3-Pyrrolidine indole derivatives as serotonergic hallucinogens for the treatment of central nervous system disorders

Abstract

The present application relates to 3-cyclic amine-indole derivatives of general formula (I), processes for preparing them, compositions containing them, and their use in activating serotonin receptors in cells, as well as to treating diseases, disorders, or conditions caused by activation of serotonin receptors in cells, including, for example, psychoses, psychiatric disorders, and other neurological diseases, disorders, and conditions. JPEG2023512821000102.jpg81106

Description

[Technical Field]

[0001] The present application relates to 3-pyrrolidine indole derivatives of general formula (I) for the treatment of various conditions, such as psychiatric disorders and other neurological diseases, disorders, and conditions, which are treated by activation of serotonin receptors in the fields of psychiatry, neurobiology, and pharmacotherapy. The present application further includes methods for making compounds of formula (I) and corresponding intermediates. [Background technology]

[0002] This application claims the benefit of priority from co-pending U.S. Provisional Patent Application No. 62 / 969,894, filed February 4, 2020, the contents of which are incorporated herein by reference in their entirety.

[0003] Mental health disorders, or mental illnesses, refer to a wide range of disorders, including, but not limited to, depressive disorders, anxiety and panic disorders, schizophrenia, eating disorders, substance misuse disorders, post-traumatic stress disorder, attention-deficit / hyperactivity disorder, and obsessive-compulsive disorder. Symptom severity varies, with some individuals experiencing debilitating illnesses that prevent normal social functioning, while others suffer intermittent, recurring episodes throughout their lifespan. While the symptoms and diagnostic criteria among various psychiatric conditions are partially distinct, there are notable endophenotypes shared among these disorders, and comorbidities often exist. Specifically, there are phenotypic endophenotypes associated with alterations in mood, cognition, and behavior. Interestingly, many of these endophenotypes extend to neurological conditions. For example, attention deficits have been reported in patients with attention deficit disorder, attention deficit hyperactivity disorder, eating disorders, substance misuse disorders, schizophrenia, depression, obsessive-compulsive disorder, traumatic brain injury, fragile X, Alzheimer's disease, Parkinson's disease, and frontotemporal dementia.

[0004] Many mental health disorders and neurological disorders are influenced by alterations, dysfunction, degeneration, and / or damage to the brain's serotonergic system, which may partially explain the common phenotypes and comorbidities among various neuropsychiatric and neurological disorders. Numerous therapeutic agents that modulate serotonergic function are commercially available, including serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, antidepressants, and monoamine oxidase inhibitors. While these therapeutic agents were primarily developed for depressive disorders, many of these therapeutic agents are used across a wide range of medical indications, including, but not limited to, depression in Alzheimer's disease and other neurodegenerative diseases, chronic pain, existential pain, bipolar disorder, obsessive-compulsive disorder, anxiety disorders, and smoking cessation. However, in many cases, commercially available medications offer limited benefit over placebo, require six weeks for some patients to return to work, and are associated with several side effects, including sleep disorders, drowsiness, fatigue, weakness, changes in blood pressure, memory impairment, digestive disorders, weight gain, and sexual problems.

[0005] The field of hallucinogen neuroscience has undergone a recent renaissance after centuries of limited research due to its legal status. Hallucinogens are the oldest class of psychopharmacological agents known to mankind and cannot be fully understood without reference to various fields of study, including anthropology, ethnopharmacology, psychiatry, psychology, sociology, and others. Hallucinogens (serotonergic hallucinogens) are potent psychoactive substances that alter perception and mood and affect many cognitive processes. Hallucinogens are generally considered physiologically safe and do not lead to dependence or addiction. The origins of hallucinogens predate documented history, with their use by early cultures in many sociocultural and ritual contexts. Following the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD) and the identification of serotonin in the brain, early research strongly emphasized the possibility that LSD and other hallucinogens may have a serotonergic basis for their action. The current consensus is that hallucinogens are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A (5-HT2A) receptors, most importantly those expressed on the apical dendrites of neocortical pyramidal cells in layer V, but also bind with lower affinity to other receptors, such as sigma-1 receptors. Several useful rodent models have been developed over the years to help elucidate the neurochemical correlates of serotonin 5-HT2A receptor activation in the brain, and various imaging techniques have been used to identify key brain regions directly affected by hallucinogens.

[0006] Psychedelics have both a rapid onset of action and persistent effects long after their acute impact, including changes in mood and brain function. These long-lasting effects may be due to their unique receptor affinity, which influences neurotransmission through neuromodulatory systems that regulate brain activity (neuroplasticity), promoting cell survival, being neuroprotective, and modulating the neuroimmune system. The mechanisms leading to these long-term neuromodulatory changes are linked to epigenetic modifications, changes in gene expression, and modulation of pre- and postsynaptic receptor density. These previously understudied psychedelics have the potential to offer a new generation of neurotherapeutics, in which treatment-resistant psychiatric and neurological disorders, such as depression, post-traumatic stress disorder, dementia, and addiction, may be treatable with a reduced pharmacological risk profile.

[0007] Although there is a general perception that hallucinogens are dangerous, from a physiological safety perspective, they are one of the safest known classes of central nervous system (CNS) drugs. Hallucinogens do not induce addiction, and no overdose deaths occur after typical doses of classic hallucinogens such as LSD, psilocybin, or mescaline (Scheme 1). Preliminary data suggest that administration of hallucinogens in humans produces a unique profile of effects and potential adverse reactions that must be appropriately addressed to maximize safety. The primary safety concern is primarily psychological rather than physiological in nature. Physical effects, while variable, are relatively insignificant, even at doses that produce strong psychological effects. Psilocybin, when administered in a controlled setting, has often been reported to produce a transient, delayed headache whose onset, duration, and severity increase dose-relatedly [Johnson et al., Drug Alcohol Depend (2012) 123(1-3):132-140]. Repeated administration of hallucinogens has been found to result in the very rapid development of tolerance known as tachyphylaxis, a phenomenon thought to be mediated in part by the 5-HT2A receptor. Indeed, some studies have shown that rapid tolerance to hallucinogens is correlated with downregulation of the 5-HT2A receptor. For example, daily administration of LSD selectively reduced 5-HT2A 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]. [ka] Scheme 1: Chemical structures of mescaline (i), LSD (ii), psilocybin (iii), and psilocin (iv).

[0008] Classical and dissociative hallucinogens are known to have rapid-onset antidepressant and anti-addictive effects unlike any currently available treatment. Randomized, controlled clinical studies have confirmed the antidepressant and anxiolytic effects of classical hallucinogens in humans. Ketamine also has well-established antidepressant and anti-addictive effects in humans, primarily through its role as an NMDA antagonist. Ibogaine has demonstrated potent anti-addictive capabilities in preclinical studies and is in the early stages of clinical trials to determine its efficacy in robust human trials [Barsuglia et al., Prog Brain Res, 2018, 242:121-158; Corkery, Prog Brain Res, 2018, 242:217-257].

[0009] Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine (iii, Scheme 1)) is a C 12 H 17It has the chemical formula N2O4P. It is a tryptamine and one of the major psychoactive components of the Psilocybin mushroom. Psilocybin was first isolated from the Psilocybin mushroom by Hofmann in 1957 and subsequently synthesized by Hofmann in 1958 [Passie et al. Addict Biol., 2002, 7(4):357-364] and was used in psychiatric and psychological research and psychotherapy from the early to mid-1960s until it was listed on the regulated drug schedule 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 exploring the effects of psilocybin resumed in the mid-1990s, and it is now the preferred compound for use in studying the effects of serotonergic hallucinogens [Carter et al. J. Cogn. Neurosci., 2005 17(10):1497-1508; Gouzoulis-Mayfrank et al. Neuropsychopharmacology 1999, 20(6):565-581; Hasler et al. Psychopharmacology (Berl) 2004, 172(2):145-156]. This is likely due to psilocybin's short duration of action and its less notorious reputation than LSD. Like other members of this class, psilocybin induces sometimes severe changes in perception, cognition, and affect, including affective lability.

[0010] In humans and other mammals, psilocybin is converted to the active metabolite psilocin or 4-hydroxy-N,N-dimethyltryptamine (iv, Scheme 1). Psilocybin likely partially or completely produces most of psilocybin's subjective and psychological effects in humans and non-human animals. Recent psilocybin studies in humans have confirmed the 5-HT2A activity of psilocybin and psilocin, providing some support for indirect effects on dopamine through 5HT2A activity and possible activity at other serotonin receptors. Indeed, the most consistent finding regarding the involvement of other receptors in the action of hallucinogens is the 5-HT1A receptor. This is particularly true for tryptamine and LSD, which generally have significant affinity and functional potency at this receptor. 5-HT1A receptors are known to co-localize with 5-HT2A receptors on cortical pyramidal cells [Martin-Ruiz et al. J Neurosci., 2001, 21(24):9856-986], where these two receptor types have opposite functional effects [Araneda et al. Neuroscience 1991, 40(2):399-412].

[0011] Although the precise role of 5-HT2A receptors and other 5-HT2 receptor family members in the amygdala remains unclear, it is clear that 5-HT2A receptors play a key role in emotional responses and are important targets for investigation into the effects of 5-HT2A agonist hallucinogens. Indeed, most known 5HT2A agonists produce hallucinogenic effects in humans, and rodents generalize from one 5HT2A agonist to another, as occurs between psilocybin and LSD [Aghajanian et al., Eur J Pharmacol., 1999, 367(2-3):197-206; Nichols et al., J Neurochem., 2004, 90(3):576-584]. Psilocybin has a stronger affinity for human 5HT2A receptors than for rat receptors and a lower K(i) for both 5HT2A and 5HT2C receptors than LSD. Furthermore, results from a series of drug discrimination studies in rats showed that 5HT2A antagonists, but not 5HT1A antagonists, prevented rats from recognizing psilocybin [Winter et al., Pharmacol Biochem Behav., 2007, 87(4):472-480]. Daily administration of LSD and psilocybin reduces 5HT2 receptor density in the rat brain.

[0012] Clinical studies in the 1960s and 1970s demonstrated that psilocybin produces altered states of consciousness with subjective symptoms such as "marked changes in perception, mood, and thought, as well as alterations in time, space, and one's experience of self." Psilocybin has been used in experimental studies to understand the etiology of selected psychological disorders and has demonstrated psychotherapeutic potential [Rucker et al., Psychopharmacol., 2016, 30(12):1220-1229]. Psilocybin became increasingly popular as a recreational drug that produces hallucinations and was eventually classified as a Schedule 1 controlled substance in 1970. Fear of abuse of hallucinogens led to a significant decline in research in this area, which persisted until the 1990s. In the 1990s, conditions for safe administration were established, and human studies of psilocybin were revived [Johnson et al., Psychopharmacol., 2008, 22(6):603-620]. Today, psilocybin is one of the most widely used hallucinogens in human research due to its relative safety, moderately long duration of activity, and good absorption in subjects. Recent studies have shown varying degrees of success in treating neurotic disorders, alcoholism, depression in terminal cancer patients, obsessive-compulsive disorder, addiction, anxiety, post-traumatic stress disorder, and even cluster headache, so psilocybin remains a strong research and therapeutic potential. Psilocybin is also useful as a psychosis model for the development of new treatments for psychiatric disorders [Dubovyk and Monahan-Vaughn, ACS Chem. Neurosci., 2018, 9(9):2241-2251].

[0013] Recent developments in this field have occurred in clinical research, where several double-blind, placebo-controlled, phase 2 trials of psilocybin-assisted psychotherapy in patients with treatment-resistant major depressive disorder and cancer-related psychosocial distress have demonstrated unprecedented positive reductions in anxiety and depression. Two recent small-scale pilot trials of psilocybin-assisted psychotherapy have also demonstrated positive benefits in treating both alcohol and nicotine addiction. Recently, blood oxygen level-dependent functional magnetic resonance imaging and magnetoencephalography have been used for in vivo brain imaging in humans after administration of hallucinogens, and results indicate that intravenously administered psilocybin and LSD produced decreases in 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 or 20 mg orally) increased absolute glucose metabolic rates in the frontal cortex and, to a lesser extent, in other cortical regions and in the striatum and limbic subcortical structures, suggesting that some of psilocybin's key behavioral effects involve the frontal cortex [Gouzoulis-Mayfrank et al., Neuropsychopharmacology, 1999, 20(6):565-581; Vollenweider et al., Brain Res. Bull. 2001, 56(5):495-507]. Although 5HT2A agonism is widely recognized as the primary action of classical hallucinogens, psilocybin has weaker affinity for a wide range of other pre- and postsynaptic serotonin and dopamine receptors, as well as for the serotonin reuptake transporter [Tyls et al., Eur. Neuropsychopharmacol., 2014, 24(3):342-356]. Psilocybin activates 5HT1A receptors, which may contribute to its antidepressant / anxiety effects.

[0015] Depression and anxiety are two of the most common mental disorders worldwide. Depression is a multifaceted condition characterized by episodes of mood disturbance and other symptoms, such as anhedonia, psychomotor complaints, feelings of guilt, attention deficits, and suicidality, all of which vary in severity. According to the World Health Organization, the discovery of mainstream antidepressants revolutionized the management of depression, yet approximately 60% of patients remain undertreated. This is often due to delayed therapeutic effects of medications (typically within the first six weeks of treatment), side effects that lead to non-adherence, or inherent non-responsiveness to such medications. Similarly, anxiety disorders are a collection of etiologically complex disorders characterized by intense psychosocial distress and other symptoms depending on the subtype. Anxiety associated with life-threatening illnesses is the only anxiety subtype that has been studied in terms of hallucinogen-assisted therapy. This form of anxiety affects up to 40% of individuals diagnosed with life-threatening illnesses such as cancer. It manifests as worry about future danger or misfortune, accompanied by physical symptoms of unpleasant sensations or tension, and often coexists with depression. This is accompanied by a reduced quality of life, decreased treatment adherence, prolonged hospitalization, increased disability, and hopelessness, which collectively contribute to reduced survival rates. Pharmacological and psychosocial interventions are commonly used to address this type of anxiety, but their efficacy is mixed and limited, as they often fail to provide satisfactory emotional relief. Recent interest in the use of hallucinogen-assisted therapy may represent a promising alternative for patients with depression and anxiety who are ineffectively treated with traditional methods.

[0016] Generally, hallucinogen treatment models involve administering orally active drugs to induce a mystical experience lasting 4–9 hours, depending on the hallucinogen [Halberstadt, Behav Brain Res., 2015, 277:99–120; Nichols, Pharmacol Rev., 2016, 68(2): 264–355]. This allows participants to overcome and integrate difficult emotions and situations, leading to lasting antidepressant and anxiolytic effects. Classic hallucinogens such as psilocybin and LSD are currently being investigated as potential candidates. One trial using classic hallucinogens to treat depression and anxiety associated with a life-threatening illness found that psilocybin and LSD consistently produced significant and long-lasting antidepressant and anxiolytic effects in a supportive setting.

[0017] Psychedelic therapy is generally well tolerated and has no lasting adverse effects. Regarding its mechanism of action, it mediates its primary therapeutic effects biochemically through serotonin receptor agonism and psychologically by producing meaningful psychospiritual experiences that contribute to psychological flexibility. Given the limited success of current treatments for anxiety and mood disorders and the high morbidity associated with these conditions, the potential exists for psychedelics to provide symptomatic relief in patients inadequately addressed by conventional methods.

[0018] Additional emerging clinical research and evidence suggests that hallucinogen-assisted therapy may offer a potential alternative treatment for refractory substance use disorders and mental health conditions, potentially becoming an important tool in crisis situations where existing approaches have yielded limited success. A recent systematic review of clinical trials published over the past 25 years outlined some of the antidepressant, anxiolytic, and antiaddictive effects of classic hallucinogens. Among these, encouraging findings were from a meta-trial of randomized controlled trials of LSD therapy and a recent pilot study of psilocybin-assisted therapy for treating alcohol use disorder (dos Santos et al., Ther Adv Psychopharmacol., 2016, 6(3):193-213). Similarly encouraging are findings from a recent pilot study of psilocybin-assisted therapy for tobacco use disorder, which demonstrated abstinence rates of 80% at 6-month follow-up and 67% at 12-month follow-up [Johnson et al., J Drug Alcohol Abuse, 2017, 43(1):55-60; Johnson et al., 2014, Psychopharmacol., 2014, 28(11):983-992], rates significantly higher than any reported in the tobacco cessation literature. Notably, mystical-type experiences emanating from psilocybin sessions were significantly correlated with positive treatment outcomes. These results are consistent with burgeoning evidence from recent clinical trials supporting the efficacy of psilocybin-assisted therapy for treatment-resistant depression and end-of-life anxiety [Carhart-Harris et al. Neuropsychopharmacology, 2017, 42(11):2105-2113]. Research is beginning to emerge on the potential benefits of hallucinogen-assisted treatment for opioid use disorder (OUD), and accumulating evidence supports the need for further investigation along this line.Available evidence from previous randomized clinical trials suggests a promising role for the treatment of OUD: Higher rates of abstinence were observed at long-term follow-up in participants receiving high-dose LSD-assisted therapy for heroin addiction and in participants receiving high-dose ketamine-assisted therapy compared with controls. Recently, a large-scale US population study of 44,000 participants found that hallucinogen use was associated with a 40% lower risk of opioid abuse and a 27% lower risk of opioid dependence in the following year, as defined by DSM-IV criteria [Pisano et al., J Psychopharmacol., 2017, 31(5):606-613]. Similarly, a protective moderating effect of hallucinogen use was found in the relationship between prescription opioid use and suicide risk among marginalized women [Argento et al., 1664872791326_1 , 2018, 32(12):1385-1391]. Despite the promise of these preliminary findings with classic hallucinogens, given the potential toxicity of hallucinogens, further research is warranted to determine their possible contribution to the opioid crisis response. Meanwhile, growing evidence of the safety and efficacy of psilocybin for the treatment of psychological and substance use disorders may help motivate further clinical investigation of its use as a novel intervention for OUD.

[0019] Regular doses of hallucinogens also improve sleep disorders. Sleep disorders are highly prevalent in depressed patients, with over 80% of depressed patients complaining of poor sleep quality. Sleep symptoms often fail to resolve with first-line treatment and are associated with a greater risk of relapse and recurrence. Interestingly, sleep problems often precede other depressive symptoms, and subjective sleep quality worsens before episodes in recurrent depression. Brain regions with increased functional connectivity associated with poor sleep scores and higher depressive symptom scores include the prefrontal cortex and limbic system, regions involved in emotional processing. Sleep disruption in healthy participants has demonstrated the involvement of sleep in mood, emotional appraisal processes, and brain reactivity to emotional stimuli. Increased negative mood and the false labeling of neutral stimuli as negative, independent of mood, have been shown in one study, while other studies have demonstrated amplified reactivity in limbic brain regions to both negative and positive stimuli. Two other studies evaluating brain activity during sleep using electroencephalography (EEG) have shown that hallucinogens such as LSD have a positive effect on sleep patterns. Additionally, partial or complete overnight sleep deprivation has been shown to alleviate depressive symptoms, likely due to a resetting of circadian rhythms through altered clock gene expression. A single dose of hallucinogens has been shown to reset the biological clock underlying the sleep / wake cycle, thereby enhancing cognitive-emotional processes in depressed individuals and improving well-being and mood in healthy individuals [Kuypers, Medical Hypotheses, 2019, 125:21-24].

[0020] A systematic meta-analysis of clinical trials conducted between 1960 and 2018 investigating the therapeutic use of psychedelic drug treatment in patients with serious or terminal illnesses and associated psychiatric disorders found that psychedelic drug treatment (mostly LSD) can improve cancer-related depression, anxiety, and fear of death. Four randomized controlled trials, mostly involving psilocybin treatment, were published between 2011 and 2016, demonstrating that psychedelic drug-assisted therapy can produce rapid, robust, and sustained improvements in cancer-related psychological and existential distress [Ross S, Int Rev Psychiatry, 2018, 30(4):317-330]. Therefore, the use of psychedelics in the fields of oncology and palliative care is intriguing for several reasons. First, many patients facing cancer or other life-threatening illnesses experience significant existential distress related to a loss of meaning or purpose in life, which can be accompanied by feelings of hopelessness, depravity, helplessness, perceived burdensomeness, and a desire for premature death. These characteristics are often at the core of clinically significant anxiety and depression and can significantly reduce quality of life in this patient population. Alleviating these forms of distress should be a central goal of palliative care. Accordingly, several manualized psychological therapies for cancer-related existential distress have been developed in recent years, emphasizing the development of dignity and meaning. However, there are currently no pharmacological interventions for existential distress itself, and available pharmacological treatments for depression in cancer patients have not demonstrated superiority over placebo. There remains a need for more effective treatments for these conditions [Rosenbaum et al., Curr. Oncol., 2019, 26(4): 225-226].

[0021] In recent years, there has been growing interest in a new dosing paradigm for hallucinogens such as psilocybin and LSD, colloquially referred to as microdosing. In this paradigm, sub-perceptual doses of serotonergic hallucinogens—approximately 10% or less of the full dose—are taken on a more consistent basis, such as once daily, every other day, or every third day. This dosing paradigm is not only more consistent with the current standard of pharmacological care, but may also be particularly beneficial for certain conditions, such as Alzheimer's disease and other neurodegenerative diseases, attention deficit disorder, and attention deficit hyperactivity disorder, as well as for specific patient populations, such as the elderly, the young, and patients who fear or are opposed to hallucinogen-assisted therapy. Furthermore, this approach may be particularly well-suited for managing cognitive impairment and preventing neurodegeneration. For example, after subthreshold psilocybin dosing that elicited the classic wet dog shake behavioral response associated with hallucinogenic doses, subpopulations of less attentive and less motivated rats showed improved performance on 5-choice serial reaction time and progressive ratio tasks, respectively (Blumstock et al., WO 2020 / 157569 A1). Similarly, treatment of patients with hallucinogenic doses of 5HT2A agonists was associated with increased brain-derived neurotrophic factor (BDNF) and activation of the mTOR pathway, which are thought to promote neuroplasticity and are hypothesized to serve as molecular targets for the treatment of dementia and other neurodegenerative disorders (Ly et al. Cell Rep., 2018, 23(11):3170-3182).Furthermore, several groups have shown that low, non-hallucinogenic, and non-psychotic doses of 5HT2A agonists also exhibit similar neuroprotective and increased neuroplastic effects (neuroplastogens) and reduced neuroinflammation, which may be beneficial in both neurodegenerative and neurodevelopmental diseases and chronic disorders (Manfredi et al., WO 2020 / 181194; Flanagan et al., Int. Rev. Psychiatry, 2018, 13:1-13; Nichols et al., 2016, Psychedelics as medicines; an emerging new paradigm). This repeated, lower-dose paradigm may extend the utility of these compounds to additional indications and may prove useful in wellness applications.

[0022] Psychosis is often referred to as an abnormal state of mind characterized by hallucinatory experiences, delusional thinking, and disorganized thinking. Furthermore, this state is accompanied by impairments in social cognition, inappropriate emotional expression, and bizarre behavior. In most cases, psychosis occurs as part of a psychiatric disorder, and psychosis represents an integral part of schizophrenia. Psychosis represents the most florid phase of the illness. The earliest manifestation of psychosis in a patient is referred to as first-episode psychosis. This reflects a critical transitional stage toward chronic establishment of the disorder and is likely mediated by progressive structural and functional abnormalities present in diagnosed patients (ACS Chem. Neurosci. 2018, 9, 2241-2251). Anecdotal evidence suggests that regularly administered low, non-hallucinogenic doses (microdosing) of hallucinogens can reduce symptoms of schizophrenia and psychosis. Summary of the Invention [Means for solving the problem]

[0023] The present application includes compounds having the general structural formula (I) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [ka] where R 1 is hydrogen, C1-C3 alkyl, C1-C6 alkylene P(O)(OR 9 )2, C(O)R 9 , CO2R 9 , C(O)N(R 9 )2, S(O)R 9 , and SO2R 9 Selected from; R 2 , R 3 , and R 4 are independently selected from hydrogen and C1-C6 alkyl; R 5 is selected from hydrogen and C1-C6 alkyl; R 6 , R 7 , and R 8 is hydrogen, halogen, CN, OR 9 , N(R 9 )2, SR 9 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, CO2R 9 , C(O)N(R 9 )2, S(O)R 9 , SO2R 9 , C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl, and O, S, S(O), SO2, N, and NR 9 wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, C3-C7 cycloalkyl group, and 3- to 7-membered heterocyclic group are optionally selected from CN, OR 9 , N(R 9 )2, and SR 9wherein the C3-C7 cycloalkyl and 3- to 7-membered heterocycle are each further optionally substituted with one or more substituents independently selected from halogen, COR 9 , C(O)N(R 9 )2, SO2R 9 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, and O, S, S(O), SO2, N, and NR 9 and is substituted with a substituent selected from a 3- to 6-membered heterocycle containing one or two heterocyclic moieties selected from Y is selected from halogen and QA; Q is O, NR 10 , S, S(O), and SO2; where each R 9 and R 10 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C6 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C6 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C6 alkylenearyl, and substituted or unsubstituted C1-C6 alkyleneheteroaryl; and A is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-C7 cycloalkyl, C4-C6 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, P(O)(OR 11 )2, C1-C6 alkylene P(O)(OR 11)2, C1-C6 alkylene C3-C7 cycloalkyl, C1-C6 alkylene C4-C6 cycloalkenyl, C1-C6 alkylene heterocycloalkyl, C1-C6 alkylene aryl, C1-C6 alkylene heteroaryl, C(O)Q', CO2Q', C(O)N(Q')2, S(O)Q', and SO2Q'; where Q' is hydrogen, C1-C20 alkyl, C1-C20 haloalkyl, C2-C20 alkenyl, C2-C20 haloalkenyl, C2-C20 alkynyl, C2-C20 haloalkynyl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and O, S, S(O), SO2, N, and NR 10 wherein the C1-C20 alkyl group, the C2-C20 haloalkyl group, the C2-C6 alkenyl group, the C2-C20 haloalkenyl group, the C2-C20 alkynyl group, the C2-C20 haloalkynyl group, the C3-C7 cycloalkyl group, the C4-C7 cycloalkenyl group, and the 3- to 7-membered heterocyclic group are selected from CN, OR 10 , N(R 10 )2, CO2R 10 , and S.R. 10 and / or C1-C6 alkyl By or To form a C3-C7 cycloalkyl ring C2-C6 alkylene By Optionally disubstituted on the same carbon atom R, and each of the C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterocycle is further optionally substituted with a substituent selected from C1-C3 alkyl and C1-C3 haloalkyl; and Each R 11are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C6 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C6 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C6 alkylenearyl, and substituted or unsubstituted C1-C6 alkyleneheteroaryl; wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes; however, A is CH3, Q is O, and R 1 is H or CH3, and R 2 , R 3 , R 4 , and R 5 If all are hydrogen, R 6 , R 7 , and / or R 8 is not OCH3; When A is CH3 and Q is O, R 1 ~R 8 is not all hydrogen; and A is hydrogen, Q is O, and R 1 , R 2 , and R 5 One of the groups is methyl and the other is R 1 , R 2 , and R 5 If the remaining two of 3 , R 4 , and R 6 ~R 8 is not all hydrogen.

[0024] In some embodiments, the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and / or prodrugs are isotopically enriched with deuterium. In some aspects of these embodiments, A, Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 R 8 , R 9 , and R 10 One or more of optionally contains deuterium.

[0025] In certain further embodiments, the claimed compounds are used as pharmaceuticals. Thus, the present application also includes the claimed compounds for use as pharmaceuticals.

[0026] The present application includes a method of activating serotonin receptors in cells in a biological sample or in a patient, comprising administering to said cells an effective amount of one or more compounds of the present application.

[0027] The present application also includes a method of treating psychosis or a psychotic condition, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application.

[0028] The present application also includes a method of treating a psychiatric disorder, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application.

[0029] The present application also includes methods for treating central nervous system diseases, disorders, or conditions, and / or neurological diseases, disorders, or conditions, comprising administering to a subject in need of such treatment a therapeutically effective amount of one or more compounds of the present application.

[0030] The present application also provides methods for preparing the present compounds, both general and specific, which are described in more detail below and in the Examples that follow.

[0031] Other features and advantages of the present application will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating embodiments of the present application, are given by way of example only, and the scope of the claims is not limited by these embodiments, but should be accorded the broadest interpretation consistent with the entire disclosure. [Brief explanation of the drawings]

[0032] Embodiments of the present application are described in more detail hereinafter with reference to the accompanying drawings, in which:

[0033] [Figure 1] Figure 1 is a graph showing the effect of various doses of I-2, an exemplary compound of Formula I, on the head-twitch response (HTR) in male C57BL6 mice. Mice were treated with compound I-2 (0.03-10 mg / kg, SC) via subcutaneous injection (SC) (N=6 mice per dose), and the total number of head twitches was recorded over a 1-hour period. Data are presented as mean ± standard error of the mean (SEM). The induction of head twitches induced by 5-HT2A receptor agonists is believed to represent a behavioral proxy for their hallucinogen effects.

[0034] [Figure 2] Figure 2 is a graph showing the involvement of the 5-HT2A receptor in HTR induced by I-2, an exemplary compound of Formula I. Male C57BL6 mice were pretreated with the selective 5-HT2A receptor antagonist M100907 (0.5 mg / kg, intraperitoneal (IP) administration; also known as vorinanserin) prior to administration of I-2, an exemplary compound of Formula I (10 mg / kg, subcutaneous injection (SC)). Pretreatment with the antagonist completely inhibited the effect of I-2, an exemplary compound of Formula I, on HTR. Data are expressed as mean ± standard error of the mean (SEM). DETAILED DESCRIPTION OF THE INVENTION

[0035] I. Definition Unless otherwise stated, the definitions and embodiments set forth in this section and other sections are intended to be applicable to all embodiments and aspects of the present application described in this disclosure where they are appropriate, as would be understood by one of ordinary skill in the art.

[0036] All features disclosed in this specification, including the claims, abstract, and drawings, and all steps in any disclosed method or process, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. Each feature disclosed in this specification, including the claims, abstract, and drawings, may also be replaced by an alternative feature serving the same, equivalent, or similar purpose, unless expressly stated otherwise.

[0037] The terms "compound(s) of the present application" or "compound(s) of the present application" and the like as used in this disclosure refer to the compounds of formula (I) and compounds of formulas (IA)-(II), as well as pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0038] The terms "composition(s) of the present application" or "composition(s) of the present application" and the like as used in this disclosure refer to compositions, e.g., pharmaceutical compositions, that include one or more compounds of the present application.

[0039] The term "and / or" as used in this disclosure means that the listed items are present or used individually or in combination. In essence, the term means that "at least one" or "one or more" of the listed items are used or present. With respect to pharmaceutically acceptable salts, solvates, and / or prodrugs, the term "and / or" means that the compounds of the present application exist as individual salts, solvates, and prodrugs, as well as in combinations, such as solvate salts, of the compounds of the present application.

[0040] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, an embodiment including "a compound" should be understood to represent an aspect having one compound, or an aspect having two or more additional compounds.

[0041] As used in this application and in the claims, the words "comprising" (and any form of "comprising", e.g., "comprise" (third person singular, with or without "s"), "having" (and any form of "having", e.g., "having" (third person singular, with or without "s"), "including" (and any form of "including", e.g., "include" (third person singular, with or without "s"), and "containing" (and any form of "containing", e.g., "including" (third person singular, with or without "s")) are inclusive and open-ended and do not exclude additional, unrecited elements or process steps.

[0042] As used in this disclosure, the term "consisting of" and its derivatives are intended to be closed terminology that specifies the presence of stated features, elements, components, groups, integers, and / or steps and excludes the presence of other, unrecited features, elements, components, groups, integers, and / or steps.

[0043] As used in this disclosure, the term "consisting essentially of" is intended to specify the presence of stated features, elements, components, groups, integers, and / or steps, and that do not materially affect the basic and novel characteristic(s) of those features, elements, components, groups, integers, and / or steps.

[0044] In embodiments that include "additional" or "second" components, e.g., additional or second compounds, the second component, as referred to in this disclosure, is chemically distinct from the other components or the first component. A "third" component is distinct from the other first and second components, and further listed or "additional" components are similarly distinct.

[0045] The term "suitable" ("preferred") as used in this disclosure means that the selection of a particular compound or conditions will depend on the particular synthetic operation to be performed, the molecule(s) to be converted, and / or the particular use for the compound, but that such selection is well within the skill of one of ordinary skill in the art. All process / method steps described in this disclosure are intended to be carried out under conditions sufficient to provide the indicated product. Those of ordinary skill in the art will understand, and it is within the skill of one of ordinary skill in the art, that all reaction conditions, e.g., reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratios, whether the reaction should be carried out in an anhydrous or inert atmosphere, etc., can be varied to maximize the yield of the desired product.

[0046] As used in this disclosure, the terms "about," "substantially," and "approximately" refer to a reasonable amount of deviation from the modified word such that the end result is not significantly different. These terms of degree should be interpreted as including a deviation of at least ±5% from the modified word unless the deviation would negate the meaning of the word it modifies or the context would suggest otherwise to one of ordinary skill in the art.

[0047] This specification describes many chemical terms and abbreviations used by those skilled in the art. However, definitions of selected terms are provided for clarity and consistency.

[0048] The term "solvate" as used in this disclosure means a compound, or a salt or prodrug of a compound, wherein molecules of a suitable solvent are incorporated into the crystal lattice, which suitable solvent is physiologically acceptable at the dosage administered.

[0049] The term "prodrug" as used in this disclosure means a compound or a salt of a compound that is converted into an active drug after administration.

[0050] As used herein, the term "alkyl," whether used alone or as part of another group, refers to a straight- or branched-chain saturated alkyl group. The number of possible carbon atoms in the alkyl group in question is indicated by the prefix "Cn1-Cn2." Thus, for example, the term "C1-6 alkyl" (or "C1-C6 alkyl") refers to an alkyl group having 1, 2, 3, 4, 5, or c carbon atoms, including, for example, any of the isotopes of hexyl alkyl and pentyl alkyl, as well as n-, iso-, sec-, and tert-butyl, n- and isopropyl, ethyl, and methyl. As another example, "C4 alkyl" refers to n-, iso-, sec-, and tert-butyl, n- and isopropyl, ethyl, and methyl.

[0051] The term "alkenyl," whether used alone or as part of another group, refers to a straight-chain or branched saturated alkylene group, i.e., a saturated carbon chain containing substituents on two of its termini. The number of possible carbon atoms in a given alkylene group is indicated by the prefix "Cn1-n2." Thus, for example, the term "C2-6 alkylene" refers to an alkylene group having 2, 3, 4, 5, or 6 carbon atoms.

[0052] As used herein, the term "alkynyl," whether used alone or as part of another group, refers to a straight- or branched-chain, unsaturated alkynyl group containing at least one triple bond. The number of possible carbon atoms in the alkyl group is indicated by the prefix "Cn1-n2." For example, the term C2-6 alkynyl refers to an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms.

[0053] As used herein, the term "cycloalkyl," whether used alone or as part of another group, refers to a saturated carbocyclic group containing 3 to 20 carbon atoms and one or more rings. The number of possible carbon atoms in a given cycloalkyl group is indicated by the prefix "Cn1-n2." For example, the term C3-10 cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0054] As used herein, the term "aryl," whether used alone or as part of another group, refers to a carbocyclic group containing at least one aromatic ring and containing from 6 to 20 carbon atoms.

[0055] The term "available" in "available hydrogen atom" or "available atom" refers to an atom that would be known to one of ordinary skill in the art as being available for replacement by a substituent.

[0056] As used herein, the term "heterocycloalkyl," whether used alone or as part of another group, refers to a cyclic group containing at least one non-aromatic ring containing 3 to 20 atoms, where one or more of the atoms is a heteromoiety selected from O, S, S(O), SO, and N, and the remaining atoms are C. Heterocycloalkyl groups can be saturated or unsaturated (i.e., contain one or more double bonds). When a heterocycloalkyl group contains the prefix C or "n," this prefix refers to the number of carbon atoms in the corresponding carbocyclic group, where one or more, preferably 1 to 5, of the ring atoms are replaced by a heteromoiety selected from O, S, S(O), SO, and N, and the remaining atoms are C. Heterocycloalkyl groups are optionally benzo-fused.

[0057] As used herein, the term "heteroaryl," whether used alone or as part of another group, refers to a cyclic group containing at least one heteroaromatic ring containing 5 to 20 atoms, one or more of which are heteroatoms selected from O, S, and N, and the remaining atoms are C. When a heteroaryl group contains a prefix Cn1-n2, the prefix refers to the number of carbon atoms in the corresponding carbocyclic group, where one or more, preferably 1 to 5, of the ring atoms are replaced by a heteroatom as defined above. The heteroaryl group is optionally benzo-fused.

[0058] All cyclic groups, including aryl, heteroaryl, heterocycloalkyl, and cycloalkyl groups, contain one or more rings (i.e., polycyclic). When a cyclic group contains more than one ring, the rings can be fused, bridged, spirofused, or joined by bonds.

[0059] As used in this disclosure, the term "benzofused" refers to a polycyclic group in which a benzene ring is fused to another ring.

[0060] A first ring is "fused" to a second ring means that the first ring and the second ring share two adjacent atoms between them.

[0061] A first ring is "bridged" to a second ring means that the first ring and the second ring share two non-adjacent atoms between them.

[0062] A first ring is "spirofused" to a second ring means that the first ring and the second ring share one atom between each other.

[0063] The term "halogen" (or "halo"), whether used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo, and iodo.

[0064] The term "haloalkyl," as used herein, refers to an alkyl group, as defined above, in which one or more available hydrogen atoms have been replaced by a halogen. Thus, for example, "C1-6 haloalkyl" (or alternatively "C1-C6 haloalkyl") refers to a C1-C6 straight or branched alkyl group, as defined above, having one or more halogen substituents.

[0065] As used herein, the term "haloalkenyl" refers to an alkenyl group, as defined above, in which one or more available hydrogen atoms have been replaced by a halogen. Thus, for example, "C1-6 haloalkenyl" (or alternatively "C1-C6 haloalkenyl") refers to a C1-C6 straight or branched alkenyl group, as defined above, having one or more halogen substituents.

[0066] The term "haloalkynyl," as used herein, refers to an alkynyl group, as defined above, in which one or more available hydrogen atoms have been replaced by a halogen. Thus, for example, "C1-C6 haloalkynyl" (or alternatively, "C1-C6 haloalkynyl") refers to a C1-C6 straight or branched alkynyl group, as defined above, having one or more halogen substituents.

[0067] The term "alkoxy," as used herein, alone or in combination, includes an alkyl group linked to an oxygen linking atom.

[0068] As used in this disclosure, the term "one or more" includes a single item selected from the list as well as mixtures of two or more items selected from the list.

[0069] The term "substituted," as used herein, unless otherwise indicated, means that the group in question is substituted with one or more substituents independently selected from halogen, COH, COCH, C(O)NH, C(O)N(CH), C(O)NHCH, SOCH, SOCH, C-C alkyl, C-C haloalkyl, C-C alkenyl, C-C haloalkenyl, C-C alkynyl, C-C haloalkynyl, C-C cycloalkyl, and 3- to 6-membered heterocycles containing 1-2 ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH.

[0070] As used in this disclosure, the term "alternative isotopes thereof" refers to isotopes of an element other than its most abundant isotope in nature.

[0071] In the compounds of general formula (I) and their pharmaceutically acceptable salts, solvates, and / or prodrugs, atoms may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. The present disclosure is intended to encompass all suitable isotopic variations of the compounds of general formula (I) and their pharmaceutically acceptable salts, solvates, and / or prodrugs. For example, different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H), and tritium (3H). Protium is the predominant hydrogen isotope found in nature.

[0072] As used in this disclosure, the phrase "all available atoms optionally replaced by alternative isotopes" means that available atoms are optionally replaced by isotopes of said atoms having the same atomic number as the atom but having an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.

[0073] The term "compound" refers to the compound, and in certain embodiments, any hydrates or solvates, so long as they are stable. A hydrate is a compound complexed with water, and a solvate is a compound complexed with a solvent, which may be an organic or inorganic solvent. A "stable" compound is one that can be prepared and isolated such that its structure and properties remain essentially unchanged or essentially unchanged for a period of time sufficient to permit the compound to be used for the purposes described in this disclosure (e.g., therapeutic administration to a subject). The compounds of the present application are limited to stable compounds encompassed by general formula (I), or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0074] The term "pharmaceutically acceptable" means suitable for treating a subject.

[0075] The term "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, formulation excipient, adjuvant, or other material with which an active ingredient is combined to form a pharmaceutical composition, i.e., a dosage form that can be administered to a subject.

[0076] The term "pharmaceutically acceptable salt" means an acid addition salt or a base addition salt that is suitable or compatible for treatment of a subject.

[0077] Acid addition salts suitable or compatible for treating a subject are any non-toxic organic or inorganic acid addition salts of any basic compounds.

[0078] A base addition salt suitable for or compatible with treating a subject is any non-toxic organic or inorganic base addition salt of any acidic compound. As used in this disclosure, the term "protecting group" or "PG" or the like refers to a chemical moiety that protects or masks reactive portions of a molecule to prevent side reactions at those reactive portions of the molecule while manipulating or reacting different portions of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not destroy or degrade the remaining portions of the molecule. The selection of an appropriate protecting group can be made by one skilled in the art. Many conventional protecting groups are known in the art, for example, "Protective Groups in Organic Chemistry" McOmie, JFW Ed., Plenum Press, 1973, in Greene, TW and Wuts, PGM, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3 rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0079] As used in this disclosure, 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 both human therapy and veterinary applications.

[0080] In this disclosure and as is well known in the art, the terms "treat" or "treatment" refer to an approach for obtaining beneficial or desired results, such as clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in the extent of disease, stabilized (i.e., not worsening) disease, prevention of disease spread, delay or slowing of disease progression, improvement or palliation of the disease state, reduction in disease recurrence, and remission (whether partial or complete), which may be detectable or undetectable. "Treat" and "treatment" may also mean prolonging survival compared to expected survival in the absence of treatment. In the present disclosure, "treat" and "treatment" also encompass prophylactic treatment. For example, a subject with early-stage cancer may be treated to prevent progression, or a subject in remission may be treated with a compound or composition of the present application to prevent recurrence. The method of treatment involves administering to the subject a therapeutically effective amount of one or more of the compounds of the present application, which optionally consists of a single dose or includes a series of multiple doses.

[0081] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of one or more compounds of the present application effective at dosages and for periods of time necessary to achieve a desired result. For example, in the context of treating a disease, disorder, or condition mediated or treated by agonism or activation of serotonergic receptors and downstream second messengers, an effective amount is, for example, an amount that increases said activation compared to activation without administration of the one or more compounds.

[0082] To "alleviate" a disease, disorder, or condition means that the severity and / or undesirable clinical manifestations of the disease, disorder, or condition are reduced and / or the time course of progression is slowed or prolonged compared to if the disorder is not treated.

[0083] As used in this disclosure, the term "administered" means administering a therapeutically effective amount of one or more compounds or compositions of the present application to a cell, tissue, organ, or subject.

[0084] As used in this disclosure, the term "prevention" or "prophylaxis," or synonyms thereof, refers to a reduction in the risk or probability that a patient will suffer from a disease, disorder, or condition, or will exhibit symptoms associated with a disease, disorder, or condition.

[0085] In the present disclosure, a "disease, disorder, or condition" refers to a condition that affects a serotonin receptor, such as 5-HT 2A , particularly those diseases, disorders, or conditions that are treated or treatable by activation of a serotonin receptor agonist, such as one or more of the compounds described in this disclosure.

[0086] As used in this disclosure, the term "treating a disease, disorder, or condition through activation of serotonin receptors" means that the disease, disorder, or condition being treated is affected by, modulated by, and / or has some biological basis that involves, directly or indirectly, serotonergic activity, particularly increased serotonergic activity. These diseases respond favorably when the serotonergic activity associated with the disease, disorder, or condition is stimulated by one or more of the compounds or compositions of the present application.

[0087] As used in this disclosure, the term "activation" encompasses agonism, partial agonism, and positive allosteric modulation of serotonin receptors.

[0088] The term "5-HT" as used in this disclosure 2A " refers to the 5-HT receptor of the 5-HT2 serotonin receptor. 2A It refers to the receptor subtype.

[0089] As used in this disclosure, the term "therapeutic agent" refers to any drug or active agent that has a pharmacological effect when administered to a subject.

[0090] II. Compounds The present application includes compounds of formula (I) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [ka] where R 1 is hydrogen, C1-C3 alkyl, C1-C6 alkylene P(O)(OR 9 )2, C(O)R 9 , CO2R 9 , C(O)N(R 9 )2, S(O)R 9 , and SO2R 9 Selected from; R 2 , R 3 , and R 4 are independently selected from hydrogen and C1-C6 alkyl; R 5 is selected from hydrogen and C1-C6 alkyl; R 6 , R 7 , and R 8 is hydrogen, halogen, CN, OR 9 , N(R 9 )2, SR 9 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, CO2R 9 , C(O)N(R 9 )2, S(O)R 9 , SO2R 9 , C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl, and O, S, S(O), SO2, N, and NR 9 wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, C3-C7 cycloalkyl group, and 3- to 7-membered heterocyclic group are optionally selected from CN, OR9 , N(R 9 )2, and SR 9 wherein the C3-C7 cycloalkyl and 3- to 7-membered heterocycle are each further optionally substituted with one or more substituents independently selected from halogen, COR 9 , C(O)N(R 9 )2, SO2R 9 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, and O, S, S(O), SO2, N, and NR 9 and is substituted with a substituent selected from a 3- to 6-membered heterocycle containing one or two heterocyclic moieties selected from Y is selected from halogen and QA; Q is O, NR 10 , S, S(O), and SO2; where each R 9 and R 10 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C6 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C6 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C6 alkylenearyl, and substituted or unsubstituted C1-C6 alkyleneheteroaryl; and A is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C6 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, P(O)(OR 11 )2, C1-C6 alkylene P(O)(OR 11)2, C1-C6 alkylene C3-C7 cycloalkyl, C1-C6 alkylene C4-C6 cycloalkenyl, C1-C6 alkylene heterocycloalkyl, C1-C6 alkylene aryl, C1-C6 alkylene heteroaryl, C(O)Q', CO2Q', C(O)N(Q')2, S(O)Q', and SO2Q'; where Q' is hydrogen, C1-C20 alkyl, C1-C20 haloalkyl, C2-C20 alkenyl, C2-C20 haloalkenyl, C2-C20 alkynyl, C2-C20 haloalkynyl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and O, S, S(O), SO2, N, and NR 10 wherein the C1-C20 alkyl group, the C2-C20 haloalkyl group, the C2-C6 alkenyl group, the C2-C20 haloalkenyl group, the C3-C7 cycloalkyl group, and the 3- to 7-membered heterocyclic group are selected from the group consisting of CN, OR 10 , N(R 10 )2, and SR 10 and / or C1-C6 alkyl By or To form a C3-C7 cycloalkyl ring C2-C6 alkylene By Optionally disubstituted on the same carbon atom R, and wherein each of said C3-C7 cycloalkyl and 3- to 7-membered heterocycle is further optionally substituted with a member of the group consisting of C1-C3 alkyl and C1-C3 haloalkyl; and Each R 11are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C6 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C6 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C6 alkylenearyl, and substituted or unsubstituted C1-C6 alkyleneheteroaryl; wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes; however, A is CH3, Q is O, and R 1 is H or CH3, and R 2 , R 3 , R 4 , and R 5 If all are hydrogen, R 6 , R 7 , and / or R 8 is not OCH3; When A is CH3 and Q is O, R 1 ~R 8 is not all hydrogen; and A is hydrogen, Q is O, and R 1 , R 2 , and R 5 One of the groups is methyl and the other is R 1 , R 2 , and R 5 If the remaining two of 3 , R 4 , and R 6 ~R 8 is not all hydrogen.

[0091] The present application further includes compounds of general formula (I) or pharmaceutically acceptable salts thereof: [ka] During the ceremony R 1 is hydrogen, C1-C3 alkyl, -(CH2)P(O)(OR 9 ); CO(R 9 ), COO(R 9 ), C(O)N(R 9 )2, SO(R 9 ), and SO2(R 9 ) selected from the group consisting of; R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of hydrogen and lower alkyl; R 6 , R 7 , and R 8 is hydrogen, halogen, CN, OR 9 , N(R 9 )2, SR 9 , C1-C6 alkyl, C1-C6 haloalkyl, OR 9 C1-C6 alkyl substituted with SR 9 C1-C6 alkyl substituted with N(R 9 )2-substituted C1-C6 alkyl, C2-C6 haloalkyl, COOR 9 , C(O)N(R 9 )2, SO2R 9 , COOR 9 , C(O)N(R 9 )2, SO2R 9 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl, and O, S, N, and NR 9 wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, C3-C7 cycloalkyl group, and 3- to 7-membered heterocyclic group are optionally selected from the group consisting of CN, OR 9, N(R 9 )2, and SR 9 and the C3-C7 cycloalkyl and 3- to 7-membered heterocycle are each optionally further substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 haloalkyl, halogen, CN, OR 9 , N(R 9 )2, COOR 9 , C(O)N(R 9 )2, SR 9 , SO2R 9 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, and O, S, N, and NR 9 and a member of the group consisting of 3- to 6-membered heterocycles containing 1 or 2 ring members selected from the group consisting of: wherein said C1-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl; and Q is O, NR 10 , S, SO, and SO2; where R 9 and R 10 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and A is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heterocycloalkynyl, aryl, heteroaryl, C0-C1 P(O)(OR 9)2, CO(Q'), COO(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), where Q' is selected from hydrogen, C1-C20 alkyl, C1-C20 haloalkyl, C2-C20 alkenyl, C2-C20 haloalkenyl, C2-C20 alkynyl, C2-C20 haloalkynyl, C3-C7 cycloalkyl, and O, S, N, and N(R 10 wherein the C1-C20 alkyl group, the C2-C20 haloalkyl group, the C2-C6 alkenyl group, the C2-C20 haloalkenyl group, the C3-C7 cycloalkyl group, and the 3- to 7-membered heterocyclic group are optionally selected from the group consisting of CN, OR 10 , N(R 10 )2, and SR 10 wherein said C3-C7 cycloalkyl and 3- to 7-membered heterocycle are each further optionally substituted with a member of the group consisting of C1-C3 alkyl and C1-C3 haloalkyl; 9 and R 10 are independently as defined above.

[0092] In certain embodiments, Q' is selected from hydrogen, C1-C20 alkyl, C1-C20 haloalkyl, C2-C20 alkenyl, C2-C20 haloalkenyl, C2-C20 alkynyl, C2-C20 haloalkynyl, C3-C7 cycloalkyl, and O, S, N, and N(R 10 wherein the C1-C20 alkyl group, the C2-C20 haloalkyl group, the C2-C6 alkenyl group, the C2-C20 haloalkenyl group, the C3-C7 cycloalkyl group, and the 3- to 7-membered heterocyclic group are optionally selected from the group consisting of CN, OR 10 , N(R 10 )2, and SR 10wherein said C3-C7 cycloalkyl and 3- to 7-membered heterocycle are each further optionally substituted with a member of the group consisting of C1-C3 alkyl and C1-C3 haloalkyl; 9 and R 10 are independently as defined above.

[0093] In some embodiments, when all available hydrogen atoms in a group are optionally replaced with a halogen atom in a compound of Formula I, the halogen atom is F, Cl, or Br. In some embodiments, when all available hydrogen atoms in a group are optionally replaced with a halogen atom, the halogen atom is F or Br. In some embodiments, when all available hydrogen atoms in a group are optionally replaced with a halogen atom, the halogen atom is F.

[0094] Thus, in some embodiments, if all available hydrogen atoms are optionally replaced with fluorine, chlorine, or bromine atoms, and / or all available atoms are optionally replaced with alternative isotopes thereof, in some embodiments, all available hydrogen atoms are optionally replaced with fluorine or bromine atoms, and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, all available hydrogen atoms are optionally replaced with fluorine or chlorine atoms, and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, all available hydrogen atoms are optionally replaced with fluorine atoms, and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, all available hydrogen atoms are optionally replaced with halogen atoms, and / or all available hydrogen atoms are optionally replaced with deuterium. In some embodiments, all available hydrogen atoms are optionally replaced by fluorine atoms and / or all available atoms are optionally replaced by deuterium, hi some embodiments, all available atoms are optionally replaced by deuterium.

[0095] In some embodiments, all available hydrogen atoms are optionally replaced by their alternative isotopes. In some embodiments, the alternative isotope of hydrogen is deuterium. Thus, in some embodiments, the compounds of the present application are isotopically enriched with deuterium. In some embodiments, A, X, Q', R 1 , R 2 , R 3 , R 4 , R5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 one or more of A, X, Q', R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 One or more of is deuterium.

[0096] In some embodiments, R 1 is S(O)R 9 and SO2R 9 In some embodiments, R is selected from the group consisting of: 1 is hydrogen, C1-C3 alkyl, C1-C3 alkylene P(O)(OR 9 )2, C(O)R 9 , CO2R 9 , and C(O)N(R 9 )2, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, R 1 is hydrogen, C1-C3 alkyl, CH2P(O)(OR 9 )2, CH2CH2P(O)(OR 9 )2, CH2CH(CH3)P(O)(OR 9 )2, CH(CH3)CH2P(O)(OR 9 )2, CH(CH3)P(O)(OR 9 )2, CH(CH2CH3)P(O)(OR 9)2, C(O)R 9 , and CO2R 9 In some embodiments, R is selected from the group consisting of: 1 is hydrogen, CH3, CH2CH3, CH2P(O)(OR 9 )2, and CH(CH3)P(O)(OR 9 )2, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, R 1 are hydrogen, deuterium, CH3, CH2CH3, CH2P(O)(OR 9 )2, and CH(CH3)P(O)(OR 9 In some embodiments, R 1 is hydrogen, CH3, CH2CH3, CH2P(O)(OR 9 )2 and CH(CH3)P(O)(OR 9 )2, C(O)R 9 , and CO2R 9 In some embodiments, R is selected from the group consisting of: 1 is selected from hydrogen, CH, and CHCH, where any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its alternative isotope. 1 is selected from hydrogen and deuterium. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is CH2P(O)(OR 9)2 and CH(CH3)P(O)(OR 9 )2, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, R 1 is CH(CH3)P(O)(OR 9 )2. In some embodiments, R 1 is CH2P(O)(OR 9 )2.

[0097] In some embodiments, R 2 , R 3 , and R 4 are independently selected from hydrogen and C1-C4 alkyl, where any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope. 2 , R 3 , and R 4 are independently selected from hydrogen, CH, CHCH, CH(CH), and C(CH), where any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its alternative isotope. In some embodiments, R 2 is selected from hydrogen, CH, CHCH, CH(CH), and C(CH), where all available hydrogen atoms are optionally replaced by fluorine atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, R 2 is selected from hydrogen and deuterium, F, CH, CF, CHCH, CDCD, CFCF, CH(CH), CD(CD), CF(CF), C(CD), C(CF), and C(CH). In some embodiments, R 2is selected from hydrogen and deuterium. In some embodiments, R 2 is hydrogen.

[0098] In some embodiments, R 3 and R 4 are independently selected from hydrogen, CH, CHCH, CH(CH), and C(CH), and all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, R 3 and R 4 are independently selected from hydrogen, CH, CHCH, CH(CH), and C(CH), where all available hydrogen atoms are optionally replaced by fluorine atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, R 3 and R 4 At least one of R is deuterium, or 3 and R 4 At least one of R 3 and R 4 are independently selected from hydrogen, deuterium, F, CH, CDH, CDH, CD, CHCH, CHCHD, CHCDH, and CDCD. 3 and R 4 are independently selected from hydrogen, deuterium, F, CH, CDH, CDH, and CD. In some embodiments, R 3 and R 4 are independently selected from hydrogen, deuterium, F, CH, and CD. In some embodiments, R 3 and R 4 are independently selected from hydrogen, deuterium, and F. In some embodiments, R 3 and R 4 At least one of R 3 and R 4are both hydrogen. In some embodiments, R 3 and R 4 and R are both F. In some embodiments, R 3 and R 4 At least one of R is deuterium. 3 and R 4 are both hydrogen. In some embodiments, R 3 and R 4 are both deuterium.

[0099] In some embodiments, R 5 is selected from hydrogen and C1-C4 alkyl, where any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope. 5 is selected from hydrogen and C1-C4 alkyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, R 5 is selected from hydrogen, CH, CHCH, CH(CH), and C(CH), where all available hydrogen atoms are optionally replaced by fluorine atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, R 5 is selected from hydrogen, deuterium, F, CH, CDH, CDH, CD, CHCH, CHCHD, CHCDH, and CDCD. 5 is selected from hydrogen, deuterium, CH3, and CD3. In some embodiments, R 5 is selected from hydrogen and deuterium. In some embodiments, R 5 is selected from CH3 and CD3. In some embodiments, R 5 is CD3.

[0100] In some embodiments, R 6 , R 7 , and R 8 is hydrogen, halogen, CN, OR 9 , N(R 9 )2, SR 9 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 9 , C(O)N(R 9 )2, S(O)R 9 , SO2R 9 , C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl, and O, S, S(O), SO2, N, and NR 9 wherein the C1-C4 alkyl group, C1-C4 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, C3-C7 cycloalkyl group, and 3- to 7-membered heterocyclic group are optionally selected from CN, OR 9 , N(R 9 )2, and SR 9 and the C3-C7 cycloalkyl and 3- to 7-membered heterocycle are each optionally further substituted with one or more substituents independently selected from halogen, COR 9 , C(O)N(R 9 )2, SO2R 9 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, and O, S, S(O), SO2, N, and NR 9 wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by alternative isotopes thereof.

[0101] In some embodiments, R 6 , R 7 , and R 8 is hydrogen, halogen, CN, OR 9 , N(R 9 )2, SR 9 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 9 , C(O)N(R 9 )2, S(O)R 9 , SO2R 9 , C2-C6 alkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl, wherein the C1-C4 alkyl group, C1-C4 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, and C2-C6 haloalkynyl group are optionally selected from CN, OR 9 , N(R 9 )2, and SR 9 and all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. 6 , R 7 , and R 8 is hydrogen, F, Cl, Br, CN, OR 9 , N(R 9 )2, SR 9 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 9 , C(O)N(R 9 )2, S(O)R 9 , SO2R 9 , C2-C6 alkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl, wherein the C1-C4 alkyl group, C1-C4 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, and C2-C6 haloalkynyl group are optionally selected from CN, OR 9 , N(R 9 )2, and SR9 wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. 6 , R 7 , and R 8 is hydrogen, F, Cl, Br, CN, OR 9 , N(R 9 )2, SR 9 , CH3, CH2CH3, CH(CH3)2, C(CH3)3, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 9 , S(O)R 9 , SO2R 9 , C(O)N(R 9 )2, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, and C2-C6 alkynyl groups are optionally selected from CN, OR 9 , N(R 9 )2, and SR 9 In some embodiments, R is substituted with one or two substituents independently selected from: 6 , R 7 , and R 8 is hydrogen, F, Cl, Br, CN, OR 9 , N(R 9 )2, SR 9 , CH3, CH2CH3, CH(CH3)2, C(CH3)3, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 9 , S(O)R 9 , SO2R 9and C2-C6 alkenyl, wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by an alternative isotope thereof. 6 , R 7 , and R 8 are independently selected from hydrogen, F, Cl, Br, and CN, where any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its alternative isotope. 6 , R 7 , and R 8 are independently selected from hydrogen, deuterium, F, Cl, Br, and CN. In some embodiments, R 6 , R 7 , and R 8 are independently selected from hydrogen and deuterium. In some embodiments, R 6 , R 7 , and R 8 are all hydrogen. In some embodiments, R 6 , R 7 , and R 8 are all deuterium. In some embodiments, R 7 is selected from hydrogen, deuterium, F, Cl, Br, and CN; R 6 and R 8 is selected from hydrogen and deuterium. In some embodiments, R 7 is selected from hydrogen, deuterium, F, and CN; R 6 and R 8 is selected from hydrogen and deuterium. In some embodiments, R 7 is selected from hydrogen, F, and CN; R 6 and R 8 is selected from hydrogen and deuterium. In some embodiments, R 7 is selected from hydrogen, F, and CN; R 6 and R 8 are both hydrogen.

[0102] In some embodiments, R 6 , R 7 , and R 8 wherein the C3-C7 cycloalkyl is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein any available hydrogen atom is optionally replaced by a halogen atom, and / or any available atom is optionally replaced by an alternative isotope thereof.

[0103] In some embodiments, R 6 , R 7 , and R 8 wherein the 3- to 7-membered heterocycle is independently a saturated or unsaturated heterocycle. 6 , R 7 , and R 8 wherein the 3- to 7-membered heterocycles are independently saturated or unsaturated bridged bicyclic heterocycles. In some embodiments, the saturated or unsaturated bridged bicyclic heterocycles are independently selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl, and oxobicycloheptanenyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes.

[0104] In some embodiments, R 6 , R 7 , and R 8 wherein the 3- to 7-membered heterocycle is independently a saturated or unsaturated heterocycle. 6 , R 7 , and R 8wherein the 3- to 7-membered heterocycles are independently saturated or unsaturated bridged bicyclic heterocycles. In some embodiments, the saturated or unsaturated bridged bicyclic heterocycles are independently selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl, and oxobicycloheptanenyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes.

[0105] In some embodiments, R 6 , R 7 , and R 8 wherein the 3- to 7-membered heterocycles are independently aziridinyl, oxiranyl, thiiranyl, oxaxyridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, 1664872791326_5 , tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, 1664872791326_6 , diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, and diazepanyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes.

[0106] In some embodiments, each R 9 and R 10are independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C4 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C4 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C4 alkylenearyl, and substituted or unsubstituted C1-C4 alkyleneheteroaryl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0107] In some embodiments, each R 9 and R 10 are independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0108] In some embodiments, each R 9 and R 10 wherein the C3-C7 cycloalkyl is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein any available hydrogen atom is optionally replaced by a halogen atom, and / or any available atom is optionally replaced by an alternative isotope thereof.

[0109] In some embodiments, each R 9 and R 10The 3- to 7-membered heterocycle in the formula (I) is aziridinyl, oxiranyl, thiiranyl, oxaxyridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, 1664872791326_7 Furanyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, 1664872791326_8 , diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, and diazepanyl, wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope.

[0110] In some embodiments, each R 9 and R 10 In some embodiments, the 3- to 7-membered heterocycles in the formula (I) are independently selected from saturated or unsaturated heterocycles. 9 and R 10 wherein the 3- to 7-membered heterocycles are independently selected from saturated or unsaturated bridged bicyclic heterocycles. In some embodiments, the saturated or unsaturated bridged bicyclic heterocycles are independently selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl, and oxobicycloheptanenyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes.

[0111] In some embodiments, each R 9 and R 10 The heteroaryl in the formula (I) is 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, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl Independently selected from sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, triazolyl, and thienyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes.

[0112] In some embodiments, each R 9 and R 10 are independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and substituted or unsubstituted C1-C4 haloalkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes.9 and R 10 is independently selected from hydrogen, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C4 haloalkyl, where any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope. 9 and R 10 are independently selected from hydrogen, C1-C4 alkyl, and C2-C6 alkenyl, where any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope. 9 and R 10 are independently selected from hydrogen and C1-C4 alkyl, where any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by an alternative isotope thereof. In some embodiments, each R 9 and R 10 is independently selected from hydrogen, deuterium, CH, CDH, CDH, CD, CHCH, and CDCD. 9 and R 10 are independently selected from hydrogen, deuterium, CH3, and CD3.

[0113] In some embodiments, each R 9 and R 10are independently selected from substituted or unsubstituted C1-C4 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C4 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C4 alkylene aryl, substituted or unsubstituted C1-C4 alkylene heteroaryl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes. 9 and R 10 are independently selected from substituted or unsubstituted C1-C4 alkylenearyl and substituted or unsubstituted C1-C4 alkyleneheteroaryl, wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope. 9 and R 10 are independently substituted or unsubstituted C1-C4 alkylenearyl, in which any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope. In some embodiments, each R 9 and R 10 is independently a substituted or unsubstituted CHaryl, where any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope. In some embodiments, each R 9 and R 10 are independently substituted or unsubstituted CH2 phenyl.

[0114] R 9 and R 10is substituted, in some embodiments, the substituents are independently selected from one or more of Br, Cl, F, COH, COCH, C(O)NH, C(O)N(CH), C(O)NHCH, SOCH, C-C alkyl, C-C fluoroalkyl, C-C alkenyl, C-C fluoroalkenyl, C-C alkynyl, C-C fluoroalkynyl, C-C cycloalkyl, and a 3- to 6-membered heterocycle containing one or two ring heteromoieties selected from O, S, S(O), SO, N, NH, and NCH. 9 and R 10 The substituents above are independently selected from one to three of Br, Cl, F, C1-C4 alkyl, C1-C4 fluoroalkyl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, C2-C6 alkynyl, and C2-C6 fluoroalkynyl. 9 and R 10 The above substituents are independently selected from one or two of Br, Cl, F, CH3, and CF3.

[0115] In some embodiments, Y is a halogen. In some embodiments, the halogen in Y is selected from F, Cl, and Br. In some embodiments, the halogen in Y is selected from F and Cl. In some embodiments, the halogen in Y is F.

[0116] In some embodiments, Y is QA.

[0117] In some embodiments, Q is selected from S, S(O), and SO. In some embodiments, Q is selected from O, NR 10 and S, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, Q is selected from NR 10and O. In some embodiments, Q is O.

[0118] In some embodiments, A is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, P(O)(OR 11 )2, C1-C3 alkylene P(O)(OR 11 )2, C1-C3 alkylene C3-C7 cycloalkyl, C1-C3 alkylene C4-C6 cycloalkenyl, C1-C3 alkylene heterocycloalkyl, C1-C3 alkylene aryl, C1-C3 alkylene heteroaryl, C(O)Q', CO2Q', C(O)N(Q')2, S(O)Q', and SO2Q', wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0119] In some embodiments, A is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, C1-C3 alkyleneC3-C7 cycloalkyl, C1-C3 alkyleneC4-C6 cycloalkenyl, C1-C3 alkyleneheterocycloalkyl, C1-C3 alkylenearyl, C1-C3 alkyleneheteroaryl, where any available hydrogen atoms are optionally replaced by halogen atoms and / or any available atom is optionally replaced by its corresponding isotope.

[0120] In some embodiments, A is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, heterocycloalkyl, C1-C3 alkyleneC3-C7 cycloalkyl, C1-C3 alkyleneC4-C6 cycloalkenyl, C1-C3 alkyleneheterocycloalkyl, C1-C3 alkylenearyl, C1-C3 alkyleneheteroaryl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, A is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and heterocycloalkyl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, A is selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, A is selected from hydrogen and C1-C4 alkyl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, A is selected from hydrogen and C1-C4 alkyl, where all available hydrogen atoms are optionally replaced with fluorine atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, A is selected from hydrogen, CH3, CF3, CH2CH3, CD2CD3, CF2CF3, CH(CH3)2, CD(CD3)2, CF(CF3)2, C(CD3)3, C(CF3)3, and C(CH3)3.In some embodiments, A is selected from hydrogen, CH3, CH2CH3, CD2CD3, CH(CH3)2, CD(CD3)2, C(CD3)3, and C(CH3)3.

[0121] In some embodiments, A is selected from C1-C3 alkyleneC3-C7 cycloalkyl, C1-C3 alkyleneC4-C6 cycloalkenyl, C1-C3 alkyleneheterocycloalkyl, C1-C3 alkylenearyl, and C1-C3 alkyleneheteroaryl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, A is selected from CH2C3-C7 cycloalkyl, CH2C4-C6 cycloalkenyl, CH2 heterocycloalkyl, CH2 aryl, and CH2 heteroaryl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, A is selected from CH2C3-C7 cycloalkyl, CH2 aryl, and CH2 heteroaryl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, A is CH2 aryl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, A is CH2 phenyl.

[0122] In some embodiments, A is hydrogen, P(O)(OR 11 )2, CH2P(O)(OR 11 )2, CH2CH2P(O)(OR 11 )2, CH2CH(CH3)P(O)(OR11 )2, CH(CH3)CH2P(O)(OR 11 )2, CH(CH3)P(O)(OR 11 )2, CH(CH2CH3)P(O)(OR 11 )2, C(O)Q', CO2Q', C(O)N(Q')2, S(O)Q', and SO2Q', where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0123] In some embodiments, A is hydrogen, P(O)(OR 11 )2, CH2P(O)(OR 11 )2, CH(CH3)P(O)(OR 11 In some embodiments, A is selected from hydrogen, P(O)(OR), C(O)N(Q'), C(O)Q', C(O)N(Q'), S(O)Q', and SO2Q', where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, A is selected from S(O)Q' and SO2Q', where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, A is selected from hydrogen, P(O)(OR), C(O)N(Q'), C(O)Q', C(O)N(Q'), S(O)Q', and SO2Q', where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. 11 )2, CH2P(O)(OR 11 )2, CH(CH3)P(O)(OR 11 )2, C(O)N(Q')2, and C(O)Q'. In some embodiments, A is selected from hydrogen, P(O)(OR 11)2, and C(O)Q'. In some embodiments, A is hydrogen. In some embodiments, A is C(O)N(Q')2, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, A is P(O)(OR 11 )2, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, A is C(O)Q', where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof.

[0124] In some embodiments, A is selected from C-C cycloalkyl, C-C cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope.

[0125] In some embodiments, the C3-C7 cycloalkyl in A is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope.

[0126] In some embodiments, the C4-C7 cycloalkenyl in A is selected from cyclobutenyl, cyclopentenyl, and cyclohexenyl, wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope.

[0127] In some embodiments, the 3- to 7-membered heterocycle in A is aziridinyl, oxiranyl, thiiranyl, oxaxyridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, 1664872791326_9 Furanyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, 1664872791326_10 , diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, and diazepanyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes.

[0128] In some embodiments, the 3- to 7-membered heterocycle in A is a saturated or unsaturated heterocycle. In some embodiments, the 3- to 7-membered heterocycle in A is a saturated or unsaturated bridged bicyclic heterocycle. In some embodiments, the saturated or unsaturated bridged bicyclic heterocycle is selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl, and oxobicycloheptanenyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes.

[0129] In some embodiments, the heteroaryl in A is 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, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl and selected from sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, triazolyl, and thienyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their corresponding isotopes.

[0130] In some embodiments, each R 11 are independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C4 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C4 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C4 alkylenearyl, and substituted or unsubstituted C1-C4 alkyleneheteroaryl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0131] In some embodiments, each R 11 are independently selected from hydrogen, C1-C4 alkyl, and C2-C6 alkenyl, where any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope. 11 are independently selected from hydrogen and C1-C4 alkyl, where any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by an alternative isotope thereof. In some embodiments, each R 11 are independently selected from hydrogen and C1-C4 alkyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, each R 11is independently selected from hydrogen, deuterium, CH, CDH, CDH, CD, CHCH, and CDCD. 11 is independently selected from hydrogen, deuterium, CH, and CD. In some embodiments, each R 11 is H.

[0132] In some embodiments, each R 11 are independently selected from substituted or unsubstituted C1-C4 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C4 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C4 alkylene aryl, substituted or unsubstituted C1-C4 alkylene heteroaryl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes. 11 are independently selected from substituted or unsubstituted C1-C4 alkylenearyl and substituted or unsubstituted C1-C4 alkyleneheteroaryl, wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope. 11 are independently substituted or unsubstituted C1-C4 alkylenearyl, where any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope. 11 is independently a substituted or unsubstituted CHaryl, where any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope. In some embodiments, each R 11 are independently substituted or unsubstituted CH2 phenyl.

[0133] R 11 is substituted, in some embodiments, the substituents are independently selected from one or more of Br, Cl, F, COH, COCH, C(O)NH, C(O)N(CH), C(O)NHCH, SOCH, C-C alkyl, C-C fluoroalkyl, C-C alkenyl, C-C fluoroalkenyl, C-C alkynyl, C-C fluoroalkynyl, C-C cycloalkyl, and a 3- to 6-membered heterocycle containing one or two ring heteromoieties selected from O, S, S(O), SO, N, NH, and NCH. 11 The substituents above are independently selected from one to three of Br, Cl, F, C1-C4 alkyl, C1-C4 fluoroalkyl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, C2-C6 alkynyl, and C2-C6 fluoroalkynyl. 11 The above substituents are independently selected from one or two of Br, Cl, F, CH3, and CF3.

[0134] In some embodiments, Q′ is selected from hydrogen, C1-C20 alkyl, C1-C20 haloalkyl, C2-C20 alkenyl, C2-C20 haloalkenyl, C2-C20 alkynyl, and C2-C20 haloalkynyl, wherein the C1-C20 alkyl, C2-C20 haloalkyl, C2-C6 alkenyl, C2-C20 haloalkenyl, C2-C20 alkynyl, and C2-C20 haloalkynyl groups are selected from CN, OR 10 , N(R 10 )2, CO2R 10 , S.R. 10 , optionally substituted with 1 to 3 substituents independently selected from C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterocycle, and / or with C1-C6 alkyl, or To form a C3-C7 cycloalkyl ring Optionally disubstituted on the same carbon atom by C2-C6 alkylene R,and each of the C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterocycle is further optionally substituted with a substituent selected from C1-C3 alkyl and C1-C3 haloalkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, Q' is selected from hydrogen, C1-C20 alkyl, C2-C20 alkenyl, and C2-C20 alkynyl, wherein the C1-C20 alkyl, C2-C6 alkenyl, and C20 alkynyl groups are optionally selected from CN, OR 10 , N(R 10 )2, CO2R 10 , and S.R. 10 wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by alternative isotopes thereof.

[0135] In some embodiments, Q′ is selected from C1-C20 alkyl, C2-C20 alkenyl, and C2-C20 alkynyl, wherein said C1-C20 alkyl, C2-C6 alkenyl, and C2-C20 alkynyl are selected from N(R 10 )2 and CO2R 10 and / or by C1-C6 alkyl, or To form a C3-C7 cycloalkyl ring Optionally disubstituted on the same carbon atom by C2-C6 alkylene R,wherein the C3-C7 cycloalkyl is further optionally substituted with a substituent selected from C1-C3 alkyl and C1-C3 haloalkyl, wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by an alternative isotope thereof. In some embodiments, Q' is N(R 10 )2 and CO2R 10 and / or by C1-C6 alkyl, or To form a C3-C7 cycloalkyl ring Optionally disubstituted on the same carbon atom by C2-C6 alkylene Ta , C1-C20 alkyl, C2-C20 alkenyl, and C2-C20 alkynyl, wherein the C3-C7 cycloalkyl ring is further optionally substituted with a substituent selected from C1-C3 alkyl and C1-C3 haloalkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof.

[0136] In some embodiments, Q′ is N(R 10 )2 and / or To form a C3-C7 cycloalkyl ring Disubstituted on the same carbon atom by C2-C6 alkylene Ta , C1-C20 alkyl, or C2-C20 alkenyl, wherein the C3-C7 cycloalkyl ring is further optionally substituted with a substituent selected from C1-C3 alkyl and C1-C3 haloalkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof.

[0137] In some embodiments, Q′ is N(R 10In some embodiments, Q′ is a C1-C20 alkyl or C2-C20 alkenyl substituted with N(R )2, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. 10 In some embodiments, Q′ is a C1-C20 alkyl substituted with N(R )2, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. 10 In some embodiments, Q′ is a C1-C10 alkyl substituted with N(R 10 ) C1-C10 alkyl substituted with 2, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium.

[0138] In some embodiments, Q′ is N(R 10 )2 and To form a C3-C7 cycloalkyl ring Disubstituted on the same carbon atom by C2-C6 alkylene Ta , C1-C20 alkyl, or C2-C20 alkenyl, wherein the C3-C7 cycloalkyl ring is further optionally substituted with a substituent selected from C1-C3 alkyl and C1-C3 haloalkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, Q' is N(R 10 )2 and To form a C3-C7 cycloalkyl ringDisubstituted on the same carbon atom by C2-C6 alkylene Ta , C1-C20 alkyl, wherein the C3-C7 cycloalkyl ring is further optionally substituted with a substituent selected from C1-C3 alkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, Q' is N(R 10 )2 and To form a C3-C7 cycloalkyl ring Disubstituted on the same carbon atom by C2-C6 alkylene Ta , C1-C10 alkyl, wherein the C3-C7 cycloalkyl ring is further optionally substituted with a substituent selected from C1-C3 alkyl, and all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, Q' is N(R 10 )2 and To form a C5-C6 cycloalkyl ring Disubstituted on the same carbon atom by C2-C6 alkylene Ta , C1-C10 alkyl, wherein the C3-C7 cycloalkyl ring is further optionally substituted with a substituent selected from C1-C3 alkyl, and all available hydrogen atoms are optionally substituted with opt In some embodiments, Q′ is N(R 10 )2 and To form a spirocyclohexanyl ring Disubstituted on the same carbon atom by C2-C6 alkylene Ta , C1-C10 alkyl, and all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available hydrogen atoms are optionally replaced by deuterium.

[0139] In some embodiments, Q′ is COR 10 In some embodiments, Q′ is C0R, optionally substituted with C0R, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. 10 In some embodiments, Q′ is C0R, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. 10 In some embodiments, Q′ is C0R, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. 10 wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium.

[0140] In some embodiments, Q' is a C1-C20 alkyl or a C2-C20 alkenyl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with their corresponding isotopes. In some embodiments, Q' is a C1-C20 alkyl or a C2-C20 alkenyl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available hydrogen atoms are optionally replaced with deuterium. In some embodiments, when Q' is a C1-C20 alkyl, Q' is a saturated fatty acid derivative, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available hydrogen atoms are optionally replaced with deuterium. In some embodiments, when Q' is C2-C20 alkenyl, Q' is an unsaturated fatty acid derivative in which all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium.

[0141] In some embodiments, Q' is C1-C10 alkyl or C2-C10 alkenyl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, Q' is C1-C6 alkyl or C2-C6 alkenyl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, Q' is C1-C4 alkyl or C2-C4 alkenyl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, Q' is C1-C4 alkyl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In certain embodiments, Q' is selected from CH3, CF3, CD2H, CDH2, CD3, CH2CH3, CF2CF3, and CD2CD3.

[0142] In some embodiments, Q' is selected from hydrogen and deuterium.

[0143] In some embodiments, Q′ is selected from the group consisting of C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and O, S, S(O), SO2, N, and NR 10 wherein the C3-C7 cycloalkyl group, the C4-C7 cycloalkenyl group, and the 3- to 7-membered heterocyclic group are optionally selected from CN, OR 10 , N(R 10 )2, CO2R 10 , S.R. 10, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterocycle, wherein each of the C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterocycle is each further optionally substituted with a substituent selected from C1-C3 alkyl; and wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by alternative isotopes thereof.

[0144] In some embodiments, Q′ is selected from the group consisting of C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and O, S, N, S(O), SO2, and NR 10 wherein the C3-C7 cycloalkyl group, the C4-C7 cycloalkenyl group, and the 3- to 7-membered heterocyclic group are optionally selected from N(R 10 )2 and CO2R 10 wherein said C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterocycle are each further optionally substituted with a substituent selected from C1-C3 alkyl; and wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by alternative isotopes thereof.

[0145] In some embodiments, Q′ is selected from the group consisting of C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and O, N, and NR 10 wherein the C3-C7 cycloalkyl group, the C4-C7 cycloalkenyl group, and the 3- to 7-membered heterocyclic group are optionally selected from CN, OR 10 , N(R 10 )2, CO2R10 , S.R. 10 and 3- to 7-membered heterocycle, wherein each of the C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterocycle is each further optionally substituted with a substituent selected from C1-C3 alkyl and C1-C3 haloalkyl; wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes. In some embodiments, Q' is selected from C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and O, N, and NR 10 wherein the C3-C7 cycloalkyl group, the C4-C7 cycloalkenyl group, and the 3- to 7-membered heterocyclic group are optionally selected from N(R 10 )2, CO2R 10 and 3- to 7-membered heterocycles, and each of the C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterocycles is each further optionally substituted with a substituent selected from C1-C3 alkyl and C1-C3 haloalkyl; wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes. In some embodiments, Q' is selected from the group consisting of N and NR 10 wherein the 3- to 7-membered heterocyclic group is optionally selected from CN, OR 10 , N(R 10 )2, CO2R 10 , S.R. 10and a 3- to 7-membered heterocycle, each of which is further optionally substituted with a substituent selected from C1-C3 alkyl; wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes. In some embodiments, Q' is selected from the group consisting of N and NR 10 wherein the 3- to 7-membered heterocyclic group is optionally substituted with a 3- to 7-membered heterocycle, wherein each of the 3- to 7-membered heterocycles is further optionally substituted with a substituent selected from C1-C3 alkyl; and wherein all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, Q' is selected from the group consisting of N and NR 10wherein the 5- to 6-membered heterocyclic group is optionally substituted with a 5- to 6-membered heterocycle, wherein all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, Q' is piperidinyl or pyrrolidinyl substituted with piperidinyl or pyrrolidinyl, wherein all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, Q' is piperidinyl substituted with piperidinyl, wherein all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof.

[0146] In some embodiments, the C3-C7 cycloalkyl in Q' is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by an alternative isotope thereof.

[0147] In some embodiments, the C4-C7 cycloalkenyl in Q' is selected from cyclobutenyl, cyclopentenyl, and cyclohexenyl, wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope.

[0148] In some embodiments, the 3- to 7-membered heterocycle in Q' is aziridinyl, oxiranyl, thiiranyl, oxaxyridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, 1664872791326_11 Furanyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, 1664872791326_12 , diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, and diazepanyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes.

[0149] In some embodiments, the 3- to 7-membered heterocycle in Q' is a saturated or unsaturated heterocycle. In some embodiments, the 3- to 7-membered heterocycle in Q' is a saturated or unsaturated bridged bicyclic heterocycle. In some embodiments, the saturated or unsaturated bridged bicyclic heterocycle is selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl, and oxobicycloheptanenyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes.

[0150] In some embodiments, the heteroaryl in Q' is 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, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl and selected from sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, triazolyl, and thienyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their corresponding isotopes.

[0151] In some embodiments, Q' is selected from the groups listed below. [ka] where: [ka] indicates a point of covalent attachment.

[0152] In some embodiments, A is C(O)Q' and Q' is selected from the groups listed above.

[0153] In certain embodiments, A is C(O)N(Q')2, and each Q' is C1-C4 alkyl or C2-C4 alkenyl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In certain embodiments, each Q' is C1-C4 alkyl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In certain embodiments, Q' is selected from CH3, CF3, CD2H, CDH2, CD3, CH2CH3, CF2CF3, and CD2CD3. In certain embodiments, A is C(O)N(Q')2, and each Q' is CH3 or CD3.

[0154] In some embodiments, Y is QA and Q is O, and the compound of formula (I) is a compound of formula (IA). Thus, in some embodiments, the present application encompasses compounds of formula (IA) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] During the ceremony, A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is as defined in formula (I), wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof; however A is CH3, Q is O, and R 1is H or CH3, and R 2 , R 3 , R 4 , and R 5 If all are hydrogen, R 6 , R 7 , and / or R 8 is not OCH3; When A is CH3 and Q is O, R 1 ~R 8 is not all hydrogen; and A is hydrogen, Q is O, and R 1 , R 2 , and R 5 One of the groups is methyl and the other is R 1 , R 2 , and R 5 If the remaining two of 3 , R 4 , and R 6 ~R 8 is not all hydrogen.

[0155] In some embodiments, Y is QA, Q is O, and A is P(O)(OR 11 )2, and the compound of formula (I) is a compound of formula (IB). Thus, in some embodiments, the present application encompasses compounds of formula (IB) and pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] During the ceremony: R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R 11 is as defined in formula (I), wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0156] In some embodiments, Y is QA, Q is O, and A is C(O)Q', and the compound of formula (I) is a compound of formula (IC). Thus, in some embodiments, the present application encompasses compounds of formula (IC) and pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] During the ceremony: Q′, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 is as defined in formula (I), wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0157] In some embodiments, Y is QA, Q is O, and A is P(O)(OH), and R 1 , R 2 , R 6 , R 7 , and R 8 are all H, and the compound of formula (I) is a compound of formula (ID). Thus, in some embodiments, the present application encompasses compounds of formula (ID) and pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] During the ceremony: R 3 , R 4 , and R 5 is as defined in formula (I), wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0158] In some embodiments, Y is QA, Q is O, and A is CHP(O)(OH), and R 1 , R 2 , R 6 , R 7 , and R 8 are all H, the compound of formula (I) is a compound of formula (IE). Thus, in some embodiments, the present application encompasses compounds of formula (IE) and pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] During the ceremony: R 3 , R 4 , and R 5 is as defined in formula (I), wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0159] In some embodiments, Y is QA, Q is O, and A is H, and R 1 is CH2P(O)(OH)2 and R 2 , R 6 , R 7 , and R 8 are all H, and the compound of formula (I) is a compound of formula (IF). Thus, in some embodiments, the present application encompasses compounds of formula (IF) and pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] During the ceremony: R 3 , R 4 , and R 5 is as defined in formula (I), wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0160] In some embodiments, Y is QA, Q is O, and A is C(O)Q′, and R 1 , R 2 , R 6 , R 7 , and R 8 are all H, and the compound of formula (I) is a compound of formula (IG). Thus, in some embodiments, the present application encompasses compounds of formula (IG) and pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] During the ceremony: Q′, R 3 , R 4 , and R 5 is as defined in formula (I), wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0161] In some embodiments, Y is QA, Q is O, and A is H, and R 1 , R 2 , R 6 , R 7 , and R 8 are all H, and the compound of formula (I) is a compound of formula (IH). Thus, in some embodiments, the present application encompasses compounds of formula (IH) and pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] During the ceremony: R 3 , R 4 , and R 5 is as defined in formula (I), wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0162] In some embodiments, Y is QA, Q is O, and A is P(O)(OH), and R 1 , R 2 , R 6 , R 7 , and R 8 are all H, and the compound of formula (I) is a compound of formula (II). Thus, in some embodiments, the present application encompasses compounds of formula (II) and pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] During the ceremony: R 3 , R 4 , and R 5 is as defined in formula (I), wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0163] In some embodiments, Y is QA and the compound of formula (I) is a compound of formula (IJ). Thus, in some embodiments, the present application encompasses a compound of formula (IJ) or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof. [ka] During the ceremony: Q, A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is as defined in formula (I), wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0164] In some embodiments, Y is halogen and the compound of Formula (I) is a compound of Formula (IK). Thus, in some embodiments, the present application encompasses compounds of Formula (IK) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] During the ceremony: Y is a halogen, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is as defined in formula (I), wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0165] In some embodiments, in the compound of Formula (IK), Y is selected from F, Cl, and Br. In some embodiments, in the compound of Formula (IK), Y is selected from F and Br. In some embodiments, in the compound of Formula (IK), Y is F.

[0166] In some embodiments, Y is QA, Q is O, and R 1 , R 2 , R 6 , R 7 , and R 8 are all H, and the compound of formula (I) is a compound of formula (IH). Thus, in some embodiments, the present application encompasses compounds of formula (IH) and pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] During the ceremony: A is C1-C6 alkyl; and R 3 , R 4 , and R 5 is as defined in formula (I), wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes, with the proviso that: A is CH3, Q is O, and R 1 is H or CH3, and R 2 , R 3 , R 4 , and R 5 If all are hydrogen, R 6 , R 7 , and / or R 8 is not OCH3; When A is CH3 and Q is O, R 1 ~R 8 is not all hydrogen.

[0167] In some embodiments, A in the compound of Formula (IL) is selected from CH3, CD2H, CDH2, CD3, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, A in the compound of Formula (IL) is selected from CH3, CD3, CH2CH3, and CD2CD3. In some embodiments, A in the compound of Formula (IL) is selected from CH3 and CD3.

[0168] In some embodiments, in compounds of Formulae (IA)-(IC), (IJ), and (IK), R 1 is hydrogen, C1-C3 alkyl, and C1-C3 alkylene P(O)(OR 9 )2, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, in compounds of formulae (IA)-(IC), (IJ), and (IK), R 1 is CH2P(O)(OR 9 )2 and CH(CH3)P(O)(OR 9 )2, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, in compounds of formulae (IA)-(IC), (IJ), and (IK), R 1 is CH2P(O)(OR 9 )2, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, in compounds of formulae (IA)-(IC), (IJ), and (IK), R 1 is CH2P(O)(OR 9)2. In some embodiments, in compounds of formulae (IA)-(IC), (IJ), and (IK), R 1 is CH2P(O)(OH)2.

[0169] In some embodiments, in compounds of Formulae (IA)-(IL), R 3 and R 4 At least one of R is deuterium, or 3 and R 4 In some embodiments, in compounds of formula (IA)-(IL), at least one of R 3 and R 4 At least one of R is deuterium, or 3 and R 4 In some embodiments, in compounds of formula (IA)-(IL), at least one of R 3 and R 4 is independently selected from hydrogen, deuterium, F, CH, CDH, CDH, CD, CHCH, CHCHD, CHCDH, and CDCD. In some embodiments, in compounds of Formulae (IA)-(IL), R 3 and R 4 is independently selected from hydrogen, deuterium, F, CH, CDH, CDH, and CD. In some embodiments, in compounds of Formula (IA)-(IL), R 3 and R 4 is independently selected from hydrogen, deuterium, F, CH3, and CD3. In some embodiments, in compounds of Formula (IA)-(IL), R 3 and R 4 is independently selected from hydrogen, deuterium, and F. In some embodiments, in compounds of Formulae (IA)-(IL), R 3 and R 4 and at least one of R is F. In some embodiments, in compounds of Formulae (IA)-(IL), 3 and R 4 In some embodiments, in compounds of formula (IA)-(IL), at least one of R3 and R 4 and R are both hydrogen. In some embodiments, in compounds of Formula (IA)-(IL), R 3 and R 4 are both deuterium.

[0170] In some embodiments, in compounds of Formulae (IA)-(IL), R 3 and R 4 At least one of R is deuterium, or 3 and R 4 At least one of R contains deuterium, and 5 is selected from hydrogen, deuterium, CH, CDH, CDH, CD, CHCH, CHCHD, CHCDH, and CDCD. In some embodiments, in compounds of Formulae (IA)-(IL), R 3 and R 4 At least one of R is deuterium, and 5 is selected from hydrogen, deuterium, CH, CD, CHCH, and CDCD. In some embodiments, in compounds of Formula (IA)-(IL), R 3 and R 4 are both hydrogen or R 3 and R 4 are both deuterium and R 5 is selected from hydrogen, deuterium, CH, CD, CHCH, and CDCD. In some embodiments, in compounds of Formula (IA)-(IL), R 3 and R 4 are both hydrogen or R 3 and R 4 are both deuterium, and R 5 is selected from hydrogen, CH3, and CD3. In some embodiments, in compounds of Formula (IA)-(IL), R 3 and R 4 are both deuterium, and R 5 is selected from hydrogen, CH3, and CD3.

[0171] In some embodiments, in compounds of Formula (IA) and Formula (IJ) where A is C(O)Q', CO2(Q'), C(O)N(Q'), SO(Q'), SO2(Q'), and in compounds of Formula (IG), Q' is selected from hydrogen, C1-C20 alkyl, and C2-C20 alkenyl, wherein said C1-C20 alkyl and C2-C6 alkenyl are optionally selected from N(R 10 )2 and CO2R 10 wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by alternative isotopes thereof.

[0172] In some embodiments, in compounds of Formula (IA) and Formula (IJ), when A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), and in compounds of Formula (IG), Q' is selected from hydrogen and deuterium.

[0173] In some embodiments, in compounds of Formula (IA) and Formula (IJ), when A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), and in compounds of Formula (IG), Q' is CO2R 10 wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, in compounds of formula (IA) and formula (IJ), when A is C(O)Q', CO2(Q'), C(O)N(Q'), SO(Q'), SO2(Q'), and in compounds of formula (IG), Q' is CO2R 10wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, in compounds of formula (IA) and formula (IJ) where A is C(O)Q', CO2(Q'), C(O)N(Q'), SO(Q'), SO2(Q'), and in compounds of formula (IG), Q' is [ka] is selected from: [ka] indicates a covalent bond point.

[0174] In some embodiments, in compounds of formula (IA) and formula (IJ), when A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), and in compounds of formula (IG), Q' is C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and O, S, N, S(O), SO2, and NR 10 wherein the C3-C7 cycloalkyl group, the C4-C7 cycloalkenyl group, and the 3- to 7-membered heterocyclic group are optionally selected from N(R 10 )2 and CO2R 10and wherein each of the C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterocycle is further optionally substituted with a substituent selected from C1-C3 alkyl; wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, in compounds of formula (IA) and formula (IJ), when A is C(O)Q', CO2(Q'), C(O)N(Q'), SO(Q'), SO2(Q'), and in compounds of formula (IG), Q' is [ka] wherein: [ka] indicates a covalent bond point.

[0175] In some embodiments, in compounds of Formula (IA) and Formula (IJ) where A is C(O)Q', CO2(Q'), C(O)N(Q'), SO(Q'), SO2(Q'), and in compounds of Formula (IG), Q' is C1-C4 alkyl or C2-C4 alkenyl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, Q' is C1-C4 alkyl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, in compounds of Formula (IA) and Formula (IJ) where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), and in compounds of Formula (IG), Q' is selected from CH3, CF3, CD2H, CDH2, CD3, CH2CH3, CF2CF3, and CD2CD3.

[0176] In some embodiments, in compounds of Formula (IA) and Formula (IJ) where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), and in compounds of Formula (IG), Q' is a C1-C20 alkyl or a C2-C20 alkenyl, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available hydrogen atoms are optionally replaced with deuterium. [ka] During the ceremony, [ka] represents a point of covalent attachment. In some embodiments, Q' is [ka] wherein: [ka] indicates a covalent bond point.

[0177] In some embodiments, in compounds of Formula (IA) and Formula (IJ), when A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), Q' is N(R 10 )2, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, in compounds of formula (IA) and formula (IJ), when A is C(O)Q', CO2(Q'), C(O)N(Q'), SO(Q'), SO2(Q'), and in compounds of formula (IG), Q' is N(R 10 )2-substituted C1-C10 alkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, Q' is [ka] is selected from: [ka] indicates a covalent bond point.

[0178] In some embodiments, in compounds of Formula (IA) and Formula (IJ), when A is C(O)Q', CO2(Q'), C(O)N(Q'), SO(Q'), SO2(Q'), and in compounds of Formula (IG), Q' is N(R 10 )2 and To form a C3-C7 cycloalkyl ring Disubstituted on the same carbon atom by C2-C6 alkylene Ta , C1-C20 alkyl, wherein the C3-C7 cycloalkyl ring is further optionally substituted with a substituent selected from C1-C3 alkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, in compounds of formula (IA) and formula (IJ), when A is C(O)Q', CO2(Q'), C(O)N(Q'), SO(Q'), SO2(Q'), and in compounds of formula (IG), Q' is N(R 10 )2 and To form a spirocyclohexanyl ring Disubstituted on the same carbon atom by C2-C6 alkylene Ta , C1-C10 alkyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, in compounds of formula (IA) and formula (IJ) where A is C(O)Q', CO2(Q'), C(O)N(Q'), SO(Q'), SO2(Q'), and in compounds of formula (IG), Q' is [ka] wherein: [ka] indicates a covalent bond point.

[0179] In some embodiments, in compounds of formula (IA) and formula (IJ), when A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), and in compounds of formula (IG), Q' is N and NR 10 wherein the 3- to 7-membered heterocyclic group is optionally selected from CN, OR 10 , N(R 10 )2, CO2R 10 , S.R. 10 and a 3- to 7-membered heterocycle, each of which is further optionally substituted with a substituent selected from C1-C3 alkyl; wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, in compounds of formula (IA) and formula (IJ), when A is C(O)Q', CO2(Q'), C(O)N(Q'), SO(Q'), SO2(Q'), and in compounds of formula (IG), Q' is selected from N and NR 10wherein the 5- to 6-membered heterocyclic group is optionally substituted with a 5- to 6-membered heterocycle, wherein all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, in compounds of formula (IA) and formula (IJ), when A is C(O)Q', CO2(Q'), C(O)N(Q'), SO(Q'), SO2(Q'), and in compounds of formula (IG), Q' is piperidinyl substituted with piperidinyl, wherein all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with alternative isotopes thereof. In some embodiments, in compounds of Formula (IA) and Formula (IJ) where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), and in compounds of Formula (IG), Q' is [ka] wherein: [ka] indicates a covalent bond point.

[0180] In some embodiments, in compounds of Formulae (IA)-(IC), (IJ), and (IK), R 6 , R 7 , and R 8 is hydrogen, F, Cl, Br, CN, OR 9 , N(R 9 )2, SR 9 , CH3, CH2CH3, CH(CH3)2, C(CH3)3, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 9 , S(O)R 9 , SO2R9 and C2-C6 alkenyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, in compounds of formula (IA)-(IC), (IJ) and (IK), R 6 , R 7 , and R 8 are independently selected from hydrogen, F, Cl, Br, and CN, where any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its alternative isotope. In some embodiments, R 6 , R 7 , and R 8 is independently selected from hydrogen, deuterium, F, Cl, Br, and CN. In some embodiments, in compounds of formula (IA)-(IC), (IJ), and (IK), R 6 , R 7 , and R 8 is independently selected from hydrogen and deuterium. In some embodiments, in compounds of formula (IA)-(IC), (IJ) and (IK), R 6 , R 7 , and R 8 are all hydrogen. In some embodiments, in compounds of formula (IA)-(IC), (IJ) and (IK), R 6 , R 7 , and R 8 are all deuterium. In some embodiments, in compounds of Formulae (IA)-(IC), (IJ), and (IK), R 7 is selected from hydrogen, deuterium, F, Cl, Br, and CN, and R 6 and R 8 is selected from hydrogen and deuterium. In some embodiments, in compounds of Formulae (IA)-(IC), (IJ) and (IK), R 7 is selected from hydrogen, deuterium, F, and CN, and R 6 and R8 is selected from hydrogen and deuterium. In some embodiments, in compounds of Formulae (IA)-(IC), (IJ) and (IK), R 7 is selected from hydrogen, F, and CN, and R 6 and R 8 is selected from hydrogen and deuterium. In some embodiments, in compounds of Formulae (IA)-(IC), (IJ) and (IK), R 7 is selected from hydrogen, F, and CN, and R 6 and R 8 are both hydrogen. In some embodiments, the compound of Formula (I) is selected from the following, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: (R)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-yl dihydrogen phosphate; (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-ol; ((R)-3-(pyrrolidin-2-ylmethyl)-1H-indol-4-ol; (S)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-yl dihydrogen phosphate; (S)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-yl dihydrogen phosphate; (R)-3-(pyrrolidin-2-ylmethyl)-1H-indol-4-yl dihydrogen phosphate; (S)-3-(pyrrolidin-2-ylmethyl)-1H-indol-4-yl dihydrogen phosphate; (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl dihydrogen phosphate; (S)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl dihydrogen phosphate; (S)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-4-yl dihydrogen phosphate; (R)-(((3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-yl)oxy)methyl)phosphonic acid; (R)-(((3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl)oxy)methyl)phosphonic acid; (R)-((4-hydroxy-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-1-yl)methyl)phosphonic acid; (R)-((4-hydroxy-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-1-yl)methyl)phosphonic acid; (R)-((4-hydroxy-3-(pyrrolidin-2-ylmethyl)-1H-indol-1-yl)methyl)-phosphonic acid; (R)-((3-((1-methylpyrrolidin-2-yl)methyl)-4-(phosphonooxy)-1H-indol-1-yl)methyl)-phosphonic acid; (1-((3-(((R)-1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-yl)oxy)ethyl)phosphonic acid; (1-((3-(((R)-pyrrolidin-2-yl)methyl)-1H-indol-4-yl)oxy)ethyl)phosphonic acid; (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl glycinate; 3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl D-alaninate; (R,Z)-4-((3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl)oxy)-4-oxobut-2-enoic acid; (R,E)-4-((3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl)oxy)-4-oxobut-2-enoic acid; (R)-4-((3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl)oxy)-4-oxobutanoic acid; (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl acetate; (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-4-yl acetate; (R)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-yl acetate; (R)-((4-acetoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-1-yl)methyl)phosphonic acid; 3-(((R)-1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-yl (9Z,12Z)-octadeca-9,12-dienoate; 3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl (9Z,12Z)-octadeca-9,12-dienoate-11,11-d2; 3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-4-yl (9Z,12Z)-octadeca-9,12-dienoate-11,11-d2; 3-(((R)-1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-yl (9Z,12Z)-octadeca-9,12-dienoate-11,11-d2; 3-(((R)-1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-yl (S)-3-(aminomethyl)-5-methylhexanoate; 3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl (S)-3-(aminomethyl)-5-methylhexanoate; (R)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-yl 2-(1-(aminomethyl)-cyclohexyl)acetate; (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl 2-(1-(aminomethyl)cyclohexyl)-acetate; (R)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-yl [1,4'-bipiperidine]-1'-carboxylate; (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl dimethylcarbamate; (R)-4-fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole; (R)-4-chloro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole; (R)-4-Methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole; (R)-4-fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole; (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl-d2)-1H-indole; (S)-4-fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole; (R)-4-(benzyloxy)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole; (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-4-ol; (R)-4-(benzyloxy)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole; (R)-4-(benzyloxy)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole; (R)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-ol; 3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl (9Z,12Z)-octadeca-9,12-dienoate; 3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-4-yl (9Z,12Z)-octadeca-9,12-dienoate; (R)-3-(pyrrolidin-2-ylmethyl-d2)-1H-indol-4-ol; (S)-3-(pyrrolidin-2-ylmethyl-d2)-1H-indol-4-ol; (S)-4-(benzyloxy)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole; (S)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-ol; and (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-4-yl dihydrogen phosphate,

[0181] In some embodiments, the compound of Formula (I) is selected from the compounds listed below or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] Table 7 Table 8 Table 9 Table 10 Table 11 Table 12

[0182] In some embodiments, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. The selection of an appropriate salt can be performed by one skilled in the art. Suitable salts include, for example, acid addition salts that can be formed by mixing a solution of a compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Additionally, acids generally considered suitable for forming pharmaceutically useful salts from the base pharmaceutical compound 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, DC on their website).

[0183] Acid addition salts suitable for or compatible with the treatment of subjects 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 amine groups.Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids. Illustrative examples of such organic acids include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In some embodiments, exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate (mesylate), naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also called tosylate), and the like. In some embodiments, the mono- or di-acid salts are formed, and such salts exist in either a hydrated, solvated, or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points than their free base forms. Criteria for selecting an appropriate salt will be known to those skilled in the art. Other non-pharmaceutically acceptable salts, including but not limited to oxalates, may be used, for example, in the isolation of the claimed compounds for laboratory use or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0184] Base addition salts suitable for or compatible with the treatment of subjects include any non-toxic organic or inorganic base addition salts of any acidic compound. Acidic compounds that form base addition salts include, for example, compounds containing a carboxylic acid group. Exemplary inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide, as well as ammonia. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. For example, if an ester functionality is present elsewhere in the compound, selecting an appropriate salt can be useful to prevent it from being hydrolyzed. Those skilled in the art will know the criteria for selecting an appropriate salt. In some embodiments, exemplary base salts include alkali metal salts such as ammonium salts, sodium salts, lithium salts, and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with organic bases (e.g., organic amines) such as dicyclohexylamine, abutylamine, and choline, and salts with amino acids such as arginine and lysine. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, and dibutyl sulfate), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl bromide and phenethyl bromide), and the like.Compounds having an acidic moiety can also be mixed with suitable pharmaceutically acceptable salts to give, for example, salts formed with suitable organic ligands, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and quaternary ammonium salts. Also, when an acid (—COOH) or alcohol group is present, pharmaceutically acceptable esters can be used to modify the solubility or hydrolysis characteristics of the compound.

[0185] All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of this application, and all acid and base salts are considered equivalent, for purposes of this application, to the free form of the corresponding compound. Additionally, when compounds of this application contain both a basic moiety (such as, but not limited to, an aliphatic primary, secondary, tertiary, or cyclic amine, an aromatic amine, or a heteroaryl amine, pyridine, or imidazole) and an acidic moiety (such as, but not limited to, a tetrazole or a carboxylic acid), zwitterions (inner salts) may be formed, and such zwitterions are also encompassed by the term "salt" herein. It is understood that certain compounds of this application may exist in zwitterionic form, having both an anionic and a cationic center in the same molecule and a net neutral charge. Such zwitterions are encompassed herein.

[0186] Solvates of the compounds of the present application include, for example, those formed with pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvates are called hydrates) and ethanol. Suitable solvents are physiologically tolerable at the administered dosage.

[0187] It is understood and appreciated that in some embodiments, the compounds of the present application may have at least one chiral center and therefore may exist as enantiomers and / or diastereomers. It is to be understood that all such isomers, and mixtures thereof in any proportion, are within the scope of the present application. The stereochemistry of the compounds may be as shown in any given compound listed in this disclosure, but it is further understood that the compounds may also contain amounts (e.g., less than 20%, preferably less than 10%, more preferably less than 5%) of compounds of the present application having alternative stereochemistries. Any optical isomer is intended to be within the scope of the present application, either as an isolated pure or partially purified optical isomer, or as a racemic mixture thereof.

[0188] In some embodiments, the compound of Formula (I) has one of the following structures, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] During the ceremony: Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is as defined in formula (I), wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes; however, A is CH3, Q is O, and R 1 is H or CH3, and R 2 , R 3 , R 4 , and R 5 If all are hydrogen, R 6 , R 7, and / or R 8 is not OCH3; When A is CH3 and Q is O, R 1 ~R 8 is not all hydrogen; and A is hydrogen, Q is O, and R 1 , R 2 , and R 5 One of the groups is methyl and the other is R 1 , R 2 , and R 5 If the remaining two of 3 , R 4 , and R 6 ~R 8 is not all hydrogen.

[0189] In some embodiments, the compound of Formula (I) has the following structure, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] During the ceremony, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is as defined in formula (I), wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes; however, A is CH3, Q is O, and R 1 is H or CH3, and R 2 , R 3 , R 4 , and R 5 If all are hydrogen, R 6 , R 7 , and / or R 8is not OCH3; When A is CH3 and Q is O, R 1 ~R 8 is not all hydrogen; and A is hydrogen, Q is O, and R 1 , R 2 , and R 5 One of the groups is methyl and the other is R 1 , R 2 , and R 5 If the remaining two of 3 , R 4 , and R 6 ~R 8 is not all hydrogen.

[0190] In some embodiments, the compounds of the present application may also include tautomeric forms, such as keto-enol tautomers. The tautomeric forms may be in equilibrium or may be sterically locked to one form by appropriate substitution. Any tautomeric forms that the compounds may form, as well as mixtures thereof, are intended to be within the scope of the present application.

[0191] The compounds of the present application may also exist in different polymorphic forms, and any polymorphic form, or mixture thereof, is intended to be within the scope of the present application.

[0192] The compounds of the present application may also be radiolabeled, and therefore all radiolabeled forms of the compounds of the present application are included within the scope of the present application, and therefore also include compounds into whose structure one or more radioactive atoms have been incorporated.

[0193] III. Composition The compounds of the present application are suitably formulated into compositions using one or more carriers in a conventional manner. Accordingly, the present application also encompasses compositions comprising one or more compounds of the present application and a carrier. The compounds of the present application are suitably formulated into pharmaceutical compositions for administration to a subject in a biologically compatible form suitable for in vivo administration. Accordingly, the present application also encompasses pharmaceutical compositions comprising one or more compounds of the present application and a pharmaceutically acceptable carrier. In some embodiments of the present application, the pharmaceutical compositions are used to treat any of the diseases, disorders, or conditions described in the present disclosure.

[0194] The compounds of the present application may be administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, the compounds of the present application may be administered orally, by inhalation, parenterally, bucally, sublingually, by insufflation, epidurally, nasally, rectally, vaginally, by patch, pump, minipump, topically, or transdermally, and the pharmaceutical composition may be formulated accordingly. In some embodiments, administration is via a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of appropriate compositions are described, for example, in Remington's Pharmaceutical Sciences (2000 - 20th edition) and The United States Pharmacopeia: The National Formulary, 1999 (USP 24 NF19).

[0195] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, and includes, for example, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary (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 may also be by continuous infusion over a selected period of time.

[0196] In some embodiments, the compounds of the present application are administered orally, for example, with an inert diluent or an assimilable edible carrier, or enclosed in a hard or soft shell gelatin capsule, or compressed into tablets, or incorporated directly with dietary food. In some embodiments, the compounds are incorporated with a formulation excipient and used in the form of orally ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions, aqueous suspensions, etc. In the case of tablets, carriers used include lactose, corn starch, sodium citrate, and salts of phosphoric acid. Pharmaceutically acceptable formulation additives 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 some embodiments, tablets are coated by methods well known in the art. For tablets, capsules, caplets, pellets, or granules for oral administration, a pH-sensitive enteric coating, such as Eudragits®, designed to control the release of the active ingredient, is optionally used. Oral dosage forms also include modified release formulations, such as immediate-release and timed-release formulations.Examples of modified-release formulations include sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin) formulations, such as coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, agglomerates (e.g., agglomerates of molecular sieve-type particles), or bundles of fine hollow permeable fibers, or chopped hollow permeable fibers assembled or held together in a fibrous packet. Timed-release compositions are formulated, for example, as liposomes or formulations in which the active compound is protected by a differentially degradable coating (e.g., by microencapsulation, multilayer coating, etc.). Liposomal delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. In some embodiments, liposomes are formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. For oral administration in capsule form, useful carriers, solvents, or diluents include lactose, medium chain triglycerides, ethanol, and dried cornstarch.

[0197] In some embodiments, liquid preparations for oral administration may take the form of, for example, solutions, syrups, or suspensions, or may be suitably presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compounds of the present application are suitably suspended or dissolved in an oily phase combined with an emulsifying and / or suspending agent. If desired, specific sweeteners and / or flavoring and / or coloring agents are added. Such liquid preparations for oral administration are prepared in a conventional manner using pharmaceutically acceptable additives. Pharmaceutically acceptable additives include, for example, suspending agents (e.g., sorbitol syrup, methylcellulose, or edible hydrogenated fats); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., medium-chain triglycerides, almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0198] For example, for the preparation of injectable products, the compounds of the present application can be lyophilized and the resulting lyophilizates used.

[0199] In some embodiments, the compounds of the present application are administered parenterally. For example, solutions of the compounds of the present application in water suitably mixed with a surfactant, such as hydroxypropylcellulose, are prepared. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof (with or without alcohol), and in oils. Under ordinary storage and use conditions, these preparations contain a preservative to prevent microbial growth. Those skilled in the art know how to prepare suitable formulations. For parenteral administration, a sterile solution of the compounds of the present application is usually prepared, and the pH of the solution is suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled so that the preparation is isotonic. For ocular administration, ointments or instillable liquids are delivered using ocular delivery systems known in the art, such as applicators or droppers. In some embodiments, such compositions comprise a mucosal mimetic such as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose, or polyvinyl alcohol, a preservative such as sorbic acid, EDTA, or benzyl chromium chloride, and a conventional amount of diluent or carrier. For pulmonary administration, the diluent or carrier will be selected to be suitable to allow the formation of an aerosol.

[0200] In some embodiments, the compounds of the present application are formulated for parenteral administration by injection, including conventional catheterization techniques or infusion. Formulations for injection are provided, for example, in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In some embodiments, the compositions take the form of a sterile suspension, solution, or emulsion in an oily or aqueous vehicle, and contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. In all cases, the form must be sterile and fluid to the extent that easy syringability exists. Alternatively, the compounds of the present application are preferably in sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0201] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels, and powders. For example, for intranasal administration or administration by inhalation, the compounds of the present application are conveniently delivered in the form of a solution, dry powder formulation, or suspension from a pump spray container that is squeezed or pumped by the patient, or as an aerosol spray from a pressurized container or nebulizer. Aerosol formulations typically contain a solution or fine suspension of the active agent in a physiologically acceptable aqueous or non-aqueous solvent, and are usually provided as single-dose or multi-dose formulations in a sterile form in a sealed container. The container may take the form of, for example, a cartridge or refill for use with an atomizer. Alternatively, the sealed container may be a unit-dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve intended to be discarded after use. When the dosage form includes an aerosol dispenser, it will also include a propellant. The propellant may be a compressed gas, such as compressed air or an organic propellant, such as a fluorochlorohydrocarbon. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide, or other suitable gases. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to dispense a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator are formulated, for example, containing a powder mix of the compound of the present application and a suitable powder base, such as lactose or starch. The aerosol dosage form may also take the form of a pump-atomizer.

[0202] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the compound is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0203] The compounds of the present application in suppository form are suitable for vaginal, urethral, ​​and rectal administration. Such suppositories are generally composed of a mixture of materials that are solid at room temperature but melt at body temperature. Materials commonly used to make such vehicles include, but are not limited to, cocoa butter (also known as cacao butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. For further description of suppository dosage forms, see, e.g., Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533.

[0204] In some embodiments, the compounds of the present application are conjugated to soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or palmitoyl-substituted polyethyleneoxide-polylysine. Furthermore, in some embodiments, the compounds of the present application are conjugated to biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0205] Although the compounds of the present application, including their pharmaceutically acceptable salts, solvates, and / or prodrugs, can be suitably used alone, they are generally administered in the form of a pharmaceutical composition in which one or more compounds of the present application (active ingredients) are administered in association with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition may contain from about 0.05% to about 99% by weight, or from about 0.10% to about 70% by weight, of the active ingredient(s), and from about 1% to about 99.95% by weight, or from about 30% to about 99.90% by weight of the pharmaceutically acceptable carrier, where all weight percentages are based on the total composition.

[0206] In some embodiments, the compounds of the present application, including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, are used and administered in compositions containing an additional therapeutic agent. Accordingly, the present application also encompasses pharmaceutical compositions containing one or more compounds of the present application, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, an additional therapeutic agent, and optionally one or more pharmaceutically acceptable formulation additives. In some embodiments, the additional therapeutic agent is another known agent useful for treating diseases, disorders, or conditions through activation of serotonin receptors, such as those listed in the "Methods and Uses" section below. In some embodiments, the additional therapeutic agent is a psychoactive agent.

[0207] In the above, the term "compound" also encompasses embodiments in which it refers to one or more compounds.

[0208] IV. Methods and Uses of the Present Application The compounds of the present application are serotonergic binding agents that act as agonists or partial agonists at serotonin receptors.

[0209] Thus, the present application includes a method of activating serotonin receptors in cells, whether in a biological sample or in a patient, by administering to the cells an 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 to activate serotonin receptors in cells, as well as the use of one or more compounds of the present application for preparing a medicament for activating serotonin receptors in cells. The present application further includes one or more compounds of the present application for use in activating serotonin receptors in cells.

[0210] Because the compounds of the present application can activate serotonin receptors, the compounds of the present application are useful for treating diseases, disorders, or conditions by activating serotonin receptors. Therefore, the compounds of the present application are useful as pharmaceuticals. Therefore, the present application also encompasses the compounds of the present application for use as pharmaceuticals.

[0211] The present application also encompasses methods for treating diseases, disorders, or conditions resulting from activation of serotonin receptors, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application.

[0212] The present application also encompasses the use of one or more compounds of the present application for the treatment of a disease, disorder, or condition caused by activation of a serotonin receptor, as well as the use of one or more compounds of the present application for the preparation of a medicament for the treatment of a disease, disorder, or condition caused by activation of a serotonin receptor. The present application further encompasses one or more compounds of the present application for use in the treatment of a disease, disorder, or condition caused by activation of a serotonin receptor.

[0213] In some embodiments, the serotonin receptor is 5-HT 2A Therefore, the present application aims to detect intracellular 5-HT, whether in a biological sample or in a patient. 2A The present application also encompasses a method for activating intracellular 5-HT2+ receptors, comprising administering to said cells an effective amount of one or more compounds of the present application. 2AThe use of one or more compounds of the present application to activate 5-HT2+ in cells 2A The present application also encompasses the use of one or more compounds of the present application for the preparation of a medicament for activating intracellular 5-HT 2A The present invention further includes one or more compounds of the present application for use in activating

[0214] The present application provides a method for treating 5-HT 2+ deficiency, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application. 2A The present application also encompasses methods for treating diseases, disorders, or conditions through activation of 5-HT. 2A Use of one or more compounds of the present application for the treatment of diseases, disorders, or conditions resulting from activation of 5-HT 2A The present application also encompasses the use of one or more compounds of the present application for the preparation of a medicament for the treatment of a disease, disorder, or condition resulting from activation of 5-HT. 2A The present invention also includes one or more compounds of the present application for use in treating a disease, disorder, or condition resulting from activation of

[0215] In some embodiments, the compounds of the present application are useful for preventing, treating, and / or reducing the severity of psychiatric disorders and / or conditions in a subject. Thus, in some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is a psychiatric disorder. Accordingly, the present application also encompasses a method for treating a psychiatric disorder, comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need of treatment. The present application also encompasses the use of one or more compounds of the present application for the treatment of a psychiatric disorder, as well as the use of one or more compounds of the present application for the preparation of a medicament for the treatment of a psychiatric disorder. The present application further encompasses one or more compounds of the present application for use in the treatment of a psychiatric disorder.

[0216] In some embodiments, the psychiatric disorder is an anxiety disorder such as generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia; depression such as hopelessness, anhedonia, fatigue, and suicidal thoughts; mood disorders such as depression, bipolar disorder, cancer-related depression, anxiety, and cyclothymic disorder; psychotic disorders such as hallucinations, delusions, and schizophrenia; impulse control and addiction disorders such as pyromania (fire-setting), kleptomania (stealing), and compulsive gambling; alcohol addiction; drug addiction such as opioid addiction; antisocial personality disorder, obsessive-compulsive personality disorder, and paranoid personality disorder. personality disorders, such as personality disorder; obsessive-compulsive disorder (OCD), such as thoughts or fears that cause a subject to perform specific rituals or routines; post-traumatic stress disorder (PTSD); stress response syndrome (formerly known as adjustment disorder); dissociative disorders, formerly known as multiple personality disorder or "multiple personalities," and depersonalization disorder; factitious disorder; sexual and gender disorders, such as sexual dysfunction, gender identity disorder, and paraphilia; somatic symptom disorders, formerly known as psychosomatic or somatoform disorders; and combinations thereof.

[0217] In some embodiments, the psychiatric disorder is selected from hallucinations and delusions, and combinations thereof.

[0218] In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, balance hallucinations, nociceptive hallucinations, thermosensory hallucinations, and time-sensory hallucinations, and combinations thereof.

[0219] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is neurodegeneration, hi some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is a decrease in brain-derived neurotrophic factor (BDNF), a mammalian target of rapamycin (mTOR) activation, and / or inflammation.

[0220] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors includes cognitive impairment; 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 pain, neuropathic pain, cluster headaches, and migraines; obesity and eating disorders; epilepsy and seizure disorders; neuronal cell death; excitotoxic cell death; or combinations thereof.

[0221] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is psychosis or a psychotic condition. Accordingly, the present application also encompasses methods of treating psychosis or a psychotic condition, comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need of treatment.

[0222] The present application also encompasses the use of one or more compounds of the present application for the treatment of psychosis or psychotic conditions, as well as the use of one or more compounds of the present application for the preparation of a medicament for the treatment of psychosis or psychotic conditions. The application further encompasses one or more compounds of the present application for use in the treatment of psychosis or psychotic conditions.

[0223] In some embodiments, administering a therapeutically effective amount of a compound of the present application to the subject in need of treatment does not result in a worsening of psychosis or psychotic symptoms, including, but not limited to, hallucinations and delusions. In some embodiments, administering a therapeutically effective amount of a compound of the present application to the subject in need of treatment results in an improvement of psychosis or psychotic symptoms, including, but not limited to, hallucinations and delusions. In some embodiments, administering a therapeutically effective amount of a compound of the present application to the subject in need of treatment results in an improvement of psychosis or psychotic symptoms.

[0224] In some embodiments, the compounds of the present application are useful for treating a central nervous system (CNS) disease, disorder, or condition, and / or a neurological disease, disorder, or condition in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0225] Thus, in some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is a disease, disorder, or condition of the central nervous system (CNS) and / or a neurological disease, disorder, or condition. Accordingly, the present application also encompasses methods of treating a CNS disease, disorder, or condition and / or a neurological disease, disorder, or condition, comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need of treatment. The present application also encompasses the use of one or more compounds of the present application for the treatment of a CNS disease, disorder, or condition and / or a neurological disease, disorder, or condition, as well as the use of one or more compounds of the present application for the preparation of a medicament for the treatment of a CNS disease, disorder, or condition and / or a neurological disease, disorder, or condition. The present application further encompasses one or more compounds of the present application for use in the treatment of a CNS disease, disorder, or condition and / or a neurological disease, disorder, or condition.

[0226] In some embodiments, the CNS disease, disorder, or condition and / or neurological disease, disorder, or condition is selected from neurological diseases, including neurodevelopmental disorders and neurodegenerative diseases, examples of which include Alzheimer's disease; presenile dementia; senile dementia; vascular dementia; dementia with Lewy bodies; cognitive disorders, Parkinson's disease, and Parkinson's disease-related disorders, such as Parkinsonism, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disorders; Fragile X syndrome; Angelman syndrome; hereditary ataxias; neuro-otological and oculomotor disorders; retinal neurodegenerative diseases amyotrophic lateral sclerosis; tardive dyskinesia; hyperactivity disorder; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette's syndrome; schizophrenia; autism spectrum disorders; These include tuberous sclerosis; Rett syndrome; cerebral palsy; eating disorders such as anorexia nervosa (AN) and bulimia nervosa (BN); and binge eating disorder (BED), trichotillomania, self-injurious dermatopathy, nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology, and combinations thereof.

[0227] In some embodiments, the subject is a mammal. In other embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. Thus, the compounds, methods, and uses herein address both human and veterinary diseases, disorders, and conditions.

[0228] In some embodiments, the compounds of the present application are useful for treating behavioral problems in subjects that are cats or dogs.

[0229] Thus, in some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a behavioral problem in a cat or dog subject. Thus, the present application also encompasses a method for treating a behavioral problem, comprising administering a therapeutically effective amount of one or more compounds of the present application to a non-human subject in need of treatment. The present application also encompasses the use of one or more compounds of the present application for treating a behavioral problem in a non-human subject, as well as the use of one or more compounds of the present application for preparing a medicament for treating a behavioral problem in a non-human subject. The present application further encompasses one or more compounds of the present application for use in treating a behavioral problem in a non-human subject.

[0230] In some embodiments, the behavioral problem is selected from, but is not limited to, anxiety, fear, stress, sleep disorders, cognitive impairment, aggression, excessive noise making, scratching, biting, and combinations thereof.

[0231] In some embodiments, the non-human subject is a dog. In some embodiments, the non-human subject is a cat.

[0232] The present application also includes a method for treating a disease, disorder, or condition caused by activation of a serotonin receptor, comprising administering to a subject in need of treatment a therapeutically effective amount of one or more compounds of the present application in combination with other known agents useful for treating diseases, disorders, or conditions caused by activation of a serotonin receptor. The present application also includes the use of one or more compounds of the present application in combination with other known agents useful for treating diseases, disorders, or conditions caused by activation of a serotonin receptor for the treatment of a disease, disorder, or condition caused by activation of a serotonin receptor, as well as the use of one or more compounds of the present application in combination with other known agents useful for treating diseases, disorders, or conditions caused by activation of a serotonin receptor for the preparation of a medicament for the treatment of a disease, disorder, or condition caused by activation of a serotonin receptor. The application further includes one or more compounds of the present application in combination with other known agents useful for treating diseases, disorders, or conditions caused by activation of a serotonin receptor for use in the treatment of a disease, disorder, or condition caused by activation of a serotonin receptor.

[0233] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is a psychiatric disorder. In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is a central nervous system (CNS) disease, disorder, or condition and / or a neurological disease, disorder, or condition. In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is a psychosis or psychotic symptom. In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is a behavioral problem in a non-human subject.

[0234] In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a psychiatric disorder, and one or more compounds of the present application are administered in combination with one or more additional treatments for the psychiatric disorder. In some embodiments, the additional treatment for the psychiatric disorder is selected from antipsychotics, including typical and atypical antipsychotics; antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and monoamine oxidase inhibitors (MAOIs) (e.g., bupropion); anti-anxiety medications, including benzodiazepines such as alprazolam; mood stabilizers, such as lithium; and anticonvulsants, such as carbamazepine, divalproex (valproic acid), lamotrigine, gabapentin, and topiramate.

[0235] In some embodiments, the disease, disorder or condition that is treated by activating serotonin receptors is selected from attention deficit hyperactivity disorder and attention deficit disorder and combinations thereof.In some embodiments, the disease, disorder or condition that is treated by activating serotonin receptors 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 treatments for attention deficit hyperactivity disorder and / or attention deficit disorder and combinations thereof are selected from methylphenidate, atomoxetine, and amphetamine and combinations thereof.

[0236] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is dementia or Alzheimer's disease, and one or more compounds of the present application are administered in combination with one or more additional therapies for the treatment of dementia or Alzheimer's disease, in some embodiments, the additional therapies for dementia or Alzheimer's disease are selected from selected acetylcholinesterase inhibitors, NMDA antagonists, and nicotinic agonists.

[0237] In some embodiments, the acetylcholinesterase inhibitor is selected from donepezil, galantamine, rivastigmine, and phenserine, and combinations thereof.

[0238] In some embodiments, the NMDA antagonist is selected from MK-801, ketamine, phencyclidine, and memantine, and combinations thereof.

[0239] In some embodiments, the nicotinic agonist is nicotine, nicotinic acid, a nicotinic alpha 7 agonist, or an alpha 2 beta 4 agonist, or a combination thereof.

[0240] In some embodiments, the muscarinic agonist is a muscarinic M1 agonist, or a muscarinic M4 agonist, or a combination thereof.

[0241] In some embodiments, the muscarinic antagonist is a muscarinic M2 antagonist.

[0242] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is psychosis or a psychotic condition, and one or more compounds of the present application are administered in combination with one or more additional treatments for the psychosis or psychotic condition, hi some embodiments, the additional treatments for the psychosis or psychotic condition are selected from typical antipsychotics and atypical antipsychotics.

[0243] In some embodiments, the typical antipsychotic is acepromazine, acetophenazine, benperidol, bromperidol, butaperazine, carfenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, dixyrazine, droperidol, fluanisone, flupenthixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, lenperone, loxapine, mesoridazine, metytepin, molindone, moperone , oxypertine, oxyprotepine, penfluridol, perazine, pericyazine, perphenazine, pimozide, pipamperone, piperacetazine, pipotiazine, prochlorperazine, promazine, prothipendyl, spiperone, sulforidazine, thiopropazate, thioproperazine, thioridazine, thiothixene, timiperone, trifluoperazine, trifluperidol, triflupromazine, and zuclopenthixol, and combinations thereof.

[0244] 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.

[0245] In some embodiments, an effective amount will vary depending on factors such as the disease state, age, sex, and / or weight, or species of the subject. In some embodiments, the amount of a given compound or compounds that would correspond to an effective amount will vary depending on factors such as the given drug or compounds, pharmaceutical composition, route of administration, type of condition, disease, or disorder, identity of the subject being treated, etc., but can nevertheless be routinely determined by one of ordinary skill in the art.

[0246] In certain embodiments, the compound of the present application is administered once, twice, three times, or four times per year. In some embodiments, the compound of the present application is administered more than once per week. However, in other embodiments, the compound is administered to a subject from about once every two weeks, about once every three weeks, or about once per month. In other embodiments, the compound is administered from about once per week to about once per day. In other embodiments, the compound is administered once, twice, three times, four times, five times, or six times per day. The length of treatment depends on various factors, such as the severity of the disease, disorder, or condition, the age of the subject, the concentration and / or activity of the compound of the present application, and / or a combination thereof. It will also be understood that the effective dosage of the compound used for treatment may increase or decrease during a particular treatment regimen. Modifications in dosage will occur and be evident using standard diagnostic assays known in the art. In some cases, chronic administration is necessary. For example, the compound is administered to a subject in an amount and for a duration sufficient to treat the subject.

[0247] In some embodiments, the compounds are administered at hallucinogenic and psychotomimetic doses, taken in conjunction with psychotherapy or treatment, and may be administered once, twice, three times, or four times per year, although in some embodiments, the compounds are administered to a subject at doses that are not hallucinogenic or psychotomimetic once per day, every other day, every third day, once per week, once every two weeks, once per month, once every two months, or once per three months.

[0248] The compounds of the present application may be used alone or in combination with other known agents (e.g., the compounds of the present application) useful for treating diseases, disorders, or conditions through activation of serotonin receptors. When used in combination with other known agents useful for treating diseases, disorders, or conditions through activation of serotonin receptors, it is one embodiment for the compounds of the present application to be administered contemporaneously with those agents. In the present disclosure, "concurrent administration" of two agents to a subject means providing each of the two agents so that they are active in the individual at the same time. The exact details of administration depend on the pharmacokinetics of the two agents in the presence of each other, but may include administering the two agents within a few hours of each other, or even administering one agent within 24 hours of the other, provided that the pharmacokinetics are suitable. Designing an appropriate dosing regimen is routine for those skilled in the art. In certain embodiments, the two agents are administered substantially simultaneously, i.e., within minutes of each other, or in a single composition containing both agents. Asynchronous administration of the agent combination is a further embodiment of the present invention. In some embodiments, the compounds of the present application are administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or together in a single unit dosage form. Thus, the present application provides unit dosage forms comprising one or more compounds of the present application, additional therapeutic agents, and a pharmaceutically acceptable carrier.

[0249] The dosage of the compounds of the present application will vary depending on many factors, including, for example, the pharmacokinetic properties of the compound, the mode of administration, the recipient's age, health, and weight, the nature and severity of symptoms, the frequency of treatment and type of concurrent treatment (if any), and the rate of clearance of the compound in the treated subject. One of skill in the art will be able to determine appropriate dosages based on the above factors. In some embodiments, one or more compounds of the present application are initially administered at an appropriate dosage, and the dosage is adjusted as needed depending on clinical response. Dosages are generally selected to maintain serum levels of one or more compounds of the present application between about 0.01 μg / cc and about 1000 μg / cc, or between about 0.1 μg / cc and about 100 μg / cc. Typically, the oral dosage of one or more compounds of the present application for an adult is about 10 μg to about 1,000 mg per day, preferably about 10 μg to about 500 mg per day, and more preferably about 10 μg to about 200 mg per day. For parenteral administration, typical dosages are 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, typical dosages are about 0.001 μg / kg to about 10 mg / kg, about 0.1 μg / kg to about 10 mg / kg, about 0.01 μg / kg to about 1 mg / kg, or about 0.1 μg / kg to about 1 mg / kg. For administration in suppository form, typical amounts are from about 0.1 mg / kg to about 10 mg / kg or from about 0.1 mg / kg to about 1 mg / kg. In some embodiments of the present application, the compositions are formulated for oral administration and the one or more compounds are suitably in tablet form containing 0.1, 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the active ingredient (one or more compounds of the present application) per tablet.In some embodiments of the present application, one or more compounds of the present application are administered in a once-daily, once-weekly, or once-monthly dose, or the total daily dose is divided into two-, three-, or four-times-daily doses.

[0250] In some embodiments, the compounds of the present application are used or administered in an effective amount, including administering a dose or dosage regimen that lacks clinically significant hallucinogenic / psychotomimetic effects. ... human plasma psilocin Cmax of 4 ng / mL or less and / or a human 5-HT 2A Clinical effects manifested by human CNS receptor occupancy, or human plasma psilocin Cmax of 1 ng / mL or less and / or human 5-HT of 30% or less 2A The compounds are used or administered in an effective amount, including administering a dose or dosage regimen that provides a clinical effect similar to that manifested by human CNS receptor occupancy. In some embodiments, the compounds are used or administered in an effective amount, including administering a dose or dosage regimen that provides a clinical effect similar to that manifested by human plasma psilocin Tmax of greater than 60 minutes, greater than 120 minutes, or greater than 180 minutes.

[0251] V. Compound Preparation The compounds of the present application can be prepared by a variety of synthetic processes. The selection of certain structural features and / or substituents may influence the selection of one process over another. Selecting a particular process for preparing a given compound of the present application is within the scope of one of ordinary skill in the art. Some starting materials for preparing the compounds of the present application are available from commercial chemical sources or can be extracted from cells, plants, animals, or fungi. Other starting materials, such as those described below, are readily prepared from available precursors using simple transformations well known to those of ordinary skill in the art. In the following schemes illustrating some embodiments of methods for preparing the compounds of the present application, all variables are as defined in Formula I unless otherwise specified.

[0252] In some embodiments of the present application, the compounds of the present application are generally prepared according to the processes illustrated in Schemes II-IV.

[0253] In some embodiments, compounds of formula (I) are prepared as shown in Scheme II. Thus, using known methods, for example, the Pd-catalyzed method found in Chem. Eur. J. 2019, 25, 897-903, an ortho-iodoaniline compound of formula (A) is coupled with a suitable unsaturated precursor, such as a disubstituted alkyne compound of formula (B), in the presence of a catalyst, such as a Pd catalyst, to provide a compound of formula (I). [ka]

[0254] In some embodiments, compounds of formula (I) are synthesized according to Scheme III. Thus, a substituted indole compound of formula (C) is coupled with a suitable pyrrolidine carboxylic acid compound of formula (E) in the presence of a suitable coupling reagent, such as oxalyl chloride, to give a compound of formula (D). Compound (D) is reduced with a suitable reducing agent, such as an Al-based reducing agent, to give a compound of general formula (I). [ka]

[0255] In some embodiments, as shown in Scheme IV, compounds of formula (I) are prepared using known methods, for example, using the synthetic techniques found in Gerasimov et al., J. Med. Chem. 1999, 42, 4257-4263 and / or Macor et al. J. Med. Chem. 1992, 35, 4503-4505. Thus, a substituted indole compound of formula (C) is brominated using a suitable brominating reagent, such as N-bromosuccinimide (NBS), to provide a brominated indole compound of formula (F). Compound (F) is coupled with a suitable pyrrolidine carboxylic acid compound of formula (E) in the presence of a suitable coupling reagent, such as oxalyl chloride, to provide a compound of formula (D). Compound (D) is reduced with a suitable reducing agent, such as an Al-based reducing agent, to provide a compound of general formula (I). [ka]

[0256] Those skilled in the art will appreciate that the intermediates and final compounds in the above schemes can be further manipulated to provide alternative compounds of the present application using known chemical methods.

[0257] Salts of the compounds of the present application may be formed by methods known to those skilled in the art, such as by reacting the compound of the present application with an amount, such as an equivalent amount, of an acid or base in a medium such as one in which the salt precipitates or in an aqueous medium, followed by lyophilization.

[0258] 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 isolating the solvate by cooling or using an anti-solvent. The solvate is typically dried or azeotroped at ambient conditions. Selection of appropriate conditions for forming a particular solvate is within the skill of one of ordinary skill in the art. Examples of suitable solvents are ethanol, water, etc. When water is the solvent, the molecule is referred to as a "hydrate." The formation of solvates of the compounds of the present application will vary depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or using an anti-solvent. The solvate is typically dried or azeotroped at ambient conditions. Selection of appropriate conditions for forming a particular solvate is within the skill of one of ordinary skill in the art.

[0259] Isotopically enriched compounds of the present application and pharmaceutically acceptable salts, solvates, and / or prodrugs thereof can be prepared without undue experimentation by conventional techniques known to those skilled in the art or by processes analogous to those described in the schemes and examples in this disclosure using appropriate isotopically enriched reagents and / or intermediates.

[0260] It should be understood that throughout the processes described in this disclosure, suitable protecting groups are added to, and subsequently removed from, various reactants and intermediates, where appropriate, in a manner that would be readily understood by one of ordinary skill in the art. Conventional techniques for using such protecting groups, and examples of suitable protecting groups, are described, for example, in "Protective Groups in Organic Synthesis," T.W. Green, P.G.M. Wuts, Wiley-Interscience, New York (1999). It should also be understood that, on intermediates along a synthetic route to a final product or on the final product, groups or substituents can be converted to other groups or substituents by chemical manipulation, with the scope of the possible transformations being limited only by the inherent incompatibility of other functionality possessed by the molecule at that stage with the conditions or reagents used in the transformation. Such inherent incompatibilities, and how to circumvent them by carrying out appropriate transformations and synthetic steps in the appropriate order, will be readily apparent to one of ordinary skill in the art. While examples of transformations are given in this disclosure, it should also be understood that the described transformations are not limited to only the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are provided in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations" by R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions can be found in organic chemistry textbooks, such as "Advanced Organic Chemistry", March, 4th ed., McGraw Hill (1992) or "Organic Synthesis", Smith, McGraw Hill, (1994). Techniques for purification of intermediates and final products include, for example, normal and reverse phase chromatography on columns or spinning plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, and will be readily apparent to those skilled in the art.

[0261] Example The following non-limiting examples are illustrative of the present application. A: Synthesis Protocol General method

[0262] All starting materials used herein are either commercially available or previously described in the literature. 1 H and 13 C NMR spectra were obtained in deuterated chloroform as solvent, unless otherwise noted, using TMS or residual solvent signals as internal references. 1 H NMR was recorded on a Bruker 300, Bruker DPX 400, or Varian + 400 spectrometer operating at 300 MHz, 400 MHz, and 400 MHz, respectively. All reported chemical shifts are expressed in ppm on the delta scale, and signal fine splittings appearing in the recordings are generally expressed as, for example, s: singlet, br s: broad singlet, d: doublet, t: triplet, q: quartet, m: multiplet. Unless otherwise stated, in the following tables: 1 1 H NMR data was obtained at 400 MHz using CDCl3 as the solvent.

[0263] Product purification was achieved using Chem Elut Extraction columns (Varian, cat. no. 1219-8002), Mega BE-SI (Bond Elut Silica) SPE columns (Varian, cat. nos. 12256018; 12256026; 12256034), or flash chromatography in silica-packed glass columns.

[0264] The following compounds were prepared using one or more of the synthetic methods outlined in Schemes II-IV. Example 1: (R)-4-Fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole (I-37) [ka] (R)-2-(2-(4-fluoro-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2l 2 Synthesis of -ethan-1-one (3):

[0265] (2-oxo-2-phenyl-1H-isothiazolinone) in dry THF (150 mL) 2 A solution of (17.0 g, 68.20 mmol) of (-ethyl)-D-proline (17.0 g, 68.20 mmol) was treated with thionyl chloride (10.0 mL, 136.40 mmol) at 0 °C. The reaction mixture was allowed to reach room temperature and refluxed for 2 h. The reaction mixture was allowed to reach room temperature, the solvent was evaporated, and the crude product was dried under vacuum to give the corresponding acid chloride. A solution of 4-fluoro-1H-indole (9.2 g, 68.20 mmol) in dry CHCl (100 mL) at 5 °C-10 °C was treated simultaneously with the above crude acid chloride and ethylmagnesium bromide (45.5 mL, 136.40 mmol, 3 M in THF) in dry CHCl (100 mL) over a period of 15 min and stirred at the same temperature for an additional 15 min. The reaction was quenched with concentrated HCl (10 mL) followed by water (150 mL), and the product was extracted into CHCl (2 × 150 mL). The CHCl layer was washed with saturated NaHCO solution (50 mL), brine (25 mL), and dried (NaSO). The solvent was evaporated, and the crude product was purified by flash column chromatography on silica gel (CHCl to 1:4 EtOAc:CHCl) to give title compound 3 (15.5 g, 62%) as a beige solid. 1 H NMR (CDCl3): δ 10.43, 9.92 (2s, 1H), 7.79, 7.64 (2d, 1H, J = 3.0 Hz), 7.47-6.91 (m, 7H), 6.71-6.64 (m, 1H), 5.32-5.15 (m, 3H), 3.87-3.72 (m, 1H), 3.68-3.56 (m, 1H), 2.38-2.22 (m, 1H), 2.10-1.85 (m, 3H); ESI-MS (m / z, %): 389 (M+Na, 100). Synthesis of (R)-4-fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole (I-37):

[0266] A suspension of lithium aluminum deuteride (0.57 g, 13.64 mmol) in dry THF (10 mL) was dissolved in (R)-2-(2-(4-fluoro-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2H-indole (15 mL) in dry THF (15 mL). 2 The reaction mixture was treated with 1-ethan-1-one (1.0 g, 2.72 mmol) at 0 °C for a period of 10 minutes. The reaction mixture was allowed to reach room temperature and refluxed for an additional 16 hours. The reaction mixture was cooled to 0 °C and then quenched by the sequential addition of water (0.57 mL), 1N NaOH solution (0.57 mL), and water (0.57 mL) over a period of 15 minutes. The reaction mixture was allowed to reach room temperature and stirred for an additional 30 minutes. The solid was removed by filtration and washed with THF (2 × 50 mL). The combined THF layers were evaporated, and the crude product was purified by column chromatography on silica gel (2 M NH in MeOH:CHCl = 5:95) to give title compound I-37 (0.5 g, 77%) as an off-white solid. 1 H NMR (CDCl3): δ 8.37 (s, 1H), 7.18-7.05 (m, 2H), 6.99 (d, 1H, J = 1.5 Hz), 6.80-6.73 (m, 1H), 3.21-3.15 (m, 1H), 2.60-2.52 (m, 1H), 2.32-2.22 (m, 1H), 1.90-1.58 (m, 4H); ESI-MS (m / z, %): 238 (MH + , 100). Example 2: (R)-4-chloro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole (I-38) [ka] (R)-2-(2-(4-chloro-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2l 2 Synthesis of -ethan-1-one (6):

[0267] Synthesis was carried out according to the reported procedure for compound 3, starting from 4-chloro-1H-indole (1.0 g, 8.02 mmol), to give the title compound 6 (3.7 g, 60%) as a light brown solid. 1 H NMR (CDCl3): δ 9.96, 9.52 (2s, 1H), 7.67, 7.53 (2d, 1H, J = 3.0 Hz), 7.45-7.26 (m, 4H), 7.22-7.05 (m, 3H), 6.98-6.92 (m, 1H), 5.32-4.98 (m, 3H), 3.88-3.72 (m, 1H), 3.68-3.58 (m, 1H), 2.30-1.85 (m, 4H); ESI-MS (m / z, %): 405 (M+Na, 100). Synthesis of (R)-4-chloro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole (I-38):

[0268] (R)-2-(2-(4-chloro-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl- ... 2 The synthesis was carried out starting from -ethan-1-one (1.0 g, 2.61 mmol) to afford the title compound I-38 (0.48 g, 73%) as an off-white solid. 1 H NMR (CDCl3): δ 8.53 (s, 1H), 7.30-7.24 (m, 1H), 7.12-7.05 (m, 3H), 3.22-3.13 (m, 1H), 2.65 (t, 1H, J = 6.0 Hz), 2.33-2.24 (m, 1H), 1.90-1.57 (m, 4H); ESI-MS (m / z, %): 254 (MH + , 100). Example 3: (R)-4-Methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole (I-39): [ka] (R)-2-(2-(4-methoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ 2 Synthesis of -ethan-1-one (9):

[0269] The synthesis was carried out according to the reported procedure for compound 3, starting from 4-methoxy-1H-indole (2.3 g, 15.64 mmol), to give the title compound 9 (4.4 g, 74%) as a light brown solid. 1 H NMR (CDCl3): δ 9.90, 9.40 (2s, 1H), 7.67, 7.65 (2d, 1H, J = 6.0 Hz), 7.45-7.30 (m, 3H), 7.22-7.05 (m, 3H), 6.95 (d, 1H, J = 6.0 Hz), 6.67, 6.54 (2d, 1H, J = 6.0 Hz), 5.56-5.50 (m, 1H), 5.30-5.00 (m, 2H), 3.90, 3.89 (2s, 3H), 3.85-3.75 (m, 1H), 3.65-3.55 (m, 1H), 2.30-2.17 (m, 1H), 2.12-1.84 (m, 3H); ESI-MS (m / z, %): 401 (M+Na, 100). Synthesis of (R)-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole (I-39):

[0270] (R)-2-(2-(4-methoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl- ... 2 The synthesis was carried out starting from -ethan-1-one (1.0 g, 2.64 mmol) to afford the title compound I-39 (0.5 g, 76%) as a pale yellow solid.1 H NMR (CDCl3): δ 8.19 (s, 1H), 7.10 (t, 1H, J = 6.0 Hz), 6.98 (dd, 1H, J = 0.6, 6.0 Hz), 6.89 (d, 1H, J = 3.0 Hz), 6.51 (d, 1H, J = 6.0 Hz), ESI-MS (m / z, %): 250 (MH + , 100). Example 4: (R)-4-Fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole (I-40) [ka] (R)-2-(2-((4-fluoro-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenyl-2λ 2 Synthesis of -ethan-1-one (11)

[0271] A(R)-2-(2-(4-fluoro-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ in dry THF (45 mL) 2A solution of 1-ethan-1-one (2.0 g, 5.45 mmol) was treated with a solution of lithium borohydride (10.9 mL, 21.83 mmol, 2 M solution in THF) at room temperature over a period of 5 minutes, and the reaction was refluxed for an additional 4 hours. The reaction was cooled to 0 °C and quenched by careful addition of methanol (10 mL) over a period of 15 minutes. The reaction was allowed to reach room temperature and stirred for an additional hour. The reaction was treated with saturated NaHCO solution (30 mL), and the product was extracted into ethyl acetate (3 × 50 mL). The combined ethyl acetate layers were washed with brine (20 mL) and dried (NaSO). The solvent was evaporated, and the crude product was purified by flash column chromatography on silica gel (MeOH:CHCl = 2:98) to give title compound 11 (1.43 g, 74%) as a pale yellow semi-solid. ESI-MS (m / z, %): 375 (M+Na, 100). Synthesis of (R)-4-fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole (I-40)

[0272] A suspension of lithium aluminum deuteride in dry THF (15 mL) was dissolved in (R)-2-(2-((4-fluoro-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenyl-2-( ... 2 The resulting mixture was treated with -ethan-1-one (1.43 g, 4.05 mmol) at 0° C. for a period of 10 min. The reaction mixture was allowed to reach room temperature and refluxed for an additional 16 h, worked up, and purified as described for compound I-37 to give title compound I-40 (0.68 g, 72%) as an off-white solid. 1H NMR (CDCl3): δ 8.46 (s, 1H), 7.15-7.05 (m, 2H), 7.00-6.96 (m, 1H), 6.79-6.73 (m, 1H), 3.40-3.33 (m, 1H), 3.20-3.14 (m, 1H), 2.72-2.63 (m, 1H), 2.60-2.52 (m, 1H), 2.32-2.22 (m, 1H), 1.89-1.76 (m, 2H), 1.72-1.56 (m, 2H); ESI-MS (m / z, %): 236 (MH + , 100). Example 5: (R)-4-Fluoro-3-(pyrrolidin-2-ylmethyl-d2)-1H-indole (I-41) [ka] Synthesis of (R)-4-fluoro-3-propyl-1H-indole (13)

[0273] (R)-2-(2-(4-fluoro-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2H in methanol (50 mL) 2 A suspension of 1-ethan-1-one (2.34 g, 0.6 mmol) was treated with 10% palladium on carbon (2.3 g) and hydrogenated at 33 PSI for 50 min using a Parr apparatus. The reaction product was filtered through a pad of Celite and washed with methanol (3 × 25 mL). The combined methanol layers were evaporated, and the crude product was purified by crystallization from a CHCl:hexane (1:1) mixture to give title compound 13 (1.1 g, 74%) as a light brown solid. 1H NMR (DMSO-d6): δ 8.43 (s, 1H), 7.35-7.30 (m, 1H), 7.25-7.19 (m, 1H), 6.96-6.90 (m, 1H), 4.49-4.44 (m, 1H), 3.10-3.05 (m, 1H), 2.80-2.73 (m, 1H), 2.21-2.10 (m, 1H), 1.80-1.57 (m, 3H); ESI-MS (m / z, %): 233 (MH + , 100). Synthesis of (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl-d2)-1H-indole (I-41)

[0274] A suspension of (R)-4-fluoro-3-propyl-1H-indole (0.535 g, 2.30 mmol) in dry THF (20 mL) was treated with lithium aluminum deuteride (0.24 g, 5.75 mmol) at 0 °C. The reaction mixture was allowed to reach room temperature and then refluxed for an additional 16 h. The reaction mixture was worked up and purified as described for compound I-37 to give the title compound I-41 (0.17 g, 34%) as a pale yellow solid. 1 H NMR (DMSO-d6): δ 11.12 (s, 1H), 7.19-7.14 (m, 2H), 7.04-6.97 (m, 1H), 6.73-6.67 (m, 1H), 3.32-3.22 (m, 1H), 2.96-2.90 (m, 1H), 2.80-2.72 (m, 1H), 1.77-1.57 (m, 3H), 1.41-1.32 (m, 1H); ESI-MS (m / z, %): 221 (MH + , 100). Example 6: (S)-4-Fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole (I-42) [ka] (S)-2-(2-(4-fluoro-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ 2 Synthesis of -ethan-1-one (19)

[0275] (2-oxo-2-phenyl-1H-isothiazolinone) in dry THF (30 mL) 2 A solution of (-ethyl)-L-proline (1.86 g, 7.46 mmol) was treated with thionyl chloride (1.08 mL, 14.92 mmol) at 0 °C. The reaction was allowed to reach room temperature and then refluxed for 2 h. The reaction was allowed to reach room temperature, the solvent was evaporated, and the crude product was dried under vacuum to give the corresponding acid chloride. A solution of 4-fluoro-1H-indole (1.0 g, 7.46 mmol) in dry CHCl (10 mL) at 5 °C–10 °C was simultaneously treated with the crude acid chloride and ethylmagnesium bromide (5.0 mL, 14.92 mmol, 3 M in THF) in dry CHCl (15 mL) over a 10 min period and stirred at the same temperature for an additional 15 min. The reaction was quenched with concentrated HCl (10 mL) followed by water (150 mL), and the product was worked up and purified as described for compound 3 to give the title compound 19 (1.75 g, 65%) as an off-white solid. 1 H NMR (CDCl3): δ 10.44, 9.93 (2s, 1H), 7.79, 7.63 (2d, 1H, J = 3.0 Hz), 7.45-6.93 (m, 7H), 6.69-6.64 (m, 1H), 5.39-5.31 (m, 3H), 3.86-3.74 (m, 1H), 3.66-3.59 (m, 1H), 2.37-2.26 (m, 1H), 2.11-1.89 (m, 3H); ESI-MS (m / z, %): 389 (M+Na, 100). Synthesis of (S)-4-fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole (I-42)

[0276] A suspension of lithium aluminum deuteride (0.57 g, 13.64 mmol) in dry THF (10 mL) was added to (S)-2-(2-(4-fluoro-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ in dry THF (15 mL). 2 The reaction mixture was treated with 1-ethan-1-one (1.0 g, 2.72 mmol) at 0° C. over a period of 10 minutes. The reaction mixture was allowed to reach room temperature and then refluxed for an additional 16 hours. The reaction mixture was cooled to 0° C. and then quenched by the sequential addition of water (0.57 mL), 1N NaOH solution (0.57 mL), and water (0.57 mL) over a period of 15 minutes. The reaction mixture was allowed to reach room temperature, worked up, and purified as described for compound I-37 to give title compound I-42 (0.5 g, 78%) as an off-white solid. 1 H NMR (CDCl3): δ 8.43 (s, 1H), 7.15-7.06 (m, 2H), 6.97 (d, 1H, J = 3.0 Hz), 6.79-6.74 (m, 1H), 3.18-3.13 (m, 1H), 2.55-2.51 (m, 1H), 2.29-2.23 (m, 1H), 1.87-1.77 (m, 2H), 1.73-1.57 (m, 2H); ESI-MS (m / z, %): 238 (MH + , 100). Example 7 (I-43) and Example 8 (I-44) [ka] Example 7: (R)-4-(benzyloxy)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole (I-43) Synthesis of (R)-2-(2-(4-(benzyloxy)-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ2-ethan-1-one (22)

[0277] (2-oxo-2-phenyl-2λ) was prepared in the same manner as described for compound 3.2 Compound 22 was prepared from 4-(benzyloxy)-1H-indole (1.5 g, 6.71 mmol) and 4-(benzyloxy)-1H-indole (1.5 g, 6.71 mmol) to give the title compound 22 (1.41 g, 46%) as a white foam. 1 H NMR (CDCl3): δ 9.90, 9.30 (2s, 1H), 7.72, 7.70 (2d, 1H, J = 3.0 Hz), 7.54-7.02 (m, 12H), 6.59, 6.57 (2d, 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 + ). Synthesis of (R)-4-(benzyloxy)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole (I-43)

[0278] (R)-2-(2-(4-(benzyloxy)-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ was prepared in a manner similar to that described for compound I-37. 2 -ethan-1-one (1.41 g, 2.58 mmol) to afford the title compound I-43 (0.98 g, 97%) as a white foam. 1 H NMR (DMSO-d6): 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). Example 8: (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-4-ol (I-44)

[0279] (R)-2-(2-(4-(benzyloxy)-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2H in anhydrous (dry) methanol (20 mL) 2 A solution of 1-ethan-1-one (0.95 g, 2.91 mmol) was treated with Pd—C (0.25 g) and hydrogenated under a hydrogen atmosphere for an additional 2 h. The reaction product was filtered through a pad of Celite and washed with methanol (2×15 mL). The combined methanol layers were evaporated, and the crude product was purified by flash column chromatography on silica gel (2 M NH in MeOH:CH2Cl2 = 5:95) to give the title compound I-44 (0.6 g, 87%) as a white foam. The TFA salt 1 H NMR (DMSO-d6): 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). Example 9 (I-45) and Example 10 (I-2) [ka] Example 9: (R)-4-(benzyloxy)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole (I-45) (R)-2-(2-((4-(benzyloxy)-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenyl-2λ 2 Synthesis of -ethan-1-one (25)

[0280] (R)-2-(2-(4-(benzyloxy)-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2H-indole was prepared in a similar manner as described for compound 11. 2 -ethan-1-one (5.7 g, 12.54 mmol) to give title compound 25 (4.34 g, 78.6%) as a light brown semi-solid. ESI-MS (m / z, %): 463 (M+Na, 100), 441 (MH + ). Synthesis of (R)-4-(benzyloxy)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole (I-45)

[0281] (R)-2-(2-((4-(benzyloxy)-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenyl-2λ was prepared in a manner similar to that described for compound I-43. 2 -ethan-1-one (4.3 g, 9.76 mmol) to afford the title compound I-45 (2.55 g, 80.7%) as a tan solid. 1 H NMR (CDCl3): δ 8.19 (s, 1H), 7.53-7.50 (m, 2H), 7.43-7.33 (m, 3H), 7.08 (t, 1H, J = 6.0 Hz), 6.99 (d, 1H, J = 6.0 Hz), 6.91 (s, 1H), 6.57 (d, 1H, J = 6.0 Hz), 5.25-5.18 (m, 2H), 3.49-3.45 (m, 1H), 3.09-3.04 (m, 1H), 2.63-2.52 (m, 2H), 2.17-2.10 (m, 1H), 1.75-1.54 (m, 4H); ESI-MS (m / z, %): 324 (MH + , 100). Example 10: (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-ol (I-2) Synthesis of (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-ol (I-2)

[0282] The title compound I-2 (0.3 g, 94%) was prepared as a white foam from (R)-4-(benzyloxy)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole (0.445 g, 1.37 mmol) in a similar manner as described for compound I-44. 1 H NMR (DMSO-d6): δ 10.80 (s, 1H), 9.60 (brs, 1H), 7.11-7.06 (m, 1H), 6.87-6.79 (m, 2H), 6.37 (dd, 1H, J = 3.0 Hz), 3.69-3.59 (m, 2H), 3.45-3.41 (m, 1H), 3.16-3.07 (m, 1H), 2.98-2.90 (m, 1H), 2.06-1.73 (m, 4H); ESI-MS (m / z, %): 234 (MH + , 100). Example 11 (I-46) and Example 12 (I-47) [ka] Example 11: (R)-4-(benzyloxy)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (I-46) Synthesis of (R)-4-(benzyloxy)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (I-46)

[0283] (R)-2-(2-((4-(benzyloxy)-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenyl-2λ was prepared in a manner similar to that described for compound I-43. 2 The reaction mixture was prepared from -ethan-1-one (2.0 g, 4.40 mmol) and LiAlH4 (0.83 g, 22.00 mmol) to afford the title compound I-46 (0.9 g, 64%) as a tan solid. Example 12: (R)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-ol (I-47)

[0284] Prepared from (R)-4-(benzyloxy)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (0.87 g, 2.71 mmol) in a similar manner as described for compound I-2 to give the title compound (0.55 g, 88%) as an off-white solid. 1 H NMR (DMSO-d6): 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). Example 13: (R)-3-(pyrrolidin-2-ylmethyl)-1H-indol-4-ol (I-3) [ka] Synthesis of (R)-3-(pyrrolidin-2-ylmethyl)-1H-indol-4-ol:

[0285] (R)-2-(2-((4-(benzyloxy)-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenyl-2λ was prepared in a manner similar to that described for compound I-44 (Example 8). 2 The title compound I-3 (0.32 g, 54%) was prepared from 1-ethan-1-one (1.2 g, 2.72 mmol) to give the title compound I-3 (0.32 g, 54%) as an off-white solid. 1H NMR (DMSO-d6): δ 10.81 (s, 1H), 9.54 (brs, 1H), 8.96 (brs, 1H), 8.42 (brs, 1H), 7.05 (s, 1H), 6.87-6.80 (m, 2H), 6.37 (d, 1H, J = 6.0 Hz), 3.92-3.85 (m, 1H), 3.26-3.15 (m, 4H), 2.04-1.67 (m, 4H); ESI-MS (m / z, %): 217 (MH + , 100). Example 14: 3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl(9Z,12Z)-octadeca-9,12-dienoate (I-48) [ka] Synthesis of 3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl(9Z,12Z)-octadeca-9,12-dienoate (I-48)

[0286] A solution of linoleic acid (0.22 g, 0.77 mmol) in dry CHCl (10 mL) was treated with oxalyl chloride (0.09 mL, 1.02 mmol) followed by one drop of dry DMF at room temperature and stirred for an additional 2 h. The solvent was evaporated and dried under high vacuum to give the crude acid chloride. A solution of (R)-3-((1-(methyl-d)pyrrolidin-2-yl)methyl)-1H-indol-4-ol (0.12 g, 0.51 mmol) in dry CHCl (10 mL) and triethylamine (0.21 mL, 1.54 mmol) was treated with the above crude acid chloride in dry CHCl (10 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for an additional 2 h. The reaction was quenched with water (50 mL) and the product was extracted into CH2Cl2 (2 x 50 mL). The combined CH2Cl2 layers were washed with brine (25 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by column chromatography on silica gel (2 M NH3 in MeOH:CH2Cl2 = 5:95) to give the title compound I-48 (0.21 g, 84%) as a pale yellow oil. The TFA salt 1 H NMR (DMSO-d6): δ 11.29 (s, 1H), 9.61 (brs, 1H), 7.30-7.28 (m, 2H), 7.09 (t, 1H, J = 6.0 Hz), 6.73 (d, 1H, J = 6.0 Hz), 5.41-5.32 (m, 4H), 3.66-3.57 (m, 2H), 3.29-3.10 (m, 2H), 2.93-2.88 (m, 1H), 2.78-2.69 (m, 4H), 2.10-1.66 (m, 12H), 1.37-1.25 (m, 12H), 0.87 (t, 3H, J = 6.0 Hz); ESI-MS (m / z, %): 496 (MH + , 100). Example 15: 3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-4-yl(9Z,12Z)-octadeca-9,12-dienoate (I-49) [ka] Synthesis of 3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-4-yl(9Z,12Z)-octadeca-9,12-dienoate:

[0287] (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-4-ol (1.2 g, 5.09 mmol) I-44 was used to give the title compound I-49 (2.26 g, 89%) as a pale yellow oil. 1 H NMR (DMSO-d6): δ 11.30 (s, 1H), 9.80 (brs, 1H), 7.30-7.27 (m, 2H), 7.08 (t, 1H, J = 6.0 Hz), 6.71 (d, 1H, J = 3.0 Hz). 5.39-5.30 (m, 4H), 3.63-3.56 (m, 2H), 3.14-3.09 (m, 1H), 2.77-2.69 (m, 4H), 2.09-1.65 (m, 10H), 1.42-1.24 (m, 14H), 0.86 (t, 3H, J = 6.0 Hz); ESI-MS (m / z, %): 498 (MH + , 100). Example 16: (R)-3-(pyrrolidin-2-ylmethyl-d2)-1H-indol-4-ol (I-50) [ka] Synthesis of (R)-4-hydroxy-3-propyl-1H-indole (33)

[0288] (R)-2-(2-(4-(benzyloxy)-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2-(4- ... 2 -ethan-1-one (2.8 g, 62.87 mmol) to give title compound 33 (0.87 g, 61.3%) as a pale yellow solid.1 H NMR (DMSO-d6): δ 11.44 (s, 1H), 8.53 (s, 1H), 7.14-7.08 (m, 1H), 6.92 (d, 1H, J = 6.0 Hz), 6.55 (d, 1H, J = 6.0 Hz), 4.56-4.52 (m, 1H), 3.09-3.03 (m, 1H), 2.86-2.78 (m, 1H), 2.22-2.15 (m, 1H), 1.78-1.67 (m, 3H); ESI-MS (m / z, %): 231 (MH + , 100). Synthesis of (R)-3-(pyrrolidin-2-ylmethyl-d2)-1H-indol-4-ol (I-50)

[0289] The title compound (0.52 g, 65%) was prepared as a pale yellow solid from (R)-4-hydroxy-3-propyl-1H-indole (0.85 g, 3.69 mmol) and LiAlD4 (0.46 g, 11.07 mmol) in a similar manner as described for compound I-37. 1 H NMR (DMSO-d6): δ 10.81 (s, 1H), 9.53 (brs, 1H), 8.94 (s, 1H), 8.40 (s, 1H), 7.05 (d, 1H, J = 3.0 Hz), 6.96-6.80 (m, 2H), 6.37 (dd, 1H, J = 1.5, 3.0 Hz), 3.90-3.83 (m, 1H), 3.26-3.09 (m, 2H), 2.04-1.65 (m, 4H); ESI-MS (m / z, %): 219 (MH + , 100). Example 17: (S)-3-(pyrrolidin-2-ylmethyl-d2)-1H-indol-4-ol (I-51) [ka] Synthesis of (S)-2-(2-(4-(benzyloxy)-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ2-ethan-1-one (35)

[0290] (2-oxo-2-phenyl-1-methyl-2-methyl ... 2 Compound 35 was prepared from 4-(benzyloxy)-1H-indole (5.01 g, 22.46 mmol) and 4-(benzyloxy)-1H-indole (5.01 g, 22.46 mmol) to give title compound 35 (7.8 g, 76.5%) as an off-white foam. 1 H NMR (CDCl3): δ 9.88, 9.30 (2s, 1H), 7.72, 7.70 (2d, 1H, J = 3.0 Hz), 7.54-7.02 (m, 12H), 6.59, 6.57 (2d, 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), 455 (MH + ). Synthesis of (S)-4-hydroxy-3-propyl-1H-indole (36)

[0291] (S)-2-(2-(4-(benzyloxy)-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2-(4- ... 2 -ethan-1-one (3.0 g, 6.60 mmol) to give the title compound 36 (0.9 g, 59%) as a pale yellow solid. 1H NMR (DMSO-d6): δ 11.45 (s, 1H), 8.52 (s, 1H), 7.14-7.07 (m, 1H), 6.92 (d, 1H, J = 6.0 Hz), 6.50 (d, 1H, J = 6.0 Hz), 4.57-4.52 (m, 1H), 3.08-3.03 (m, 1H), 2.88-2.78 (m, 1H), 2.28-2.16 (m, 1H), 1.77-1.67 (m, 3H); ESI-MS (m / z, %): 231 (MH + , 100). Synthesis of (S)-3-(pyrrolidin-2-ylmethyl-d2)-1H-indol-4-ol (I-51)

[0292] (S)-2-(2-(4-(benzyloxy)-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2-(4- ... 2 The title compound I-51 (0.27 g, 32.5%) was prepared from 1-ethan-1-one (0.88 g, 3.82 mmol) and LiAlD4 (0.48 g, 11.46 mmol) to give the title compound I-51 (0.27 g, 32.5%) as a tan foam. 1 H NMR (DMSO-d6): δ 10.82 (s, 1H), 9.55 (brs, 1H), 8.96 (s, 1H), 8.42 (s, 1H), 7.06 (d, 1H, J = 1.5 Hz), 6.88-6.81 (m, 2H), 6.38 (dd, 1H, J = 1.5, 3.0 Hz), 3.99-3.86 (m, 1H), 3.26-3.13 (m, 2H), 2.04-1.65 (m, 4H); ESI-MS (m / z, %): 219 (MH + , 100). Example 18 (I-52) and Example 19 (I-53) [ka] Example 18: (S)-4-(benzyloxy)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole (I-52) (S)-2-(2-((4-(benzyloxy)-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenyl-2l 2 Synthesis of -ethan-1-one (38)

[0293] (S)-2-(2-(4-(benzyloxy)-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2H-indole was prepared in a similar manner as described for compound 11. 2 -ethan-1-one (1.78 g, 3.91 mmol) to give title compound 38 (1.25 g, 72.6%) as a pale yellow semi-solid. 1 H NMR (CDCl3): δ; ESI-MS (m / z, %): 463 (M+Na), 441 (MH + ), 307 (100). Synthesis of (S)-4-(benzyloxy)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole (I-52)

[0294] (S)-2-(2-((4-(benzyloxy)-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenyl-2-methyl-4- ... 2 -ethan-1-one (1.2 g, 2.72 mmol) to give the title compound (0.78 g, 88.6%) as a tan foam. 1H NMR (CDCl3): δ 8.19 (s, 1H), 7.53-7.50 (m, 2H), 7.42-7.33 (m, 3H), 7.08 (t, 1H, J = 6.0 Hz), 6.99 (d, 1H, J = 6.0 Hz), 6.92 (s, 1H), 6.57 (d, 1H, J = 6.0 Hz), 5.25-5.17 (m, 2H), 3.51-3.44 (m, 1H), 3.09-3.04 (m, 1H), 2.63-2.53 (m, 2H), 2.17-2.11 (m, 1H), 1.78-1.54 (m, 4H); ESI-MS (m / z, %): 324 (MH + , 100). Example 19: (S)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-ol (I-53) Synthesis of (S)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-ol:

[0295] Prepared from (S)-4-(benzyloxy)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole (0.73 g, 2.25 mmol) in a similar manner as described for compound I-3 to give the title compound (0.35 g, 67%) as a white foam. 1 H NMR (DMSO-d6): δ 10.82 (s, 1H), 9.64 (brs, 1H), 7.12-7.07 (m, 1H), 6.88-6.80 (m, 2H), 6.38 (d, 1H, J = 6.0 Hz), 3.70-3.59 (m, 2H), 3.46-3.42 (m, 1H), 3.18-3.08 (m, 1H), 2.99-2.93 (m, 1H), 2.07-1.77 (m, 4H); ESI-MS (m / z, %): 234 (MH + , 100). Example 20: (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-4-yl dihydrogen phosphate (I-54) [ka] Synthesis of (R)-dibenzyl(3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-4-yl)phosphate (47)

[0296] A solution of (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-4-ol (I-44, 0.3 g, 1.27 mmol) in dry THF (15 mL) was treated with n-BuLi (0.58 mL, 1.46 mmol, 2.5 M in hexane) at −78° C. The reaction mixture was stirred at the same temperature for 10 minutes and then treated with tetrabenzyl pyrophosphate (0.89 g, 1.65 mmol) in dry THF (10 mL). The reaction mixture was allowed to warm to room temperature over a period of 1 hour and stirred for an additional hour at 0° C. The reaction mixture was treated with aminopropyl silica gel (0.6 g) and diluted with ethyl acetate (50 mL). The reaction mixture was filtered through a pad of Celite® and washed with ethyl acetate (2×25 mL). Evaporation of the ethyl acetate gave crude (R)-dibenzyl (3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-4-yl)phosphate as a light brown semi-solid. Synthesis of (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-4-yl dihydrogen phosphate (I-54)

[0297] A solution of the above crude (R)-dibenzyl(3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-4-yl)phosphate in dry methanol (25 mL) was treated with Pd—C (0.15 g) and hydrogenated for 2 h. Water (5 mL) was added and hydrogenation was carried out for an additional 14 h. The reaction product was filtered through a pad of Celite and washed with methanol (2×25 mL). The solvent was evaporated, dried under high vacuum, and the crude product was crystallized from ethanol to give title compound I-54 (0.3 g, 75%) as an off-white solid. 1 H NMR (D2O): δ 7.19-7.06 (m, 3H), 7.00-6.95 (m, 1H), 3.67 (t, 1H, J = 6.0 Hz), 3.61-3.55 (m, 1H), 3.04-2.97 (m, 1H), 2.13-1.75 (m, 4H); ESI-MS (m / z, %): 338 (M+Na), 316 (MH + ), 238 (100). Example 21: (R)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-yl dihydrogen phosphate [ka] Synthesis of (R)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-yl dihydrogen phosphate:

[0298] Prepared similarly as described for compound I-47 from (R)-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-4-ol (I-47, 0.225 g, 0.97 mmol) to give the title compound I-1 (0.15 g, 50%) as a light brown solid. 1H NMR (D2O): δ 7.28-7.15 (m, 2H), 7.09 (t, 1H, J = 6.0 Hz), 6.94 (d, 1H, J = 6.0 Hz); 3.84-3.71 (m, 2H), 3.42-3.37 (m, 1H), 3.18-3.02 (m, 2H), 2.70 (s, 3H), 2.17-1.79 (m, 4H); 31 P NMR (DO): δ -4.8 Example 22: (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl dihydrogen phosphate [ka] Synthesis of (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl dihydrogen phosphate (I-7):

[0299] Prepared in a similar manner as described for compound I-2 from (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-ol (0.1 g, 0.43 mmol), the title compound I-7 (0.12 g, 75%) was obtained as a light brown solid. 1 H NMR (D2O): δ 7.29-7.10 (m, 2H), 7.08 (t, 1H, J = 6.0 Hz), 6.95 (d, 1H, J = 6.0 Hz); 3.83-3.72 (m, 1H), 3.64-3.52 (m, 1H), 3.43-3.27 (m, 1H), 3.09-3.03 (m, 2H), 2.16-1.80 (m, 4H); 31 P NMR (DO): δ -4.5 B. Biological Testing Example 23: FLIPR Assay: Human 5-HT2A I. Evaluation of the Activated Effects of Exemplary Compounds of Formula I Targeting the Human 5-HT2A (h5-HT2A) Receptor in Agonist Mode: Exemplary Compound Preparation and Assay Controls [Table 13] [Table 14] Experimental Methods and Procedures:

[0300] 1. Culture the cells in cell culture medium (DMEM containing 10% FBS, 1× penicillin-streptomycin, 300 μg / ml G418, and 100 μg / ml hygromycin B) at 37° C., 5% (v / v) CO 2 .

[0301] 2. One day before the assay, detach the cells using TrypLE™ Express and count the cells using a cell counter. Only cells with a viability greater than 85% are used in the assay.

[0302] 3. Seed 20,000 cells / well in 30 μl / well of culture medium into a 384-well cell plate and incubate the cells overnight at 37° C., 5% (v / v) CO 2 .

[0303] 4. On the day of the assay, prepare the 2x dye solution according to the FLIPR® Calcium 6 Assay Kit manual: i. Dilute the dye in assay buffer (20 mM HEPES in 1x HBSS, pH 7.4); ii. Add probenecid to a final concentration of 5mM; iii. Vortex vigorously for 1-2 minutes.

[0304] 5. Release the medium from the cell plate by tapping the cell plate on a paper towel.

[0305] 6. Add 10 μl of assay buffer and 10 μl of 2× dye solution to each well of the cell plate.

[0306] 7. Place the cell plate on a plate shaker and shake the plate at 600 rpm for 2 minutes. Incubate the plate at 37°C for 2 hours, followed by an additional 15 minutes at 25°C.

[0307] 8. Prepare 3x compounds in assay buffer: a. Dilute reference compounds to required concentrations in DMSO. Add compounds to 384-well compound plate; b. Perform serial dilutions; c. Add 10mM test compound to the compound plate and perform 3-fold serial dilutions; d. Echo transfer 60nl / well of compound from source plate to 384-well compound plate (Corning, 3657); e. Add 20µl / well of assay buffer to the compound plate; f. Mix the plate on a plate shaker for 2 minutes;

[0308] 9. Place the cell plate, compound plate, and chips into the FLIPR and allow the FLIPR to transfer 10 μl per well of 3× compound to the cell plate. Identity Data Analysis

[0309] i. Calculate the normalized fluorescence reading (RFU) as follows, where Fmax and Fmin represent the maximum and minimum calcium signals during the defined time window: RFU=Fmax-Fmin

[0310] ii. Calculate the percent activation using the following formula:

number

[0311] iii. Calculate EC50 using XLfit by fitting % activation against the log value of compound concentration to the Hill equation.

[0312] Exemplary compounds of the present application were found to be 5-HT2A agonists. Results for representative compounds are shown as EC50 in Table 1. The letter "A" indicates an EC50 "B" represents an EC of greater than 1,000 nM and less than 10,000 nM 50 "C" indicates an EC50 > 10,000 nM. Table 1: Effect of exemplary compounds of formula I targeting human 5-HT2A (h5-HT2A) receptors in agonist mode: [Table 15] II. Results and Discussion Exemplary compounds of Formula I were functionally evaluated for their effects in the agonist mode on the h5-HT2A receptor using the FLIPR assay. 50 The concentrations (nM) are shown in Table 5. This assay confirms that the exemplified compounds of the present application are effective inhibitors of the targeted human 5-HT2A receptor. Example 24: Human 5-HT2A: Radioligand Binding Assay: [Table 16] [Table 17] Testing Procedure:

[0313] i. Prepare assay buffer according to the table below; [Table 18]

[0314] ii. Preparation of eight doses of the reference compound and exemplary test compound starting from a 10 mM stock solution required in five-fold serial dilutions at 100%;

[0315] iii. Preparation of (v / v) DMSO: a. Add 50 μl / well of 0.5% (v / v) PEI to a UniFilter-96 GF / B plate. Seal the plate and incubate at 4° C. for 3 hours; b. After incubation, wash the plate three times with ice-cold water buffer (50 mM Tris, pH 7.4);

[0316] iv. Assay plate preparation: a. Cell membranes are diluted with assay buffer and 330 μl / well is added to a 96-round, deep-well plate to reach a concentration of 20 μg / well; b. Eight concentrations of reference compound and exemplary test compound are prepared and 110 μl / well is added to a 96-round, deep-well plate; c. [3H]-ketanserin is diluted with assay buffer to 5 nM (5× final concentration) and 110 μl / well is added to a 96-round, deep-well plate.

[0317] v. The plate is centrifuged at 1000 rpm for 30 seconds, then agitated at 600 rpm for 5 minutes at room temperature.

[0318] vi. Seal the plate and incubate at 27° C. for 90 minutes.

[0319] vii. The incubation is terminated by vacuum filtration onto GF / B filter plates, followed by four washes with ice-cold water buffer (50 mM Tris, pH 7.4).

[0320] vii. Dry the plate at 37°C for 45 minutes

[0321] ix. Seal the filter plate and add 40 μl / well of scintillation cocktail.

[0322] x. Read the plate using a Microbeta2 microplate counter. Data Analysis:

[0323] For the reference compound and exemplary test compound, normalize the results using the formula: N = 100 - 100 × (U - C2) / (C1 - C2) where U is the unknown, C1 is the mean of the high controls, and C2 is the mean of the low controls. IC50s were determined by fitting the percent inhibition as a function of compound concentration to the Hill equation using XLfit. Results and Discussion

[0324] The results of the potential competitive binding properties of exemplary compounds targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A) are summarized in Table 2. The results for representative compounds are shown in the IC given in Table 2. 50 The symbol "#" is IC 50 <500 nM; "# #" indicates IC greater than 500 nM and less than 5,000 nM 50 "# # #" represents IC 50 represents >5,000 nM. [Table 19]

[0325] Exemplary compounds of Formula I were evaluated using a radioligand binding assay at the human 5-HT2A receptor. IC 50 Concentrations (nM) are shown in Table 2. This assay confirms that the exemplified compounds of the present application are effective ligands of the targeted human 5-HT2A receptor. Example 25: Human, rat, and mouse liver microsome stability the purpose

[0326] The purpose of this study was to estimate the in vitro metabolic stability of exemplified compounds in pooled human, male rat, and male mouse liver microsomes. The concentrations of exemplified compounds in the reaction systems were assessed by LC-MS / MS to estimate their stability in pooled human, male rat, and male mouse liver microsomes. The in vitro intrinsic clearance of the test compounds was also determined. Protocol

[0327] A master solution in an "incubation plate" containing phosphate buffer, ultrapure H2O, MgCl2 solution, and liver microsomes was prepared according to Table 3. This mixture was pre-warmed in a 37°C water bath for 5 minutes. [Table 20]

[0328] 40 μL of 10 mM NADPH solution was added to each well. The final concentration of NADPH was 1 mM. A negative control sample was prepared by replacing NADPH with 40 μL of ultrapure HO. Samples were prepared in duplicate. The negative control was prepared in single replicate.

[0329] Reactions were initiated by adding 4 μL of 200 μM of an exemplary test compound or control compound to each master solution for a final concentration of 2 μM. The experiments were performed in duplicate.

[0330] Aliquots of 50 μL were taken from the reaction mixture at 0, 15, 30, 45, and 60 min. The reaction mixture was stopped by adding 4 volumes of cold methanol containing internal standards (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol, and 2 μM ketoprofen). The samples were centrifuged at 3,220 g for 40 min. A 90 μL aliquot of the supernatant was mixed with 90 μL of ultrapure HO and then used for LC-MS / MS analysis.

[0331] All samples in this study were analyzed using a Shimadzu liquid chromatographic separation system equipped with a degasser DGU-20A5R, a solvent delivery unit LC-30AD, a system controller SIL-30AC, a column oven CTO-30A, and a CTC analyzer HTC PAL system. Mass spectrometry analysis was performed using a Triple Quad™ 5500 instrument.

[0332] All calculations were performed using Microsoft Excel. Peak area ratios of test compounds relative to internal standards (listed in the table below) were determined from extracted ion chromatograms.

[0333] All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The slope value "k" was determined by linear regression of the curve of the natural logarithm of the percent parent drug remaining versus incubation time.

[0334] The in vitro half-life (in vitro t) was determined from the slope value: In vitro 1 / 2 =-(0.693 / k)

[0335] Conversion of in vitro t (min) to in vitro intrinsic clearance (in vitro CLint, in μL / min / mg protein) was performed using the following formula (mean of duplicate determinations):

number

[0336] For example compounds or control compounds that showed an initial rapid elimination followed by a slower elimination, time points within the initial rate range were included in the calculations. Results and Discussion

[0337] Human, rat, and mouse liver microsomes contain a variety of drug-metabolizing enzymes and are commonly used to support in vitro ADME (absorption, distribution, metabolism, and excretion) studies. These microsomes are used to investigate possible first-pass metabolic byproducts of orally administered drugs. Exemplary compounds of the present invention were evaluated for their stability in human, rat, and mouse liver microsomes. In liver microsomes from three species, human, rat, and mouse, the exemplary compounds of the present invention were largely recovered within a 60-minute period, indicating that the exemplary compounds are not rapidly eliminated (see Table 4 for exemplary compounds of Formula I). [Table 21] Example 26: In vivo evaluation of pharmacokinetics in mice and rats I. Formulation Preparation and Storage [Table 22] II. Sample Collection [Table 23] III. Exam Details animal:

[0338] Male C57BL / 6 mice (25-30 g) obtained from Charles River Laboratories were acclimated for a minimum of 5 days prior to dosing. Body weights were recorded on the day of dosing. Food Restrictions:

[0339] Orally dosed animals were food deprived overnight and fed approximately 2 hours after dosing. Clinical findings:

[0340] Animals will be observed at the time of dosing and at each sample collection, and any abnormalities will be recorded. dosage

[0341] The formulations were administered intravenously (iv) through the tail vein or orally (po) by gavage through a disposable feeding needle. Sample Collection:

[0342] Serial blood samples were taken by tail snip, with a terminal blood sample being taken by cardiac puncture under isoflavone anesthesia. Sample Processing / Storage:

[0343] All blood samples were transferred to K2EDTA tubes on wet ice and centrifuged within a 5-minute period (3200 x g for 5 minutes at 4°C) to obtain plasma, which was stored at -80°C until analysis. Sample Retention:

[0344] Plasma samples were to be analyzed and any remaining samples were stored frozen at -80°C until testing was completed. IV. Bioanalytical Method Improvement and Sample Analysis Matrix: Mouse plasma

[0345] Equipment: AB Sciex QTRAP 4000 or 6500 MS / MS system equipped with a binary pump, solvent degasser, thermostated column compartment, and liquid chromatography system with a multiplate autosampler. V. Method Improvements:

[0346] i. Selection of ion transitions for test compounds (i.e., identification of parent and product ions)

[0347] ii. Optimization of mass spectrometry operating parameters

[0348] iii. Establishing chromatographic conditions

[0349] iv. Appropriate internal standard(s) (IS)

[0350] V. Sample Cleanup Methods Using Protein Precipitation VI. Method Qualification:

[0351] i. Determining the qualified dynamic range using a series of non-zero calibration standards (STDs) consisting of a blank matrix sample (no internal standard), a zero sample (with internal standard), and six or more non-zero STDs covering the expected range and including the lower limit of quantitation (LLOQ).

[0352] ii. Three injections of system suitability samples (solvent-free solutions containing analytes and internal standards) before and after the batch VII. Method Acceptance Criteria:

[0353] i. At least 75% of non-zero STDs are included in the calibration curve and all back-calculated concentrations deviate from the nominal concentration by within ±20% (within ±25% for the lower limit of quantitation (LLOQ)).

[0354] ii. The correlation coefficient (r) of the calibration curve was 0.99 or higher.

[0355] iii. The area ratio of the system suitability sample injection before and after the run varies within ±25%. VIII. Sample Analysis Batch:

[0356] i. Three injections of system suitability samples before and after the batch

[0357] II. Ascending STD(s)

[0358] iii. Test samples and dosage compositions are diluted in blank matrix (plasma) at three independent dilutions.

[0359] iv. For cases where there were more than 40 test samples in a batch, two sets of STDs were used, one before the other after the sample group.

[0360] v. Samples that are 25% greater than the highest calibration standard should be diluted and re-assayed along with the corresponding diluted quality control standard. Diluted standards are acceptable if they are accurate to within 25% deviation from the target concentration. IX.PK analysis

[0361] i. Analysis software: Phoenix® WinNonlin® 8.2 (Pharsight, Certara, Mountainview, CA)

[0362] ii. Analysis method: Non-compartmental analysis, linear up / log down trapezoidal method

[0363] iii.PK parameters: C0, t as appropriate 1 / 2 , AUC 0-tlast . AUC 0-∞ , C.L., V. ss ,MRT,t max(po) , C max(po) , F X. Results and Discussion [Table 24] (a) I-39 is hydrolyzed to I-44 after intravenous administration. (b) nc indicates that the terminal phase is not defined and therefore cannot be calculated. [Table 25] (a) I-39 is hydrolyzed to I-44 after intravenous administration. (b) nc indicates that the terminal phase is not defined and therefore cannot be calculated. [Table 26] (a) I-39 is hydrolyzed to I-44 after intravenous administration. (b) nc indicates that the terminal phase is not defined and therefore cannot be calculated. [Table 27] (a) I-39 is hydrolyzed to I-44 after oral administration. (b) nc indicates that the terminal phase is not defined and therefore cannot be calculated. [Table 28] Example 27: Hallucinogenic-like effects of exemplary compounds of Formula I

[0364] The effects of various doses of exemplary compounds of Formula I were evaluated based on the head-twitch response (HTR) as a behaviorally based model of hallucinogenic activity. 1. Protocol Mouse head spasms

[0365] Male C57BL / 6J mice (weight range, 20-30 g) were dosed with the appropriate dose of test substance and, after a 1-minute pretreatment period, placed in individual observation chambers. Animals were visually assessed continuously for head jerks over a 1-hour period. A head jerk was defined as a rapid jerking of the head not elicited by external tactile stimulation (Corne and Pickering, Psychopharmacologia, 1967, 11(1): 65-78). Each head jerk was counted individually by a trained observer, and data are presented as the mean ± standard error of the mean (SEM) for 6-10 mice per group. Mice were used in only a single experiment. Rat behavioral tests

[0366] Male Sprague-Dawley rats (weight range 250-400 g) were administered the appropriate dose of test article. After a 1-minute pretreatment period, the rats were placed in a locomotor activity box (dimensions: 17 inches wide x 17 inches long x 12 inches high) and continuously monitored for a 1-hour period, with data collected in 10-minute bins. Animals were visually assessed for overt behavioral signs, including behavioral characteristics of 5-HT2A receptor activation (wet dog shakes, back contractions), 5-HT2A receptor activation (yawning, penile grooming), and 5-HT1A behaviors (forepaw stepping, hindlimb abduction) (Halberzettl et al., Behav Brain Res. 256: 328-345, 2013). Additional behavioral and physical signs characteristic of 5-HT syndrome (e.g., shivering, salivation, prone flat posture, and core temperature changes) are also measured. Concurrently, spontaneous behavior of the rats is measured using an automated tracking system (Med Associates, VT, USA). Activity data collected include total distance traveled, rearing counts, and ambulatory episodes. All data are expressed as the mean ± standard error of the mean (SEM) for 6–10 rats per group. Drug discrimination in rats

[0367] Male Sprague-Dawley rats are initially food-restricted (single housing) by presenting 18–20 g of food at the end of each day. After 7 days of acclimation to the food-restriction procedure, the rats are trained daily to lever press for food (45 mg Bioserve pellets) for 1 week in a standard two-lever operant conditioning chamber controlled by Med-PC software (Med. Associates Ins., St. Albans, VT). The rats are trained to lever press for food up to an FR10 value (i.e., 10 lever presses for one food reward). Once stable food responding is acquired on both response levers, discrimination training begins. Over a period of 20–50 training sessions, rats are trained to associate one lever with a 1 mg / kg subcutaneous psilocybin training dose and the second lever with a neutral stimulus (saline, subcutaneous) (Winter et al., Pharmacol Biochem Behav. 87(4): 472–480, 2007). Training sessions last 30 min or until 50 pellets have been delivered, and the animals achieve adequate stimulus control (defined as six consecutive sessions in which the animals make 16 or fewer lever presses before the first reward is delivered, and 95% or more of the total responses are on the appropriate lever). Rats continue to receive their daily food allotment in their home cages at the end of each day.

[0368] Once trained, substitution testing is performed. On the test day, both levers are active, meaning that the 10th response on either lever delivers a food pellet. Test sessions continue until 50 pellets are obtained or 30 minutes have elapsed. Response rates are also measured during these sessions. Results and Discussion

[0369] The effect of various doses of I-2, an exemplary compound of Formula I, on head twitch response (HTR) in male C57BL6 mice was measured. Mice were treated with compound I-2 (0.03-10 mg / kg, subcutaneous injection) via the subcutaneous route (N=6 mice / dose), and the total number of head twitches was recorded over a 1-hour period. Data are expressed as mean ± standard error of the mean (SEM). The induction of head twitches by 5-HT2A receptor agonists is believed to represent a behavioral proxy for the hallucinogenic effects of these 5-HT2A receptor agonists.

[0370] To assess the involvement of the 5-HT2A receptor in HTR-induced by an exemplary compound of Formula I, mice were pretreated with the selective 5-HT2AR antagonist M100907 (also known as vorinanserin) prior to administration of an exemplary compound of Formula I, e.g., I-2 (10 mg / kg SC). As expected, pretreatment with the antagonist completely blocked the effect of the exemplary compound of Formula I (I-2) on HTR (Figure 2).

[0371] Although the present application has been described with reference to examples, it should be understood that the scope of the claims is not limited to the embodiments set forth in the examples, but is to be accorded the broadest interpretation consistent with the entire disclosure.

[0372] All patents, patent applications, and publications cited in this disclosure are hereby incorporated by reference in their entireties. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as of the filing date of the application described and claimed in this disclosure. The present disclosure also includes the following aspects. <1> Compounds of formula (I) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [ka] R 1 is hydrogen, C1-C3 alkyl, C1-C6 alkylene P(O)(OR 9 ) 2 , C(O)R 9 , CO 2 R 9 , C(O)N(R 9 ) 2 , S(O)R 9 , and SO 2 R 9 Selected from; R 2 、R 3 , and R 4 are independently selected from hydrogen and C1-C6 alkyl; R 5 is selected from hydrogen and C1-C6 alkyl; R 6 、R 7 , and R 8 is hydrogen, halogen, CN, OR 9 , N(R 9 ) 2 , S.R. 9 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, CO 2 R 9 , C(O)N(R 9 ) 2 , S(O)R 9 , SO 2 R 9 , C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl, and O, S, S(O), SO 2 , N, and NR 9 wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, C3-C7 cycloalkyl group, and 3- to 7-membered heterocyclic group are optionally selected from CN, OR 9 , N(R 9 ) 2 , and S.R. 9 wherein the C3-C7 cycloalkyl and 3- to 7-membered heterocycle are each optionally further substituted with one or more substituents independently selected from halogen, CO 2 R 9 , C(O)N(R 9 ) 2 , SO 2 R 9 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, as well as O, S, S(O), SO 2 , N, and NR 9 and is substituted with a substituent selected from a 3- to 6-membered heterocycle containing 1 to 2 heterocyclic moieties selected from Y is selected from halogen and QA; Q is O, NR 10 , S, S(O), and SO 2 Selected from; Here, each R 9 and R 10 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C6 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C6 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C6 alkylenearyl, and substituted or unsubstituted C1-C6 alkyleneheteroaryl; and A is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C6 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, P(O)(OR 11 ) 2 , C1-C6 alkylene P(O)(OR 11 ) 2 , C1-C6 alkylene C3-C7 cycloalkyl, C1-C6 alkylene C4-C6 cycloalkenyl, C1-C6 alkylene heterocycloalkyl, C1-C6 alkylene aryl, C1-C6 alkylene heteroaryl, C(O)Q', CO 2 (Q'), C(O)N(Q') 2 , SO(Q'), and SO 2 (Q') is selected from; Here, Q' is hydrogen, C1-C20 alkyl, C1-C20 haloalkyl, C2-C20 alkenyl, C2-C20 haloalkenyl, C2-C20 alkynyl, C2-C20 haloalkynyl, C3-C7 cycloalkyl, and O, S, S(O), SO 2 , N, and NR 10 wherein the C1-C20 alkyl group, the C2-C20 haloalkyl group, the C2-C6 alkenyl group, the C2-C20 haloalkenyl group, the C3-C7 cycloalkyl group, and the 3- to 7-membered heterocyclic group are selected from the group consisting of CN, OR 10 , N(R 10 ) 2 , and S.R. 10 and / or optionally disubstituted on the same carbon atom by C1-C6 alkyl or by C2-C6 alkylene to form a C3-C7 cycloalkyl ring, wherein said C3-C7 cycloalkyl and 3- to 7-membered heterocycle are each further optionally substituted by a member of the group consisting of C1-C3 alkyl and C1-C3 haloalkyl; and Each R 11 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C6 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C6 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C6 alkylenearyl, and substituted or unsubstituted C1-C6 alkyleneheteroaryl; wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes; however, A is CH 3 and Q is O and R 1 is H or CH 3 and R 2 、R 3 、R 4 , and R 5 If all are hydrogen, R 6 、R 7 , and / or R 8 OCH 3 rather than; A is CH 3 and Q is O, then R 1 ~R 8 is not all hydrogen; and A is hydrogen, Q is O, and R 1 、R 2 , and R5 One of the groups is methyl, and R 1 、R 2 , and R 5 If the other two of are hydrogen, R 3 、R 4 , and R 6 ~R 8 is not all hydrogen. <2> R 1 is S(O)R 9 and SO 2 R 9 wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof; <1> The compound described in <3> R 1 is hydrogen, C1-C3 alkyl, C1-C3 alkylene P(O)(OR 9 ) 2 , C(O)R 9 , CO 2 R 9 , and C(O)N(R 9 ) 2 wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof; <1> The compound described in <4> R 1 is hydrogen, C1-C3 alkyl, CH 2 P(O)(OR 9 ) 2 , C.H. 2 CH 2 P(O)(OR 9 ) 2 , C.H. 2 CH(CH 3 )P(O)(OR 9 ) 2 , CH(CH 3 )CH 2 P(O)(OR 9 ) 2 , CH(CH 3 )P(O)(OR 9 ) 2 , and CH(CH 2 CH 3 )P(O)(OR9 ) 2 , C(O)R 9 , and CO 2 R 9 wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof; <3> The compound described in <5> R 1 is hydrogen, CH 3 , C.H. 2 CH 3 , C.H. 2 P(O)(OR 9 ) 2 , and CH(CH 3 )P(O)(OR 9 ) 2 wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof; <4> The compound described in <6> R 1 are hydrogen, deuterium, and CH 3 , C.H. 2 CH 3 , C.H. 2 P(O)(OR 9 ) 2 , and CH(CH 3 )P(O)(OR 9 ) 2 Selected from: <5> The compound described in <7> R 2 、R 3 , and R 4 are independently selected from hydrogen and C1-C4 alkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes; <1> ~ <6> The compound according to any one of the above. <8> R 2 、R 3 , and R 4 is hydrogen, CH 3 , C.H. 2 CH 3 , CH(CH 3 ) 2 , and C(CH 3 ) 3 wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium, <7> The compound described in <9> R 2 is selected from hydrogen and deuterium; <8> The compound described in <10> R 3 and R 4 are hydrogen, deuterium, F, CH 3 , CD 2 H, CDH 2 , CD 3 , C.H. 2 CH 3 , C.H. 2 CH 2 D, C.H. 2 CD 2 H, and CD 2 CD 3 are independently selected from <1> ~ <9> The compound according to any one of the above. <11> R 3 and R 4 At least one of R is deuterium, or 3 and R 4 At least one of the groups contains deuterium, <1> ~ <10> The compound according to any one of the above. <12> R 3 and R 4 are both hydrogen or R 3 and R 4 are both deuterium, <11> The compound described in <13> R 5 is selected from hydrogen and C1-C4 alkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes; <1> ~ <12> The compound according to any one of the above. <14> R 5 is hydrogen, CH 3 , C.H. 2 CH 3 , CH(CH 3 ) 2 , and C(CH 3 ) 3 wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof; <13> The compound described in <15> R 5 are hydrogen, deuterium, and CH 3 , and CD 3 Selected from: <14> The compound described in <16> R3 、R 4 , and R 5 At least one of the groups contains deuterium, or R 3 、R 4 , and R 5 at least one of which is deuterium, <1> ~ <15> The compound according to any one of the above. <17> R 6 、R 7 , and R 8 is hydrogen, F, Cl, Br, CN, OR 9 , N(R 9 ) 2 , S.R. 9 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO 2 R 9 , C(O)N(R 9 ) 2 , S(O)R 9 , SO 2 R 9 , C2-C6 alkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl, wherein the C1-C4 alkyl group, C1-C4 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, and C2-C6 haloalkynyl group are optionally selected from CN, OR 9 , N(R 9 ) 2 , and S.R. 9 wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof; <1> ~ <16> The compound according to any one of the above. <18> R 6 、R 7 , and R 8 are independently selected from hydrogen, deuterium, F, Cl, Br, and CN; <17> The compound described in <19> R 9 and R 10 are independently selected from hydrogen, C1-C4 alkyl, and C2-C6 alkenyl, wherein any available hydrogen atom is optionally replaced by a halogen atom, and / or any available atom is optionally replaced by its alternative isotope; <1> ~ <18> The compound according to any one of the above. <20> Y is a halogen, and the halogen in Y is selected from F, Cl, and Br; <1> ~ <19> The compound according to any one of the above. <21> Y is QA, <1> ~ <19> The compound according to any one of the above. <22> Q is S, S(O), and SO 2 Selected from: <21> The compound described in <23> Q is O, NR 10 and S, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof; <21> The compound described in <24> Q is O, <23> The compound described in <25> A is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, P(O)(OR 11 ) 2 , C1-C3 alkylene P(O)(OR 11 ) 2 , C1-C3 alkylene C3-C7 cycloalkyl, C1-C3 alkylene C4-C6 cycloalkenyl, C1-C3 alkylene heterocycloalkyl, C1-C3 alkylene aryl, C1-C3 alkylene heteroaryl, C(O)Q′, CO 2 Q′, C(O)N(Q′) 2 , S(O)Q′, and SO 2 Q', wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof; <1> ~ <24> The compound according to any one of the above. <26> A is hydrogen, P(O)(OR 11 ) 2 , C.H. 2 P(O)(OR 11 ) 2 , C.H. 2 CH 2 P(O)(OR 11 ) 2 , C.H. 2 CH(CH 3 )P(O)(OR 11 ) 2 , CH(CH 3 )CH 2 P(O)(OR 11 ) 2 , CH(CH 3 )P(O)(OR 11 ) 2 , CH(CH 2 CH 3 )P(O)(OR 11 ) 2 , C(O)Q′, CO 2 Q′, C(O)N(Q′) 2 , S(O)Q′, and SO 2 Q', wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof; <25> The compound described in <27> A is hydrogen, P(O)(OR 11 ) 2 , C.H. 2 P(O)(OR 11 ) 2 , CH(CH 3 )P(O)(OR11 ) 2 , C(O)N(Q′) 2 and C(O)Q′, <26> The compound described in <28> Each R 11 are independently selected from hydrogen, C1-C4 alkyl, and C2-C6 alkenyl, wherein any available hydrogen atom is optionally replaced by a halogen atom, and / or any available atom is optionally replaced by its corresponding isotope; <27> The compound described in <29> A is selected from hydrogen and C1-C4 alkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes; <25> The compound described in <30> A is CH 2 C3-C7 cycloalkyl, CH 2 C4-C6 cycloalkenyl, CH 2 Heterocycloalkyl, CH 2 Aryl and CH 2 heteroaryl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof; <25> The compound described in <31> A is selected from C3-C7 cycloalkyl, C4-C7 cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, wherein any available hydrogen atom is optionally replaced by a halogen atom, and / or any available atom is optionally replaced by its corresponding isotope; <25> The compound described in <32> Q' is selected from hydrogen, C1-C20 alkyl, C1-C20 haloalkyl, C2-C20 alkenyl, C2-C20 haloalkenyl, C2-C20 alkynyl, and C2-C20 haloalkynyl, wherein the C1-C20 alkyl, C2-C20 haloalkyl, C2-C6 alkenyl, C2-C20 haloalkenyl, C2-C20 alkynyl, and C2-C20 haloalkynyl groups are selected from the group consisting of CN, OR 10 , N(R 10 ) 2 , CO 2 R 10 , S.R. 10 , optionally substituted by 1 to 3 substituents independently selected from C3 to C7 cycloalkyl, C4 to C7 cycloalkenyl, and a 3- to 7-membered heterocycle, and / or optionally disubstituted on the same carbon atom by C1 to C6 alkyl or by C2 to C6 alkylene to form a C3 to C7 cycloalkyl ring, and each of the C3 to C7 cycloalkyl, C4 to C7 cycloalkenyl, and 3- to 7-membered heterocycle is further optionally substituted by a substituent selected from C1 to C3 alkyl and C1 to C3 haloalkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. <33> Q′ is N(R 10 ) 2 and CO 2 R 10 and / or optionally disubstituted on the same carbon atom by C1-C6 alkyl or by C2-C6 alkylene to form a C3-C7 cycloalkyl ring, wherein said C3-C7 cycloalkyl ring is further optionally substituted with substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof; <32> The compound described in <34> Q′ is N(R 11 ) 2 C1-C20 alkyl or C2-C20 alkenyl substituted with, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof; <33> The compound described in <35> Q′ is N(R 10 ) 2 wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium; <34> The compound described in <36> Q′ is N(R 10 ) 2 and disubstituted on the same carbon atom by C2-C6 alkylene to form a C3-C7 cycloalkyl ring, wherein said C3-C7 cycloalkyl ring is further optionally substituted with a substituent selected from C1-C3 alkyl and C1-C3 haloalkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof; <33> The compound described in <37> Q′ is N(R10 ) 2 and disubstituted on the same carbon atom with C2-C6 alkylene to form a C5-C6 cycloalkyl ring, wherein said C3-C7 cycloalkyl ring is further optionally substituted with substituents selected from C1-C3 alkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium; <36> The compound described in <38> Q' is CO 2 R 10 C1-C20 alkyl or C2-C20 alkenyl optionally substituted with, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes; <33> The compound described in <39> Q' is CO 2 R 10 C1-C6 alkyl or C2-C6 alkenyl substituted with, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium; <38> The compound described in <40> Q' is a C1-C20 alkyl or a C2-C20 alkenyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof; <33> The compound described in <41> Q' is a C1-C6 alkyl or a C2-C6 alkenyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes; <40> The compound described in <42> Q' is selected from hydrogen and deuterium; <32> The compound described in <43> Q' is C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and O, S, S(O), SO 2 , N, and NR 10 wherein the C3-C7 cycloalkyl group, the C4-C7 cycloalkenyl group, and the 3- to 7-membered heterocyclic group are optionally selected from CN, OR 10 , N(R 10 ) 2 , CO 2 R 10 , S.R. 10 , substituted by 1 to 3 substituents independently selected from C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterocycle, wherein each of said C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterocycle is each further optionally substituted with a substituent selected from C1-C3 alkyl; wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by alternative isotopes thereof, <1> ~ <27> The compound according to any one of the above. <44> Q' is N and NR 10 wherein the 5- to 6-membered heterocyclic group is optionally substituted with a 5- to 6-membered heterocyclic ring, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by alternative isotopes thereof; <41> The compound described in <45> Q' is selected from the groups listed below: <1> ~ <27> The compound according to any one of the following:

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Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof: 【Chemistry 1】 where: R １ is hydrogen, CH ２ P(O)(OR ９ ) ２ , and CH(CH ３ ) P (O) (OR ９ ) ２ Selected from: R ２ is hydrogen; R ３ and R ４ are independently selected from hydrogen and C1-C6 alkyl; R ５ is hydrogen; R ６ , R ７ , and R ８ are independently selected from hydrogen, F, Cl, Br, and CN; Each R ９ are independently selected from hydrogen, C1-C4 alkyl, and C2-C6 alkenyl; Y is Q-A; Q is O, S, S(O), and SO ２ Selected from: A is hydrogen, P(O)(OR １１ ) ２ , C.H. ２ P(O)(OR １１ ) ２ , CH(CH ３ ) P (O) (OR １１ ) ２ , C(O)Q', CH ２ C3-C7 cycloalkyl, CH ２ C4-C6 cycloalkenyl, CH ２ Heterocycloalkyl, CH ２ Aryl, CH ２ selected from heteroaryl, and C1-C4 alkyl; Q' is selected from the groups listed below: 【Chemistry 2】 【Transformation 3】 During the ceremony, 【Chemistry 4】 indicates a point of covalent attachment; Each R １１ are independently selected from hydrogen, C1-C4 alkyl, and C2-C6 alkenyl; wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes; however, A is CH ３ and when Q is O, then R １ ~R ８ is not all hydrogen.

2. 2. The compound of claim 1, wherein the compound of formula (I) is selected from the compounds listed below, or a pharmaceutically acceptable salt and / or solvate thereof. Table 12 Table 13

3. 10. A pharmaceutical composition comprising one or more compounds of claim 1 or pharmaceutically acceptable salts and / or solvates thereof, and a pharmaceutically acceptable carrier.

4. 10. A pharmaceutical composition comprising 0.5 mg to 500 mg of one or more compounds of claim 2 or pharmaceutically acceptable salts and / or solvates thereof, and a pharmaceutically acceptable carrier.

5. The compound I-41 below or a pharmaceutically acceptable salt and / or solvate thereof. Table 14

6. 10. A pharmaceutical composition comprising a compound of claim 5 or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising 0.5 mg to 500 mg of the compound of claim 5 or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier.

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