )、SR 12 、C 1 -C 6 alkyl、C 1 -C6 Halogenoalkyl, C 2 -C 6 Halogenovinyl, CO 2 R 12 、C(O)N(R 12 )(R 13 )、S(O)R 12 、SO 2 R 12 、C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 2 -C 6 Halogenoalkynyl, C 3 -C 7 Cycloalkyl and C 2 -C 14 heterocycloalkyl containing one or two hetero moieties selected from O, S, S(O), SO 3 -C 7 wherein the C 1 -C 6 alkyl, C 1 -C 6 halogenoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 halogenovinyl, C 2 -C 6 alkynyl, C 2 -C 6 halogenoalkynyl, C 3 -C 7 cycloalkyl and C 3 -C 7 heterocycloalkyl is optionally substituted by one or more substituents independently selected from CN, OR 15 、N(R 15 )(R 16 ) and SR 15 and wherein the C 3 -C 7 cycloalkyl and C 3 -C 7 heterocycloalkyl are each further optionally substituted by one or more substituents selected from halogen, CO 2 R 17 、C(O)N(R 17 )(R 18 )、SO 2 R 17 、C 1 -C 6 alkyl, C 1 -C 6 halogenoalkyl, C2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl and C having 1 to 2 hetero moieties selected from O, S, S(O), SO 2 , N and NR 19 and the C 3 -C 6 heterocycloalkyl is substituted,

[0117] Q' is selected from a direct bond, C 1 -C 20 alkylene, C 1 -C 20 haloalkylene, C 2 -C 20 alkenylene, C 2 -C 20 haloalkenylene, C 2 -C 20 alkynylene, C 2 -C 20 haloalkynylene, C 3 -C 7 cycloalkylene and C having 1 to 2 hetero moieties selected from O, S, S(O), SO 2 , N and NR 20 and the C 3 -C 7 heterocycloalkylene, wherein the C 1 -C 20 alkylene, C 2 -C 20 haloalkylene, C 2 -C 6 alkenylene, C 2 -C 20 haloalkenylene, C 3 -C 7 cycloalkylene and C 3 -C 7 heterocycloalkylene is 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 C 3 -C 7a cycloalkyl ring, and wherein said C 3 -C 7 subcycloalkyl and C 3 -C 7 subheterocycloalkyl are each further optionally substituted by one or more substituents selected from C 1 -C 3 alkyl and C 1 -C 3 haloalkyl; and

[0118] 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 C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 3 -C 7 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 6 alkylene C 3 -C 7 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkylene C 3 -C 7 heterocycloalkyl, substituted or unsubstituted C 1 -C 6 alkylene aryl and substituted or unsubstituted C 1 -C 6 alkylene heteroaryl;

[0119] 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.

[0120] In some embodiments, all available hydrogen atoms are optionally replaced by their substitution isotopes. In some embodiments, the substitution isotope of hydrogen is deuterium. Thus, in some embodiments, the compounds of the present application are isotopically enriched in deuterium.

[0121] In some embodiments, R 1 is selected from H, C 1 -C 3 alkyl, C(O)R 10 , CO 2 R 10 and C(O)N(R 10 )(R 11 ), where all available hydrogen atoms are optionally replaced by fluorine atoms or chlorine atoms, and / or all available atoms are optionally replaced by their substitution isotopes. In some embodiments, R 1 is selected from H, C 1 -C 3 alkyl, C(O)R 10 and CO 2 R 10 , where all available hydrogen atoms are optionally replaced by fluorine atoms or chlorine atoms, and / or all available atoms are optionally replaced by their substitution isotopes. In some embodiments, R 1 is selected from H, CH 3 and CH 2 CH 3 , where all available hydrogen atoms are optionally replaced by fluorine atoms or chlorine atoms, and / or all available atoms are optionally replaced by their substitution isotopes. In some embodiments, R 1 is selected from H, CH 3 , CH 2 CH 3 , where all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, R 1 is selected from H, D, F, CH 3 , CD 2 H, CDH 2 , CD 3 , CF 3 , CHF 2 , CFH 2 , CH 2 CH 3 , CH 2 CH 2 , CH 2 CD 2 H and CD 2 CD 3 . In some embodiments, R 1 is independently selected from H, D, F, CH 3 , CD 2H, CDH 2 , CD 3 , CF 3 , CHF 2 , CF 2 H, CH 2 CH 3 , CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 . In some embodiments, R 1 is selected from H, D, CH 3 and CD 3 . In some embodiments, R 1 is selected from H, CH 3 , CH 2 CH 3 , C(O)R 10 and CO 2 R 10 , 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, R 1 is selected from H, CH 3 and CH 2 CH 3 , wherein all available hydrogen atoms are optionally and independently replaced by fluorine or deuterium atoms. In some embodiments, R 1 is selected from H, D, F, CH 3 , CD 2 H, CDH 2 , CD 3 , CF 3 , CHF 2 , CF 2 H, CH 2 CH 3 , CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 . In some embodiments, R 1 is selected from H and D. In some embodiments, R 1 is H. In some embodiments, R 1 is selected from S(O)R 10 and SO 2 R 10 , 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.

[0122] In some embodiments, R 2 , R 3 and R 4 are independently selected from hydrogen and C 1 -C 4 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 and R 4 are independently selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and C(CH 3 ) 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. In some embodiments, R 2 is selected from hydrogen, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and C(CH 3 ) 3 , wherein all available hydrogen atoms are optionally and independently substituted with fluorine or deuterium atoms. In some embodiments, R 2 , R 3 and R 4 are independently selected from H, D, F, CH 3 , CD 2 H, CDH 2 , CD 3 , CF 3 , CHF 2 , CFH 2 , CH 2 CH 3 , CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 . In some embodiments, R 2 is selected from H, D, F, CH 3 , CD 2 H, CDH 2 , CD 3 , CF 3 , CHF 2 , CF 2 H, CH 2 CH3 , CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 . In some embodiments, R 2 is selected from H, D, F, CH 3 , CF 3 , CH 2 CH 3 , CD 2 CD 3 , CF 2 CF 3 , CH(CH 3 ) 2 , CD(CD 3 ) 2 , CF(CF 3 ) 2 , C(CD 3 ) 3 , C(CF 3 ) 3 and C(CH 3 ) 3 . In some embodiments, R 2 is selected from H and D. In some embodiments, R 2 is H.

[0123] In some embodiments, R 3 and R 4 are independently selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and C(CH 3 ) 3 , where all available hydrogen atoms are optionally substituted with fluorine atoms or chlorine atoms, and / or all available hydrogen atoms are optionally substituted with deuterium. In some embodiments, R 3 and R 4 are independently selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and C(CH 3 ) 3 , where all available hydrogen atoms are optionally and independently replaced with fluorine atoms or deuterium atoms. In some embodiments, at least one of R 3 and R 4 is D, or R 3 and R 4At least one of them contains D. In some embodiments, R 3 and R 4 are independently selected from H, D, F, CH 3 , CD 2 H, CDH 2 , CD 3 , CF 3 , CHF 2 , CFH 2 , CH 2 CH 3 , CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 。 In some embodiments, R 3 and R 4 are independently selected from H, D, F, CH 3 , CD 2 H, CDH 2 , CD 3 , CF 3 , CHF 2 , CF 2 H, CH 2 CH 3 , CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 。 In some embodiments, R 3 and R 4 are independently selected from H, D, F, CH 3 , CD 2 H, CDH 2 and CD 3 。 In some embodiments, R 3 and R 4 are independently selected from H, D, F, CH 3 and CD 3 。 In some embodiments, R 3 and R 4 are independently selected from H, D, and F. In some embodiments, at least one of R 3 and R 4 is F. In some embodiments, both R 3 and R 4 are H. In some embodiments, both R 3 and R 4 are F. In some embodiments, R 3 and R4 At least one of them is H. In some embodiments, R 3 and R 4 are both H. In some embodiments, R 3 and R 4 are both D.

[0124] In some embodiments, R 5 is selected from H and C 1 -C 4 alkyl, 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 5 is selected from H and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with fluorine atoms or chlorine atoms, and / or all available hydrogen atoms are optionally substituted with deuterium. In some embodiments, R 5 is selected from hydrogen, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and C(CH 3 ) 3 , wherein all available hydrogen atoms are optionally substituted with fluorine atoms or chlorine atoms, and / or all available hydrogen atoms are optionally substituted with deuterium. In some embodiments, R 5 is selected from H, D, F, CH 3 , CD 2 H, CDH 2 , CD 3 , CF 3 , CHF 2 , CFH 2 , CH 2 CH 3 , CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 . In some embodiments, R 5 is selected from H, D, F, CH 3 , CD 2 H, CDH 2 , CD 3 , CF 3 , CHF 2 , CF 2 H, CH 2 CH 3 , CH 2 CH 2 D, CH2 CD 2 H and CD 2 CD 3 。In some embodiments, R 5 is selected from H, D, CH 3 and CD 3 。In some embodiments, R 5 is selected from H and D. In some embodiments, R 5 is H. In some embodiments, R 5 is selected from CH 3 and CD 3 。In some embodiments, R 5 is CD 3 。

[0125] In some embodiments, R 6 , R 7 and R 8 are independently selected from H, halogen, CN, OR 12 , N(R 12 )(R 13 ), SR 12 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 6 haloalkenyl, CO 2 R 12 , C(O)N(R 12 )(R 13 ), S(O)R 12 , SO 2 R 12 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl and C 2 -C 14 heterocycloalkyl containing one or two hetero moieties selected from O, S, S(O), SO 3 -C 7 wherein the C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6Halogenated alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 halogenated alkynyl, C 3 -C 7 cycloalkyl and C 3 -C 7 heterocycloalkyl is optionally substituted by one or more substituents independently selected from CN, OR 15 , N(R 15 )(R 16 ) and SR 15 , and wherein said C 3 -C 7 cycloalkyl and C 3 -C 7 heterocycloalkyl are each further optionally substituted by one or more substituents selected from halogen, CO 2 R 17 , C(O)N(R 17 )(R 18 ), SO 2 R 17 , C 1 -C 4 alkyl, C 1 -C 4 halogenated alkyl, C 2 -C 6 alkenyl, C 2 -C 6 halogenated alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 halogenated alkynyl, C 3 -C 6 cycloalkyl and C containing 1 to 2 hetero moieties selected from O, S, S(O), SO 2 , N and NR 19 of C 3 -C 6 heterocycloalkyl; 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.

[0126] In some embodiments, R 6 , R 7 and R 8 are independently selected from H, halogen, CN, OR 12 , N(R 12 )(R 13 ), SR 12 , C 1 -C 4 alkyl, C 1 -C4 haloalkyl, C 2 -C 6 haloalkenyl, CO 2 R 12 , C(O)N(R 12 )(R 13 ), S(O)R 12 、SO 2 R 12 、C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C 2 -C 6 haloalkynyl, wherein the C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl and C 2 -C 6 haloalkynyl groups are optionally substituted with one or more substituents independently selected from CN, OR 15 , N(R 15 )(R 16 ) and SR 15 , and 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, 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 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 6 haloalkenyl, CO 2 R 12 , C(O)N(R 12 )(R 13 ), S(O)R 12 , SO 2 R 12 , C 2 -C 6 alkenyl, C2 -C 6 Alkynyl and C 2 -C 6 Halogenated alkynyl, wherein said C 1 -C 4 Alkyl, C 1 -C 4 Halogenated alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Halogenated alkenyl, C 2 -C 6 Alkynyl and C 2 -C 6 The halogenated alkynyl group is 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 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , C 1 -C 4 Halogenated alkyl, C 2 -C 6 Halogenated alkenyl, CO 2 R 12 , S(O)R 12 , SO 2 R 12 , C(O)N(R 12 )(R 13 ), C 2 -C 6 Alkenyl and C 2 -C 6 Alkynyl, wherein said C 1 -C 4 Alkyl, C 1 -C 4 Halogenated alkyl, C 2 -C 6 Alkenyl, C2 -C 6 haloalkenyl and C 2 -C 6 alkynyl groups are optionally substituted with one or two substituents independently selected from CN, OR 15 , N(R 15 )(R 15 ), and SR 2 , 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 15 , R 6 , and R 7 are independently selected from H, F, Cl, Br, CN, OR 8 , N(R 12 )(R 12 ), SR 13 , CH 12 , CH 3 , CH 2 CH 3 , CH(CH 3 ), C(CH 2 ), C(CH 3 ), C 3 -C 1 haloalkyl, C 4 -C 2 haloalkenyl, CO 6 R 2 , S(O)R 12 , SO 12 R 2 , and C 12 -C 2 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 6 , and R 7 are independently selected from hydrogen, F, Cl, Br, and CN. In some embodiments, R 8 , R 6 , and R 7 are independently selected from H, D, F, Cl, Br, and CN. In some embodiments, R 8 , R 6 , and R 7 are independently selected from H and D. In some embodiments, R 8 , R 6 , and R 7 are all H. In some embodiments, R 8 , R 6 , and R 7 and R 8All are D. In some embodiments, R 7 is selected from H, D, F, Cl, Br, and CN, and R 6 and R 8 are each independently 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 each independently selected from H and D. In some embodiments, R 7 is selected from H, F, and CN, and R 6 and R 8 are each independently 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.

[0127] In some embodiments, the C 6 -C 7 -C 8 ring alkyl groups in R 3 -C 7 are each 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.

[0128] In some embodiments, the C 6 -C 7 -C 8 heterocycloalkyl groups in R 3 -C 7 are each independently a saturated or unsaturated heterocycle. In some embodiments, the C 6 -C 7 -C 8 heterocycloalkyl groups in R 3 -C 7 are each independently a saturated or unsaturated bridged bicyclic heterocycle. In some embodiments, the saturated or unsaturated bridged bicyclic heterocycles are each independently selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl, and oxobicycloheptanenyl, 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.

[0129] In some embodiments, the C 6 -C 7 -C 8 in R3 -C 7 The heterocycloalkyl group is independently selected from aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxathiolanyl, thiazolidinyl, isothiazolanyl, 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.

[0130] In some embodiments, Q is selected from P(O)OR 9 、C 1 -C 2 alkylene-P(O)OR 9 -C 1 -C 2 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), 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 、C 1 -C 2 alkylene-P(O)OR 9 -C 1 -C 2 alkylene, C(O), SO 2and 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 C 1 -C 2 alkylene-P(O)OR 9 -C 1 -C 2 alkylene. In some embodiments, Q is C 1 -C 2 alkylene-P(O)OR 9 -C 1 -C 2 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 CH 2 -P(O)OR 9 -CH 2 , 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 SO 2 .

[0131] In some embodiments, Q′ is selected from C 1 -C 10 alkylene, C 2 -C 10 alkenylene and C 2 -C 10 alkynylene, wherein the C 1 -C 10 alkylene, C 2 -C 10 alkenylene and C2 -C 10 The alkynylene group is optionally substituted with one to three substituents independently selected from CN, OR 21 , N(R 21 )(R 22 ), and SR 21 , and / or is disubstituted on the same carbon atom with C 1-6 alkyl or with C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, wherein the C 3 -C 7 cycloalkyl ring is further optionally substituted with a substituent selected from C 1 -C 3 alkyl and C 1 -C 3 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 C 1 -C 6 alkylene, C 2 -C 6 alkenylene, and C 2 -C 6 alkynylene, which are optionally substituted with one or two substituents independently selected from OR 21 and N(R 21 )(R 22 ), and / or is disubstituted on the same carbon atom with C 1-6 alkyl or with C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, wherein the C 3 -C 7 cycloalkyl ring is further optionally substituted with a substituent selected from C 1 -C 3 alkyl and C 1 -C 3 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 C 1 -C 4 alkylene and C 2 -C 4 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 CH 2 、CH 2 CH 2 、CH 2 CH2 CH 2 and CH═CH.

[0132] In some embodiments, when Q is C(O)Q'C(O), Q' is a direct bond. In some embodiments, Q' is a direct bond.

[0133] In some embodiments, Q' is selected from C 3 -C 7 -cycloalkyl and C 2 -heterocyclyl containing one or two heteroatoms independently selected from O, S, S(O), SO 20 , N, and NR 3 -C 7 -heterocyclylalkyl, wherein the C 3 -C 7 -cycloalkyl and C 3 -C 7 -heterocyclylalkyl is optionally substituted with one to three substituents independently selected from CN, OR 21 , N(R 21 )(R 22 ), SR 21 , C 1 -C 3 -alkyl, and C 1 -C 3 -haloalkyl. In some embodiments, the C 3 -C 7 -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.

[0134] In some embodiments, the C 3 -C 7The heterocycloalkyl group is selected from saturated or unsaturated heterocycles. In some embodiments, Q' is selected from aziridinylene, oxiranylene, thiiranylene, oxaxiridinylene, dioxiranylene, azetidinylene, oxetanylene, theitanylene, diazetidinylene, dioxetanylene, dithietanylene, tetrahydrofuranylene, tetrahydrothiophenylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, isoxthiolidinylene, thiazolidinylene, isothiazolidinylene, dioxolanylene, dithiolanylene, piperidinylene, triazolylene, furazanylene, oxadiazolyene, thiadiazolylene, dioxazolylene, dithiazolylene, tetrazolylene, oxatetrazolylene, tetrahydropyranylene, diazinanylene (e.g., piperazinylene), morpholinylene, thiomorpholinylene, dioxanylene, dithianylene, azepanylene, oxepanylene, thiepanylene, and diazepanylene,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.

[0135] 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 C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 4 haloalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 3 -C 7 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 4 alkylene C 3 -C 7 cycloalkyl, substituted or unsubstituted C 1 -C 4 alkylene C 3 -C 7 heterocycloalkyl, substituted or unsubstituted C 1 -C 4 alkylene aryl and substituted or unsubstituted C 1 -C 4 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.

[0136] 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 selected from H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 4 haloalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0137] 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 the C 3 -C 7 cycloalkyl is 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.

[0138] 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 the C 3 -C 7 heterocycloalkyl is independently selected from saturated or unsaturated heterocycles. In some embodiments, each R 9 , R10 , 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 C in 3 -C 7 The heterocycloalkyl is independently selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxathiolanyl, thiazolidinyl, isothiazolyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, diazanyl (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.

[0139] In some embodiments, R 9 and R 10 the C in 3 -C 7 The heterocycloalkyl is independently selected from saturated or unsaturated bridged bicyclic heterocycles. In some embodiments, the saturated or unsaturated bridged bicyclic heterocycles are independently selected from 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, 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 therein are independently selected from azepinyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thioxanyl, thioxane sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothiophenyl, triazolyl and thienyl, 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.

[0141] 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 C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl and substituted or unsubstituted C 1 -C4 A haloalkyl group in which all available hydrogen atoms are optionally substituted by fluorine or chlorine atoms, and / or all available atoms are optionally substituted 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 is independently selected from H, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C 1 -C 4 haloalkyl, in which all available hydrogen atoms are optionally substituted by fluorine or chlorine atoms, and / or all available atoms are optionally substituted 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 is independently selected from H, C 1 -C 4 alkyl and C 2 -C 6 alkenyl, in which all available hydrogen atoms are optionally substituted by fluorine or chlorine atoms, and / or all available atoms are optionally substituted 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 、R21 and R 22 are independently selected from H and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally and independently replaced by 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 and R 22 are independently selected from H, D, CH 3 、CD 2 H、CDH 2 、CD 3 、CF 3 、CHF 2 、CF 2 H、CH 2 CH 2 D、CH 2 CD 2 H、CH 2 CH 3 and CD 2 CD 3 。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 H, D, CH 3 and CD 3 。

[0142] In some embodiments, each R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R18 , R 19 , R 20 , R 21 and R 22 are independently selected from substituted or unsubstituted C 1 -C 4 alkylene C 3 -C 7 cycloalkyl, substituted or unsubstituted C 1 -C 4 alkylene C 3 -C 7 heterocycloalkyl, substituted or unsubstituted C 1 -C 4 alkylene aryl, substituted or unsubstituted C 1 -C 4 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. 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 C 1 -C 4 alkylene aryl and substituted or unsubstituted C 1 -C 4 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. 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 substituted or unsubstituted C 1 -C 4An alkylene aryl, 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. 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 and R 20 is independently a substituted or unsubstituted CH 2 aryl, 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. 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 a substituted or unsubstituted CH 2 phenyl.

[0143] 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 22 is substituted, in some embodiments, the substituents are independently selected from Br, Cl, F, CO 2 H、CO 2 CH 3 、C(O)NH 2 、C(O)N(CH 3 ) 2 、C(O)NHCH 3 、SO 2 CH 3 、C 1-C 4 alkyl, C 1 -C 4 fluoroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 fluoroalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 fluoroalkynyl, C 3 -C 6 cycloalkyl and one or more of 3- to 6-membered heterocycles containing 1 to 2 ring heteroatoms selected from O, S, S(O), SO 2 , N, NH, and NCH 3 . In some embodiments, the substituents on 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 Br, Cl, F, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 fluoroalkenyl, C 2 -C 6 alkynyl, and C 2 -C 6 fluoroalkynyl, one to three. In some embodiments, the substituents on 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 Br, Cl, F, CH 3 , and CF 3 , one or two.

[0144] In some embodiments, R 9’ is selected from H and C 1 -C 4 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 C 1 -C 4 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’ is selected from hydrogen, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and C(CH 3 ) 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, CH 3 , CD 2 H, CDH 2 , CD 3 , CF 3 , CHF 2 , CFH 2 , CH 2 CH 3 , CH 2 CH 2 D, CH 2 CD 2 H, CD 2 CD 3 , CD(CD 3 ) 2 and CH(CH 3 ) 2 . In some embodiments, R 9’ is selected from H, D, CH 3 , CD 3 , CH 2 CH 3 and CH(CH 3 ) 2 . In some embodiments, R 9’ is selected from H, D, CH 3 and CD 3 . In some embodiments, R 9’ is selected from H and D. In some embodiments, R 9’ is selected from CH 3and CD 3 。In some embodiments, R 9’ is CD 3 。In some embodiments, R 9’ is H.

[0145] In some embodiments, Q is P(O)(OH), and the compound of formula I is a compound of formula IA or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof:

[0146]

[0147] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in formula I.

[0148] In some embodiments, Q is CH 2 P(O)(OH)CH 2 , and the compound of formula I is a compound of formula IB or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof:

[0149]

[0150] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in formula I.

[0151] In some embodiments, Q is C(O)-Q'-C(O), and the compound of formula I is a compound of formula IC or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof:

[0152]

[0153] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 and Q' are as defined in formula I.

[0154] In some embodiments, Q is SO 2, and the compound of formula I is a compound of formula ID or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof:

[0155]

[0156] wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 are as defined in formula I.

[0157] In some embodiments, Q is C(O)-Q'-C(O), and the compound of formula I is a compound of formula IE or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof:

[0158]

[0159] wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 and Q' are as defined in formula I.

[0160] In some embodiments, Q is C(O)-Q'-C(O), and the compound of formula I is a compound of formula IF or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof:

[0161]

[0162]

[0163] wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9’ and Q' are as defined in formula I.

[0164] 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.

[0165] Table 1

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172] 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.

[0173] In some embodiments, the compound of Formula I decomposes in vivo to provide an active metabolite. Accordingly, in some embodiments, the present application includes the compound of Formula I and its metabolites. In some embodiments, the present application includes the compound of Formula I or a pharmaceutically acceptable salt, solvate, metabolite, and / or prodrug thereof.

[0174] In some embodiments, the active metabolite is a compound of Formula II:

[0175]

[0176] wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 are as defined above for Formula I, including its embodiments.

[0177] In some embodiments, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. 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. (eds) 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).

[0178] 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 amine 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 monosodium phosphate and potassium bisulfate. 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 (e.g., 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, methanesulfonate (“mesylate”), naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), etc. In some embodiments, mono- or di-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 application for laboratory applications or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0179] 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, picoline, 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. Criteria for the selection of suitable salts 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 sulfate, diethyl sulfate and dibutyl sulfate), 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.

[0180] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the present application, and all acid salts and base salts are considered equivalent to the free form of the corresponding compound for the purposes of the present application. In addition, when the compounds of the present application contain 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 within the term "salt" as used herein. It should be understood that certain compounds of the present application may 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 application.

[0181] Solvates of the compounds of the present application include, for example, solvates made with pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvate being called a hydrate) and ethanol, etc. Suitable solvents are physiologically tolerable at the administered dosage.

[0182] Prodrugs of the compounds of the present application 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 (C 1 -C 24 ) esters, acyloxymethyl esters, carbamates and amino acid esters.

[0183] It should be understood and appreciated that in some embodiments, the compounds of the present application may have at least one chiral center and thus can exist as enantiomers and / or diastereomers. It should be understood that all such isomers and mixtures of any ratio thereof are included within the scope of the present application. It should also be understood that although the stereochemistry of the compounds may be as shown for any given compound listed herein, such compounds may 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 application 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 application.

[0184] In some embodiments, the compounds of the present application may 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 application.

[0185] The compounds of the present application may also exist in various amorphous and polymorphic forms, and any amorphous form, polymorph or mixtures thereof are expected to be included within the scope of the present application.

[0186] The compounds of the present application can also be radiolabeled, and thus all radiolabeled forms of the compounds of the present application are included within the scope of the present application. The compounds of the present application also include those compounds in which one or more radioactive atoms are incorporated into their structures.

[0187] III. Compositions

[0188] The compounds of the present application are suitably formulated into compositions using one or more carriers in a conventional manner. Accordingly, the present application also includes compositions comprising one or more compounds of the present application and a carrier. The compounds of the present application are suitable for formulation into pharmaceutical compositions for administration to a subject in a biocompatible form suitable for in vivo administration. Accordingly, the present application also includes pharmaceutical compositions comprising one or more compounds of the present application and a pharmaceutically acceptable carrier. In an embodiment of the present application, the pharmaceutical composition is for treating any disease, disorder or condition described herein.

[0189] As will be understood by those skilled in the art, the compounds of the present application are administered to a subject in a variety of forms depending on the chosen route of administration. For example, the compounds of the present application are administered by oral, inhalation, parenteral, buccal, sublingual, insufflation, epidural, intranasal, rectal, vaginal, patch, pump, micropump, topical or transdermal administration, 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.

[0190] Parenteral administration includes systemic delivery routes 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.

[0191] In some embodiments, the compounds of the present application 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 compound is mixed with excipients and used in the form of ingestible tablets, lozenges, troches, capsules, caplets, pills, granules, pastilles, 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, a pH-sensitive enteric coating (such as Eudragits TM ) designed to control the release of the active ingredient may be optionally used. Oral dosage forms also include modified-release formulations, such as immediate-release formulations and timed-release formulations. Examples of modified-release formulations include, for example, sustained release (SR), extended release (ER, XR, or XL), time-release or timed-release, controlled release (CR), or continuous release (CR or Contin), e.g., used in the form of coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, agglomerated particles (such as molecular sieve-type particles), or fine hollow permeable fiber bundles or chopped hollow permeable fibers, agglomerated or held in a fiber package. 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 (e.g., cholesterol, stearylamine, or phosphatidylcholine). For oral administration in capsule form, useful carriers, solvents, or diluents include lactose, medium-chain triglycerides, ethanol, and dried corn starch.

[0192] 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 application 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., methylparaben or propylparaben or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0193] The compounds of the present application can also be lyophilized, and the obtained lyophilizates are used, for example, for the preparation of injectable products.

[0194] In some embodiments, the compounds of the present application are administered parenterally. For example, solutions of the compounds of the present application are prepared in water and suitably mixed with surfactants such as hydroxypropyl cellulose. 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 application are usually prepared, and the pH of the solution is suitably adjusted and buffered. For intravenous use, the total concentration of the solute should be controlled to make the formulation isotonic. For ophthalmic administration, for example, an ointment or a droppable liquid is delivered through an ophthalmic delivery system known in the art such as an applicator or an eyedropper. In some embodiments, such compositions include muco-mimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose 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.

[0195] In some embodiments, the compounds of the present application are formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Injectable formulations are, for example, present in unit dosage forms, such as in ampoules or multi-dose containers, and contain 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 application are suitably in the form of sterile powders for reconstitution with a suitable vehicle (such as sterile pyrogen-free water) before use.

[0196] In some embodiments, the compositions for nasal administration are conveniently formulated as aerosols, drops, gels, and powders. For nasal or inhalation administration, the compounds of the present application are conveniently delivered from a pump spray container that is squeezed or pumped by the patient in the form of a solution, dry powder formulation, or suspension, 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 generally present in a sealed container in sterile form in single-dose or multi-dose, such as in the form of a cartridge or refill for use with a nebulizing device. Alternatively, the sealed container is an integral dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser equipped 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, heptafluoropropane, 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, for example, formulated to contain a powder mixture of the compounds of the present application and a suitable powder matrix (such as lactose or starch). The aerosol dosage form can also take the form of a pump nebulizer.

[0197] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and troches, in which the compounds of the present application 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 a conventional suppository base (such as cocoa butter).

[0198] The suppository form of the compounds of the present application can be used for vaginal administration, urethral administration, and rectal administration. Such suppositories are generally 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 cocoa fat), glycerogelatin, other glycerides, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and mixtures of polyethylene glycol fatty acid esters. For further discussion of suppository dosage forms, see, for example: Remington’s Pharmaceutical Sciences, 16th Ed, Mack Publishing, Easton, PA, 1980, pp. 1530-1533.

[0199] In some embodiments, the compounds of the present application are conjugated with soluble polymers as targeted drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymers, poly(hydroxypropyl methacrylamide)-phenol, poly(hydroxyethyl aspartamide)-phenol, or poly(ethylene oxide)-polylysine substituted with palmitoyl residues. In addition, in some embodiments, the compounds of the present application are conjugated with a class of biodegradable polymers that can be used to achieve controlled release of drugs, such 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.

[0200] The compounds of the present application 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 application includes compositions that comprise one or more compounds of the present application and one or more components of a nanocarrier system.

[0201] The compounds of the present application, 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 application (active ingredients) are combined with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will contain from about 0.05 wt% to about 99 wt% or from about 0.10 wt% to about 70 wt% of the active ingredient and from about 1 wt% to about 99.95 wt% or from about 30 wt% to about 99.90 wt% of the pharmaceutically acceptable carrier, all weight percentages being based on the total composition.

[0202] In some embodiments, the compounds of the present application, 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 present application also includes pharmaceutical compositions comprising one or more compounds of the present application 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.

[0203] As used above, the term "compound" also includes embodiments referring to one or more compounds.

[0204] IV. Methods and Uses of the Present Application

[0205] The compounds of the present application are used for treating a disease, disorder or condition by activating serotonin receptors. Accordingly, the compounds of the present application can be used as a medicament. Accordingly, the present application also includes the compounds of the present application for use as a medicament.

[0206] The present application also includes a method for treating a disease, disorder or condition treatable by activating serotonin receptors, the method comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof (i.e., a subject suffering from the disease, disorder or condition).

[0207] The present application also includes the use of one or more compounds of the present application for treating a disease, disorder or condition treatable by activating serotonin receptors, and the use of one or more compounds of the present application for the manufacture of a medicament for treating a disease, disorder or condition treatable by activating serotonin receptors. The present application also includes one or more compounds of the present application for treating a disease, disorder or condition treatable by activating serotonin receptors.

[0208] In some embodiments, the serotonin receptor is 5-HT 2A . Accordingly, the present application includes a method for activating 5-HT in a biological sample or cells in a patient, which comprises administering an effective amount of one or more compounds of the present application to the cells. The present application also includes the use of one or more compounds of the present application for activating 5-HT in cells 2A , and the use of one or more compounds of the present application for the manufacture of a medicament for activating 5-HT in cells 2A . The present application also includes one or more compounds of the present application for activating 5-HT in cells 2A . In some embodiments, the method for activating 5-HT2A is in or on the cells. 2A ​

[0209] The present application also includes methods for treating diseases, disorders or conditions that are treated by activating 5-HT 2A which comprise 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 present application. The present application also includes the use of one or more compounds of the present application for treating diseases, disorders or conditions that are treated by activating 5-HT 2A and the use of one or more compounds of the present application for the preparation of a medicament for treating diseases, disorders or conditions that are treated by activating 5-HT 2A The present application also includes one or more compounds of the present application for treating diseases, disorders or conditions that are treated by activating 5-HT 2A The present application also includes methods for treating diseases, disorders or conditions that are treated by activating 5-HT

[0210] In some embodiments, the compounds of the present application can be used to prevent, treat and / or reduce the severity of mental disease disorders and / or conditions in a subject that are treated by activating 5-HT 2A Accordingly, in some embodiments, the diseases, disorders or conditions that are treated by activating serotonin receptors are mental diseases. Accordingly, the present application also includes methods for treating mental diseases, which comprise administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application. The present application also includes the use of one or more compounds of the present application for treating mental diseases and the use of one or more compounds of the present application for the preparation of a medicament for treating mental diseases. The present application also includes one or more compounds of the present application for treating mental diseases.

[0211] In some embodiments, the mental disorders are selected from anxiety disorders (such as generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia); depressive disorders (such as hopelessness, 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); alcoholism; 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 lead a subject to perform certain rituals or life habits); post-traumatic stress disorder (PTSD); stress response syndromes (formerly called adjustment disorders); dissociative disorders (formerly called multiple personality disorder, or "split personality") and depersonalization disorder; 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.

[0212] In some embodiments, the diseases, disorders, or conditions treatable by activating serotonin receptors include cognitive disorders; ischemia (including stroke); neurodegeneration; refractory substance use disorders; sleep disorders; 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.

[0213] In some embodiments, the mental disorders are selected from hallucinations and delusions and combinations thereof.

[0214] 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.

[0215] In some embodiments, the disease, disorder, or condition treatable by activating serotonin receptors is psychosis or psychotic symptoms. Accordingly, the present application also includes a method of treating psychosis or psychotic symptoms, which comprises administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application.

[0216] The present application also includes the use of one or more compounds of the present application for treating psychosis or psychotic symptoms, and the use of one or more compounds of the present application for preparing a medicament for treating psychosis or psychotic symptoms. The present application also includes one or more compounds of the present application for treating psychosis or psychotic symptoms.

[0217] In some embodiments, administering a therapeutically effective amount of a compound of the present application 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 present application 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 present application to a subject in need thereof results in the improvement of psychosis or psychotic symptoms.

[0218] In some embodiments, the diseases, disorders or conditions treated by activating serotonin receptors are central nervous system (CNS) diseases, disorders or conditions and / or neurological diseases, disorders or conditions. Accordingly, the present application also includes a method for treating CNS diseases, disorders or conditions and / or neurological diseases, disorders or conditions treated by activating serotonin receptors, the method comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof (i.e., a subject suffering from a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition). The present application also includes the use of one or more compounds of the present application for treating CNS diseases, disorders or conditions and / or neurological diseases, disorders or conditions treated by activating serotonin receptors, and the use of one or more compounds of the present application for preparing a medicament for treating CNS diseases, disorders or conditions and / or neurological diseases, disorders or conditions treated by activating serotonin receptors. The present application also includes one or more compounds of the present application for treating CNS diseases, disorders or conditions and / or neurological diseases, disorders or conditions treated by activating serotonin receptors.

[0219] 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; dementia with Lewy bodies; cognitive impairment, Parkinson’s disease, and Parkinson-related diseases (e.g., Parkinson 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; hyperactivity; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette's 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”)); as well as binge eating disorder (“BED”), trichotillomania, dermotillomania, nail biting); migraine; fibromyalgia; and peripheral neuropathy of any etiology, and combinations thereof.

[0220] 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 application are directed to human and veterinary diseases, disorders, and conditions.

[0221] In some embodiments, a “subject in need” is a subject suffering from a disease, disorder, or condition to be treated.

[0222] In some embodiments, the compounds of the present application can be used to treat behavioral problems in feline or canine subjects.

[0223] Accordingly, in some embodiments, the diseases, disorders or conditions treated by activating serotonin receptors are behavioral problems in feline or canine subjects. Accordingly, the present application also includes methods of treating behavioral problems, which methods comprise administering to a non-human subject in need thereof (i.e., a non-human subject having a behavioral problem) a therapeutically effective amount of one or more compounds of the present application. The present application also includes the use of one or more compounds of the present application for treating behavioral problems in non-human subjects, and the use of one or more compounds of the present application for the manufacture of a medicament for treating behavioral problems in non-human subjects. The present application also includes one or more compounds of the present application for treating behavioral problems in non-human subjects.

[0224] In some embodiments, the behavioral problems are selected from, but not limited to, anxiety, fear, stress, sleep disorders, cognitive dysfunction, aggression, excessive noise making, scratching, biting, and combinations thereof.

[0225] In some embodiments, the non-human subject is a canine. In some embodiments, the non-human subject is a feline.

[0226] The present application also includes a method of treating a disease, disorder or condition by activating serotonin receptors, which method comprises administering to a subject in need thereof a therapeutically effective amount of a combination of one or more compounds of the present application and another agent known to be used for treating a disease, disorder or condition by activating serotonin receptors. The present application also includes the use of a combination of one or more compounds of the present application and another agent known to be useful for treating a disease, disorder or condition treated by activating serotonin receptors for treating a disease, disorder or condition by activating serotonin receptors, and the use of a combination of one or more compounds of the present application and another agent known to be useful for treating a disease, disorder or condition treated by activating serotonin receptors for the manufacture of a medicament for treating a disease, disorder or condition treated by activating serotonin receptors. The present application also includes a combination of one or more compounds of the present application and another agent known to be useful for treating a disease, disorder or condition treated by activating serotonin receptors for treating a disease, disorder or condition by activating serotonin receptors.

[0227] In some embodiments, the diseases, disorders or conditions treated by activating serotonin receptors are mental diseases. In some embodiments, the mental diseases are selected from hallucinations and delusions and combinations thereof. In some embodiments, the diseases, disorders or conditions treated by activating serotonin receptors are central nervous system (CNS) disorders. In some embodiments, the diseases, disorders or conditions treated by activating serotonin receptors are psychoses or psychotic symptoms. In some embodiments, the diseases, disorders or conditions treated by activating serotonin receptors are behavioral problems in non-human subjects.

[0228] 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 present application 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 antipsychotics (including typical and atypical antipsychotics); antidepressants (including selective serotonin reuptake inhibitors (SSRI) and selective norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants, monoamine oxidase inhibitors (MAOI) (e.g., bupropion)), GABA A allosteric modulators of receptors (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 anticonvulsants (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 present application 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 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 anticonvulsants (such as carbamazepine, divalproex sodium (valproic acid), lamotrigine, gabapentin, and topiramate)).

[0229] 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 present application are administered in combination with one or more additional treatments for attention deficit hyperactivity disorder and / or attention deficit disorder and combinations thereof. In some embodiments, the additional treatment for attention deficit hyperactivity disorder and / or attention deficit disorder and combinations thereof is selected from methylphenidate, atomoxetine, and amphetamine and combinations thereof.

[0230] 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 present application are administered in combination with one or more additional treatments for dementia or Alzheimer's disease. In some embodiments, the additional treatments for dementia and Alzheimer's disease are selected acetylcholinesterase inhibitors, NMDA antagonists, and muscarinic agonists and antagonists, and nicotinic agonists.

[0231] In some embodiments, the acetylcholinesterase inhibitor is selected from donepezil, galantamine, rivastigmine, and beneserine, and combinations thereof.

[0232] In some embodiments, the NMDA antagonist is selected from MK-801, ketamine, phencyclidine, and memantine, and combinations thereof.

[0233] In some embodiments, the nicotinic agonist is nicotine, niacin, a nicotinic α7 agonist, or an α2β4 agonist, or combinations thereof.

[0234] In some embodiments, the muscarinic agonist is a muscarinic M1 agonist or a muscarinic M4 agonist, or combinations thereof.

[0235] In some embodiments, the muscarinic antagonist is a muscarinic M2 antagonist.

[0236] In some embodiments, the disease, disorder, or condition treated by activating a serotonin receptor is psychosis or psychotic symptoms, and one or more compounds of the present application are administered in combination with one or more additional treatments for psychosis or psychotic symptoms. In some embodiments, the additional treatments for psychosis or psychotic symptoms are selected from typical antipsychotics and atypical antipsychotics.

[0237] 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.

[0238] In some embodiments, the atypical antipsychotic 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.

[0239] In some embodiments, the disease, disorder, or condition treated by activating a serotonin receptor is a mental disease, and one or more compounds of the present application are administered in combination with one or more additional treatments for mental diseases. In some embodiments, the additional treatment for mental diseases is selected from typical antipsychotics and atypical antipsychotics.

[0240] In some embodiments, the effective amount varies according to 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 according to a variety of factors (e.g., the given drug or compound, pharmaceutical formulation, route of administration, disorder, type of disease or condition, identity of the subject to be treated, etc.), but can still be routinely determined by those skilled in the art.

[0241] In some embodiments, the compounds of the present application are administered once, twice, three times, or four times per year. In some embodiments, the compounds of the present application are administered at least once per week. However, in another embodiment, the compounds are administered to the subject at a frequency of approximately 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 various 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 present application, and / or their combination. It should also be understood that the effective dose of the compounds used for treatment can be increased or decreased during the course of a particular treatment regimen. Dose variations can occur and become apparent through standard diagnostic assays known in the art. In some cases, long-term administration is required. For example, the compounds are administered to the subject in an amount and for a duration sufficient to treat the subject.

[0242] In some embodiments, the compounds of the present application are administered at a hallucinogenic or psychotomimetic dose and taken in combination with psychotherapy or therapy, and can be performed once, twice, three times, or four times a year. However, in some embodiments, the compounds are administered to the subject at a non-hallucinogenic or non-psychotomimetic dose 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.

[0243] The compounds of the present application are used alone or in combination with another agent known to be useful for treating a disease, disorder, or condition by activating serotonin receptors (such as the compounds of the present application). 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 present application simultaneously with those agents. As used herein, "simultaneously 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 the 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 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 present application is to administer the combination of agents to the subject in a non-simultaneous manner. In some embodiments, the compounds of the present application and another therapeutic agent are administered simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. Accordingly, the present application provides a single unit dosage form comprising one or more compounds of the present application, an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0244] The dosage of the compounds of the present application varies according to many factors, such as the pharmacodynamic properties of the compounds, the mode of administration, the age, health and weight of the recipient, the nature and severity of the symptoms, the frequency of treatment and the type of concurrent treatment (if any), and the clearance rate of the compounds in the subject to be treated. A person skilled in the art can determine the appropriate dosage based on the above factors. In some embodiments, one or more compounds of the present application are initially administered at an appropriate dosage, which is adjusted as needed based on the clinical response. The dosage is generally selected to maintain the serum level of one or more compounds of the present application at about 0.01 μg / cc to about 1000 μg / cc or 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 application will be in the range of about 10 μg / day to about 1000 mg / day, suitably about 10 μg / day to about 500 mg / day, more suitably about 10 μg / day to about 200 mg / day. For parenteral administration, the representative amount administered is about 0.0001 mg / kg to about 10 mg / kg, about 0.0001 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, or about 0.0001 mg / kg to about 0.01 mg / kg. For oral administration, the representative amount is about 0.001 μg / kg to about 10 mg / kg, about 0.1 μg / kg to about 10 mg / kg, about 0.01 μg / kg to about 1 mg / kg, or about 0.1 μg / kg to about 1 mg / kg. For administration in the form of suppositories, the representative amount is about 0.1 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 1 mg / kg. In some embodiments of the present application, the composition is formulated for oral administration, and one or more compounds are suitably in the form of tablets, each tablet containing 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 5.0 mg, 10.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 40.0 mg, 50.0 mg, 60.0 mg, 70.0 mg, 75.0 mg, 80.0 mg, 90.0 mg, 100.0 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg of the active ingredient (one or more compounds of the present application). In some embodiments of the present application, one or more compounds of the present application are administered at a daily, weekly, or monthly dosage, or the total daily dosage is divided into two, three, or four daily dosages.

[0245] In some embodiments, the compounds of the present application are used or administered in an effective amount, including administering a dose or dosing regimen that does not have clinically significant hallucinogenic / psychomimetic effects. In some embodiments, the compounds of the present application 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 lower and / or a 5-HT 2A clinical effect exhibited by a human CNS receptor occupancy of 40% or lower or a psilocybin Cmax in human plasma of 1 ng / mL or lower and / or a 5-HT 2A clinical effect exhibited by a human CNS receptor occupancy of 30% or lower. In some embodiments, the compounds of the present application 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.

[0246] For clarity, in the above text, the term "compound" also includes embodiments that refer to one or more compounds. Similarly, the term "compounds of the present application" also includes embodiments that refer to only one compound.

[0247] V. Preparation of Compounds

[0248] The compounds of the present application can be prepared by various synthetic methods. The choice of specific structural features and / or substituents may affect the choice of one method over another. The choice of a specific 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 present application 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 present application below, all variables are defined as in formula I, unless otherwise stated.

[0249] In some embodiments of the present application, the compounds of the present application are generally prepared according to the methods described in Schemes I-III.

[0250] 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.

[0251]

[0252] Scheme I

[0253] 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.

[0254] In some embodiments, the compound of formula (I) is prepared as shown in Scheme II, where Q is C 1 -C 4 alkylene - P(O)OR 9 -C 1 -C 6 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.

[0255]

[0256] Scheme II

[0257] 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, pages: 373 - 380, 1969 are used to provide the compound of formula (I).

[0258] 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 from about 0 °C to about room temperature (e.g., from 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.

[0259]

[0260] Scheme III

[0261] In some embodiments, as shown in Scheme III, reaction conditions found, for example, 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).

[0262] In some embodiments, as shown in Scheme III, reaction conditions found, for example, in Gerasimov et al., J. Med. Chem. 1999, 42, 4257 - 4263 and / or Macor et al. J. Med. Chem. 1992, 35, 4503 - 4505 are used to provide the compound of formula (I).

[0263] 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), with the difference that a suitable compound of formula C is used.

[0264] 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 H 2 O), at a suitable temperature (such as upon heating (e.g., greater than about 25 °C)), the compound of formula A is reacted with the compound of formula D (triphosphene) to obtain the compound of formula I.

[0265]

[0266] Scheme IV

[0267] 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.

[0268] In some embodiments, the compound of formula (I) is prepared as shown in Scheme V, where Q is SO 2 . Thus, in the presence of a suitable base (such as cesium carbonate), in a suitable solvent (such as tetrahydrofuran), at a suitable temperature (such as from about reflux to about room temperature (e.g., about 70 °C to about 25 °C)), the compound of formula A is reacted with N,N'-sulfonyldiimidazole D1 and / or using sulfonyl chloride D 2 to obtain the compound of formula I.

[0269]

[0270] Scheme V

[0271] 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 compounds of formula (I).

[0272] In some embodiments, known methods are used, such as using the synthetic procedures found in WO 2 021 / 155467A1 (Mindset Pharma Inc.) to prepare the compounds of formula A.

[0273] Those skilled in the art will understand that further manipulation of the substituents on the intermediates and final compounds in the above schemes can be carried out using known chemistry to provide alternative compounds of the present application.

[0274] The salts of the compounds of the present application can be formed by methods known to those of ordinary skill in the art, for example, by reacting the compounds of the present application with a certain amount of acid or base (e.g., an equivalent amount of acid or base) in a medium (e.g., a medium in which the salt precipitates) or in an aqueous medium, and then lyophilizing.

[0275] 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 usually dried or azeotroped under ambient conditions. Those skilled in the art can select the appropriate conditions for forming a particular solvate. Examples of suitable solvents are ethanol, water, etc. When water is the solvent, the molecule is called a "hydrate". The formation of solvates of the compounds of the present application 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 usually dried or azeotroped under ambient conditions. Those skilled in the art can select the appropriate conditions for forming a particular solvate.

[0276] The isotope-enriched compounds of the present application 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 isotope-enriched reagents and / or intermediates, without undue experimentation.

[0277] Throughout the processes described herein, it should be understood that, where appropriate, suitable protecting groups will be added to the various reactants and intermediates in a manner readily understandable by one of ordinary skill in the art and subsequently removed therefrom. Conventional procedures for the use of 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 should also 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 route towards the final product, where the possible types of conversion 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 by one of ordinary skill in the art. Examples of conversions are given herein, and it should be understood that the conversions described are not limited to the general groups or substituents exemplified as 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 ed McGraw Hill (1992) or “Organic Synthesis”, Smith, McGraw Hill, (1994).

[0278] 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 can be used to prepare the compounds of the present application. In some embodiments, such conditions include combining the reactants in a suitable solvent in the presence of a base.

[0279] 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 by one of ordinary skill in the art.

[0280] Examples

[0281] The following non-limiting examples illustrate the present application.

[0282] A. Synthetic Scheme

[0283] General Method

[0284] All starting materials used herein are commercially available or have been described in the literature. 1 H and 13 C NMR spectra were recorded on a Bruker 300, Bruker DPX 400 or Varian +400 spectrometer, which operates at 1 H NMR at 300 MHz, 400 MHz and 400 MHz respectively. In deuterochloroform as the solvent, unless otherwise stated, TMS or the residual solvent signal was used as the internal reference. All reported chemical shifts are in ppm on the δ scale, and the fine splitting of the signals appearing in the record is usually denoted 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 H NMR data was obtained at 400 MHz using CDCl 3 as the solvent.

[0285] 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.

[0286] Synthesis of Representative Exemplary Compounds of the Present Application

[0287] The following compounds were prepared using one or more of the synthetic methods outlined in Schemes I to III:

[0288]

[0289]

[0290] Example 1: Bis(3 - (((R)-1 - methylpyrrolidin - 2 - yl)methyl)-1H - indol - 4 - yl) glutarate (I - 13)

[0291]

[0292] (R)-2-(2-(4-(Benzyloxy)-1H - indole - 3 - carbonyl)pyrrolidin - 1 - yl)-1 - phenyl - 2l 2 - ethan - 1 - one (8) synthesis:

[0293] At 0 °C, (2 - oxo - 2 - phenyl - 1l2 A solution of (1 - ethyl)-D-proline (1.67 g, 6.71 mmol) in anhydrous THF (20 mL) was treated with thionyl chloride (0.98 mL, 13.434 mmol). The reaction was heated to room temperature and then refluxed for 2 h. The reaction was heated to room temperature, the solvent was evaporated and the crude product was dried under vacuum to obtain the corresponding acid chloride.

[0294] At 5 - 10 °C, a solution of 4-(benzyloxy)-1H-indole (1.5 g, 6.71 mmol) in anhydrous CH 2 Cl 2 (50 mL) was treated simultaneously with a solution of the above crude acid chloride in anhydrous CH 2 Cl 2 (10 mL) and ethylmagnesium bromide (4.48 mL, 13.434 mmol, 3 M in THF) for 15 min. And stirred for an additional 15 min at the same temperature. The reaction was quenched with concentrated HCl (10 mL), followed by water (50 mL), and the product was extracted into CH 2 Cl 2 (2 x 50 mL). The CH 2 Cl 2 layer was washed with saturated NaHCO 3 solution (50 mL), brine (25 mL) and dried (Na 2 SO 4 ). The solvent was evaporated and the crude product was purified by flash column chromatography (CH 2 Cl 2 to EtOAc:CH 2 Cl 2 , 1:4) on silica gel to obtain the title compound 8 as a white foam (1.41 g, 46%). 1 H NMR (CDCl 3 ): δ 9.90, 9.30 (2 s, 1H), 7.72, 7.70 (2 d, 1H, J = 3.0 Hz), 7.54 - 7.02 (m, 12H), 6.59, 6.57 (2 d, 1H, J = 3.0 Hz), 5.59 - 5.55 (m, 1H), 5.32 - 4.96 (m, 4H), 3.67 - 3.60 (m, 1H), 3.50 - 3.30 (m, 1H), 1.90 - 1.50 (m, 4H); ESI-MS (m / z, %): 477 (M + Na, 100), 455 (MH + ).

[0295] Synthesis of (R)-4-(benzyloxy)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (9):

[0296] At 0 °C, a suspension of lithium aluminum hydride (0.63 g, 16.720 mmol) in anhydrous THF (10 mL) was treated with a solution of (R)-2-(2-(4-(benzyloxy)-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2l 2 -ethan-1-one (1.52 g, 3.344 mmol) in anhydrous THF (25 mL) for 10 min. The reaction mixture was warmed to room temperature and then refluxed for 16 h. The reaction mixture was worked up and purified as described for compound 3 to afford the title compound 9 (0.858 g, 80%) as an off-white solid. 1 H NMR (CDCl 3 ): δ 8.07 (s, 1H), 7.52 - 7.29 (m, 5H), 7.07 - 6.91 (m, 3H), 6.58 - 6.55 (m, 1H), 5.25 - 5.17 (m, 2H), 3.51 - 3.44 (m, 1H), 3.08 - 3.03 (m, 1H), 2.62 - 2.50 (m, 2H), 2.15 - 2.10 (m, 1H), 2.08 (s, 3H), 1.68 - 1.57 (m, 4H).

[0297] Synthesis of (R)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-ol (10):

[0298] A solution of (R)-4-(benzyloxy)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (0.87 g, 2.71 mmol) in methanol (25 mL) was treated with 10% palladium on carbon (0.15 g, 10%) and hydrogenated under balloon pressure for 2 h. The reaction mixture was filtered through a Celite pad and washed with methanol (2 x 20 mL). The combined methanol layers were evaporated and the crude product was purified by flash column chromatography (MeOH:CH 3 containing 2M NH 2 Cl 2 , 5:95) on silica gel to afford the title compound 10 (0.52 g, 85%) as an off-white solid. 1 H NMR (DMSO-d 6 ): δ 10.81 (s, 1H), 9.61 (brs, 1H), 7.06 (d, 1H, J = 3.0 Hz), 6.87 - 6.79 (m, 2H), 6.36 (dd, 1H, J = 3.0 Hz), 3.70 - 3.58 (m, 2H), 3.46 - 3.41 (m, 1H), 3.16 - 3.09 (m, 1H), 2.98 - 2.84 (m, 4H), 2.06 - 1.76 (m, 4H); ESI-MS (m / z, %): 231 (MH+ , 100).

[0299] Synthesis of bis(3 - (((R)-1 - methylpyrrolidin - 2 - yl)methyl)-1H - indol - 4 - yl) glutarate (I - 13):

[0300] At 0 °C, a solution of (R)-3 - ((1 - methylpyrrolidin - 2 - yl)methyl)-1H - indol - 4 - ol (1.28 g, 5.59 mmol) in anhydrous THF (50 mL) was treated with Et 3 N (1.41 mL, 10.16 mmol), followed by treatment with a solution of glutaroyl dichloride (0.32 mL, 2.54 mmol) in anhydrous THF (20 mL). The reaction mixture was warmed to room temperature and stirred overnight (16 h). The reaction 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 (Na 2 SO 4 ). The solvent was evaporated and the crude product was purified by flash column chromatography (MeOH:CH 3 containing 2M NH 2 Cl 2 , 5:95 to 1:9) on silica gel to afford the title compound I - 13 as a pale yellow oil (0.42 g, 29.6%). The title compound was converted to the dihydrochloride with a solution of 2M HCl in diethyl ether. 1 H NMR (HCl salt, DMSO - d 6 ): δ 11.31 (s, 2H), 10.85 (s, 2H), 7.33 - 7.27 (m, 4H), 7.11 - 7.06 (m, 2H), 6.81 - 6.74 (m, 2H), 3.63 - 3.59 (m, 3H), 3.42 - 3.31 (m, 3H), 3.12 - 3.02 (m, 6H), 2.81 - 2.73 (m, 6H), 2.52 - 2.48 (m, 2H), 2.16 - 1.71 (m, 10H); ESI - MS (m / z, %): 557 (MH + , 100).

[0301] Example 2: Bis(bis(3 - (((R)-1 - (methyl - d 3 ))pyrrolidin - 2 - yl)methyl - d 2 )) - 1H - indol - 4 - yl) glutarate (I - 22)

[0302]

[0303] (R)-4 - (benzyloxy)-3 - ((1 - (methyl - d3 )(pyrrolidin-2-yl)methyl-d 2 )Synthesis of (R)-3-((1-(methyl-d

[0304] The title compound 12 (0.98 g, 97%) as a white foam was obtained as described for compound 3 from (R)-2-(2-(4-(benzyloxy)-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2l 2 -ethan-1-one (1.41 g, 2.58 mmol). 1 H NMR (DMSO-d 6 ): δ 10.77 (s, 1H), 7.54 - 7.51 (m, 2H), 7.42 - 7.32 (m, 3H), 6.98 - 6.90 (m, 3H), 6.54 - 6.50 (m, 1H), 5.20 - 5.13 (m, 2H), 2.91 - 2.86 (m, 1H), 2.40 - 2.36 (m, 1H), 2.06 - 2.00 (m, 1H), 1.61 - 1.45 (m, 4H); ESI-MS (m / z, %): 326 (MH + , 100).

[0305] (R)-3-((1-(methyl-d 3 )pyrrolidin-2-yl)methyl-d 2 )-1H-indol-4-ol (13):

[0306] A solution of (R)-2-(2-(4-(benzyloxy)-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2l 2 -ethan-1-one (0.95 g, 2.91 mmol) in anhydrous methanol (20 mL) was treated with Pd - C (0.25 g) and hydrogenated for an additional 2 h under a hydrogen atmosphere. The reaction was filtered through a Celite pad and washed with methanol (2 x 15 mL). The combined methanol layers were evaporated and the crude product was purified by flash column chromatography (MeOH:CH 3 containing 2M NH 2 Cl 2 , 5:95) on silica gel to afford the title compound 13 (0.6 g, 87%) as a white foam. 1 H NMR of the TFA salt in DMSO-d 6): δ 10.80 (s, 1H), 9.54 (brs, 1H), 7.11 - 7.06 (m, 1H), 6.87 - 6.79 (m, 2H), 6.37 (d, 1H, J = 3.0 Hz), 3.68 - 3.57 (m, 2H), 3.16 - 3.07 (m, 1H), 2.11 - 1.73 (m, 4H); ESI-MS (m / z, %): 236 (MH + , 100).

[0307] Bis(3 - (((R)-1-(methyl-d 3 )pyrrolidin-2-yl)methyl-d 2 )-1H-indol-4-yl)glutarate (I-22) Synthesis:

[0308] At 0 °C, a solution of (R)-3 - ((1-(methyl-d 3 )pyrrolidin-2-yl)methyl-d 2 )-1H-indol-4-ol (1.38 g, 5.86 mmol) in anhydrous THF (50 mL) was treated with Et 3 N (1.55 mL, 11.16 mmol), followed by treatment with glutaroyl dichloride (0.35 mL, 2.79 mmol) in anhydrous THF (20 mL). 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-13 to afford the title compound I-22 (0.8 g, 50.6%) as a pale yellow oil, which was converted to the dihydrochloride with a solution of 2M HCl in diethyl ether. 1 1H NMR (HCl salt, DMSO-d 6 ): δ 11.31 (s, 2H), 10.80 (s, 2H), 7.33 - 7.27 (m, 4H), 7.11 - 7.07 (m, 2H), 6.81 - 6.74 (m, 2H), 3.64 - 3.56 (m, 3H), 3.42 - 3.37 (m, 2H), 3.12 - 3.02 (m, 3H), 2.52 - 2.48 (m, 2H), 2.13 - 1.75 (m, 10H); ESI-MS (m / z, %): 567 (MH + , 100).

[0309] Use one or more of the synthetic methods outlined in Schemes I to III and Examples 1 and 2 to prepare the following compounds:

[0310]

[0311]

[0312] B. Biological Testing

[0313] Example 3: Human 5-HT2A: Functional FLIPR Assay

[0314] Objective:

[0315] The potential excitatory effects of compounds targeting the human serotonin receptor 2A (5-HT2A) in agonist mode were evaluated.

[0316] 1 Materials and Instruments Used

[0317] 1.1 Cell Line

[0318]

[0319] 1.2 Materials

[0320]

[0321] 1.3 Instruments and Consumables Used

[0322]

[0323] 2 Experimental Methods

[0324] 2.1 Cell Culture

[0325] The HTR2A&Gα15-HEK293 cells were cultured in DMEM medium containing 10% dialyzed FBS, 1× penicillin-streptomycin, 100 μg / mL hygromycin B, and 300 μg / mL G418. The cells were passaged approximately three times a week, maintaining a confluence of approximately 30% to approximately 90%.

[0326] 2.2 Cell Seeding

[0327] 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.

[0328] 2. For induction, add 1 μg / ml tetracycline (final concentration) to the cell culture medium and incubate for 48 hours before seeding the cells into the plate at 37°C, 5% (v / v) CO 2 2. Remove the cell culture medium from the flask. Wash the cells with DPBS.

[0329] 3. Add 2 mL of TrypLE TM Express to the flask, mix well by gentle shaking, and incubate the cells at 37°C for a few minutes.

[0330] 4. Examine the morphological changes of the cells under a microscope. When most cells become round, stop the digestion by adding 4 mL of cell culture medium to the flask.

[0331] 5. Transfer the cell suspension to a 15 mL centrifuge tube and then centrifuge at 1,200 rpm for 5 minutes.

[0332] 6. Remove the supernatant. Resuspend the cell pellet in 2 mL of cell culture medium.

[0333] 7. Use a cell counter to calculate the cell density. Only use cells with a viability > 85% for the assay.

[0334] 8. Dilute the cells with cell culture medium to 6.67×10 5 / mL.

[0335] 9. Add 30 μL / well of the cell suspension to a 384-well cell plate (cell density: 20,000 cells / well).

[0336] 10. Incubate the cell plate overnight at 37 °C, 5% (v / v) CO 2 2.

[0337] 2.3 Cell treatment

[0338] On the day of the experiment, remove the culture medium from the cell plate.

[0339] Add 10 μL of assay buffer (20 mM HEPES in 1×HBSS, pH 7.4) to each well of the cell plate.

[0340] Prepare a 2-fold dye solution according to the user manual of the Calcium 6 Assay Kit:

[0341] i. Dilute the dye with assay buffer.

[0342] ii. Add probenecid to a final concentration of 5 mM.

[0343] iii. Vortex vigorously for 1 - 2 minutes.

[0344] 4. Add 10 μL of the 2-fold dye solution to each well of the cell plate.

[0345] 5. Place the cell plate on a plate shaker and then shake at 600 rpm for 2 minutes.

[0346] 6. Incubate the plate at 37 °C for 2 hours and then at 25 °C for an additional 15 minutes.

[0347] 2.4 Preparation of 3-fold compound

[0348] 1. Prepare serotonin HCl to a concentration of 10 mM with DMSO.

[0349] 2. Prepare the test compound to a concentration of 10 mM with DMSO.

[0350] 3. Add the compound to a 384-well compound source plate.

[0351] 4. Perform 3-fold serial dilution with DMSO.

[0352] 5. Transfer 90 nL / well of the serially diluted compound from the source plate to a 384-well compound plate by using Echo.

[0353] 6. Add 30 μL / well of the assay buffer (20 mM HEPES in 1×HBSS, pH 7.4) to the compound plate.

[0354] 7. Mix the plate on a plate shaker for 2 minutes.

[0355] 2.5 FLIPR Assay

[0356] 1. After the cells are incubated with the dye solution, place the cell plate, the compound plate containing 3-fold compound, and the FLIPR tip in the FLIPR.

[0357] 2. Transfer 10 μL of 3-fold compound from the compound plate to the cell plate by FLIPR.

[0358] 3. Read the plate at 1-second intervals for 160 seconds and obtain agonist mode data.

[0359] 3 Data Analysis

[0360] 1. The calculation of the normalized fluorescence reading (RFU) is as follows, where Fmax and Fmin represent the maximum and minimum values of the calcium signal within a defined time window:

[0361] RFU = Fmax – Fmin

[0362] 2. Use XLfit to calculate the EC by fitting the logarithm of the compound concentration to the RFU with the Hill equation 50 .

[0363] Results and Discussion

[0364] The results of the potential competitive binding properties of the exemplary dimer compounds (I-13 and I-22) of the present application and their corresponding metabolites (10 and 13, see Examples 1 and 2 respectively) targeting human serotonin receptor 2A (5-HT2A) are summarized in Table 2. The results of the exemplary compounds of the present application are provided in Table 2 as shown by IC 50 .

[0365] Table 2: Effects of Exemplary Compounds of Formula I on the Human 5-HT2A Receptor Using FLIPR Functional Assay

[0366] Compound ID# <![CDATA[h5-HT2A, EC 50 [nM]]]> <![CDATA[RFU at 10 μM (1) > Psilocybin <![CDATA[ND (2) > 257 Psilocin 72.5 308 I-13 (Example 1) 32.33 3887 10 (Metabolite of I-13) 47 2929 I-22 (Example 2) 13.06 5409 13 (Metabolite of I-22) 44 3108

[0367] (1) Curve fitting of activation (%) vs. RFU at 10 mM

[0368] (2) ND: Not detected

[0369] Exemplary compounds of Formula I were evaluated using a radioligand binding assay for the human 5-HT2A receptor. The EC 50 (nM) concentrations are shown in Table 2. This assay confirmed that the compounds or metabolites of the present application are effective ligands for the target human 5-HT2A receptor.

[0370] Example 4: Human 5-HT2A: Radioligand Binding Assay

[0371] Objective

[0372] The objective of this study was to evaluate the binding characteristics of exemplary compounds of Formula I to the serotonin receptor 2A (5-HT2A).

[0373] 1 Materials and Instruments Used

[0374] 1.1 Reagents

[0375]

[0376] 1.2 Instruments and Consumables Used

[0377]

[0378]

[0379] 2 Experimental Methods

[0380] 1. Prepare the assay buffer according to the following table.

[0381]

[0382] Adjust the pH to 7.4 and then perform 0.2 μM sterile filtration

[0383] 2. Prepare 8 doses of the reference compound and the test compound by 5-fold serial dilution of 100% (v / v) DMSO starting from a 10 mM stock solution as needed.

[0384] 3. Pretreat the UniFilter-96 GF / B plate:

[0385] 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.

[0386] ii. After incubation, wash the plate three times with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0387] 4. Prepare the assay plate:

[0388] i. Dilute the cell membrane with assay buffer and add 330 μl / well to a 96-well round bottom plate to achieve a concentration of 20 μg / well.

[0389] ii. Prepare eight concentrations of the reference compound or test compound and add 110 μl / well to the 96-well round bottom plate.

[0390] iii. Dilute [3H]-ketanserin with assay buffer to 5 nM (5X final concentration) and add 110 μl / well to the 96-well round bottom plate.

[0391] 5. Centrifuge the plate at 1000 rpm for 30 seconds, then stir at 600 rpm for 5 minutes at room temperature.

[0392] 6. Seal the plate and incubate the plate at 27 °C for 90 min.

[0393] 7. Stop the incubation by vacuum filtration on a GF / B filter plate, then wash four times with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0394] 8. Dry the plate at 37 °C for 45 min.

[0395] 8. Seal the filter plate and add 40 μl / well of scintillation mixture.

[0396] 10. Read the plate using a Microbeta2 microplate counter.

[0397] 3 Data analysis

[0398] 1. For the reference compound and test compound, 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.

[0399] 2. The IC50 is determined by fitting the percent inhibition as a function of compound concentration using the Hill equation with XLfit.

[0400] Results and discussion

[0401] The results of the potential competitive binding properties of the exemplary prodrug compounds I-13 and I-22 of the present application and their corresponding metabolites 10 and 13 targeting the human serotonin receptor 2A (5-HT2A) are summarized in Table 3. The results of the exemplary compounds of the present application are shown as IC 50 as shown.

[0402] Table 3: Effects of Exemplary Compounds of Formula I on the Human 5-HT2A Receptor Using Radioligand Binding Assay

[0403] Compound ID# <![CDATA[h5-HT2A, IC 50 [nM]]]> Psilocybin 4248 Psilocin 187.2 I-13 (Example 1) 37.01 10 (Metabolite of I-13) 218.8 I-22 (Example 2) 44.81 13 (Metabolite of I-22) 219.2

[0404] II. Results and Discussion

[0405] The 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 application or their corresponding metabolites are effective ligands for the target human 5-HT2A receptor.

[0406] Example 5: Human 5-HT1A: Functional FLIPR Assay

[0407] 1 Objectives

[0408] The potential excitatory effects of compounds targeting the serotonin receptor 1A (5-HT1A) in agonist mode were evaluated.

[0409] 2 Materials and Instruments Used

[0410] 2.1 Cell Lines

[0411]

[0412] 2.2 Materials

[0413]

[0414]

[0415] 2.3 Instruments and Consumables Used

[0416]

[0417] 3 Experimental Methods

[0418] 3.1 Cell Culture

[0419] 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%.

[0420] 3.2 Cell seeding

[0421] 1. 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.

[0422] 2. Remove the cell culture medium from the flask. Wash the cells with DPBS.

[0423] 3. Add 1 mL of TrypLE TM Express to the flask, mix well by gentle shaking, and incubate the cells at 37 °C for a few minutes.

[0424] 4. Examine the morphological changes of the cells under the microscope. When most of the cells become round, stop the digestion by adding 2 mL of cell culture medium to the flask.

[0425] 5. Transfer the cell suspension to a 15 mL centrifuge tube and then centrifuge at 1,200 rpm for 5 minutes.

[0426] 6. Remove the supernatant. Resuspend the cell pellet in 2 mL of cell culture medium.

[0427] 7. Use a cell counter to calculate the cell density. Only cells with a viability > 85% are used for the assay.

[0428] 8. Dilute the cells with cell culture medium to 4×10 5 / mL.

[0429] 9. Add 30 μL / well of the cell suspension to a 384-well cell plate (cell density is 12,000 cells / well).

[0430] 10. Incubate the cell plate overnight at 37 °C, 5% (v / v) CO 2 .

[0431] 3.3 Cell treatment

[0432] 1. On the day of the experiment, remove the medium from the cell plate.

[0433] 2. Add 10 μL of the assay buffer (20 mM HEPES, in 1× HBSS, pH 7.4) to each well of the cell plate.

[0434] 3. Prepare according to the manufacturer's instructions for the calcium 6 assay kit to prepare a 2-fold dye solution:

[0435] i. Dilute the dye with the assay buffer.

[0436] ii. Add probenecid to a final concentration of 5 mM.

[0437] iii. Vortex vigorously for 1 - 2 minutes to adjust the pH to 7.4.

[0438] 4. Add 10 μL of the 2-fold dye solution to each well of the cell plate.

[0439] 5. Place the cell plate on a plate shaker and then shake at 600 rpm for 2 minutes.

[0440] 6. Incubate the plate at 37 °C for 2 hours and then at 25 °C for an additional 15 minutes.

[0441] 3.4 Preparation of 3-fold compounds.

[0442] 1. Prepare serotonin at a concentration of 10 mM with DMSO and perform 3-fold serial dilutions with DMSO.

[0443] 2. Prepare the test compound at a concentration of 10 mM with DMSO and perform 3-fold serial dilutions with DMSO.

[0444] 3. Add the compounds to a 384-well compound source plate.

[0445] 4. Transfer 90 nL / well of the serial diluted compounds from the source plate to a 384-well compound plate using an Echo.

[0446] 5. Add 30 μL / well of the assay buffer to the compound plate.

[0447] 6. Mix the plate on a plate shaker for 2 minutes.

[0448] 3.5 FLIPR assay

[0449] 1. After the cells are incubated with the dye solution, place the cell plate, the compound plate containing 3-fold compounds, and the FLIPR tip in the FLIPR.

[0450] 2. Transfer 10 μL of the 3-fold compounds from the compound plate to the cell plate via the FLIPR.

[0451] 3. Read the plate at 1-second intervals for 160 seconds to obtain agonist mode data.

[0452] 4 Data analysis

[0453] 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 a defined time window:

[0454] RFU = Fmax – Fmin

[0455] 2. Using XLfit, the EC is calculated by fitting the logarithm of the compound concentration against the RFU with the Hill equation 50 .

[0456] Results and Discussion

[0457] The results of the potential competitive binding properties of the exemplary prodrug compounds (I-13 and I-22) of the present application and their corresponding metabolites (10 and 13) targeting the human 5-hydroxytryptamine receptor 1A (5-HT1A) are summarized in Table 4. The results of the exemplary compounds of the present application are as shown by the EC 50 shown.

[0458] Table 4: Effects of exemplary compounds of Formula I on the human 5-HT1A receptor using the FLIPR functional assay

[0459] Compound ID# <![CDATA[h5-HT1A, EC 50 [nM]]]> <![CDATA[RFU at 10 μM (1) > Psilocybin <![CDATA[ND (2) > 143 Psilocin ND 140 I-13 (Example 1) ND 87 10 (Metabolite of I-13) ND 425 I-22 (Example 2) ND 130 13 (Metabolite of I-22) ND 307

[0460] (1) Curve fitting of activation (%) at 10 mM against RFU

[0461] (2) Not detected

[0462] The exemplary compounds of Formula I were evaluated using a functional FLIPR assay for the human 5-HT1A receptor. The EC 50 (nM) concentrations are shown in Table 4. This assay confirmed that the compounds or metabolites of the present application have moderate functional activity at the target human 5-HT1A receptor.

[0463] Example 6: Human 5-HT1A: Radioactive Ligand Binding Assay:

[0464] 1 Objective

[0465] The objective of this study was to evaluate the binding properties of the test compounds to the 5-hydroxytryptamine receptor 1A (5-HT1A).

[0466] 2 Materials and Instruments Used

[0467] 2.1 Reagents

[0468]

[0469] 2.2 Instruments and Consumables Used

[0470]

[0471] 3 Experimental methods

[0472] 1. Prepare the assay buffer according to the following table.

[0473]

[0474] Adjust the pH to 7.4, and then perform 0.2 μM sterile filtration.

[0475] 2. Prepare 8 doses of the reference compound and the test compound by 5-fold serial dilution of 100% (v / v) DMSO starting from a 10 mM stock solution as needed.

[0476] 3. Pretreat the UniFilter-96 GF / B plate:

[0477] 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.

[0478] ii. After incubation, wash the plate 3 times with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0479] 4. Prepare the assay plate:

[0480] i. Dilute the cell membrane with the assay buffer and add it to a 96-well round-bottom plate at 100 μl / well to reach a concentration of 20 μg / well.

[0481] ii. Prepare 8 concentrations of the reference compound or the test compound and add them to a 96-well round-bottom deep-well plate at 50 μl / well.

[0482] iii. Dilute [3H]-8-hydroxy-DPAT with the assay buffer to 2 nM (4X final concentration) and add it to a 96-well round-bottom plate at 50 μl / well.

[0483] 5. Centrifuge the plate at 1000 rpm for 30 seconds, and then stir at 600 rpm at room temperature for 5 minutes.

[0484] 6. Seal the plate and incubate the plate at 27 °C for 90 min.

[0485] 7. Stop the incubation by vacuum filtration on the GF / B filter plate, and then wash 4 times with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0486] 8. Dry the plate at 37 °C for 45 min.

[0487] 9. Seal the filter plate and add 40 μl / well of scintillation mixture.

[0488] 10. Read the plate using a Microbeta2 microplate counter.

[0489] 4 Data analysis

[0490] 1. For reference compounds 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.

[0491] 2. IC 50 Determined by fitting the percent inhibition as a function of compound concentration to the Hill equation using XLfit.

[0492] Results and discussion

[0493] The results of the potential competitive binding properties of the exemplary prodrug compounds I-13 and I-22 of the present application and their corresponding metabolites 10 and 13 targeting the human serotonin receptor (5-HT1A) are summarized in Table 5. The results of the exemplary compounds of the present application are shown as IC 50 as shown.

[0494] Table 5: Effects of exemplary compounds of formula I on the human 5-HT1A receptor using radioligand binding assay

[0495] Compound ID# <![CDATA[h5-HT1A, IC 50 [nM]]]> Psilocybin 4785 Psilocin 195.7 I-13 (Example 1) 153.6 10 (Metabolite of I-13) 148 I-22 (Example 2) 123.9 13 (Metabolite of I-22) 156

[0496] Results and discussion

[0497] The exemplary compounds of formula I and their metabolites were evaluated using a radioligand binding assay for the human 5-HT1A receptor. The IC50 (nM) concentrations are shown in Table 5. This assay confirmed that the precursor parent compounds of the present application or their corresponding metabolites are effective ligands for the target human 5-HT1A receptor.

[0498] Example 7: Human, rat, and mouse liver microsome stability

[0499] Objective

[0500] The objective of this study was to evaluate the in vitro metabolic stability of the exemplary compounds of the present application 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 to assess the stability in pooled human, male rat, and male mouse liver microsomes. The in vitro intrinsic clearance of the test compounds was also determined.

[0501] Protocol

[0502] Prepare the stock solution in an "incubation plate" containing phosphate buffer, ultrapure H 2 O, MgCl2 solution, and liver microsomes. Preheat the mixture in a 37 °C water bath for 5 minutes.

[0503] Table 6: Preparation of Stock Solution

[0504]

[0505]

[0506] Add 40 μL of 10 mM NADPH solution to each well. The final concentration of NADPH is 1 mM. Prepare negative control samples by replacing NADPH with 40 μL of ultrapure H 2 O. Samples are prepared in duplicate. Negative controls are prepared as single aliquots.

[0507] At the start of the reaction, add 4 μL of 200 μM exemplary test compound or control compound of the present application to each stock solution to obtain a final concentration of 2 μM. This study is conducted in duplicate.

[0508] At 0 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes, remove 50 μL aliquots from the reaction solution. 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 3,220 g for 40 minutes. Mix 90 μL aliquots of the supernatant with 90 μL of ultrapure H 2 O and then use for LC-MS / MS analysis.

[0509] Perform LC / MS analysis on all samples of this study using a Shimadzu liquid chromatography separation system equipped with a degasser DGU-20A5R; solvent delivery device LC-30AD; system controller SIL-30AC; column oven CTO-30A; CTC analysis HTC PAL system. Perform mass spectrometry analysis using a Triple QuadTM 5500 instrument.

[0510] All calculations are performed using Microsoft Excel. The peak area ratio of the test compound to the internal standard (listed in the table below) is determined from the extracted ion chromatogram.

[0511] All calculations are performed using Microsoft Excel. Determine the peak area from the extracted ion chromatogram. The slope value k is determined by linear regression of the natural logarithm of the percentage of parent drug remaining versus incubation time curve.

[0512] The in vitro half-life (in vitro t1 / 2) is determined from the slope value:

[0513] in vitro t 1 / 2 = -(0.693 / k)

[0514] The in vitro t1 / 2 (min) was converted to in vitro intrinsic clearance (in vitro CLint, in μL / min / mg protein) using the following equation (average of two determinations):

[0515]

[0516] For the exemplary compounds or control compounds of the present application that show an initial rapid disappearance followed by a slow disappearance, only the time points within the initial rate were included in the calculation.

[0517] Results and Discussion

[0518] 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 are used to examine potential first-pass metabolism by-products of orally administered drugs. The stability of the exemplary compounds of the present application in human, rat, and mouse liver microsomes was evaluated. In the three species, human, rat, and mouse liver microsomes, most of the exemplary compounds of the present application 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).

[0519] Table 7: Metabolic stability of exemplary dimer compounds of Formula I (I-13 and I-22) and control compounds diclofenac and psilocybin in humans, rats, and mice with NADPH

[0520]

[0521]

[0522] * If the remaining percentage at 30 minutes is less than 1%, CLint and t1 / 2 are reported as ">307.01" and "<4.51", respectively. Table 8: Metabolic stability of exemplary dimer compounds of Formula I (I-13 and I-22) and control compounds diclofenac and psilocybin in human, rat, and mouse liver microsomes

[0523]

[0524] (1) Not tested

[0525] Discussion:

[0526] The results indicate that the exemplary compounds (I-13 and I-22) were rapidly metabolized.

[0527] Example 8: Humans, Rats, Mice, and Dogs: Plasma Stability

[0528] 1. Preparation of stock solutions

[0529] Stock solutions of the test compounds were prepared in DMSO and diluted to a final concentration of 200 μM. 1 mM working solutions of lovastatin and propantheline were prepared in DMSO and acetonitrile, respectively. Lovastatin was used as a positive control for rat and dog plasma stability assays. Propantheline was used as a positive control for human, mouse, and monkey plasma stability assays.

[0530] 2. Plasma stability procedures

[0531] 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.

[0532] b. The reaction samples were incubated in a water bath at approximately 60 rpm at 37 °C.

[0533] 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).

[0534] d. All samples were vortexed for 2 minutes and then centrifuged at 3,220 g for 30 minutes to precipitate proteins. 100 μL of the supernatant was transferred to a new plate. The supernatant was diluted with ultrapure water according to the LC-MS signal response and peak shape.

[0535] 3. Sample analysis

[0536] The samples were analyzed by LC-MS / MS.

[0537] · LC system: Shimadzu

[0538] · MS analysis: Triple QuadTM 6500+ with ESI interface from AB Inc (Canada)

[0539] · Column temperature: 40 °C

[0540] · Column: Hss T3 2.5 μ (2.1 × 30 mm) coupled with a preguard column Hss T3 2.5 μ(2.1×30mm)

[0541] · Mobile phase: Aqueous solution of 0.1% formic acid (A) and acetonitrile solution of 0.1% formic acid (B)

[0542]

[0543] 4. Data analysis

[0544] 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.

[0545] Table 9. Stability results of exemplary compounds in plasma of different species

[0546]

[0547] 1. If no peak was detected at 30 min, the T1 / 2 was reported as "N.A.".

[0548] 2. For compounds showing an initial rapid disappearance followed by a slow disappearance, only the time points within the initial rate were included in the calculation.

[0549] Example 9: Intestinal mucosal permeability of the exemplary compounds of the present application and their metabolites using Caco-2 cell monolayers

[0550] 1. Cell seeding preparation

[0551] 1) The Caco-2 cell medium was prepared by composing Dulbecco's Modified Eagle's Medium (DMEM) containing high glucose and L-glutamine supplemented with 10% FBS, 1× penicillin-streptomycin mixture, and 1× non-essential amino acids (NEAA).

[0552] 2) 50 μL of the medium was added to each well of the Transwell insert. The Transwell insert was taken out from the reservoir and 25 mL of the medium was added.

[0553] 3) Incubate at 37 °C, 5% CO 2 for 1 hour. The plate was prepared for cell seeding.

[0554] 4) The cells were cultured in a T-75 flask in a cell culture incubator set at 37 °C, 5% CO 2 , 95% relative humidity. The cells were allowed to reach 80%-90% confluence before dissociation and splitting.

[0555] 5) Rinse the cultured cells in a T-75 flask with 5 mL of PBS. Aspirate the cells, then 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.

[0556] 6) Transfer the cell suspension to a conical tube and pellet the cells by centrifugation at 120 × g for 10 minutes.

[0557] 7) Resuspend the cells at a density of 6.86 × 10 5 cells / mL in seeding medium. This cell concentration is used to seed 2.40 × 10 5 cells / cm 2 .

[0558] 2. Seeding and Culturing of Caco-2 Cells in Transwell Plates

[0559] 1) Add 50 μL of the above cell suspension to each well of a pre-prepared Transwell plate.

[0560] 2) Incubate the plate for 14 - 18 days. The medium is changed every other day, starting no earlier than 48 hours after initial seeding.

[0561] 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 bottle tray. Return the plate to the incubator.

[0562] 3. Assessment of Cell Monolayer Integrity

[0563] 1) When the 14-day-old Caco-2 cultured cells reach confluence and differentiation, they are ready for transport studies.

[0564] 2) Remove the medium from the storage bottle and the Transwell insert.

[0565] 3) Add 75 μL of pre-warmed medium to each Transwell insert and 25 mL to the storage bottle tray.

[0566] 4) Measure the electrical resistance across the monolayer using an automated tissue resistance measurement system (World Precision Instruments, Sarasota, FL).

[0567] 5) Record the electrical resistance of each well.

[0568] 6) Once all the wells have been measured, place the plate back into the incubator.

[0569] 7) The TEER for each well is calculated using the equation below. The TEER value for each well should be greater than 230 ohms·cm 2 .

[0570] TEER measurement (ohms) × membrane area (cm 2 ) = TEER value (ohm·cm 2 )

[0571] 4. Conduct drug transport assays

[0572] 1) Remove the Caco-2 plate from the incubator. Next, wash the monolayer and exchange the volume twice with pre-warmed HBSS (10 mM HEPES, pH 7.4). Then incubate the plate at 37 °C for 30 minutes.

[0573] 2) 1 mM stock solutions of the control compound and the test compound are prepared in DMSO and diluted 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.

[0574] 3) After pre-incubation for 30 minutes, remove the HBSS (10 mM HEPES, pH 7.4).

[0575] 4) To determine the drug transport rate in the apical-to-basolateral direction: Add 75 μL of the control compound and the test compound to the Transwell insert (apical compartment). Fill the wells in the receiver plate (basolateral compartment) with 235 μL of HBSS (10 mM HEPES, pH 7.4).

[0576] 5) To determine the drug transport rate in the basolateral-to-apical direction: Add 235 μL of the control compound and the test compound to the wells in the receiver plate (basolateral compartment). Fill the Transwell insert (apical compartment) with 75 μL of HBSS (10 mM HEPES, pH 7.4).

[0577] 6) Prepare samples at 0 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).

[0578] 7) Incubate at 37 °C for 2 hours.

[0579] 8) At the end of the transport period, 50 μL of the sample was 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. Vortex for 5 minutes. Centrifuge the sample at 3,220 g for 40 minutes. Mix an aliquot of 100 μL of the supernatant with 100 μL of ultrapure water for LC-MS / MS analysis. All incubations were performed in duplicate.

[0580] 9) Discard the solution from the transwell plate. Add 100 μL of Lucifer Yellow solution (100 μM in HBSS solution) to each well of the transwell insert, and add 300 μL of HBSS to each well of the receiver. Incubate at 37 °C for 30 minutes. Remove 80 μL from each well on the apical side and the basolateral side to a solid black plate. Read the plate with a Tecan InfiniteTM M 200 (excitation / emission wavelength 485 nM / 530 nM).

[0581] Results and Discussion

[0582] The Papp(A→B) and Papp(B→A) values of Compound 10 (a metabolite of I-13) were 23.20 cm / s × 10 -6 and 18.75 cm / s × 10 -6 , respectively, and the corresponding efflux ratio was 0.81. The permeability results of Compound 10 in the Caco-2 cell monolayer are listed in Table 10.

[0583] The results indicate that the exemplary dimer compounds of Formula I and their corresponding metabolites are highly permeable compounds and are unlikely to be substrates of efflux transporters.

[0584] Table 10: Permeability Results of Representative Compounds of Formula I and Their Corresponding Metabolites in the Caco-2 Cell Monolayer (Mean, n = 2)

[0585]

[0586] *Values represent the mean of n = 3

[0587] **Not tested

[0588] Table 11: Evaluation of Caco-2 Cell Monolayer Integrity

[0589]

[0590] *Values represent the mean of n = 3

[0591] Although the present application 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 therein, but rather should be given the broadest interpretation consistent with the overall description.

[0592] All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications are incorporated into the present application by reference so as to more fully describe the prior art as known to those of ordinary skill 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 , C 1 -C 4 alkylene-P(O)OR 9 -C 1 -C 6 alkylene, C(O), S(O) 2 , 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, C 1 -C 3 alkyl, C(O)R 10 , CO 2 R 10 , C(O)N(R 10 )(R 11 ), S(O)R 10 and SO 2 R 10 ; R 2 、R 3 、R 4 and R 5 are independently selected from H and C 1 -C 6 alkyl; R 6 , R 7 and R 8 are independently selected from H, halogen, CN, OR 12 、N(R 12 )(R 13 ), SR 12 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Halogenated olefins, CO 2 R 12 、C(O)N(R 12 )(R 13 )、S(O)R 12 、SO 2 R 12 , C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 2 -C 6 Haloalkynyl, C 3 -C 7 Cycloalkyl and containing 1 to 2 selected from O, S, S(O), SO 2 , N and NR 14 C 3 -C 7 Heterocycloalkyl, wherein the C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Halogenated alkenyl, C 2 -C 6 Alkynyl, C 2 -C 6 Haloalkynyl, C 3 -C 7 Cycloalkyl and C 3 -C 7 Heterocycloalkyl is optionally substituted by one or more independently selected from CN, OR 15 、N(R 15 )(R 16 ) and SR 15 Substituents, and wherein the C 3 -C 7 Cycloalkyl and C 3 -C 7 The heterocycloalkyl groups are each further optionally substituted by one or more substituents selected from halogen, CO 2 R 17 、C(O)N(R 17 )(R 18 )、SO 2 R 17 、C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl and C 2 -C 19 heterocycloalkyl containing one or two hetero moieties selected from O, S, S(O), SO 3 、N and NR 6 ; Q' is selected from a direct bond, C 1 -C 20 alkylene, C 1 -C 20 haloalkylene, C 2 -C 20 alkenylene, C 2 -C 20 haloalkenylene, C 2 -C 20 alkynylene, C 2 -C 20 haloalkynylene, C 3 -C 7 cycloalkylene and C containing 1 to 2 hetero moieties selected from O, S, S(O), SO 2 , N and NR 20 heterocycloalkylene, where the C 3 -C 7 alkylene, C 1 -C 20 haloalkylene, C 2 -C 20 alkenylene, C 2 -C 6 haloalkenylene, C 2 -C 20 cycloalkylene and C 3 -C 7 heterocycloalkylene is optionally substituted by one or more substituents independently selected from CN, OR 3 -C 7 , N(R 21 )(R 21 )(R 22 ) and SR 21 , and / or is disubstituted on the same carbon atom by C 1-6 alkyl or by C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, and where the C 3 -C 7 cycloalkylene and C 3 -C 7 heterocycloalkylene are each further optionally substituted by one or more substituents selected from C 1 -C 3 alkyl and C 1 -C 3 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; 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 H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 3 -C 7 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 6 alkylene C 3 -C 7 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkylene C 3 -C 7 heterocycloalkyl, substituted or unsubstituted C 1 -C 6 alkylene aryl and substituted or unsubstituted C 1 -C 6 alkylene heteroaryl; and R 9’ independently selected from H and C 1 -C 6 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.

2. The compound according to claim 1, wherein R 1 is selected from H, C 1 -C 3 alkyl, C(O)R 10 , CO 2 R 10 and C(O)N(R 10 )(R 11 ), wherein all available hydrogen atoms are optionally substituted with fluorine or chlorine atoms, 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, CH 3 and CH 2 CH 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.

4. The compound according to claim 3, wherein R 1 is independently selected from H, D, F, CH 3 , CD 2 H, CDH 2 , CD 3 , CF 3 , CHF 2 , CF 2 H, CH 2 CH 3 , CH 2 CH 2 , CH 2 CD 2 H and CD 2 CD 3 .

5. The compound according to claim 4, wherein in some embodiments, R 1 is selected from H, D, CH 3 and CD 3 .

6. The compound according to any one of claims 1 to 5, wherein R 2 , R 3 and R 4 are independently selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and C(CH 3 ) 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, CH 3 , CD 2 H, CDH 2 , CD 3 , CF 3 , CHF 2 , CF 2 H, CH 2 CH 3 CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 .

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 and R 4 are independently selected from H, D, F, CH 3 , CD 2 H, CDH 2 , CD 3 , CF 3 , CHF 2 , CFH 2 , CH 2 CH 3 , CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 .

10. The compound according to claim 9, wherein R 3 and R 4 are independently selected from H, D, F, CH 3 and CD 3 .

11. The compound according to any one of claims 1 to 10, wherein R 5 is selected from H, D, F, CH 3 , CD 2 H, CDH 2 , CD 3 , CF 3 , CHF 2 , CFH 2 , CH 2 CH 3 , CH 2 CH 2 , D, CH 2 , CD 2 H and CD 2 , CD 3 .

12. The compound according to claim 11, wherein R 5 is selected from H, D, CH 3 and CD 3 .

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 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 6 haloalkenyl, CO 2 R 12 , C(O)N(R 12 )(R 13 ), S(O)R 12 , SO 2 R 12 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C 2 -C 6 haloalkynyl, wherein the C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl and C 2 -C 6 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.

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 C 1 -C 2 -alkylene-P(O)OR 9 -C 1 -C 2 -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 CH 2 -P(O)OR 9 -CH 2 , where 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 C 1 -C 10 alkylene, C 2 -C 10 alkenylene and C 2 -C 10 alkynylene, wherein the C 1 -C 10 alkylene, C 2 -C 10 alkenylene and C 2 -C 10 alkynylene is optionally substituted by one to three substituents independently selected from CN, OR 21 , N(R 21 )(R 22 ) and SR 21 , and / or is disubstituted on the same carbon atom by C 1-6 alkyl or by C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, wherein the C 3 -C 7 cycloalkyl is further optionally substituted by substituents selected from C 1 -C 3 alkyl and C 1 -C 3 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 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, which are optionally substituted by one or two substituents independently selected from OR 21 and N(R 21 )(R 22 ), and / or disubstituted on the same carbon atom by C 1-6 alkyl or by C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, wherein the C 3 -C 7 cycloalkyl ring is further optionally substituted by substituents selected from C 1 -C 3 alkyl and C 1 -C 3 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 C 1 -C 4 alkylene and C 2 -C 4 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 C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 4 haloalkyl, substituted or unsubstituted C 3 -C 7 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 C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl and substituted or unsubstituted C 1 -C 4 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.

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, CH 3 、CD 2 H、CDH 2 、CD 3 、CF 3 、CHF 2 、CF 2 H、CH 2 CH 2 D、CH 2 CD 2 H、CH 2 CH 3 and CD 2 CD 3 。 25. The compound according to any one of claims 1 to 24, wherein R 9’ is selected from H and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted by fluorine atoms or chlorine atoms, and / or all available hydrogen atoms are optionally substituted by deuterium.

26. The compound according to claim 1, which is selected from: Or their pharmaceutically acceptable salts, solvates, and / or prodrugs.

27. A pharmaceutical composition comprising one or more compounds according to 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, the method comprising administering to a subject suffering from the disease, disorder, or condition a therapeutically effective amount of one or more compounds according to any one of claims 1 to 26 or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

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