Indole derivatives as serotonergic agents useful for the treatment of serotonergic drug-related disorders

Abstract

The present application relates to 3-aminoindole derivatives of general formula (IA), processes for their preparation, compositions comprising the same, and their use in activating serotonin receptors in cells and in treating diseases, disorders, or conditions, such as, for example, psychoses, psychiatric disorders, and CNS disorders, through activation of serotonin receptors in cells. JPEG2024508545000033.jpg125126

Description

[Technical field]

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

[0002] This application claims the benefit of priority from co-pending U.S. Provisional Patent Application No. 63 / 155,634, filed March 2, 2021, the contents of which are incorporated by reference in their entirety into this disclosure.

[0003] Mental health disorders, or psychiatric illnesses, refer to a wide range of disorders, including but not limited to depressive disorders, anxiety and panic disorders, schizophrenia, eating disorders, substance misuse disorders, post-traumatic stress disorder, attention-deficit / hyperactivity disorder, and obsessive-compulsive disorder. The severity of symptoms varies such that some individuals experience a debilitating illness that precludes normal social functioning, whereas others suffer from intermittent recurring episodes throughout their lifespan. Although symptoms and diagnostic criteria are partially distinct among various psychiatric conditions, there are notable endomorphs that are common among the disorders, and often comorbidities exist. Specifically, there are phenotypic endomorphs associated with changes in mood, cognition, and behavior. Interestingly, many of these endomorphs extend to neurotic 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 affected by alterations, dysfunction, degeneration, and / or damage to the brain's serotonergic system, which may partially explain the common endophenotypes and comorbidities among various neuropsychiatric and neurological disorders. Many therapeutic agents that modulate serotonergic function are available on the market, including serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, antidepressants, and monoamine oxidase inhibitors. Although these therapeutic agents were primarily developed for depressive disorders, many of these therapeutic agents are used throughout multiple medical applications, including, but not limited to, depression in Alzheimer's disease and other neurodegenerative diseases, chronic pain, existential pain, bipolar disorder, obsessive-compulsive disorder, anxiety disorder, and smoking cessation. However, in many cases, over-the-counter drugs show only limited benefit over placebo, can take up to six weeks to work in some patients, and are associated with a number of side effects, including sleep disorders, drowsiness, fatigue, weakness, changes in blood pressure, memory problems, digestive problems, weight gain, and sexual problems.

[0005] The field of psychedelic neuroscience has undergone a recent renaissance after ages of limited research due to its legal status. Hallucinogens are one of the oldest classes of psychopharmacological agents known to mankind and cannot be fully understood without reference to a variety of fields of study, including anthropology, ethnopharmacology, psychiatry, psychology, sociology, and others. Hallucinogens (serotonergic hallucinogens) are powerful 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 date back further than documented history, with early cultures using them in many sociocultural and ritual contexts. Following the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD, 5, Scheme 1) 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. Today, the 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 the sigma-1 receptor. 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 effects that persist long after their acute impact, including changes in mood and brain function. Long-lasting effects can be attributed to the unique receptor affinity of psychedelics, which affects neurotransmission through neuromodulatory systems that serve to regulate brain activity, i.e., neuroplasticity, and promote cell survival, are neuroprotective, and modulate the brain 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 provide a new generation of neurotherapeutics, where 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 standpoint, they are one of the safest known classes of central nervous system (CNS) drugs. Hallucinogens do not cause addiction, and no overdose deaths have occurred following ingestion of doses typical of classical psychotic agents such as LSD, psilocybin, or mescaline (1, Scheme 1). Preliminary data indicate that administration of hallucinogens in humans produces a unique profile of effects and potential adverse reactions that need to be appropriately addressed to maximize safety. The primary safety concerns are primarily psychological rather than physiological in nature. Physical effects are variable but relatively insignificant, even at doses that cause 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 in a dose-related manner [Johnson et al., Drug Alcohol Depend (2012), 123(1-3):132-140]. Repeated administration of hallucinogens has been found to result in the development of very rapid tolerance, known as tachyphylaxis, a phenomenon believed 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-HT2 receptor density in rat brain [Buckholtz et al., Eur. J. Pharmacol. 1990, 109:421-425. 1985; Buckholtz et al., Life Sci. 1985, 42:2439-2445]. [ka] Scheme 1: Chemical structures of mescaline (1), DMT (2), 5-MeO-DMT (3), LSD (4), psilocybin (5), and psilocin (6).

[0008] Classical and dissociative hallucinogens are known to have rapid onset antidepressant and antiaddictive effects unlike any currently available treatment. Randomized controlled clinical trials have confirmed the antidepressant and anxiolytic effects of classical hallucinogens in humans. Ketamine also has well-established antidepressant and antiaddictive effects in humans, primarily through its action as an NMDA antagonist. Ibogaine has shown strong antiaddictive capabilities in preclinical studies and is in early stages of clinical trials to determine 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 (5, Scheme 1)) is a C 12 H 17 N 2 O 4Psilocybin has the chemical formula of P. It is a tryptamine and one of the major psychoactive components in the mushrooms of the genus Psilocybin. Psilocybin was first isolated from the mushroom Psilocybin by Hofmann in 1957 and then 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 placed on the controlled drug schedule in the United States in the 1970s and in Germany in the 1980s [Passie 2005; Passie et al. Addict Biol., 2002, 7(4):357-364]. Research exploring the effects of psilocybin resumed in the mid-1990s, and psilocybin is now the preferred compound for use in testing 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 because psilocybin has a short duration of action and is less notorious than LSD. Like other members of this class, psilocybin induces sometimes severe changes in perception, cognition, and emotion, including affective lability.

[0010] In humans and other mammals, psilocybin is converted to the active metabolite psilocin or 4-hydroxy-N,N-dimethyltryptamine (6, Scheme 1). It is likely that psilocybin partially or completely produces most of the subjective and psychological effects of psilocybin in humans and non-human animals. Recently, psilocybin studies in humans have confirmed the 5-HT2A activity of psilocybin and psilocin, which provides some support for indirect effects on dopamine through 5HT2A activity and possible activity at other serotonin receptors. In fact, the most consistent finding for the involvement of other receptors in the action of hallucinogens is the 5-HT1A receptor. This is especially true in the case of tryptamines and LSD, which generally have significant affinity and functional potency at this receptor. It is known that 5-HT1A receptors colocalize 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 exact role of 5-HT2A receptors and other 5-HT2 receptor family members is not well understood in the amygdala, it is clear that 5-HT2A receptors play a key role in emotional responses and are important targets to consider in the action of 5-HT2A agonist hallucinogens. Indeed, most known 5HT2A agonists produce hallucinogenic effects in humans, and rodents generalize from one 5HT2A agonist to another, such as between psilocybin and LSD [Aghajanian et al., Eur J Pharmacol., 1999, 367(2-3):197-206; Nichols at al., J Neurochem., 2004, 90(3):576-584]. Psilocybin has a stronger affinity for the human 5HT2A receptor than for the rat receptor, and has a lower Ki than LSD for both the 5HT2A and 5HT2C receptors. Furthermore, results from a series of drug discrimination studies in rats found 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 trials in the 1960s and 1970s showed that psilocybin produces altered states of consciousness with subjective symptoms such as "marked changes in perception, mood, and thought, as well as changes in time, space, and experience of oneself." Psilocybin has been used in experimental studies to understand the pathogenesis of selected psychological disorders and has shown psychotherapeutic potential [Rucker et al., Psychopharmacol., 2016, 30(12):1220-1229]. Psilocybin became increasingly popular as a recreational drug that produced hallucinations, eventually being classified as a Schedule 1 controlled substance in 1970. Fears of abuse of hallucinogens led to a major decline in research conducted in this area, which remained so 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 trials due to its relative safety, moderately long duration of activity, and good absorption in subjects. Recent studies have shown varying degrees of success in neurotic disorders, alcoholism, depression in terminal cancer patients, obsessive-compulsive disorder, addiction, anxiety, post-traumatic stress disorder, and even cluster headaches, so there remains strong research and therapeutic potential for psilocybin. Psilocybin may also be 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 exciting developments in this field have come in the area of ​​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 shown unprecedented positive relief from anxiety and depression. Two recent small-scale pilot trials of psilocybin-assisted psychotherapy have also shown 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, with results indicating that intravenously administered psilocybin and LSD produced a decrease in oscillatory power in regions of the brain's default mode network [Nichols DE. Pharmacol Rev. ( 2016) 68(2):264-355].

[0014] Preliminary studies using positron emission tomography (PET) have shown that psilocybin ingestion (15 or 20 mg orally) increased absolute glucose metabolic rates in healthy participants in the frontal cortex and to a lesser extent in other cortical areas and in the striatum and limbic subcortical structures, suggesting that some of the key behavioral effects of psilocybin involve the frontal cortex [Gouzoulis-Mayfrank et al., Neuropsychopharmacology, 1999, 20(6):565-581; Vollenweider et al., Brain Res. Bull. 2001, 56(5):495-507]. Although 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 disorders and other symptoms, such as anhedonia, psychomotor complaints, feelings of guilt, attention deficit, and suicidality, all of which vary in severity. According to the World Health Organization, the discovery of mainstream antidepressants revolutionized the management of depression, but still, up to about 60% of patients remain undertreated. This is often due to delayed therapeutic effects of the medication (usually 6 weeks after the start of treatment), side effects that lead to non-compliance, 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. It is accompanied by 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 effectiveness 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 addressed by traditional methods.

[0016] In general, the hallucinogen treatment model consists of administering orally active drugs to induce a mystical experience that lasts 4-9 hours depending on the type of 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. Classical hallucinogens such as psilocybin and LSD are currently being investigated as potential candidates. One trial using classical hallucinogens for the treatment of depression and anxiety associated with a life-threatening illness found that in a supportive setting, psilocybin and LSD consistently produced significant and long-lasting antidepressant and anxiolytic effects.

[0017] Psychedelic treatments are generally well tolerated and have no lasting adverse effects. With regard to their mechanism of action, they mediate their 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, as well as the high morbidity associated with these conditions, the potential exists for psychedelics to provide symptomatic relief in patients inadequately addressed by traditional methods.

[0018] Further emerging clinical research and evidence indicates that psychedelic-assisted therapy may be an alternative treatment for refractory substance use disorders and mental health conditions, and may be an important tool in crisis situations where existing approaches have produced limited success. A recent systematic review of clinical trials published in the last 25 years outlined some of the antidepressant, anxiolytic, and antiaddictive effects of classic psychedelics. Among them, the findings from a meta-analysis of randomized controlled trials of LSD therapy and a recent pilot study of psilocybin-assisted therapy to treat alcohol use disorder were encouraging [dos Santos et al., Ther Adv Psychopharmacol., 2016, 6(3):193-213]. Equally encouraging are findings from a recent pilot study of psilocybin-assisted therapy for tobacco use disorder, which showed 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 generated from psilocybin sessions were significantly correlated with positive treatment outcomes. These results are consistent with a burgeoning body of evidence from recent clinical trials providing support for the efficacy of psilocybin-assisted therapy for treatment-resistant depression and end-of-life anxiety [Carhart-Harris et al. Neuropsychopharmacology, 2017 42(11):2105-2113]. Research on the potential benefits of hallucinogen-assisted treatment for opioid use disorder (OUD) is beginning to emerge, and accumulating evidence supports the need for further investigation along this line.Available evidence from previous randomized trials suggests a promising role for the treatment of OUD: higher rates of drug withdrawal 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 to controls. Recently, a large US population study of 44,000 individuals 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., J. Psychopharmacol., 2018, 32(12):1385-1391]. Despite the promise of these preliminary findings with classical hallucinogens, given the potential toxicity of hallucinogens, further research is warranted to determine what contribution they may make to the opioid crisis response. Meanwhile, the growing evidence on the safety and efficacy of psilocybin for the treatment of psychological and substance use disorders may help motivate further clinical research into 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 more than 80% of depressed patients complaining of poor sleep quality. Sleep symptoms often fail to resolve with first-line treatments and are associated with a greater risk of relapse and recurrence. Interestingly, sleep problems often precede other depressive symptoms, with subjective sleep quality worsening before the onset of an episode in recurrent depression. Brain regions with increased functional connectivity to poor sleep scores and higher depressive symptom scores included prefrontal and limbic regions, regions involved in emotion processing. Sleep disruption in healthy participants has shown that sleep is indeed involved in mood, emotional appraisal processes, and brain reactivity to emotional stimuli. Increased negative mood and false labeling of neutral stimuli as negative, occurring independently of mood, were shown in one study, for example, while another study showed amplified reactivity in limbic brain regions in response to both negative and positive stimuli. Two other studies evaluating brain activity on electroencephalography (EEG) during sleep have shown that hallucinogens such as LSD have a positive effect on sleep patterns. In addition, partial or complete overnight sleep deprivation has been shown to alleviate symptoms of depression, possibly by resetting circadian rhythms through altered expression of clock genes. It has been further suggested that a single dose of hallucinogens results in a reset of the biological clock underlying the sleep / wake cycle, thereby enhancing cognitive-emotional processes in depressed people, and improving well-being and mood in healthy individuals [Kuypers, Medical Hypotheses, 2019, 125:21-24].

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

[0021] In recent years, there has been a growing interest in a new dosing paradigm for psychedelic drugs such as psilocybin and LSD, colloquially referred to as microdosing. In this paradigm, sub-perceptive doses of serotonergic psychedelics, which are 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 of particular benefit for certain conditions, such as Alzheimer's disease and other neurodegenerative diseases, attention deficit disorder, attention deficit hyperactivity disorder, and for certain patient populations, such as the elderly, the young, and patients who fear or are opposed to psychedelic drug-assisted therapy. Moreover, this approach may be particularly well suited to manage cognitive impairment and prevent neurodegeneration. For example, following subthreshold psilocybin dosing that elicited the classical wet dog shake behavioral response associated with hallucinogenic doses, subpopulations of less alert 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 believed 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)).Additionally, several groups have shown that low, non-hallucinogenic and non-psychotic doses of 5HT2A agonists also exhibit similar neuroprotective and increased neuroplastic effects (neuroplastogens) as well as 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 also prove useful in wellness applications.

[0022] 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT; 3, Scheme 1) is a C 13 H 18 N 2 N,N-Dimethyltryptamine (DMT; 2, Scheme 1) is a tryptamine natural compound that has the chemical formula C,N-dimethyltryptamine (DMT) and is most commonly identified as the major psychoactive component in the parotid secretions of the Sonoran Desert toad, Incilius alvarius, and is present in low concentrations in various plants, shrubs, and seeds [Uthaug, MV et al., Psychopharmacology 2019, 236:2653-2666; Weil et al., J. Ethnopharmacol. 1994, 41(1-2):1-8]. 12 H 15 N 2and is a tryptamine natural compound identified as the primary psychoactive component of various natural plants and vines, most commonly those of the genera Acacia, Desmodium, Mimosa, Virola, Delosperma, and Phalaris. Human ingestion of these materials for their psychoactive properties has been reported for hundreds of years [Agurell et al., Acta Chem. Scand. 1969, 23(3):903-916; Torres et al., Haworth Herbal Press: New York, 2014].

[0023] 5-MeO-DMT exhibits sub-micromolar binding affinity across most serotonin receptor subtypes expressed in the central nervous system, with 300-fold selectivity for the human 5-HT1A (3±0.2 nM) receptor subtype compared to the 5-HT2A (907±170 nM) receptor subtype [Halberstadt et al., Psychopharmacology, 2012, 221(4):709-718]. DMT has more than three-fold binding affinity for 5-HT1A (0.075 nM) compared to 5-HT2A (0.237 nM). Data indicate that 5HT2A activation, in a synergistic manner, may also play an important role in contributing to the subjective and behavioral effects of hallucinogens. In contrast to 5-MeO-DMT and DMT, psilocin (the active metabolite of psilocybin) is approximately five-fold more selective for the human 5-HT2A receptor (107 nM) compared with 5-HT1A (567 nM) [Sherwood et al., ACS Omega, 2020, 5(49):32067-32075].

[0024] Ingestion of 5-MeO-DMT has been reported to generally result in a lack of colorful geometric hallucinations typically associated with other hallucinogens such as DMT. It has also been suggested that both 5-MeO-DMT and DMT may be useful in treating clinical mental health conditions [Barsuglia et al. Front. Psychol. 2018, 9:2459; Davis et al., Am. J. Drug Alcohol Abuse, 2019, 45(2):161-169; Malcolm et al., Mental Health Clinician, 2017, 7(1):39-45; Uthaug, MV et al., Psychopharmacology 2019, 236:2653-2666]. These data indicate that 5-MeO-DMT and DMT produce mystical experiences of equal or greater intensity than those produced by psilocybin, but the duration of effects is shorter, lasting between 10 and 60 minutes depending on the route of administration.

[0025] Thus, 5-MeO-DMT and DMT appear to be pharmacodynamically unique compared to previous clinically tested hallucinogens, particularly psilocybin and LSD, and may provide useful comparators in controlled clinical trials with modern hallucinogens, thereby allowing a better understanding of their mode of action. Unlike psilocybin, hallucinogenic tryptamines such as DMT and 5-MeO-DMT undergo rapid first-pass metabolism by monoamine oxidase and are therefore not orally active [Mckenna, DJ et. al., J. Ethnopharmacol., 1984, 12(2):179-211]. When taken parenterally, they exhibit a significantly shorter duration of action, typically less than one hour, compared to the 5-8 hour duration of effects produced by psilocybin.

[0026] 5-MeO-DMT and DMT have unique pharmacodynamic and pharmacokinetic properties compared to other clinically tested psychedelics due to their short duration of action and possibly their remarkable 5-HT2A receptor selectivity. These characteristics may correlate with more positive treatment outcomes in controlled human clinical trials, and the shorter duration of action helps reduce the time patients spend in the clinic during psychedelic-assisted psychotherapy. To test this hypothesis and to better understand the psychotherapeutic utility of 5-MeO-DMT and DMT, proper controls are needed to ensure potency, purity, and strength during the preparation of active pharmaceutical ingredients (API). This application reports novel analogs of both 5-MeO-DMT and DMT with the goal of pharmacologically optimizing the next generation of short-acting psychedelic medicines related to these compounds. Summary of the Invention [Means for solving the problem]

[0027] The present application encompasses compounds having the general structural formula (IA) or pharma- ceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] During the ceremony, R 1 are hydrogen, deuterium, and C 1 ~C 3 Alkyl, C 1~6 Alkylene P(O)(OR 6 ) 2 , C 1~6 Alkylene OP(O)(OR 6 ) 2 , C(O)R 6 , CO 2 R 6 , C(O)N(R 6 ) 2 , S(O)R 6 and S.O. 2 R 6 Selected from; R 2 , R 7, R 8 , R 9 and R 10 is hydrogen, deuterium, halogens and C 1 ~C 6 independently selected from alkyl; R 3 are hydrogen, deuterium, CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Haloalkenyl, CO 2 R 18 , C(O)N(R 18 ) 2 , C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 7 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 18 wherein each of the C's is independently selected from a 3- to 7-membered heterocycle containing one or two hetero moieties selected from 1 ~C 6 Alkyl group, C 1 ~C 6 Haloalkyl group, C 2 ~C 6 Alkenyl group, C 2 ~C 6 Haloalkenyl group, C 2 ~C 6 Alkynyl group, C 2 ~C 6 Haloalkynyl group, C 3 ~C 7 The cycloalkyl group and the 3- to 7-membered heterocyclic group are CN, OR 18 , N(R 18 ) 2 and S.R. 18 and wherein the C 3 ~C 7Cycloalkyl and 3- to 7-membered heterocycles are each independently selected from halogen, CO 2 R 18 , C(O)N(R 18 ) 2 , S.O. 2 R 18 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 6 Cycloalkyl, as well as O, S, S(O), and SO 2 , N, and NR 18 and optionally further substituted by substituents selected from a 3- to 6-membered heterocycle containing one or two ring hetero moieties selected from R 4 and R 5 is hydrogen, deuterium, halogen, CN, OR 18 , N(R 18 ) 2 , S.R. 18 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Haloalkenyl, CO 2 R 18 , C(O)N(R 18 ) 2 , S(O)R 18 , S.O. 2 R 18 , C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 7 Cycloalkyl, as well as O, S, S(O), and SO2 , N and NR 18 wherein each of the C's is independently selected from a 3- to 7-membered heterocycle containing one or two hetero moieties selected from 1 ~C 6 Alkyl group, C 1 ~C 6 Haloalkyl group, C 2 ~C 6 Alkenyl group, C 2 ~C 6 Haloalkenyl group, C 2 ~C 6 Alkynyl group, C 2 ~C 6 Haloalkynyl group, C 3 ~C 7 The cycloalkyl group and the 3- to 7-membered heterocyclic group are CN, OR 18 , N(R 18 ) 2 and S.R. 18 and wherein the C 3 ~C 7 Cycloalkyl and 3- to 7-membered heterocycles are each independently selected from halogen, CO 2 R 18 , C(O)N(R 18 ) 2 , S.O. 2 R 18 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 6 Cycloalkyl, as well as O, S, S(O), and SO 2 , N, and NR 18 and optionally further substituted by substituents selected from a 3- to 6-membered heterocycle containing one or two ring hetero moieties selected from R 6 is hydrogen, deuterium and C 1 ~C 6 independently selected from alkyl; R 11 and R 12 is hydrogen, deuterium and C 1 ~C 6 independently selected from alkyl; A is hydrogen, deuterium, halogen, OR 19 , N(R 19 )(R 19a ), S.R. 19 , S(O)R 19 and S(O 2 )R 19 Selected from; Each R 18 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 7 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 20 wherein each of said C is independently selected from a 3- to 7-membered heterocycle containing one to two ring hetero moieties selected from 1 ~C 6 Alkyl group, C 1 ~C 6 Haloalkyl group, C 2 ~C 6 Alkenyl group, C 2 ~C 6 Haloalkenyl group, C 2 ~C 6 Alkynyl group, C 2 ~C 6 Haloalkynyl group, C 3 ~C 7 The cycloalkyl group and the 3- to 7-membered heterocyclic group are CN, OR 20 , N(R 20 )2 and S.R. 20 and wherein the C 3 ~C 7 Cycloalkyl and 3- to 7-membered heterocycles are each independently selected from halogen, CO 2 R 20 , C(O)N(R 20 ) 2 , S.O. 2 R 20 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 6 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 20 and optionally further substituted by a substituent selected from a 3- to 6-membered heterocycle containing 1 to 2 ring hetero moieties selected from R 19 , R 19a and each R 20 is hydrogen, deuterium, substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 2 ~C 6 Alkenyl, substituted or unsubstituted C 2 ~C 6 Alkynyl, substituted or unsubstituted C 1 ~C 6 Haloalkyl, substituted or unsubstituted C 3 ~C 7 Cycloalkyl, substituted or unsubstituted C 3 ~C 7 are independently selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0028] In some embodiments, the compounds of formula (IA) and their pharma- ceutically acceptable salts, solvates, and / or prodrugs are isotopically enriched with deuterium. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 18 , R 19 , R 19a and R 20 One or more of optionally contains deuterium.

[0029] In some embodiments, the present application encompasses compounds of formula (IA) or pharma- ceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] During the ceremony, R 1 are hydrogen, deuterium, and C 1 ~C 3 Alkyl, C 1 ~C 3 Deuteroalkyl, C 1 ~C 3 Fluoroalkyl, C 1 ~C 6 Alkylene P(O)(OR 6 ) 2 , C 1 ~C 6 Alkylene OP(O)(OR 6 )2 , C(O)R 6 , CO 2 R 6 , C(O)N(R 6 ) 2 , S(O)R 6 and S.O. 2 R 6 Selected from; R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen and deuterium; R 7 , R 8 , R 9 and R 10 are hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl and C 1 ~C 6 independently selected from fluoroalkyl; A is hydrogen, deuterium and OR 19 Selected from; R 6 are hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl and C 1 ~C 6 fluoroalkyl; R 11 and R 12 are hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl and C 1 ~C 6 fluoroalkyl; and R 19 is C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl and C 1 ~C6 fluoroalkyl; however, (1)R 2 , R 3 , R 4 and R 5 are all D, and A, R 1 , R 6 ~R 12 and R 19 is as defined above in this disclaimer, or (2) A is OR 19 where R 19 is C 1 ~C 6 Deuteroalkyl and C 1 ~C 6 fluoroalkyl; and R 1 ~R 12 is as defined above in this disclaimer.

[0030] In certain further embodiments, the compounds of the present application are used as pharmaceuticals. Thus, the present application also includes compounds of the present application for use as pharmaceuticals.

[0031] The present application includes a method of activating serotonin receptors in a cell in a biological sample or in a patient, comprising administering to the cell an effective amount of one or more compounds of the present application.

[0032] The present application also includes a method of treating a psychosis or a psychotic condition, comprising administering to a subject in need of such treatment a therapeutically effective amount of one or more compounds of the present application.

[0033] 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.

[0034] The present application further provides processes for preparing the compounds of the present application, the general and specific processes being explained in more detail below and in the Examples which follow.

[0035] 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, although showing embodiments of the present application, are given by way of example only, and the claims are not limited by these embodiments, but should be given the broadest interpretation consistent with the entire disclosure. [Brief description of the drawings]

[0036] The present application is described in more detail hereinafter with reference to the accompanying drawings and tables, wherein:

[0037] [Figure 1] Figure 1 is a graph showing the effect of various doses of an exemplary compound of formula IA, IA-6, on head twitch response (HTR) in male mice. Mice were treated with compound IA-6 (0.3, 1, 3, 10 mg / kg) by subcutaneous injection (SC) route in saline and the total number of head twitches was recorded. Data are expressed as mean ± standard error of the mean (SEM). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] I. Definition Unless otherwise stated, the definitions and embodiments described 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.

[0039] "Compound(s) of the present application" or "compound(s) of the present application" and the like as described in this disclosure refer to compounds of formula (IA), (I-A1), (I-A2), (I-A3), (I-A4), and also include pharma- ceutically acceptable salts, solvates, and / or prodrugs thereof.

[0040] The terms "composition of the present application" or "compositions of the present application" or "compositions of the present application" and the like as used in this disclosure refer to compositions, e.g., pharmaceutical compositions, that include one or more of the compounds of the present application.

[0041] The term "and / or" as used in this disclosure means that the listed items are present or used individually or in combination. In effect, the term means that "at least one" or "one or more" of the listed items are used or present. With respect to pharma-ceutically acceptable salts and / or solvates, the term "and / or" means that the compounds of the present application are present as individual salts and solvates as well as combinations, such as salts of solvates, of the compounds of the present application.

[0042] 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 present an aspect having one type of compound, or an aspect having two or more additional compounds.

[0043] As used in this application and in the claims, the words "comprising" (and any form of comprising, e.g., "including" (present tense) (with or without s attached to the third person singular)), "having" (and any form of having, e.g., "having" (present tense) (with or without s attached to the third person singular)), "including" (and any form of including, e.g., "including" (present tense) (with or without s attached to the third person singular)), and "containing" (and any form of containing, e.g., "including" (present tense) (with or without s attached to the third person singular)) are inclusive and open-ended and do not exclude additional, unrecited elements or process steps.

[0044] 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.

[0045] 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.

[0046] In embodiments that include an "additional" or "second" component, e.g., an additional or second compound, a second component, as used herein, is chemically distinct from the other components or from the first component. A "third" component is distinct from the other first and second components, and further recited or "additional" components are similarly distinct.

[0047] 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 application for the compound, but is well within the skill of the artisan. All process / method steps described in this disclosure are to be performed under conditions sufficient to provide the indicated product. The artisan will understand, and it is within the skill of the artisan to do so, that all reaction conditions, e.g., reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratios, whether the reaction should be performed in anhydrous or inert atmosphere, etc., can be varied to maximize the yield of the desired product.

[0048] The terms "about," "substantially," and "approximately" as used in this disclosure refer to a reasonable amount of deviation from the modified word that does not significantly change the end result. These terms of degree should be interpreted as including deviations 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 a different meaning to one of ordinary skill in the art.

[0049] This specification describes many chemical terms and abbreviations used by those of skill in the art. However, definitions of selected terms are provided for clarity and consistency.

[0050] 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 is physiologically acceptable at the dosage administered.

[0051] 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.

[0052] 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 determined by the prefix "C n1~Cn2 ". Thus, for example, the term "C 1~6 Alkyl" (or "C 1 ~C 6 "C 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 ter-butyl, n- and iso-propyl, ethyl, and methyl. Other examples include "C 4 "Alkyl" refers to n-, iso-, sec- and tert-butyl, n- and isopropyl, ethyl and methyl.

[0053] The term "alkenyl," whether used alone or as part of another group, refers to a straight or branched saturated alkylene group, i.e., a saturated carbon chain containing substituents on two of its termini. The number of possible carbon atoms in the alkylene group in question is determined by the prefix "C n1~n2 ". Thus, for example, the term "C 2~6 "Alkylene" means an alkylene group having 2, 3, 4, 5, or 6 carbon atoms.

[0054] The term "alkynyl" as used herein, 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 of interest is determined by the prefix "C n1~n2 For example, the term C 2~6 Alkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms.

[0055] As used herein, the term "cycloalkyl," whether used alone or as part of another group, refers to a saturated carbocyclic group containing from 3 to 20 carbon atoms and one or more rings. The number of possible carbon atoms in a given cycloalkyl group can be determined by the prefix "C n1~n2 For example, the term C 3 ~ 10 Cycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0056] 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.

[0057] 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 to be capable of being replaced by a substituent / substituent.

[0058] As used herein, the term "heterocycloalkyl," whether used alone or as part of another group, refers to a non-aromatic ring containing 3 to 20 atoms, one or more of which are O, S, S(O), SO 2 and N, with the remaining atoms being C. Heterocycloalkyl groups can be saturated or unsaturated (i.e., contain one or more double bonds). Heterocycloalkyl groups are defined as groups beginning with the prefix C. n1~n2 or "n1-n2", this prefix represents the number of carbon atoms in the corresponding carbocyclic group, where one or more, preferably 1 to 5, of the ring atoms are O, S, S(O), SO 2 and N, and the remaining atoms are C. The heterocycloalkyl group is optionally benzo-fused.

[0059] The term "heteroaryl," as used herein, whether used alone or as part of another group, refers to a cyclic group that includes at least one heteroaromatic ring containing 5 to 20 atoms, one or more of which are heteroatoms selected from O, S, and N, with the remaining atoms being C. Heteroaryl groups are identified by the prefix C. n1~n2 When the prefix "" represents 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.

[0060] 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 multiple rings can be fused, bridged, spiro-fused, or joined by bonds.

[0061] The term "benzofused" as used in this disclosure refers to a polycyclic group in which a benzene ring is fused to another ring.

[0062] A first ring is "fused" to a second ring means that the first ring and the second ring share two adjacent atoms between each other.

[0063] A first ring is "bridged" to a second ring means that the first ring and the second ring share two non-adjacent atoms between each other.

[0064] A first ring is "spirofused" to a second ring means that the first ring and the second ring share one atom between each other.

[0065] 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.

[0066] The term "haloalkyl" as used herein refers to an alkyl group, as defined above, in which one or more of the available hydrogen atoms have been replaced by a halogen. Thus, for example, "C 1~6 haloalkyl" (or "C 1 ~C 6 "Haloalkyl" refers to 1 ~C 6 "R" refers to a linear or branched alkyl group as defined above having one or more halogen substituents.

[0067] The term "haloalkenyl" as used herein refers to an alkenyl group, as defined above, in which one or more of the available hydrogen atoms is replaced by a halogen. Thus, for example, "C 1~6 haloalkenyl" (or "C 1 ~C 6 "haloalkenyl" refers to 1 ~C 6 "Alkenyl groups" refers to straight or branched alkenyl groups as defined above, having one or more halogen substituents.

[0068] The term "haloalkynyl" as used herein refers to an alkynyl group, as defined above, in which one or more of the available hydrogen atoms is replaced by a halogen. Thus, for example, "C 1~6 haloalkynyl" (or "C 1 ~C 6 "haloalkynyl" refers to 1 ~C 6 "Alkynyl groups" refers to straight or branched alkynyl groups as defined above, which have one or more halogen substituents.

[0069] The term "alkoxy," as used in this disclosure, alone or in combination, includes an alkyl group connected to a connecting atom which is oxygen.

[0070] 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.

[0071] As used in this disclosure, the term "substituted" means, unless otherwise specified, that the referenced group is not a halogen, CO 2 H, CO 2 CH 3 , C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)NHCH 3 , S.O. 2 CH 3、 SOCH3 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 6 Cycloalkyl, as well as O, S, S(O), and SO 2 , N, NH and NCH 3 and a 3- to 6-membered heterocycle containing 1 to 2 ring members selected from the group consisting of 1 to 6 heterocycles.

[0072] As used in this disclosure, the term "alternative isotope thereof" refers to an isotope of an element other than the isotope that is most abundant in nature.

[0073] In the compounds of general formula (IA) and their pharma- ceutically 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 different atomic mass or mass number from the atomic mass or mass number predominantly found in nature. The present disclosure is intended to encompass all suitable isotopic variations of the compounds of general formula (IA) and their pharma-ceutically 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.

[0074] As used in this disclosure, the term "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 but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.

[0075] The term "compound" refers to the compound, and in some 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, and whose structure and properties remain essentially unchanged or essentially unchanged for a period of time sufficient to enable 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 the general formula (IA), or pharma- ceutically acceptable salts, solvates, and / or prodrugs thereof.

[0076] The term "pharmaceutical acceptable" means compatible with treating a subject.

[0077] The term "pharmaceutical acceptable carrier" means a non-toxic solvent, dispersant, 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.

[0078] The term "pharmaceutical acceptable salt" means an acid addition salt or a base addition salt which is suitable or compatible for the treatment of a subject.

[0079] An acid addition salt suitable or compatible for treating a subject is any non-toxic organic or inorganic acid addition salt of any basic compound.

[0080] A base addition salt suitable or compatible for treating a subject is any non-toxic organic or inorganic base addition salt of any acidic compound.

[0081] The term "protecting group" or "PG" or the like, as used in this disclosure, 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. Selection of an appropriate protecting group can be made by one of ordinary skill in the art. Many conventional protecting groups are known in the art and can be found, for example, in "Protective Groups in Organic Chemistry" McOmie, JFW Ed., Plenum Press, 1973, in Greene, TW and Wuts, PGM, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3 rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0082] As used in this disclosure, the term "subject" includes all members of the animal kingdom, including mammals, and preferably refers to humans, and thus the methods of the present application are applicable to both human therapy and veterinary applications.

[0083] The term "treat" or "treatment" as used in this disclosure refers to an approach for obtaining beneficial or desired results, such as clinical results, as is well known in the art. 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) state of disease, prevention of spread of disease, delay or slowing of disease progression, improvement or palliation of disease state, reduction in recurrence of disease, and remission (whether partial or complete), which may be detectable or undetectable. "Treat" and "treatment" may also mean an increase in survival time compared to expected survival time 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 compounds of the present application, which optionally consists of a single dose or includes a series of multiple doses.

[0084] The term "effective amount" or "therapeutically effective amount" as used in the present disclosure 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 said one or more compounds.

[0085] "Palliating" 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.

[0086] The term "administered" as used in this disclosure means administration of a therapeutically effective amount of one or more compounds or compositions of the present application to a cell, tissue, organ, or subject.

[0087] 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.

[0088] In the present disclosure, a "disease, disorder, or condition" refers to an impairment of a serotonin receptor, such as 5-HT 2A , particularly those diseases, disorders, or conditions that are treated or treatable with a serotonin receptor agonist, such as one or more of the compounds of the present disclosure.

[0089] 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 agonized by one or more of the compounds or compositions of the present application.

[0090] The term "activation" as used in this disclosure encompasses agonism, partial agonism, and positive allosteric modulation of serotonin receptors.

[0091] As used in this disclosure, the term "5-HT 1A " and "5-HT 2A " is 5-HT 2 5-HT serotonin receptors 2A Receptor Subtypes and 5-HT 2A Receptor subtypes are meant.

[0092] The term "therapeutic agent" as used in this disclosure refers to any drug or active agent that has a pharmacological effect when administered to a subject.

[0093] II. Compounds The present application includes compounds of general formula (IA) or their pharma- ceutically acceptable salts, solvates, and / or prodrugs: [ka] During the ceremony R 1 are hydrogen, deuterium, and C 1 ~C 3 Alkyl, C 1~6 Alkylene P(O)(OR 6 ) 2 , C 1~6 Alkylene OP(O)(OR 6 ) 2 , C(O)R 6 , CO 2 R 6 , C(O)N(R 6 ) 2 , S(O)R 6 and S.O. 2 R 6 Selected from; R 2 , R 7 , R 8 , R 9 and R 10 is hydrogen, deuterium, halogens and C 1 ~C 6 independently selected from alkyl; R 3 are hydrogen, deuterium, CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Haloalkenyl, CO 2 R 18 , C(O)N(R 18 ) 2 , C 2 ~C 6 Alkenyl, C 2 ~C 6Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 7 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 18 wherein each of the C's is independently selected from a 3- to 7-membered heterocycle containing one or two hetero moieties selected from 1 ~C 6 Alkyl group, C 1 ~C 6 Haloalkyl group, C 2 ~C 6 Alkenyl group, C 2 ~C 6 Haloalkenyl group, C 2 ~C 6 Alkynyl group, C 2 ~C 6 Haloalkynyl group, C 3 ~C 7 The cycloalkyl group and the 3- to 7-membered heterocyclic group are CN, OR 18 , N(R 18 ) 2 and S.R. 18 and wherein the C 3 ~C 7 Cycloalkyl and 3- to 7-membered heterocycles are each independently selected from halogen, CO 2 R 18 , C(O)N(R 18 ) 2 , S.O. 2 R 18 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 6 Cycloalkyl, as well as O, S, S(O), and SO 2, N, and NR 18 and optionally further substituted by substituents selected from a 3- to 6-membered heterocycle containing one or two ring hetero moieties selected from R 4 and R 5 is hydrogen, deuterium, halogen, CN, OR 18 , N(R 18 ) 2 , S.R. 18 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Haloalkenyl, CO 2 R 18 , C(O)N(R 18 ) 2 , S(O)R 18 , S.O. 2 R 18 , C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 7 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 18 wherein each of the C's is independently selected from a 3- to 7-membered heterocycle containing one or two hetero moieties selected from 1 ~C 6 Alkyl group, C 1 ~C 6 Haloalkyl group, C 2 ~C 6 Alkenyl group, C 2 ~C 6 Haloalkenyl group, C 2 ~C 6 Alkynyl group, C 2 ~C 6 Haloalkynyl group, C 3 ~C 7 The cycloalkyl group and the 3- to 7-membered heterocyclic group are CN, OR 18 , N(R 18 ) 2 and S.R.18 and wherein the C 3 ~C 7 Cycloalkyl and 3- to 7-membered heterocycles are each independently selected from halogen, CO 2 R 18 , C(O)N(R 18 ) 2 , S.O. 2 R 18 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 6 Cycloalkyl, as well as O, S, S(O), and SO 2 , N, and NR 18 and optionally further substituted by substituents selected from a 3- to 6-membered heterocycle containing one or two ring hetero moieties selected from A is hydrogen, deuterium, halogen, OR 19 , N(R 19 )(R 19a ), S.R. 19 , S(O)R 19 and S(O 2 )R 19 Each R 18 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 7Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 20 wherein each of said C is independently selected from a 3- to 7-membered heterocycle containing one to two ring hetero moieties selected from 1 ~C 6 Alkyl group, C 1 ~C 6 Haloalkyl group, C 2 ~C 6 Alkenyl group, C 2 ~C 6 Haloalkenyl group, C 2 ~C 6 Alkynyl group, C 2 ~C 6 Haloalkynyl group, C 3 ~C 7 The cycloalkyl group and the 3- to 7-membered heterocyclic group are CN, OR 20 , N(R 20 ) 2 and S.R. 20 and wherein the C 3 ~C 7 Cycloalkyl and 3- to 7-membered heterocycles are each independently selected from halogen, CO 2 R 20 , C(O)N(R 20 ) 2 , S.O. 2 R 20 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 6 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 20and optionally further substituted by a substituent selected from a 3- to 6-membered heterocycle containing 1 to 2 ring hetero moieties selected from R 6 is hydrogen, deuterium and C 1 ~C 6 independently selected from alkyl; R 11 and R 12 is hydrogen, deuterium and C 1 ~C 6 independently selected from alkyl; R 19 , R 19a and each R 20 is hydrogen, deuterium, substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 2 ~C 6 Alkenyl, substituted or unsubstituted C 2 ~C 6 Alkynyl, substituted or unsubstituted C 1 ~C 6 Haloalkyl, substituted or unsubstituted C 3 ~C 7 Cycloalkyl, substituted or unsubstituted C 3 ~C 7 are independently selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their corresponding isotopes.

[0094] The present application encompasses compounds of formula (I) or pharma- ceutically acceptable salts, solvates, and / or prodrugs thereof: [ka] During the ceremony, R 1 are hydrogen, deuterium, and C 1 ~C 3 Alkyl, CH2 P(O)(OR 6 ) 2 ;C(O)R 6 , CO 2 R 6 , C(O)N(R 6 ) 2 , S(O)R 6 and S.O. 2 R 6 Selected from; Q is, [ka] and; R 2 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is hydrogen, deuterium, halogens and C 1 ~C 6 independently selected from alkyl; R 3 , R 4 and R 5 is hydrogen, deuterium, halogen, CN, OR 18 , N(R 18 ) 2 , S.R. 18 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Haloalkenyl, CO 2 R 18 , C(O)N(R 18 ) 2 , S(O)R 18 , S.O. 2 R 18 , C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 7 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR18 wherein each of the C's is independently selected from a 3- to 7-membered heterocycle containing one or two hetero moieties selected from 1 ~C 6 Alkyl group, C 1 ~C 6 Haloalkyl group, C 2 ~C 6 Alkenyl group, C 2 ~C 6 Haloalkenyl group, C 2 ~C 6 Alkynyl group, C 2 ~C 6 Haloalkynyl group, C 3 ~C 7 The cycloalkyl group and the 3- to 7-membered heterocyclic group are CN, OR 18 , N(R 18 ) 2 and S.R. 18 and wherein the C 3 ~C 7 Cycloalkyl and 3- to 7-membered heterocycles are each independently selected from halogen, CO 2 R 18 , C(O)N(R 18 ) 2 , S.O. 2 R 18 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 6 Cycloalkyl, as well as O, S, S(O), and SO 2 , N, and NR 18 and optionally further substituted by substituents selected from a 3- to 6-membered heterocycle containing one or two ring hetero moieties selected from A is hydrogen, deuterium, halogen, OR19 , N.R. 19 , S.R. 19 , S(O)R 19 and S(O 2 )R 19 Selected from; Each R 18 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 7 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 20 wherein each of said C is independently selected from a 3- to 7-membered heterocycle containing one to two ring hetero moieties selected from 1 ~C 6 Alkyl group, C 1 ~C 6 Haloalkyl group, C 2 ~C 6 Alkenyl group, C 2 ~C 6 Haloalkenyl group, C 2 ~C 6 Alkynyl group, C 2 ~C 6 Haloalkynyl group, C 3 ~C 7 The cycloalkyl group and the 3- to 7-membered heterocyclic group are CN, OR 20 , N(R 20 ) 2 and S.R. 20 and wherein the C 3 ~C 7 Cycloalkyl and 3- to 7-membered heterocycles are each independently selected from halogen, CO 2 R 20 , C(O)N(R 20 ) 2 , S.O.2 R 20 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 6 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 20 and optionally further substituted by a substituent selected from a 3- to 6-membered heterocycle containing 1 to 2 ring hetero moieties selected from R 19 and R 20 is hydrogen, deuterium, halogen, substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 2 ~C 6 Alkenyl, substituted or unsubstituted C 2 ~C 6 Alkynyl, substituted or unsubstituted C 1 ~C 6 Haloalkyl, substituted or unsubstituted C 3 ~C 7 Cycloalkyl, substituted or unsubstituted C 3 ~C 7 are independently selected from heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their corresponding isotopes.

[0095] In some embodiments, when all available hydrogen atoms in a group are optionally replaced by halogen atoms, the halogen atom is F, Cl, or Br. In some embodiments, when all available hydrogen atoms in a group are optionally replaced by halogen atoms, the halogen atom is F or Br. In some embodiments, when all available hydrogen atoms in a group are optionally replaced by halogen atoms, the halogen atom is F or Cl. In some embodiments, when all available hydrogen atoms in a group are optionally replaced by halogen atoms, the halogen atom is F.

[0096] Thus, in some embodiments, all available hydrogen atoms are optionally replaced independently by fluorine, chlorine, or bromine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, all available hydrogen atoms are optionally replaced independently by fluorine or bromine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, all available hydrogen atoms are optionally replaced independently by fluorine or chlorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, all available hydrogen atoms are optionally replaced independently by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0097] In some embodiments, all available hydrogen atoms are optionally replaced by their alternative isotopes. Thus, in some embodiments, all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, all available hydrogen atoms are optionally replaced independently by fluorine and / or chlorine atoms, and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, all available atoms are optionally replaced by deuterium. Thus, in some embodiments, all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, all available hydrogen atoms are optionally replaced by deuterium.

[0098] 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, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 R 8 , R 9 , R 10 , R 11 , R 12 , R 18 , R 19 , R 19a and R 20 One or more of A, R1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 18 , R 19 , R 19a and R 20 One or more of is deuterium.

[0099] In some embodiments, R 1 is S(O)R 6 and S.O. 2 R 6 wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their corresponding isotopes.

[0100] In some embodiments, R 1 are hydrogen, deuterium, and C 1 ~C 3 Alkyl, C 1 ~C 3 Alkylene P(O)(OR 6 ) 2 , C 1 ~C 3 Alkylene OP(O)(OR 6 ) 2 , C(O)R 6 , CO 2 R 6 and C(O)N(R 6 ) 2 In some embodiments, R is selected from the group consisting of: 1 are hydrogen, deuterium, and C 1 ~C 3 Alkyl, CH 2P(O)(OR 6 ) 2 , C.H. 2 CH 2 P(O)(OR 6 ) 2 , C.H. 2 CH(CH 3 )P(O)(OR 6 ) 2 , CH(CH 3 )CH 2 P(O)(OR 6 ) 2 , CH(CH 3 )P(O)(OR 6 ) 2 , CH(CH 2 CH 3 )P(O)(OR 6 ) 2 , (CH 2 )OP(O)(OR 6 ) 2 , C(O)R 6 and CO 2 R 6 In some embodiments, R is selected from the group consisting of: 1 is hydrogen, deuterium, CH 3 , C.H. 2 CH 3 , C.H. 2 P(O)(OR 6 ) 2 , CH(CH 3 )P(O)(OR 6 ) 2 , and (CH 2 )OP(O)(OR 6 ) 2 In some embodiments, R is selected from the group consisting of: 1 is hydrogen, deuterium, CH 3 , C.H. 2 CH 3, C.H. 2 P(O)(OR 6 ) 2 , CH(CH 3 )P(O)(OR 6 ) 2 and (CH 2 )OP(O)(OR 6 ) 2 In some embodiments, R is selected from the group consisting of: 1 is hydrogen, deuterium, CH 3 , C.H. 2 CH 3 , C.H. 2 P(O)(OR 6 ) 2 and (CH 2 )OP(O)(OR 6 ) 2 In some embodiments, R 1 is hydrogen, CH 3 , C.H. 2 CH 3 , C.H. 2 P(O)(OR 6 ) 2 , (CH 2 )OP(O)(OR 6 ) 2 , C(O)R 6 and CO 2 R 6 In some embodiments, R is selected from the group consisting of: 1 is hydrogen, deuterium, CH 3 , and C.H. 2 CH 3 In some embodiments, R is selected from the group consisting of:1 is selected from hydrogen and deuterium. 1 is hydrogen.

[0101] In some embodiments, R 2 , R 7 , R 8 , R 9 and R 10 are hydrogen, deuterium, and C 1 ~C 4 Alkyl and C 1~4 In some embodiments, R is independently selected from fluoroalkyl, where any available hydrogen atom is optionally replaced by a halogen atom, and / or any available atom is optionally replaced by an isotope thereof. 2 , R 7 , R 8 , R 9 and R 10 are hydrogen, deuterium, F, Br, Cl, and CH 3 , CD 2 H, C.D.H. 2 , CD 3、 CH 2 CH 3 , C.H. 2 CH 2 D, C.H. 2 CD 2 H and CD 2 CD 3 In some embodiments, R 2 , R 7 , R 8 , R 9 and R 10 are hydrogen, deuterium, F, Br, and CH 3 , CD 2 H, C.D.H. 2 , and CD 3 In some embodiments, R 2 , R 7 , R 8 , R 9 and R 10 is hydrogen, deuterium, CH 3 and CDs 3 are independently selected from

[0102] In some embodiments, R 2 is hydrogen, deuterium, CH 3 and CDs 3 In some embodiments, R 2 is selected from hydrogen and deuterium.

[0103] In some embodiments, R 6 are hydrogen, deuterium, and C 1 ~C 4 Alkyl and C 1~4 In some embodiments, R is selected from fluoroalkyl, where any available hydrogen atom is optionally replaced by a halogen atom, and / or any available atom is optionally replaced by an isotope thereof. 6 is hydrogen, deuterium, CH 3 , CD 2 H, C.D.H. 2 , CD 3 , C.F. 3 , CHF 2 , C.H. 2 CH 3 , C.H. 2 CH 2 D, C.H. 2 CD 2 H and CD 2 CD 3 In some embodiments, R 6 is hydrogen, deuterium, CH 3 , C.F. 3 , CHF 2 , CD 2 H, C.D.H. 2 , and CD 3 In some embodiments, R 6 is CH 3 and CDs 3 is selected from.

[0104] In some embodiments, R 7 , R 8 , R 9 and R 10 At least one of R7 , R 8 , R 9 and R 10 At least one of R 7 , R 8 , R 9 and R 10 are hydrogen, deuterium, F, Br, and CH 3 , C.F. 3 , CHF 2 , CD 2 H, C.D.H. 2 , CD 3、 CH 2 CH 3 , C.H. 2 CH 2 D, C.H. 2 CD 2 H and CD 2 CD 3 In some embodiments, R 7 , R 8 , R 9 and R 10 are hydrogen, deuterium, F, Br, and CH 3 , CD 2 H, C.D.H. 2 , and CD 3 In some embodiments, R 7 , R 8 , R 9 and R 10 are hydrogen, deuterium, F, Br, and CH 3 , and CD 3 In some embodiments, R 7 , R 8 , R 9 and R 10 are independently selected from hydrogen, deuterium, and F. In some embodiments, R 7 , R 8 , R 9 and R 10 At least one or at least two of R 7 , R 8 , R 9 and R 10 are all hydrogen. In some embodiments, R 7 , R8 , R 9 and R 10 are all deuterium. In some embodiments, R 7 and R 8 are both deuterium, and R 9 and R 10 Both are hydrogen.

[0105] In some embodiments, R 11 and R 12 is hydrogen, deuterium and C 1 ~C 4 alkyl, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available hydrogen atoms are optionally replaced by deuterium. 11 and R 12 is hydrogen, deuterium, 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 fluorine atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, R 11 and R 12 is hydrogen, deuterium, CH 3 , CD 2 H, C.D.H. 2 , CD 3、 CH 2 CH 3 , C.H. 2 CH 2 D, C.H. 2 CD 2 H and CD 2 CD 3 In some embodiments, R 11 and R 12 is hydrogen, deuterium, CH 3 and CDs 3In some embodiments, R 11 and R 12 Both are CDs. 3 or CH 3 It is.

[0106] In some embodiments, R 7 , R 8 , R 9 , R 10 , R 11 and R 12 At least one of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 At least one of R 7 , R 8 , R 9 and R 10 are hydrogen, deuterium, F, Br, and CH 3 , C.F. 3 , CHF 2 , CD 2 H, C.D.H. 2 , CD 3、 CH 2 CH 3 , C.H. 2 CH 2 D, C.H. 2 CD 2 H and CD 2 CD 3 are independently selected from and R 11 and R 12 is hydrogen, deuterium, CH 3 , CD 2 H, C.D.H. 2 , CD 3、 CH 2 CH 3 , C.H. 2 CH 2 D, C.H. 2 CD 2 H and CD 2 CD 3 In some embodiments, R 7 , R 8 , R 9 and R 10are all hydrogen, and R 11 and R 12 Deuterium and CD 3 In some embodiments, R 7 , R 8 , R 9 and R 10 are all deuterium, and R 11 and R 12 is hydrogen and CH 3 In some embodiments, R 7 , R 8 , R 9 and R 10 are all deuterium, and R 11 and R 12 Deuterium and CD 3 In some embodiments, R 7 and R 8 is deuterium and R 9 and R 10 is hydrogen and R 11 and R 12 is hydrogen, deuterium, CH 3 and CDs 3 is selected from.

[0107] In some embodiments, R 3 are hydrogen, deuterium, CN, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 6 Haloalkenyl, CO 2 R 18 , C(O)N(R 18 ) 2 , C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 7 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 18wherein the C is selected from 3 to 7 membered heterocycles containing 1 to 2 ring hetero moieties selected from 1 ~C 4 Alkyl group, C 1 ~C 4 Haloalkyl group, C 2 ~C 6 Alkenyl group, C 2 ~C 6 Haloalkenyl group, C 2 ~C 6 Alkynyl group, C 2 ~C 6 Haloalkynyl group, C 3 ~C 7 The cycloalkyl group and the 3- to 7-membered heterocyclic group are CN, OR 18 , N(R 18 ) 2 and S.R. 18 and wherein the C 3 ~C 7 Cycloalkyl and 3- to 7-membered heterocycles are each independently selected from halogen, CO 2 R 18 , C(O)N(R 18 ) 2 , S.O. 2 R 18 , C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 6 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 18wherein any available hydrogen atom is optionally replaced by a halogen atom, and / or any available atom is optionally replaced by an isotope thereof.

[0108] In some embodiments, R 3 are hydrogen, deuterium, CN, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 6 Haloalkenyl, CO 2 R 18 , C(O)N(R 18 ) 2 , C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl and C 2 ~C 6 haloalkynyl, wherein said C 1 ~C 4 Alkyl group, C 1 ~C 4 Haloalkyl group, C 2 ~C 6 Alkenyl group, C 2 ~C 6 Haloalkenyl group, C 2 ~C 6 Alkynyl groups and C 2 ~C 6 Haloalkynyl groups include CN, OR 18 , N(R 18 ) 2 and S.R. 18 and wherein all available hydrogen atoms are optionally replaced by fluorine and / or all available atoms are optionally replaced by alternative isotopes thereof. In some embodiments, R 3are hydrogen, deuterium, CN, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 6 Haloalkenyl, CO 2 R 18 , C(O)N(R 18 ) 2 , C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl and C 2 ~C 6 haloalkynyl, wherein said C 1 ~C 4 Alkyl group, C 1 ~C 4 Haloalkyl group, C 2 ~C 6 Alkenyl group, C 2 ~C 6 Haloalkenyl group, C 2 ~C 6 Alkynyl groups and C 2 ~C 6 Haloalkynyl groups include CN, OR 18 , N(R 18 ) 2 and S.R. 18 wherein all available hydrogen atoms are optionally replaced by fluorine atoms and / or all available atoms are optionally replaced by their corresponding isotopes. 3 are hydrogen, deuterium, CN, and SR 18 , C.H. 3 , C.H. 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , C 1 ~C 4 Haloalkyl, C 2 ~C 6 Haloalkenyl, CO 2 R18 , C(O)N(R 18 ) 2 , C 2 ~C 6 Alkenyl and C 2 ~C 6 alkynyl, wherein said C 1 ~C 4 Alkyl group, C 1 ~C 4 Haloalkyl group, C 2 ~C 6 Alkenyl group, C 2 ~C 6 Haloalkenyl groups and C 2 ~C 6 Alkynyl groups are CN, OR 18 , N(R 18 ) 2 and S.R. 18 wherein all available hydrogen atoms are optionally replaced by fluorine atoms and / or all available atoms are optionally replaced by their corresponding isotopes. 3 are hydrogen, deuterium, CN, CH 3 , C.H. 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , C 1 ~C 4 Haloalkyl, C 2 ~C 6 Haloalkenyl, CO 2 R 18 , and C 2 ~C 6 alkenyl, where all available hydrogen atoms are optionally replaced by fluorine atoms and / or all available hydrogen atoms are optionally replaced by deuterium. 3 is selected from hydrogen and deuterium. 3is hydrogen. In some embodiments, R 3 is deuterium.

[0109] In some embodiments, R 4 and R 5 is hydrogen, deuterium, halogen, CN, OR 18 , N(R 18 ) 2 , S.R. 18 , C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 6 Haloalkenyl, CO 2 R 18 , C(O)N(R 18 ) 2 , S(O)R 18 , S.O. 2 R 18 , C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 7 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 18 wherein each of said C is independently selected from a 3- to 7-membered heterocycle containing one to two ring hetero moieties selected from 1 ~C 4 Alkyl group, C 1 ~C 4 Haloalkyl group, C 2 ~C 6 Alkenyl group, C 2 ~C 6 Haloalkenyl group, C 2 ~C 6 Alkynyl group, C 2 ~C 6 Haloalkynyl group, C 3 ~C 7 The cycloalkyl group and the 3- to 7-membered heterocyclic group are CN, OR 18 , N(R 18 ) 2 and S.R. 18and wherein said C is optionally substituted by one or more substituents independently selected from 3 ~C 7 Cycloalkyl and 3- to 7-membered heterocycles are each independently selected from halogen, CO 2 R 18 , C(O)N(R 18 ) 2 , S.O. 2 R 18 , C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 6 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 18 wherein any available hydrogen atom is optionally replaced by a halogen atom, and / or any available atom is optionally replaced by an isotope thereof.

[0110] In some embodiments, R 4 and R 5 is hydrogen, deuterium, halogen, CN, OR 18 , N(R 18 ) 2 , S.R. 18 , C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 6 Haloalkenyl, CO 2 R 18 , C(O)N(R 18 )2 , S(O)R 18 , S.O. 2 R 18 , C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl and C 2 ~C 6 haloalkynyl, wherein 1 ~C 4 Alkyl group, C 1 ~C 4 Haloalkyl group, C 2 ~C 6 Alkenyl group, C 2 ~C 6 Haloalkenyl group, C 2 ~C 6 Alkynyl groups and C 2 ~C 6 Haloalkynyl groups include CN, OR 18 , N(R 18 ) 2 and S.R. 18 and wherein any available hydrogen atom is optionally replaced by a fluorine atom and / or any available atom is optionally replaced by an isotope thereof. In some embodiments, R 4 and R 5 is hydrogen, deuterium, F, Cl, Br, CN, OR 18 , N(R 18 ) 2 , S.R. 18 , C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 6 Haloalkenyl, CO 2 R 18 , C(O)N(R 18 ) 2 , S(O)R 118 , S.O. 2 R 18 , C 2 ~C 6Alkenyl, C 2 ~C 6 Alkynyl and C 2 ~C 6 haloalkynyl, wherein 1 ~C 4 Alkyl group, C 1 ~C 4 Haloalkyl group, C 2 ~C 6 Alkenyl group, C 2 ~C 6 Haloalkenyl group, C 2 ~C 6 Alkynyl groups and C 2 ~C 6 Haloalkynyl groups include CN, OR 18 , N(R 18 ) 2 and S.R. 18 wherein all available hydrogen atoms are optionally replaced by fluorine atoms and / or all available atoms are optionally replaced by their corresponding isotopes. 4 and R 5 is hydrogen, deuterium, F, Cl, Br, CN, OR 18 , N(R 18 ) 2 , S.R. 18 , C.H. 3 , C.H. 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , C 1 ~C 4 Haloalkyl, C 2 ~C 6 Haloalkenyl, CO 2 R 18 , S(O)R 18 , S.O. 2 R 18 , C(O)N(R 18 ) 2 , C 2 ~C 6 Alkenyl and C 2~C 6 alkynyl, wherein C 1 ~C 4 Alkyl group, C 1 ~C 4 Haloalkyl group, C 2 ~C 6 Alkenyl group, C 2 ~C 6 Haloalkenyl groups and C 2 ~C 6 Alkynyl groups are CN, OR 18 , N(R 18 ) 2 and S.R. 18 wherein all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their corresponding isotopes. In some embodiments, R 4 and R 5 is hydrogen, deuterium, F, Cl, Br, CN, OR 18 , N(R 18 ) 2 , S.R. 18 , C.H. 3 , C.H. 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , C 1 ~C 4 Haloalkyl, C 2 ~C 6 Haloalkenyl, CO 2 R 18 , S(O)R 18 , S.O. 2 R 18 and C 2 ~C 6 alkenyl, where all available hydrogen atoms are optionally replaced by fluorine atoms and / or all available hydrogen atoms are optionally replaced by deuterium. 4 and R5 is independently selected from hydrogen, deuterium, F, Cl, and Br, where any available hydrogen atom is optionally replaced by a fluorine atom and / or any available atom is optionally replaced by its alternative isotope. In some embodiments, R 4 and R 5 is independently selected from hydrogen, deuterium, F, Cl, and Br. In some embodiments, R 4 and R 5 are independently selected from hydrogen and deuterium. 4 and R 5 are both hydrogen. In some embodiments, R 4 and R 5 are both deuterium.

[0111] In some embodiments, R 3 , R 4 and R 5 are independently selected from hydrogen and deuterium. 3 , R 4 and R 5 are all hydrogen. In some embodiments, R 3 , R 4 and R 5 are all deuterium.

[0112] In some embodiments, R 3 , R 4 and R 5 In the above C 3 ~C 7 Cycloalkyl is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, where any available hydrogen atom is optionally replaced by a halogen atom, and / or any available atom is optionally replaced by its alternative isotope.

[0113] In some embodiments, R 3 , R 4 and R 5In some embodiments, the 3- to 7-membered heterocycle in R 3 , R 4 and R 5 wherein the 3-7 membered heterocycle is independently a substituted or unsubstituted bridged bicyclic heterocycle. In some embodiments, the substituted or unsubstituted bridged bicyclic heterocycle is 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.

[0114] In some embodiments, R 3 , R 4 and R 5 In some embodiments, the 3- to 7-membered heterocycle in R 3 , R 4 and R 5 wherein the 3-7 membered heterocycle is independently a substituted or unsubstituted bridged bicyclic heterocycle. In some embodiments, the substituted or unsubstituted bridged bicyclic heterocycle is 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.

[0115] In some embodiments, R 3 , R 4 and R 5The 3- to 7-membered heterocycle in the formula (I) is selected from the group consisting of aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxythiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, triazolidinyl, and the like. and wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by an isotope thereof.

[0116] In some embodiments, each R 18 is hydrogen, deuterium, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 4 Alkenyl, C 2 ~C 4 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 7 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 20 wherein each of said C is independently selected from a 3- to 7-membered heterocycle containing one to two ring hetero moieties selected from 1 ~C 4 Alkyl group, C 1 ~C 4 Haloalkyl group, C 2 ~C 6 Alkenyl group, C2 ~C 6 Haloalkenyl group, C 2 ~C 6 Alkynyl group, C 2 ~C 6 Haloalkynyl group, C 3 ~C 7 The cycloalkyl group and the 3- to 7-membered heterocyclic group are CN, OR 20 , N(R 20 ) 2 and S.R. 20 and wherein the C is optionally substituted with 1 to 3 substituents independently selected from 3 ~C 7 Cycloalkyl and 3- to 7-membered heterocycles are each independently selected from halogen, CO 2 R 20 , C(O)N(R 20 ) 2 , S.O. 2 R 20 , C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 6 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 20 and optionally further substituted by a substituent selected from a 3- to 6-membered heterocycle containing 1 to 2 ring hetero moieties selected from:

[0117] In some embodiments, each R 18 is hydrogen, deuterium, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 4 Alkenyl, C 2 ~C4 Haloalkenyl, C 2 ~C 6 Alkynyl, and C 2 ~C 6 haloalkynyl, wherein 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl and C 2 ~C 6 Haloalkynyl is CN, OR 20 , N(R 20 ) 2 and S.R. 20 In some embodiments, each R 18 is hydrogen, deuterium, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 4 Alkenyl, C 2 ~C 4 Haloalkenyl, and C 2 ~C 6 alkynyl, wherein C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl and C 2 ~C 6 Alkynyl is CN, OR 20 , N(R 20 ) 2 and S.R. 20wherein all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their corresponding isotopes. 18 are hydrogen, deuterium, and C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 4 Alkenyl, C 2 ~C 4 Haloalkenyl, and C 2 ~C 6 alkynyl, wherein C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl and C 2 ~C 6 Alkynyl is CN, OR 20 and N(R 20 ) 2 wherein all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their corresponding isotopes. In some embodiments, each R 18 are hydrogen, deuterium, F, Cl, and CH 3 , C.H. 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , C 1 ~C 4 Haloalkyl, C 2 ~C 4 Alkenyl and C 2 ~C4 haloalkenyl, wherein said CH 3 , C.H. 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , C 1 ~C 4 Haloalkyl, C 2 ~C 6 Alkenyl, and C 2 ~C 6 Haloalkenyl is CN, OR 20 and N(R 20 ), wherein all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their corresponding isotopes. In some embodiments, each R 18 are hydrogen, deuterium, F, Cl, and CH 3 , C.H. 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , C 1 ~C 4 Haloalkyl, C 2 ~C 4 Alkenyl and C 2 ~C 4 haloalkenyl, where any available hydrogen atom is optionally replaced by a fluorine atom, and / or any available atom is optionally replaced by an isotope thereof. 18 are hydrogen, deuterium, F, Cl, and CH 3 , C.H. 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 and C 1 ~C 4haloalkyl, where any available hydrogen atom is optionally replaced by a fluorine atom, and / or any available atom is optionally replaced by an isotope thereof. 18 are hydrogen, deuterium, F, Cl, and CH 3 , C.H. 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 CF 3 , CHF 2 , CD 2 H, C.D.H. 2 , CD 3、 CH 2 CH 3 and CDs 2 CD 3 In some embodiments, each R 18 is hydrogen, deuterium, CH 3 , C.H. 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , C.F. 3 , CHF 2 , CD 2 H, C.D.H. 2 , CD 3、 CH 2 CH 3 and CDs 2 CD 3 are independently selected from

[0118] In one embodiment, each R 18 is C 3 ~C 7 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 20 wherein each of the heterocyclic rings is independently selected from a 3- to 7-membered heterocycle containing 1 to 2 heterocyclic moieties selected from 3 ~C 7 The cycloalkyl group and the 3- to 7-membered heterocyclic group are each represented by CN, OR 20 , N(R20 ) 2 and S.R. 20 and optionally substituted with 1 to 3 substituents independently selected from halogen, CO 2 R 20 , C(O)N(R 20 ) 2 , S.O. 2 R 20 , C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Haloalkynyl, C 3 ~C 6 Cycloalkyl, as well as O, S, S(O), and SO 2 , N and NR 20 and optionally further substituted by a substituent selected from a 3- to 6-membered heterocycle containing 1 to 2 ring hetero moieties selected from:

[0119] In one embodiment, each R 18 is C 3 ~C 7 Cycloalkyl, as well as O, S, N and NR 20 wherein each of the heterocyclic rings is independently selected from a 3- to 7-membered heterocycle containing 1 to 2 heterocyclic moieties selected from 3 ~C 7 The cycloalkyl group and the 3- to 7-membered heterocyclic group are each represented by CN, OR 20 , N(R 20 ) 2 and S.R. 20 and optionally substituted with 1 to 3 substituents independently selected from halogen, CO 2 R 20 , C(O)N(R 20 ) 2 , S.O. 2 R 20, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Haloalkenyl, C 2 ~C 6 Alkynyl and C 2 ~C 6 haloalkynyl. In one embodiment, each R 18 is C 3 ~C 7 Cycloalkyl, as well as O, S, N and NR 20 wherein each of the heterocyclic rings is independently selected from a 3- to 7-membered heterocycle containing 1 to 2 heterocyclic moieties selected from 3 ~C 7 The cycloalkyl group and the 3- to 7-membered heterocyclic group are each represented by OR 20 , N(R 20 ) 2 and S.R. 20 and optionally substituted by one or two substituents independently selected from halogen, C 1 ~C 4 Alkyl and C 1 ~C 4 Optionally further substituted with substituents selected from haloalkyl.

[0120] In one embodiment, each R 18 is C 3 ~C 7 Cycloalkyl, as well as O, S, N and NR 20 wherein each of the heterocyclic rings is independently selected from a 3- to 7-membered heterocycle containing 1 to 2 heterocyclic moieties selected from 3 ~C 7 The cycloalkyl group and the 3- to 7-membered heterocyclic group are each represented by CN, OR 20 , N(R 20 ) 2 and S.R. 20and optionally substituted with 1 to 3 substituents independently selected from C 3 ~C 6 Cycloalkyl and O, S, S(O), SO 2 , N and NR 20 In one embodiment, each R 18 is C 3 ~C 7 Cycloalkyl and O, S, N, and NR 20 wherein each of the heterocyclic rings is independently selected from a 3- to 7-membered heterocycle containing 1 to 2 heterocyclic moieties selected from 3 ~C 7 The cycloalkyl group and the 3- to 7-membered heterocyclic group are each represented by OR 20 , N(R 20 ) 2 and S.R. 20 and optionally substituted with 1 to 3 substituents independently selected from C 3 ~C 6 Cycloalkyl and O, S, N, and NR 20 and optionally further substituted by a substituent selected from a 3- to 6-membered heterocycle containing 1 to 2 ring hetero moieties selected from:

[0121] In some embodiments, R 18 Each C in 3 ~C 7 Cycloalkyl or C 3 ~C 6 Cycloalkyl is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, where any available hydrogen atom is optionally replaced by a halogen atom, and / or any available atom is optionally replaced by its alternative isotope.

[0122] In some embodiments, R 18Each 3- to 7-membered heterocycle in the formula (I) is selected from the group consisting of aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxythiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, triazolidinyl, and the like. and wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by an isotope thereof.

[0123] In some embodiments, R 18 In some embodiments, the 3- to 7-membered heterocycles in R are independently selected from substituted or unsubstituted heterocycles. 18 The 3-7 membered heterocycles in the ring are independently selected from substituted or unsubstituted bridged bicyclic heterocycles. In some embodiments, the substituted or unsubstituted 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.

[0124] In some embodiments, R 18Each 3- to 6-membered heterocycle in the formula is aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxythiolidinyl, thiazolidinyl, isothiazolidinyl, and dioxolanyl. , dithiolanyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, dioxanyl, and dithianyl, wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its alternative isotope.

[0125] In some embodiments, R 18 In some embodiments, the 3-6 membered heterocycles in R are independently selected from substituted or unsubstituted heterocycles. 18 The 3-7 membered heterocycles in the ring are independently selected from substituted or unsubstituted bridged bicyclic heterocycles. In some embodiments, the substituted or unsubstituted 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.

[0126] In some embodiments, R 19 , R 19a and each R 20 is hydrogen, deuterium, substituted or unsubstituted C 1 ~C 4Alkyl, substituted or unsubstituted C 2 ~C 6 Alkenyl, substituted or unsubstituted C 2 ~C 6 Alkynyl, substituted or unsubstituted C 1 ~C 4 Haloalkyl, substituted or unsubstituted C 3 ~C 7 and independently selected from cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted 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.

[0127] In some embodiments, R 19 , R 19a and each R 20 is hydrogen, deuterium, substituted or unsubstituted C 1 ~C 4 Alkyl, substituted or unsubstituted C 2 ~C 6 Alkenyl, substituted or unsubstituted C 2 ~C 6 Alkynyl, substituted or unsubstituted C 1 ~C 4 Haloalkyl, substituted or unsubstituted C 3 ~C 7 and independently selected from cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted 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.

[0128] In some embodiments, R 19 , R 19a and each R 20 is hydrogen, deuterium, substituted or unsubstituted C 1 ~C 4Alkyl, substituted or unsubstituted C 2 ~C 6 Alkenyl, substituted or unsubstituted C 2 ~C 6 Alkynyl, substituted or unsubstituted C 1 ~C 4 Haloalkyl, substituted or unsubstituted C 3 ~C 7 It is independently selected from cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0129] In some embodiments, R 19 , R 19a and each R 20 In the above C 3 ~C 7 Cycloalkyl is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, where any available hydrogen atom is optionally replaced by a halogen atom, and / or any available atom is optionally replaced by its alternative isotope.

[0130] In some embodiments, R 19 , R 19a and each R 20The 3- to 7-membered heterocycle in the formula (I) is selected from the group consisting of aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxythiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, triazolidinyl, and the like. and wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by an isotope thereof.

[0131] In some embodiments, R 19 , R 19a and each R 20 In some embodiments, the 3- to 7-membered heterocycles in each ring are independently selected from substituted or unsubstituted heterocycles. 19 , R 19a and each R 20 wherein the 3-7 membered heterocycle is independently selected from substituted or unsubstituted bridged bicyclic heterocycles. In some embodiments, the substituted or unsubstituted bridged bicyclic heterocycle is 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.

[0132] In some embodiments, R19 , R 19a and each R 20 wherein the heteroaryl 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-oxopiperdiyl, and wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by an isotope thereof.

[0133] In some embodiments, R 19 , R 19a and each R 20 is hydrogen, deuterium, substituted or unsubstituted C 1 ~C 4 Alkyl, substituted or unsubstituted C 2 ~C 6 Alkenyl, substituted or unsubstituted C 2 ~C 6 Alkynyl and substituted or unsubstituted C 1 ~C 4haloalkyl, where any available hydrogen atom is optionally replaced by a fluorine atom, and / or any available atom is optionally replaced by an isotope thereof. In some embodiments, R 19 , R 19a and each R 20 are hydrogen, deuterium, and C 1 ~C 4 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl and C 1 ~C 4 haloalkyl, where any available hydrogen atom is optionally replaced by a fluorine atom, and / or any available atom is optionally replaced by an isotope thereof. In some embodiments, R 19 , R 19a and each R 20 are hydrogen, deuterium, and C 1 ~C 4 Alkyl and C 2 ~C 6 alkenyl, where any available hydrogen atom is optionally replaced by a fluorine atom, and / or any available atom is optionally replaced by an isotope thereof. 19 , R 19a and each R 20 is hydrogen, deuterium and C 1 ~C 4 alkyl, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available hydrogen atoms are optionally replaced by deuterium. 19 , R 19a and each R 20 is hydrogen, deuterium, CH 3 , C.F. 3 , CHF 2, CD 2 H, C.D.H. 2 , CD 3、 CH 2 CH 3 and CDs 2 CD 3 In some embodiments, R 19 , R 19a and R 20 is hydrogen, deuterium, CH 3 , C.F. 3 , CHF 2 and CDs 3 are independently selected from

[0134] R 19 , R 19a and each R 20 When is substituted, in some embodiments the substituents are Cl, F, Br, CO 2 H, CO 2 CH 3 , C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)NHCH 3 , S.O. 2 CH 3 , C 1 ~C 4 Alkyl, C 1 ~C 4 Fluoroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Fluoroalkenyl, C 2 ~C 6 Alkynyl, C 2 ~C 6 Fluoroalkynyl, C 3 ~C 6 Cycloalkyl, as well as O, S, S(O), and SO 2 , N, NH and NCH 3 In some embodiments, R 19 , R 19a and each R 20 The above substituents are Cl, F, C 1 ~C4 Alkyl, C 1 ~C 4 Fluoroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Fluoroalkenyl, C 2 ~C 6 Alkynyl and C 2 ~C 6 In some embodiments, R 19 , R 19a and each R 20 The above substituents are Cl, F, Br, CH 3 , and C.F. 3 are independently selected from one or two of:

[0135] In some embodiments, A is C 3 ~C 7 Cycloalkyl, C 4 ~C 7 and selected from 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.

[0136] In some embodiments, A is hydrogen, deuterium, C 1~6 Alkyl, OR 19 , N.H.R. 19 and S.R. 19 In some embodiments, A is selected from the group consisting of hydrogen, deuterium, C ... 1~6 Alkyl or OR 19In some embodiments, A is selected from the group consisting of hydrogen, deuterium, and OR, wherein all available hydrogen atoms are optionally replaced by fluorine atoms and / or all available atoms are optionally replaced by alternative isotopes thereof. 19 In some embodiments, A is selected from hydrogen, deuterium, OCH 3 , OCD 3 , O.C.H.D. 2 , O.C.D.H. 2 , OCF 3 , O.C.F.H. 2 , and O.C.H.F. 2 In some embodiments, A is selected from hydrogen, deuterium, OCH 3 , OCD 3 , OCF 3 , and O.C.H.F. 2 In some embodiments, A is selected from hydrogen, deuterium, OCH 3 and OCD 3 is selected from.

[0137] In some embodiments, A is O.C. 1~6 Alkyl, OC 3 ~C 7 Cycloalkyl, OC 4 ~C 7 In some embodiments, A is selected from cycloalkenyl, O-heterocycloalkyl, O-aryl, and O-heteroaryl, where any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its corresponding isotope. 1~6 Alkyl, OC 3 ~C 7 Cycloalkyl, OC 4 ~C 7and selected from cycloalkenyl, O-heterocycloalkyl, O-aryl and O-heteroaryl, 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, the C in A 3 ~C 7 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, where any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by its alternative isotope.

[0139] In some embodiments, the C in A 4 ~C 7 Cycloalkenyl is selected from cyclobutenyl, cyclopentenyl, and cyclohexenyl, where any available hydrogen atom is optionally replaced by a halogen atom, and / or any available atom is optionally replaced by its corresponding isotope.

[0140] In some embodiments, the 3- to 7-membered heterocycle in A is aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxythiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, or aryl. and wherein any available hydrogen atom is optionally replaced by a halogen atom and / or any available atom is optionally replaced by an isotope thereof.

[0141] 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, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their corresponding isotopes.

[0142] 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-oxopiperazin ... -oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl 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 alternative isotopes thereof.

[0143] In some embodiments, A is hydrogen or OR. 19 and the compound of formula (IA) is a compound of formula (I-A1) or formula (I-A2). Thus, in some embodiments, the present application encompasses a compound of formula (I-A1) or formula (I-A2) or a pharma- ceutically acceptable salt, solvate, and / or prodrug thereof: [ka] During the ceremony: R 1 , R 2 , R3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 11 and R 12 is as defined in formula (IA); and R 19 is C 1~6 is alkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes, in some embodiments, all available hydrogen atoms are optionally replaced by fluorine or deuterium.

[0144] In some embodiments, R 1 , R 2 , R 3 , R 4 and R 5 are all H, and A is H or OC 1~6 is alkyl, and the compound of formula (IA) is a compound of formula (I-A3) or formula (I-A4). Thus, in some embodiments, the present application encompasses a compound of formula (I-A3) or formula (I-A4) or a pharma- ceutically acceptable salt, solvate, and / or prodrug thereof: [ka] During the ceremony: R 7 , R 8 , R 9 , R 10 , R 11 and R 12 is as defined in formula (IA); and R 19 is C 1~6 is alkyl, wherein all available hydrogen atoms are optionally replaced by deuterium atoms and / or all available atoms are optionally replaced by their alternative isotopes, in some embodiments, all available hydrogen atoms are optionally replaced by fluorine or deuterium.

[0145] In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3), and (I-A4), R 7 , R 8 , R 9 , R 10 , R 11 and R 12 At least one of the R 7 , R 8 , R 9 , R 10 , R 11 and R 12 is deuterium. In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 7 , R 8 , R 9 and R 10 In some embodiments, in the compounds of formula (IA), (I-A1), (I-A2), (I-A3), and (I-A4), at least one of R 7 , R 8 , R 9 and R 10 is independently selected from hydrogen and deuterium. In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3), and (I-A4), R 7 , R 8 , R 9 and R 10 In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3), and (I-A4), at least one of R 7 and R 8 , or R 9and R 10 are both hydrogen or both deuterium. In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 7 and R 8 are both deuterium, and R 9 and R 10 and R are both hydrogen. In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3), and (I-A4), R 7 and R 8 are both hydrogen, and R 9 and R 10 and R are both deuterium. In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3), and (I-A4), R 7 , R 8 , R 9 and R 10 are all deuterium. In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 7 , R 8 , R 9 and R 10 are all hydrogen.

[0146] In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3), and (I-A4), R 11 and R 12 are both deuterium, and R 11 and R 12 In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 11 and R 12 In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 11 and R 12 Both are hydrogen, deuterium, and CH 3 , CD 2 H, C.D.H. 2 , CD3、 CH 2 CH 3 , C.H. 2 CH 2 D, C.H. 2 CD 2 H or CD 2 CD 3 In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 11 and R 12 are both deuterium, CH 3 , CD 2 H, C.D.H. 2 , CD 3、 CH 2 CH 3 , C.H. 2 CH 2 D, C.H. 2 CD 2 H or CD 2 CD 3 In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 11 and R 12 Both are CH 3 , CD 2 H, C.D.H. 2 , CD 3、 CH 2 CH 3 , C.H. 2 CH 2 D, C.H. 2 CD 2 H or CD 2 CD 3 In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 11 and R 12 Both are CH 3 or neither CD 3 In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 11 and R 12 One of them is hydrogen, and the other is hydrogen, deuterium, and CH 3 , CD 2 H, C.D.H.2 , CD 3、 CH 2 CH 3 , C.H. 2 CH 2 D, C.H. 2 CD 2 H and CD 2 CD 3 In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 11 and R 12 One of them is hydrogen, and the other is deuterium, CH 3 , CD 2 H, C.D.H. 2 , CD 3、 CH 2 CH 3 , C.H. 2 CH 2 D, C.H. 2 CD 2 H and CD 2 CD 3 In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 11 and R 12 One of them is hydrogen and the other is CH 3 , CD 2 H, C.D.H. 2 , CD 3、 CH 2 CH 3 , C.H. 2 CH 2 D, C.H. 2 CD 2 H and CD 2 CD 3 In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 11 and R 12 One of them is hydrogen and the other is CH 3 and CDs 3 is selected from.

[0147] In some embodiments, the present application encompasses a compound of formula (IA) or a pharma- ceutically acceptable salt, solvate, and / or prodrug thereof: [ka] During the ceremony R 1 is hydrogen, deuterium, C 1 ~C 3 Alkyl, C 1 ~C 3 Deuteroalkyl, C 1 ~C 3 Fluoroalkyl, C 1 ~C 6 Alkylene P(O)(OR 6 ) 2 , C 1 ~C 6 Alkylene OP(O)(OR 6 ) 2 , C(O)R 6 , CO 2 R 6 , C(O)N(R 6 ) 2 , S(O)R 6 and S.O. 2 R 6 Selected from; R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen and deuterium; R 7 , R 8 , R 9 and R 10 is hydrogen, deuterium, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl and C 1 ~C 6 independently selected from fluoroalkyl; A is hydrogen, deuterium and OR 19 Selected from; R 6 is hydrogen, deuterium, C 1 ~C 6Alkyl, C 1 ~C 6 Deuteroalkyl and C 1 ~C 6 fluoroalkyl; R 11 and R 12 is hydrogen, deuterium, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl and C 1 ~C 6 fluoroalkyl; and R 19 is C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl and C 1 ~C 6 fluoroalkyl; however (3)R 2 , R 3 , R 4 and R 5 are all D and A, R 1 , R 6 ~R 12 and R 19 is as defined above in this disclaimer; or (4) A is OR 19 where R 19 is C 1 ~C 6 Deuteroalkyl and C 1 ~C 6 fluoroalkyl; and R 1 ~R 12 is as defined above in this disclaimer.

[0148] In some embodiments, R 1 is hydrogen, deuterium, C 1 ~C 3 Deuteroalkyl, C 1 ~C 3Fluoroalkyl, fluoro-substituted C 1 ~C 3 Alkyl, C 1 ~C 3 Alkylene P(O)(OR 6 ) 2 , C 1 ~C 3 Alkylene OP(O)(OR 6 ) 2 , C(O)R 6 , CO 2 R 6 and C(O)N(R 6 In some embodiments, R 1 is hydrogen, deuterium, CH 3 , C.F. 3 , CD 3 , C.H. 2 CH 3 , C.F. 2 CF 3 , CD 2 CD 3 , C.H. 2 P(O)(OR 6 ) 2 , CH(CH 3 )P(O)(OR 6 ) 2 and (CH 2 )OP(O)(OR 6 ) 2 is selected from.

[0149] In some embodiments, R 6 is hydrogen, deuterium, CH 3 , C.F. 3 , CHF 2 , CD 2 H, C.D.H. 2 , and CD 3 In some embodiments, R 6 is CH 3 and CDs 3 is selected from.

[0150] In some embodiments, R 1 is hydrogen, deuterium, CH 3 , C.F. 3 , CD 3 , C.H. 2 CH3 , C.F. 2 CF 3 and CDs 2 CD 3 In some embodiments, R 1 is hydrogen or deuterium.

[0151] In some embodiments, R 7 , R 8 , R 9 and R 10 is hydrogen, deuterium, C 1 ~C 4 Alkyl, C 1 ~C 4 Deuteroalkyl and C 1 ~C 4 In some embodiments, R 7 , R 8 , R 9 and R 10 is hydrogen, deuterium, CH 3 , CD 2 H, C.D.H. 2 , CD 3、 CH 2 CH 3 , C.H. 2 CH 2 D, C.H. 2 CD 2 H and CD 2 CD 3 In some embodiments, R 7 , R 8 , R 9 and R 10 is hydrogen, deuterium, CH 3 , C.F. 3 , CHF 2 , CD 2 H, C.D.H. 2 , CD 3、 CH 2 CH 3 , C.H. 2 CH 2 D, C.H. 2 CD 2 H and CD 2 CD 3 are independently selected from

[0152] In some embodiments, R 7 , R 8 , R 9 and R 10 At least one of R 7 , R 8 , R 9 and R 10 At least one of R 7 , R 8 , R 9 and R 10 At least one or at least two of R 7 , R 8 , R 9 and R 10 are all hydrogen or R 7 , R 8 , R 9 and R 10 are all deuterium.

[0153] In some embodiments, R 11 and R 12 is hydrogen, deuterium, C 1 ~C 4 Alkyl, C 1 ~C 4 Deuteroalkyl and C 1 ~C 4 fluoroalkyl.

[0154] In some embodiments, R 11 and R 12 is hydrogen, deuterium, CH 3 , CD 2 H, C.D.H. 2 , CD 3、 CH 2 CH 3 , C.H. 2 CH 2 D, C.H. 2 CD 2 H and CD 2 CD 3 are independently selected from

[0155] In some embodiments, R 7 , R 8 , R 9 and R 10 are all hydrogen, and R 11 and R 12 Deuterium and CD 3 are independently selected from

[0156] In some embodiments, R 7 , R 8 , R 9 and R 10 are all deuterium, and R 11 and R 12 is hydrogen and CH 3 are independently selected from

[0157] In some embodiments, R 7 , R 8 , R 9 and R 10 are all deuterium, and R 11 and R 12 Deuterium and CD 3 is selected from.

[0158] In some embodiments, A, R 2 , R 3 , R 4 and R 5 are all deuterium.

[0159] In some embodiments, R 19 CF 3 , CHF 2 , CD 2 H, C.D.H. 2 , CD 3、 and CDs 2 CD 3 In some embodiments, R 19 is CHF 2 and CDs 3 It is.

[0160] In some embodiments, A is hydrogen, deuterium, OCH 3 , OCD 3 , OCF 3, and OCHF 2 In some embodiments, A is selected from deuterium, OCD 3 and OCHF 2 is selected from.

[0161] In some embodiments, the compound of formula (IA) is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4; 2-(1H-indol-3-yl-2,4,5,6,7-d5)-N,N-dimethylethan-1-amine; 2-(1H-indol-3-yl-2,4,5,6,7-d5)-N,N-dimethylethan-1-amine-1,1,2,2-d4; 2-(1H-indol-3-yl-2,4,5,6,7-d5)-N,N-dimethylethan-1-amine-2,2-d2; 2-(1H-indol-3-yl-2,4,5,6,7-d5)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4; 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4; 2-(5-Methoxy-1H-indol-3-yl-2,4,6,7-d4)-N,N-dimethylethan-1-amine; 2-(5-(methoxy-d3)-1H-indol-3-yl-2,4,6,7-d4)-N,N-dimethylethan-1-amine; 2-(5-Methoxy-1H-indol-3-yl-2,4,6,7-d4)-N,N-bis(methyl-d3)ethan-1-amine; 2-(5-(methoxy-d3)-1H-indol-3-yl-2,4,6,7-d4)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4; 2-(5-(difluoromethoxy)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4; and 2-(5-(difluoromethoxy)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1,2,2-d4; or a pharma- ceutically acceptable salt, solvate, and / or prodrug thereof.

[0162] In some embodiments, the compound of formula (IA) is selected from the compounds listed below or pharma- ceutically acceptable salts, solvates, and / or prodrugs thereof: [Table 1-1] [Table 1-2]

[0163] In some embodiments, the compound of formula (IA) is selected from the compounds listed below or pharma- ceutically acceptable salts, solvates, and / or prodrugs thereof: [Table 1-3]

[0164] In some embodiments, the pharma- ceutically acceptable salt is an acid addition salt or a base addition salt.The selection of suitable salts can be performed by those skilled in the art.Suitable salts include acid addition salts, which may be formed, for example, by mixing a solution of the compound with a solution of a pharma-ceutically acceptable acid, such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Additionally, acids that are generally considered suitable for forming pharma- ceutically useful salts from basic pharmaceutical compounds are discussed, for example, in P. Stahl et al, Camille G. (eds.) and Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley VCH; S. Berge et al, Journal of Pharmaceutical Sciences 1977 66(1)1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC on their website).

[0165] Suitable or compatible acid addition salts for 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 that contain 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 of such organic acids are, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In some embodiments, exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate ("mesylate"), naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), and the like. In some embodiments, monoacid salts or diacid salts are formed, and such acids are present in either 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. The criteria for selecting an appropriate salt will be known to those skilled in the art.Other pharma-ceutically unacceptable salts, such as, but not limited to, oxalates, may be used, for example, in the isolation of compounds of the present application for experimental use, or for subsequent conversion to a pharma-ceutically acceptable acid addition salt.

[0166] Suitable or compatible base addition salts for the treatment of subjects are 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 hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, 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, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.Selecting an appropriate salt can be useful, for example, to prevent the ester function of another part of the compound, if present, from being hydrolyzed.The criteria for selecting an appropriate salt will be known to those skilled in the art.In some embodiments, exemplary salts with bases 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, butylamine, choline, and salts with amino acids such as arginine, lysine, and the like.Basic nitrogen-containing groups may be quartenized 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 acidic moieties can be mixed with appropriate pharma- ceutically acceptable salts to give, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with appropriate organic ligands, such as quaternary ammonium salts. Also, when an acid group (-COOH) or alcohol group is present, pharma-ceutically acceptable esters can be used to modify the solubility or hydrolysis properties of the compound.

[0167] All such acid salts and base salts are intended to be pharma- ceutically acceptable salts within the scope of this application, and all acid salts and base salts are considered equivalent to the free form of the corresponding compound for the purposes of this application. In addition, when the compounds of this application contain both a basic moiety (e.g., but not limited to, aliphatic primary, secondary, tertiary, or cyclic amines, aromatic or heteroaryl amines, pyridines, or imidazoles) and an acidic moiety (e.g., but not limited to, tetrazoles or carboxylic acids), zwitterions ("internal salts") may result and are also included within the scope of the term "salt" as used herein. It is understood that some of the compounds of this application may exist in the form of zwitterions, which have both anionic and cationic centers within the same compound and have a net neutral charge. Such zwitterions are included within the scope of this application.

[0168] Solvates of the compounds of the present application include, for example, those formed with pharma- ceutically acceptable solvents. Examples of such solvents include water (the resulting solvates are called hydrates) and ethanol, etc. Suitable solvents are physiologically tolerable at the dosages administered.

[0169] In some embodiments, it is understood and appreciated that the compounds of the present application may have at least one chiral center and therefore may exist as enantiomers and / or diastereomers. It should be understood that all such isomers and mixtures thereof in any ratio are encompassed within the scope of the present application. The stereochemistry of a compound may be as shown in a given compound listed in the present disclosure, but it should be further understood that the compound may contain a certain amount (e.g., less than 20%, suitably less than 10%, more suitably less than 5%) of a compound of the present application having an alternative stereochemistry. Any optical isomers as separated, pure, or partially purified optical isomers, or racemic mixtures thereof, are intended to be encompassed within the scope of the present application.

[0170] 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 included within the scope of the present application.

[0171] The compounds of the present application may further exist in different amorphous forms and polymorphic forms, and any amorphous forms, polymorphs, or mixtures thereof are intended to be within the scope of the present application.

[0172] The compounds of the present application may further be radiolabeled, and therefore all radiolabeled forms of the compounds of the present application are within the scope of the present application, including compounds having one or more radioactive atoms incorporated into their structure.

[0173] III. Composition The compounds of the present application are suitably formulated into compositions using one or more carriers in a conventional manner. Thus, 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. Thus, the present application also encompasses pharmaceutical compositions comprising one or more compounds of the present application and a pharma- ceutically 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.

[0174] The compounds of the present application may be administered to a subject in various forms depending on the route of administration selected, as will be understood by those skilled in the art. For example, the compounds of the present application may be administered orally, by inhalation, parenterally, bucally, sublingually, by insufflation, epidurally, nasally, rectally, vaginally, by patch, pump, minipump, topically, or transdermally, and the pharmaceutical compositions may be formulated accordingly. In some embodiments, administration may be by pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000 - 20th edition) and The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999.

[0175] 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.

[0176] 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 directly incorporated with food in the diet. In some embodiments, the compounds are incorporated with a formulation excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gums, powders, syrups, elixirs, wafers, aqueous solutions, aqueous suspensions, and the like. 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, the tablets are coated by methods well known in the art. For tablets, capsules, caplets, pellets, or granules for oral administration, pH-sensitive enteric coatings such as Eudragits®, which are designed to control the release of the active ingredient, are optionally used. Oral dosage forms also include modified release formulations, such as immediate release formulations and timed-release formulations.Examples of modified release formulations include, for example, sustained release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled release (CR), or continuous-release (CR or Contin) formulations, for example, in the form of 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 that are 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 (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.

[0177] 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 flavorings and / or colorings 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); emulsifying agents (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.

[0178] It is also possible to lyophilize the compounds of the present application and use the resulting lyophilizates, for example for the preparation of injectable products.

[0179] 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 glycols, DMSO, and mixtures thereof (with or without alcohol), and in oils. Under normal storage and use conditions, these preparations contain a preservative to prevent the growth of microorganisms. 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 appropriately 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 droppable liquids are delivered, for example, by an ocular delivery system known in the art, such as an applicator or dropper. In some embodiments, such compositions include 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 a diluent or carrier. For pulmonary administration, the diluent or carrier will be selected to be suitable to allow the formation of an aerosol.

[0180] In some embodiments, the compounds of the present application are formulated for parenteral administration by injection, including conventional catheter insertion techniques or infusion. Formulations for injection are provided, for example, in unit dosage form, with added preservatives, for example, in ampoules or in multi-dose containers. 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 must be fluid to the extent that easy syringability exists. Alternatively, the compounds of the present application are preferably in sterile powder form for reconstitution before use with a suitable vehicle, for example, sterile pyrogen-free water.

[0181] 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 substance in a physiologically acceptable aqueous or non-aqueous solvent, and are usually provided as single or multiple doses in a sterile form in a sealed container. The container may, for example, take the form of a cartridge or refill for use with a nebulizer device. Alternatively, the sealed container may be a unitary dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser fitted with a metering valve that is intended to be discarded after use. When the dosage form includes an aerosol dispenser, it will also include a propellant. The propellant is, for example, a compressed gas, such as compressed air or an organic propellant, such as 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 (e.g., made of 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 take the form of a pump-atomizer.

[0182] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the compound of the present application 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.

[0183] The compounds of the present application in the form of suppositories 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, cacao fat (also known as cocoa 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, for example, Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533.

[0184] In some embodiments, the compounds of the present application are conjugated to soluble polymers as targetable drug carriers, such as polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, the compounds of the present application are conjugated to a class of biodegradable polymers useful for achieving controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0185] Although the compounds of the present application, including their pharma- ceutically acceptable salts and / or solvates, are suitably used alone, one or more compounds of the present application (active ingredients) are generally administered in the form of a pharmaceutical composition in association with a pharma- ceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition may contain about 0.05% to about 99% by weight or about 0.10% to about 70% by weight of the active ingredient and about 1% to about 99.95% by weight or about 30% to about 99.90% by weight of the pharma- ceutically acceptable carrier, where all weight percentages are based on the total composition.

[0186] In some embodiments, the compounds of the present application, including pharma- ceutically acceptable salts, solvates, and / or prodrugs thereof, are used and administered in compositions containing additional therapeutic agents. Thus, the present application also encompasses pharmaceutical compositions containing one or more compounds of the present application, or pharma- ceutically acceptable salts, solvates, and / or prodrugs thereof, and additional therapeutic agents, and optionally one or more pharma- ceutical acceptable excipients. In some embodiments, the additional therapeutic agent is another known agent useful for treating diseases, disorders, or conditions by activating serotonin receptors, such as those listed in the "Methods and Uses" section below. In some embodiments, the additional therapeutic agent is a psychoactive agent.

[0187] In the above, the term "compound" also encompasses embodiments that refer to one or more compounds.

[0188] 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.

[0189] Thus, the present application includes a method of activating serotonin receptors in cells, whether in a biological sample or in a patient, by administering an effective amount of one or more compounds of the present application to the cells.The present application also includes the use of one or more compounds of the present application for activating 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.

[0190] The compounds of the present application can activate serotonin receptors, and therefore the compounds of the present application are useful for treating diseases, disorders, or conditions by activating serotonin receptors.Therefore, the compounds of the present application are useful as pharmaceuticals.Therefore, the present application also includes the compounds of the present application for use as pharmaceuticals.

[0191] The present application also includes a method of treating a disease, disorder, or condition caused by activation of serotonin receptors, comprising administering to a subject in need of treatment a therapeutically effective amount of one or more compounds of the present application.

[0192] The present application also includes 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 includes 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.

[0193] In some embodiments, the serotonin receptor is 5-HT 2A Thus, the present application provides a method for determining intracellular 5-HT, whether in a biological sample or in a patient. 2A The present application also encompasses a method of activating intracellular 5-HT 2+ 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-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 activating intracellular 5-HT 2A The present invention further includes one or more compounds of the present application for use in the activation of

[0194] The present application provides a method for treating 5-HT 2+ deficiency, comprising administering to a subject in need of treatment a therapeutically effective amount of one or more compounds of the present application. 2A The present application also encompasses methods of treating a disease, disorder, or condition through activation of 5-HT 2A Use of one or more compounds of the present application for the treatment of a disease, disorder, or condition 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 includes one or more compounds of the present application for use in treating a disease, disorder, or condition resulting from activation of the

[0195] 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. Thus, the present application also includes 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 includes 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 includes one or more compounds of the present application for use in the treatment of a psychiatric disorder.

[0196] In some embodiments, the psychiatric illness is an anxiety disorder, such as generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia; depression, such as hopelessness, loss of pleasure, fatigue, and suicidal thoughts; mood disorders, such as depression, bipolar disorder, cancer-related depression, anxiety, and cyclothymic disorder; psychiatric disorders, such as hallucinations, delusions, and schizophrenia; impulse control and addiction disorders, such as pyromania (fire starting), kleptomania (stealing), and compulsive gambling; alcohol addiction; drug addiction, such as opioid addiction; personality disorders, such as antisocial personality disorder, obsessive-compulsive personality disorder, and paranoid personality disorder; obsessive-compulsive disorder (OCD), such as thoughts or fears that cause a subject to perform certain rituals or routines; post-traumatic stress disorder (PTSD); stress response disorder (formerly known as adjustment disorder); dissociation, which was formerly known as multiple personality disorder, or "split personality disorder" (SPD). sexual and gender disorders, such as sexual dysfunction, gender identity disorder, and paraphilia; somatic symptom disorder, formerly known as psychosomatic or somatoform disorders; and combinations thereof.

[0197] 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.

[0198] In some embodiments, the psychiatric disorder is selected from hallucinations and delusions, and combinations thereof.

[0199] 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.

[0200] In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is psychosis or a psychotic condition. Thus, the present application also encompasses a method of treating a psychosis or a psychotic condition, comprising administering to a subject in need of treatment a therapeutically effective amount of one or more compounds of the present application.

[0201] The present application also includes the use of one or more compounds of the present application for the treatment of psychosis or psychotic symptoms, 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 symptoms. The present application further includes one or more compounds of the present application for use in the treatment of psychosis or psychotic symptoms.

[0202] In some embodiments, administration of a therapeutically effective amount of a compound of the present application to a 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, administration of a therapeutically effective amount of a compound of the present application to a 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, administration of a therapeutically effective amount of a compound of the present application to a subject in need of treatment results in an improvement of psychosis or psychotic symptoms.

[0203] In some embodiments, the compounds of the present application are useful for treating a disorder of the central nervous system (CNS) in a subject in need of such treatment, the treatment comprising administering to said subject a therapeutically effective amount of a compound of general formula (IA) or a pharma- ceutical acceptable salt thereof.

[0204] 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. Thus, the present application also includes a method of treating a disease, disorder, or condition of the CNS 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 includes the use of one or more compounds of the present application for the treatment of a disease, disorder, or condition of the CNS 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 disease, disorder, or condition of the CNS and / or a neurological disease, disorder, or condition. The present application further includes one or more compounds of the present application for use in the treatment of a disease, disorder, or condition of the CNS and / or a neurological disease, disorder, or condition. In some embodiments, the CNS disease, disorder, or condition and / or neurological disease, disorder, or condition is selected from neurological diseases including neurodevelopmental and neurodegenerative disorders, examples of which include Alzheimer's disease; presenile dementia; senile dementia; vascular dementia; Lewy body dementia; cognitive impairment; Parkinson's disease and Parkinson's disease related disorders, such as Parkinsonism, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disorders; Fragile X syndrome; Angelman syndrome; 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 headaches; fibromyalgia; and peripheral neuropathy of any etiology, and combinations thereof.

[0205] In some embodiments, the subject is a mammal. In other embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. Thus, the compounds, methods, and uses of the present application address both human and veterinary diseases, disorders, and conditions.

[0206] In some embodiments, the compounds of the present application are useful for treating behavioral problems in feline or canine subjects.

[0207] Thus, in some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is behavioral problems in a cat or dog subject.Thus, the present application also includes a method for treating behavioral problems, 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 includes the use of one or more compounds of the present application for treating behavioral problems in non-human subjects, as well as the use of one or more compounds of the present application for preparing a medicament for treating behavioral problems in non-human subjects.The present application further includes one or more compounds of the present application for use in treating behavioral problems in non-human subjects.

[0208] 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 behavior, biting, and combinations thereof.

[0209] In some embodiments, the non-human subject is a dog, hi some embodiments, the non-human subject is a cat.

[0210] The present application also includes a method of treating a disease, disorder, or condition by activating 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 together with other known agents useful for treating the disease, disorder, or condition by activating 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 the disease, disorder, or condition by activating a serotonin receptor for the treatment of a disease, disorder, or condition by activating 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 the disease, disorder, or condition by activating a serotonin receptor for the preparation of a medicament for the treatment of a disease, disorder, or condition by activating a serotonin receptor. The present application further includes one or more compounds of the present application in combination with other known agents useful for treating the disease, disorder, or condition by activating a serotonin receptor for use in the treatment of a disease, disorder, or condition by activating a serotonin receptor.

[0211] In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a psychiatric disorder. In some embodiments, the psychiatric disorder is selected from hallucinations and delusions, and combinations thereof. In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a disorder of the central nervous system (CNS). In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a psychosis or psychotic symptom. In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a behavioral problem in a non-human subject.

[0212] 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.

[0213] In some embodiments, the disease, disorder or condition that is treated by activating serotonin receptor is selected from attention deficit hyperactivity disorder and attention deficit disorder and combinations thereof.In some embodiments, the disease, disorder or condition that is treated by activating serotonin receptor is 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.

[0214] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is dementia or Alzheimer's disease, and one or more compounds of the present application are administered in combination with one or more additional treatments for the treatment of dementia or Alzheimer's disease. In some embodiments, the additional treatments for dementia or Alzheimer's disease are selected from selected acetylcholinesterase inhibitors, NMDA antagonists, muscarinic agonists and antagonists, and nicotinic agonists.

[0215] In some embodiments, the acetylcholinesterase inhibitor is selected from donepezil, galantamine, rivastigmine, and phenserine, and combinations thereof.

[0216] In some embodiments, the NMDA antagonist is selected from MK-801, ketamine, phencyclidine, and memantine, and combinations thereof.

[0217] In some embodiments, the nicotinic agonist is nicotine, nicotinic acid, a nicotinic alpha7 agonist, an alpha2beta4 agonist, or a combination thereof.

[0218] In some embodiments, the muscarinic agonist is a muscarinic M1 agonist, or a muscarinic M4 agonist, or a combination thereof.

[0219] In some embodiments, the muscarinic antagonist is a muscarinic M2 antagonist.

[0220] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is psychosis or a psychotic condition, and one or more compounds of the present application are administered in combination with one or more additional treatments for the psychosis or psychotic condition. In some embodiments, the additional treatment for the psychosis or psychotic condition is selected from a typical antipsychotic and an atypical antipsychotic.

[0221] In some embodiments, the typical antipsychotic is acepromazine, acetophenazine, benperidol, bromperidol, butaperazine, carfenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, dixyrazine, droperidol, fluanisone, flupentixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, lenperone, loxapine, mesoridazine, methythepin, 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.

[0222] In some embodiments, the atypical antipsychotic is selected from amoxapine, amisulpride, aripiprazole, asenapine, blonanserin, brexpiprazole, cariprazine, carpipramine, clocapramine, clorotepine, clothiapine, 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.

[0223] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is psychosis, and one or more compounds of the present application are administered in combination with one or more additional treatments for the psychosis. In some embodiments, the additional treatments for the psychosis are selected from typical antipsychotics and atypical antipsychotics.

[0224] In some embodiments, an effective amount will vary depending on factors such as the disease state, age, sex, and / or weight of the subject or species. In some embodiments, the amount of a given compound or compounds that would correspond to an effective amount will vary depending on factors such as the given drug or compounds, pharmaceutical formulation, 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 skill in the art.

[0225] 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 once or more per week. However, in other embodiments, the compound is administered to the 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 the treatment period depends on various factors, such as the severity of the disease, disorder, or condition, the age of the subject, the concentration and / or activity of the compound of the present application, and / or a combination thereof. It will also be understood that the effective dosage of the compound used in the treatment may increase or decrease during a particular treatment regimen. Modifications in dosage may occur and be evident by standard diagnostic assays known in the art. In some cases, chronic administration is necessary. For example, the compound is administered to the subject in an amount and for a period of time sufficient to treat the subject.

[0226] In some embodiments, the compounds of the present application are administered in a hallucinogenic or psychotomimetic dose and are taken in conjunction with psychotherapy or treatment and may be administered once, twice, three times, or four times per year, however, in some embodiments, the compounds are administered to a subject in a dose that is not hallucinogenic or psychotomimetic once per day, once every other day, once every third day, once per week, once every two weeks, once per month, once every two months, or once per three months.

[0227] 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) that are useful for treating diseases, disorders, or conditions by activating serotonin receptors. When used in combination with other known agents that are useful for treating diseases, disorders, or conditions by activating serotonin receptors, it is an embodiment that the compounds of the present application are administered contemporaneously with the other agents. In the present disclosure, "concurrent administration" of two substances to a subject means providing each of the two substances so that they are active in the individual at the same time. The exact details of administration depend on the pharmacokinetics of the two substances in the presence of each other, but may include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of the administration of the other substance, if the pharmacokinetics are suitable. Designing an appropriate dosing regimen is routine for one of ordinary skill in the art. In certain embodiments, the two substances are administered substantially simultaneously, i.e., within minutes of each other, or in a single composition containing both substances. It is a further embodiment of the present invention that the combination of agents is administered to a subject asynchronously. In some embodiments, the compound of the present application is 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 a unit dosage form that includes one or more compounds of the present application, additional therapeutic agents, and a pharma- ceutically acceptable carrier.

[0228] The dosage of the compounds of the present application varies depending on many factors, including, for example, the pharmacokinetic properties of the compound, the mode of administration, the age, health, and weight of the recipient, the nature and extent of symptoms, the frequency of treatment, and the type of concurrent treatment (if any), and the rate of clearance of the compound in the subject being treated. Those skilled in the art can determine the appropriate dosage based on the above factors. In some embodiments, the compound or compounds of the present application are initially administered at an appropriate dosage, and the dosage is adjusted as necessary depending on the clinical response. The dosage is generally selected to maintain a serum level of the compound or 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. As a representative example, the oral dosage of one or more compounds of the present application is about 10 μg to about 1000 mg per day for adults, preferably about 10 μg to about 500 mg per day, more preferably about 10 μg to about 200 mg per day. In the case of parenteral administration, a representative amount is about 0.0001 mg / kg to about 10 mg / kg, about 0.0001 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, or about 0.0001 mg / kg to about 0.01 mg / kg. In the case of oral administration, a representative amount is about 0.001 μg / kg to about 10 mg / kg, about 0.1 μg / kg to about 10 mg / kg, about 0.01 μg / kg to about 1 mg / kg, or about 0.1 μg / kg to about 1 mg / kg. For administration in suppository form, representative amounts are from about 0.1 mg / kg to about 10 mg / kg or from about 0.1 mg / kg to about 1 mg / kg. In some embodiments of the present application, the compositions are formulated for oral administration and the one or more compounds are preferably 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.

[0229] In some embodiments, the compounds of the present application are used or administered in an effective amount, including administering a dose or dosage regimen that lacks clinically meaningful hallucinogenic / psychotomimetic effects. In some embodiments, the compounds of the present application are ... 2A Clinical efficacy expressed through human CNS receptor occupancy or human plasma psilocin Cmax of 1ng / mL or less and / or 30% or less of human 5-HT 2A The compounds are used or administered in an effective amount, including administration of a dose or dosage regimen that provides a clinical effect similar to that expressed by human CNS receptor occupancy. In some embodiments, the compounds of the present application are used or administered in an effective amount, including administration of a dose or dosage regimen that provides a clinical effect similar to that expressed by human plasma psilocin Tmax of greater than 60 minutes, greater than 120 minutes, or greater than 180 minutes.

[0230] For clarity, above, the term "a compound" includes embodiments in which one or more compounds are referenced. Similarly, references to "a compound of the present application" also include embodiments in which only one compound is referenced.

[0231] V. Compound Preparation

[0232] 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. It is within the scope of one of ordinary skill in the art to select a particular process for preparing a given compound of the present application. Some starting materials for preparing the compounds of the present application are available from commercial chemical sources or may be extracted from cells, plants, animals, or fungi. Other starting materials, 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 showing some embodiments of the methods for preparing the compounds of the present application, all variables are as defined in Formula I unless otherwise indicated.

[0233] In some embodiments, compounds of formula IA are prepared as shown in Schemes I-II. [ka]

[0234] Thus, in some embodiments, compounds of formula (IA) can be synthesized by treating an orthoiodoaniline (A) derivative with a suitable unsaturated precursor (B). Through this route, compounds of formula (IA) are formed directly using a Pd catalyst [Fricke et al., Chem. Eur. J., 2019, 25(4):897-903]. Alternatively, compounds of formula (IA) can be synthesized according to Scheme II. [ka]

[0235] Thus, in some embodiments, as shown in Scheme II, compounds of formula (IA) can be prepared by first treating an appropriately substituted indole (C) with oxalyl chloride, followed by the reaction of the amine NHR 11 R 12The intermediate indole (D) can be synthesized by treatment with LiCl to give the intermediate indole (D), which can then be subjected to Al-based reduction, for example in the presence of lithium aluminum hydride or lithium aluminum deuteride, to give the compound of formula IA.

[0236] A compound of formula IA, wherein R 1 ~R 5 Compounds in which one or more of A and A are deuterium can be obtained, for example, by using hydrogen-deuterium exchange on an appropriate starting substrate. This exchange reaction is described in Esaki, H. et al. Tetrahedron, 2006, 62:10954-10961, and its modifications are known to those skilled in the art, as follows: D 2 Catalyzed by Pd / C in O.

[0237] A compound of formula IA, wherein A is OCD 3 Compounds which are can be obtained, for example, using the methods described in Xu, YZ and Chen, CJ Label Compd. Radiopharm. (2006) 49:897-902, and modifications of said methods known to those skilled in the art.

[0238] 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.

[0239] For example, one skilled in the art would recognize that R 1 is H, then in the compound of formula IA, R 1 is H, then R 1 It will be appreciated that the compounds of formula IA, wherein R is H, may be further reacted to prepare additional compounds of formula I. For example, 1 The compound of formula IA, wherein is H, can be alkylated with an alkyl halide in the presence of a suitable base such as NaH, NaOtBu, or LiHMDS.

[0240] Salts of the compounds of the present application may be formed in a manner known to those skilled in the art, for example, by reacting the compounds of the present application with an amount of an acid or base, e.g., an equivalent amount of an acid or base, in a medium such as a medium in which the salt precipitates or in an aqueous medium, followed by lyophilization.

[0241] The formation of solvates will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of appropriate conditions for forming a particular solvate can be performed by one of ordinary skill in the art. Examples of suitable solvents are ethanol, water, etc. When water is the solvent, the molecule is called a "hydrate". The formation of solvates of the compounds of the present application will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of appropriate conditions for forming a particular solvate can be performed by one of ordinary skill in the art.

[0242] The isotopically enriched compounds of the present application and their pharma- ceutically acceptable salts, solvates, and / or prodrugs can be prepared without undue experimentation by conventional techniques well known to those of skill in the art or by processes analogous to those described in the schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0243] 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, as appropriate, in a manner that would be readily understood by one of skill in the art. Conventional procedures for the use of such protecting groups and examples of suitable protecting groups are described, for example, in "Protective Groups in Organic Synthesis", TW Green, PG M Huts, Wiley-Interscience, New York, (1999). It should also be understood that the conversion by chemical manipulation of one group or substituent to another group or substituent can be performed on any intermediate or final product on the synthetic route to the final product, and the types of conversions possible are limited only by the inherent incompatibility of other functionality of the molecule at that stage with the conditions or reagents used in said conversion. Such inherent incompatibilities, and how to avoid them by performing appropriate conversions and synthetic steps in the appropriate order, will be readily understood by one of skill in the art. Examples of conversions are provided in this disclosure, and it should be understood that the conversions described are not limited to only the generic groups or substituents for which the conversions are exemplified. References and descriptions of other suitable transformations are provided in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations" RC 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). Purification techniques for intermediates and final products include, for example, normal and reverse phase chromatography on columns or on rotating plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, and will be readily understood by those skilled in the art.

[0244] It should also be understood that any intermediate or final product on the synthetic route to the final product may be subjected to chemical manipulation to convert a group or substituent to another group or substituent, with the possible types of transformations being limited only by the inherent incompatibility of other functionalities carried by the molecule at that stage with the conditions or reagents used in the transformation. Such inherent incompatibilities, and how to avoid them by carrying out appropriate transformations and synthetic steps in the appropriate order, will be readily understood by those skilled in the art. Examples of transformations are provided in this disclosure, and 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" RC 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).

[0245] 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.

[0246] The products of the processes of the present application may be isolated by known methods, for example the compounds may be isolated by evaporation of the solvent, filtration, centrifugation, chromatography or other suitable methods.

[0247] Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups. For example, available hydroxyl or amino groups may be acylated with activated acids (e.g., acid chlorides in pyridine) in the presence of a base, optionally in an inert solvent.

[0248] Those skilled in the art will appreciate that when reaction steps of the present application are carried out in various solvents or solvent systems, said reaction steps may be carried out in any suitable solvent or mixture of solvent systems. EXAMPLES

[0249] The following non-limiting examples illustrate the present application. General method

[0250] All starting materials used in this disclosure are either commercially available or previously described in the literature. 1 H and 13 C NMR spectra were obtained in deuterated chloroform as the solvent, unless otherwise noted, using TMS or residual solvent signals as the internal standard. 1 H NMR was recorded on either a Bruker 300, Bruker DPX400, or Varian +400 spectrophotometer 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 H NMR data was obtained using CDCl as the solvent. 3 The signal was obtained at 400 MHz using

[0251] Purification of products was performed using Chem Elut Extraction Columns (Varian, cat#1219-8002), Mega BE-SI (Bond Elut Silica) SPE Columns (Varian, cat#12256018; 12256026; 12256034) or by flash chromatography on silica-packed glass columns.

[0252] The following compounds were prepared using one or more of the synthetic methods outlined in Schemes I and II. A. Synthesis of Exemplary Compounds Example 1: Synthesis of 2-(1H-indol-3-yl-2,4,5,6,7-d5)-N,N-bis(methyl-d3)ethan-1-amine (IA-1) [ka] Synthesis of 2-(1H-indol-3-yl-2,4,5,6,7-d5)-N,N-bis(methyl-d3)-2-oxoacetamide:

[0253] A solution of 1H-indole-2,4,5,6,7-d5 (1, 1.4 g, 11.368 mmol) in dry ether (30 mL) was treated with oxalyl chloride (0.75 mL, 11.368 mmol) at 0° C. The reaction was allowed to reach room temperature and stirred for an additional 16 h. The reaction was cooled to 0° C. and bis(methyl-d 3 ) amine hydrochloride (3.48 g, 39.788 mmol, Et in THF (80 mL) 3 The reaction was treated with 100 mL of water (free based with N) over a period of 5 minutes. The reaction was allowed to come to room temperature and stirred for 4 hours. The reaction was quenched with water (100 mL) and the product was extracted into ethyl acetate (2×75 mL). The combined ethyl acetate layers were washed with brine (25 mL) and dried (Na 2 SO 4 The solvent was evaporated and the crude product was purified by flash column chromatography on silica gel (MeOH:CH 2 Cl 2=5:95), to give compound 2 (1.65 g, 63.9%) as described in the heading as a light yellow solid. ESI-MS (m / z, %): 249 (M+Na, 100)

[0254] Synthesis of 2-(1H-indol-3-yl-2,4,5,6,7-d5)-N,N-bis(methyl-d3)ethan-1-amine: A suspension of lithium aluminum hydride (0.82 g, 21.820 mmol) in dry THF (10 mL) was treated with 2-(1H-indol-3-yl-2,4,5,6,7-d5)-N,N-bis(methyl-d3)-2-oxoacetamide (2, 0.62 g, 2.727 mmol) in dry THF (20 mL) at 0° C. over a period of 10 minutes. The reaction was allowed to reach room temperature and refluxed for an additional 16 hours. The reaction was cooled to 0° C. and quenched by the sequential addition of water (0.82 mL), 2N NaOH solution (0.82 mL), and water (0.82 mL) over a period of 15 minutes. The reaction was allowed to reach room temperature and stirred for an additional 30 minutes. The solid was filtered and washed with THF (2×50 mL). The combined THF layers were evaporated and the crude product was purified by column chromatography on silica gel (MeOH:CH 2 Cl 2 = 2M NH in 5:95 3 ) to give compound IA-1 (0.48 g, 88.8%) as a pale yellow solid. 1H NMR (DMSO-d6): δ 10.76 (s, 1H), 7.52-7.50 (m, 0.09H), 7.34-7.32 (m, 0.04H), 7.14 (d, 0.05H, J = 1.5 Hz), 7.07-7.05 (m, 0.16H), 6.98-6.96 (m, 0.22H), 2.83-2.79 (m, 2H), 2.53-2.49 (m, 2H); ESI-MS (m / z, %): 200 (MH+, 100)

[0255] Example 2: Synthesis of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (IA-6) [ka] Synthesis of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)-2-oxoacetamide: A solution of 5-(methoxy-d3)-1H-indole (4, 1.04 g, 6.924 mmol) in dry ether (20 mL) was treated with oxalyl chloride (0.58 mL, 6.924 mmol) at 0° C. The reaction was allowed to reach room temperature and stirred for an additional 16 h. The reaction was cooled to 0° C. and bis(methyl-d 3 ) amine hydrochloride (2.1 g, 24.235 mmol, Et in THF (50 mL) 3 N) for a period of 5 minutes. The reaction was allowed to reach room temperature and stirred for 4 hours. The reaction was quenched with water (100 mL) and worked up and purified as described for compound 2 to give compound 5 (1.16 g, 66%) as a pale yellow solid. 1 H NMR (DMSO-d6): δ 12.19 (s, 1H), 8.03 (d, 1H, J = 3.0 Hz), 7.61 (d, 1H, J = 3.0 Hz), 7.43 (d, 1H, J = 6.0 Hz), 6.91 (dd, 1H, J = 3.0, 6.0 Hz); ESI-MS (m / z, %): 278 (M + Na, 100), 256 (MH + )

[0256] Synthesis of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (IA-6): A suspension of lithium aluminum deuteride (1.0 g, 23.812 mmol) in dry THF (10 mL) was treated with 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)-2-oxoacetamide (5, 0.76 g, 2.976 mmol) in dry THF (20 mL) at 0° C. for a period of 10 minutes. The reaction product was allowed to reach room temperature and refluxed for an additional 16 hours. The reaction product was worked up and purified as described for compound IA-1 to obtain compound IA-6 (0.59 g, 85.7%) as described in the heading as a pale yellow solid. 1H NMR (DMSO-d6): δ 10.59 (s, 1H), 7.22 (d, 1H, J = 6.0 Hz), 7.09 (d, 1H, J = 3.0 Hz), 6.97 (d, 1H, J = 3.0 Hz), 6.71 (dd, 1 H, J = 3.0, 6.0 Hz); ESI-MS (m / z, %): 232 (MH + , 100)

[0257] Example 3: Synthesis of 2-(1H-indol-3-yl-2,4,5,6,7-d5)-N,N-dimethylethan-1-amine (IA-2) [ka] Synthesis of 2-(1H-indol-3-yl-2,4,5,6,7-d5)-N,N-dimethyl-2-oxoacetamide: A solution of 1H-indole-2,4,5,6,7-d5 (1, 0.8 g, 6.49 mmol) in dry ether (30 mL) was treated with oxalyl chloride (0.55 mL, 6.49 mmol) at 0° C. The reaction was allowed to reach room temperature and stirred for an additional 16 h. The reaction was cooled to 0° C. and treated with dimethylamine solution (16.22 mL, 32.45 mmol, 2 M in THF) over a period of 5 min. The reaction was allowed to reach room temperature and stirred for 4 h. The reaction was worked up and purified as described for compound 2 to give compound 26 (1.1 g, 76.5%) as a light brown solid as described in the heading. 1H NMR (CDCl 3 )10.09 (s, 1H), 8.35-8.33 (m, 0.17H), 7.76 (d, 0.05H, J = 1.5 Hz), 7.38-7.26 (m, 0.85H), 3.11 (s, 3H), 3.06 (s, 3H): δ; ESI-MS (m / z, %): 244 (M+Na), 243 (100)

[0258] Synthesis of 2-(1H-indol-3-yl-2,4,5,6,7-d5)-N,N-dimethylethan-1-amine: A suspension of lithium aluminum hydride (1.34 g, 35.431 mmol) in dry THF (20 mL) was treated with 2-(1H-indol-3-yl-2,4,5,6,7-d5)-N,N-dimethyl-2-oxoacetamide (26, 0.98 g, 4.428 mmol) in dry THF (30 mL) at 0° C. for a period of 10 minutes. The reaction product was allowed to reach room temperature and refluxed for an additional 16 hours. The reaction product was worked up and purified as described for compound IA-1 to obtain compound IA-2 (0.75 g, 87.6%) as described in the heading as a pale yellow solid. 1H NMR (DMSO-d6): δ 10.76 (s, 1H), 7.51-7.49 (m, 0.18H), 7.34-7.32 (m, 0.04H), 7.14 (d, 0.05H, J = 1.5 Hz), 7.07-7.05 (m, 0.32H), 6.99-6.96 (m, 0.41H), 2.84-2.80 (m, 2H), 2.54-2.50 (m, 2H), 2.22 (s, 6H); ESI-MS (m / z, %): 194 (MH + ), 193 (100) B. Biological Testing Example 4: FLIPR Assay: Human 5-HT2A I. Evaluation of the Activated Effect of Exemplary Compounds of Formula IA Targeting the Human 5-HT2A (h5-HT2A) Receptor in Agonist Mode: Compound preparation and assay controls [Table 1-4] [Table 1-5]

[0259] IC Experimental Methods and Procedures: 1. Cells were cultured in cell culture medium (DMEM containing 10% FBS, 1× penicillin-streptomycin, 300 μg / ml G418, and 100 μg / ml hygromycin B) at 37° C. and 5% (vol / vol) CO 2 .

[0260] 2. One day before the assay, cells were detached using TrypLE™ Express and counted using a cell counter. Only cells with viability above 85% were used in the assay.

[0261] 3. Seed 20,000 cells / well in 30 μl / well of culture medium into 384-well cell plates and culture the cells at 37° C., 5% (v / v) CO 2The mixture was incubated overnight at 4°C.

[0262] 4. On the day of the assay, a 2x dye solution was prepared according to the FLIPR® Calcium 6 Assay Kit manual: i. The dye was diluted in assay buffer (20 mM HEPES in 1x HBSS, pH 7.4); ii. Probenecid was added to a final concentration of 5 mM; iii. Vortexed vigorously for 1-2 min.

[0263] 5. The medium was released from the cell plate by tapping the cell plate on a paper towel.

[0264] 6. 10 μl of assay buffer and 10 μl of 2× dye solution were added to each well of the cell plate.

[0265] 7. Place cell plate on plate shaker and agitate the plate at 600 rpm for 2 minutes. The plate was incubated at 37° C. for 2 hours, followed by an additional 15 minutes at 25° C.

[0266] 8. 3x compound in assay buffer was prepared: a. Reference compounds were diluted to required concentration in DMSO. Compounds were added to 384-well compound plate; b. Serial dilutions were performed; c. 10 mM test compound was added to the compound plate and 3-fold serial dilutions were performed; d. 60 nl / well of compound was transferred from source plate to 384-well compound plate (Corning, 3657) using Echo; e. 20 μl / well of assay buffer was added to the compound plate; f. The plate was mixed for 2 minutes on a plate shaker;

[0267] 9. The cell plate, compound plate and chips were placed in the FLIPR and the FLIPR transferred 10 μl per well of 3× compound to the cell plate.

[0268] 4. Data Analysis i. Normalized fluorescence readings (RFU) were calculated as follows, where Fmax and Fmin represent the maximum and minimum calcium signals during a defined time window: RFU=Fmax-Fmin

[0269] ii. The activation percentage was calculated using the following formula:

number

[0270] iii. EC was calculated by fitting the % activation versus log compound concentration to the Hill equation using XLfit. 50 was calculated.

[0271] The compounds of the present application were found to be 5-HT2A agonists. The results of representative compounds are shown in Table 1. 50 The letter "A" indicates an EC50 less than 1,000 nM, "B" indicates an EC50 greater than 1,000 nM and less than 10,000 nM, and "C" indicates an EC50 greater than 10,000 nM. [Table 1-6]

[0272] Results and Discussion Exemplary compounds of formula IA were functionally evaluated using the FLIPR assay for their effect on the h5-HT2A receptor in agonist mode. EC 50 Concentrations (nM) are shown in Table 5. This assay confirmed that the compounds of the present application are effective inhibitors of the targeted human 5-HT2A receptor. II. Human 5-HT2A: Radioligand Binding Assay: II.1. Materials and Equipment: [Table 1-7] II.2. Equipment and consumables: [Table 1-8] II.3 Experimental Procedure: i. Prepare assay buffer according to the table below; [Table 1-9]

[0273] ii. Preparation of eight doses of reference and test compounds starting from 10 mM stock solutions required with 5-fold serial dilutions at 100%;

[0274] iii. (v / v) DMSO was prepared: a. 50 μl / well of 0.5% (v / v) PEI was added to a UniFilter-96 GF / B plate. The plate was sealed and incubated at 4° C. for 3 hours; b. After incubation, the plate was washed 3 times with ice-cold wash buffer (50 mM Tris, pH 7.4);

[0275] iv. Assay plate preparation: a. Cell membranes were diluted in assay buffer and 330 μl / well were added to a 96 round deep well plate to reach a concentration of 20 μg / well; b. Eight concentrations of reference or test compounds were prepared and 110 μl / well were added to a 96 round deep well plate; c. [3H]-Ketanserin was diluted in assay buffer to 5 nM (5× final concentration) and 110 μl / well were added to a 96 round deep well plate.

[0276] v. The plate was centrifuged at 1000 rpm for 30 seconds and then agitated at 600 rpm for 5 minutes at room temperature.

[0277] vi. The plate was sealed and incubated at 27° C. for 90 minutes.

[0278] vii. The incubation was terminated by vacuum filtration onto GF / B filter plates, followed by four washes with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0279] viii. The plates were dried at 37° C. for 45 minutes.

[0280] ix. The filter plate was sealed and 40 μl / well of scintillation cocktail was added.

[0281] x. The plates were read using a Microbeta2 microplate counter.

[0282] Data Analysis: For reference and test compounds, 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 are determined by fitting the percent inhibition as a function of compound concentration to the Hill equation using XLfit.

[0283] Results and Discussion: The results of the potential competitive binding properties of representative compounds targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A) are summarized in Table 2. The results of the representative compounds are shown in Table 2 with IC 50 The symbol "#" stands for IC 50 is less than 500 nM, "##" indicates IC 50 indicates IC > 500nM and < 5,000nM, "###" indicates IC 50 is greater than 5,000 nM. [Table 2]

[0284] Results and Discussion Exemplary compounds of formula IA were evaluated using a radioligand binding assay for the human 5-HT2A receptor. IC 50 Concentrations (nM) are shown in Table 2. This assay confirms that the claimed compounds are effective ligands of the targeted human 5-HT2A receptor.

[0285] Example 5: Human, rat, and mouse liver microsomal stability the purpose The purpose of this study was to estimate the in vitro metabolic stability of representative compounds of the present application in pooled human and male mouse liver microsomes. The concentration of the parent compound in the reaction system was assessed by LC-MS / MS to estimate the stability in pooled human and male mouse liver microsomes. The in vitro intrinsic clearance of the test compounds was also determined.

[0286] Protocol Phosphate buffer, ultrapure H 2 O, MgCl 2 The master solutions in the "incubation plate" containing the solutions and liver microsomes were made according to Table 3. The mixtures were pre-warmed in a 37°C water bath for 5 minutes. [Table 3]

[0287] 40 μL of 10 mM NADPH solution was added to each well. The final concentration of NADPH was 1 mM. The negative control sample was prepared by dissolving NADPH in 40 μL of ultrapure H 2 The negative control was prepared in duplicate by replacing 0 with 0. Samples were prepared in duplicate. The negative control was prepared in single replicate.

[0288] Reactions were initiated by adding 4 μL of 200 μM test compound or control compound to each master solution for a final concentration of 2 μM. The assay was performed in duplicate.

[0289] Aliquots of 50 μL were taken from the reaction solution at 0, 15, 30, 45, and 60 min. The reaction solution 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). Samples were centrifuged at 3,220 g for 40 min. Aliquots of 90 μL of the supernatant were diluted with 90 μL of ultrapure H2O. 2 The mixture was mixed with O and then used for LC-MS / MS analysis.

[0290] For all samples in this test, the degasser DGU-20A 5R LC / MS analysis was performed using a Shimadzu liquid chromatographic separation system equipped with: solvent delivery unit LC-30AD; system controller SIL-30AC; column oven CTO-30A; and CTC analysis HTC PAL system. Mass spectrometry analysis was performed using a Triple Quad™ 5500 instrument.

[0291] All calculations were performed using Microsoft Excel. Peak area ratios of test compounds relative to the internal standards (listed in the table below) were determined from extracted ion chromatograms.

[0292] All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The slope value "k" was determined by linear regression of the curve of the natural logarithm of the percentage of parent drug remaining versus incubation time.

[0293] The in vitro half-time (in vitro t1 / 2) was determined from the slope value: In vitro 1 / 2 =-(0.693 / k)

[0294] In vitro t1 / 2 (min) In vitro intrinsic clearance (in vitro CL int Conversion to 100 μL / min / mg protein was performed using the following formula (average of duplicate measurements):

number

[0295] For compounds or control compounds that showed an initial rapid elimination followed by a slower elimination, only time points within the range of the initial rate were included in the calculations.

[0296] Results and Discussion 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 by-products of orally administered drugs. Representative compounds of the present application were evaluated for their stability in human, rat and mouse liver microsomes. In the liver microsomes of three species, human, rat and mouse, the majority of the compounds of the present application were recovered within a 60 minute period, indicating that the compounds are not rapidly cleared (see Table 4 for representative compounds of exemplary formula IA). [Table 4]

[0297] Example 6: Hallucinogenic-like effects of compounds of formula IA The effects of various doses of exemplary representative compounds of formula IA were evaluated based on the head-twitch response (HTR) as a behavior-based model of hallucinogenic activity.

[0298] Protocol Mouse head spasm Male C57BL / 6J mice (weight range 20-30 g) were dosed with the appropriate dose of test article and placed into individual observation chambers after a 1-minute pretreatment period. Animals were visually assessed continuously for head twitch events for a period of 1 hour. A head twitch 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 twitch 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.

[0299] Rat behavioral testing Male Sprague-Dawley rats (weight range 250g-400g) were dosed with the appropriate dose of the test article, and after a 1-minute pretreatment period, the rats were placed in a locomotor activity box (dimensions: 17" wide x 17" long x 12" 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 muscle contractions), 5-HT2A receptor activation (yawning, penile grooming), and 5-HT1A behaviors (forelimb stepping, hindlimb abduction) (Halberzettl et al, Behav Brain Res. 256:328-345, 2013). Additional behavioral and physical signs characteristic of the 5-HT syndrome (e.g., shivering, salivation, prone flat posture, core temperature changes) were also measured. Simultaneously, spontaneous behavior of the rats was measured using an automated tracking system (Med Associates, VT, USA). Activity data collected included total distance traveled, rearing counts, and ambulatory episodes. All data were expressed as the mean ± standard error of the mean (SEM) of 6–10 rats per group.

[0300] Drug discrimination in rats Male Sprague-Dawley rats were initially food restricted (single housing) by presenting 18-20 g of food at the end of the day. After 7 days of acclimation to the food restriction procedure, the rats were trained to lever press for food (45 mg Bioserve pellets) daily for 1 week in a standard two-lever operant conditioning chamber controlled by Med-PC software (Med. Associates Ins., St. Albans, VT, USA). The rats were trained to press the lever for food up to an FR10 value (i.e., 10 lever presses for one food reward). Once stable food responding was acquired for both response levers, discrimination training began. Over a period of 20-50 training sessions, rats were trained to associate one lever with a psilocybin training dose of 1 mg / kg subcutaneously and the second lever with a neutral stimulus (saline, subcutaneously) (Winter et al, Pharmacol Biochem Behav. 87(4):472-480, 2007). Training sessions lasted for 30 min or until 50 pellets had been delivered and the animals achieved adequate stimulus control (defined as six consecutive sessions in which the animals made 16 or fewer lever presses prior to the first reward delivery and 95% or more of the total responses were on the appropriate lever). Rats continued to receive their food allotment for the day in their home cages at the end of the day.

[0301] Once trained, substitution testing was performed. On the test day, both levers were active, meaning that the 10th response on either lever delivered a food pellet. Test sessions continued until 50 pellets were obtained or 30 min had elapsed. Response speed was also measured during these sessions.

[0302] Results and Discussion: Dose response (0.3-3 mg / kg subcutaneous) - 5-HT2A signs of violent trembling / back muscle contractions (WDS / BMC) were measured over a 1 hour period. Locomotor activity and other 5-HT receptor signs were also measured. Various doses of an exemplary compound of formula IA, IA-6, were tested for their effect on head twitch response (HTR) in male C57BL6 mice. Mice were treated with compound IA-6 (0.3, 1, 3, 10 mg / kg) by subcutaneous (SC) route in saline 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).

[0303] To evaluate the involvement of 5-HT2A receptor in the HTR caused by the exemplary compound of formula IA, mice were pretreated with the selective 5-HT2AR antagonist M100907 (also known as vorinancerin) before administration of the compound of formula IA.As expected, pretreatment with this antagonist completely blocked the effect of the exemplary compound of formula IA on HTR.

[0304] Although the present application has been described with reference to examples, it should be understood that the scope of the claims is not limited to the embodiments set forth in the examples, but should be accorded the broadest interpretation consistent with the entire disclosure.

[0305] All patents, patent applications, and publications cited in this disclosure are hereby incorporated by reference in their entireties 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.

Claims

1. A compound of formula (IA) or a pharma- ceutically acceptable salt, solvate, and / or prodrug thereof: 【Chemistry 1】 During the ceremony R １ is hydrogen, deuterium, C １ ~C ３ Alkyl, C １ ~C ３ Deuteroalkyl, C １ ~C ３ Fluoroalkyl, C １ ~C ６ Alkylene P(O)(OR ６ ) ２ , C １ ~C ６ Alkylene OP(O)(OR ６ ) ２ , C(O)R ６ , CO ２ R ６ , C(O)N(R ６ ) ２ , S(O)R ６ , and S.O. ２ R ６ Selected from: R ２ , R ３ , R ４ , and R ５ are independently selected from hydrogen and deuterium; R ７ , R ８ , R ９ , and R １０ is hydrogen, deuterium, C １ ~C ６ Alkyl, C １ ~C ６ Deuteroalkyl, and C １ ~C ６ independently selected from fluoroalkyl; A is hydrogen, deuterium, and OR １９ Selected from: R ６ is hydrogen, deuterium, C １ ~C ６ Alkyl, C １ ~C ６ Deuteroalkyl, and C １ ~C ６ fluoroalkyl; R １１ and R １２ is hydrogen, deuterium, C １ ~C ６ Alkyl, C １ ~C ６ Deuteroalkyl, and C １ ~C ６ fluoroalkyl; and R １９ is C １ ~C ６ Alkyl, C １ ~C ６ Deuteroalkyl, and C １ ~C ６ fluoroalkyl; however, (1) R ２ , R ３ , R ４ , and R ５ are all D, and A, R １ , R ６ ~R １２ , and R １９ is as defined above in this disclaimer; or (2) A is OR １９ where R １９ is C １ ~C ６ Deuteroalkyl and C １ ~C ６ fluoroalkyl; and R １ ~R １２ is as defined above in this disclaimer.

2. R １ is hydrogen, deuterium, C １ ~C ３ Deuteroalkyl, C １ ~C ３ Fluoroalkyl, fluoro-substituted C １ ~C ３ Alkyl, C １ ~C ３ Alkylene P(O)(OR ６ ) ２ , C １ ~C ３ Alkylene OP(O)(OR ６ ) ２ , C(O)R ６ , CO ２ R ６ , and C(O)N(R ６ 2. The compound of claim 1, wherein the compound is selected from the group consisting of

3. R １ are hydrogen, deuterium, and CH ３ , C.F. ３ , C.D. ３ , C.H. ２ CH ３ , C.F. ２ CF ３ , C.D. ２ CDs ３ , C.H. ２ P(O)(OR ６ ) ２ , CH(CH ３ ) P (O) (OR ６ ) ２ , and (CH ２ ) OP (O) (OR ６ ) ２ 3. The compound of claim 2, selected from:

4. R ６ is hydrogen, deuterium, CH ３ , C.F. ３ , C.H.F. ２ , C.D. ２ H, C.D.H. ２ , and C.D. ３ The compound according to any one of claims 1 to 3, selected from:

5. R ７ , R ８ , R ９ , and R １０ is hydrogen, deuterium, C １ ~C ４ Alkyl, C １ ~C ４ Deuteroalkyl, and C １ ~C ４ The compound of any one of claims 1 to 4, independently selected from fluoroalkyl.

6. R ７ , R ８ , R ９ , and R １０ At least one of R is deuterium or ７ , R ８ , R ９ , and R １０ The compound of claim 5 , wherein at least one of the following groups contains deuterium:

7. R １１ and R １２ is hydrogen, deuterium, C １ ~C ４ Alkyl, C １ ~C ４ Deuteroalkyl, and C １ ~C ４ The compound of any one of claims 1 to 6, independently selected from fluoroalkyl.

8. R ７ , R ８ , R ９ , and R １０ are all hydrogen, and R １１ and R １２ is deuterium and CD ３ The compound according to any one of claims 1 to 4, independently selected from:

9. R ７ , R ８ , R ９ , and R １０ are all deuterium, and R １１ and R １２ is hydrogen and CH ３ The compound according to any one of claims 1 to 4, independently selected from:

10. R ７ , R ８ , R ９ , and R １０ are all deuterium, and R １１ and R １２ is deuterium and CD ３ The compound according to any one of claims 1 to 4, selected from:

11. A, R ２ , R ３ , R ４ , and R ５ The compound according to any one of claims 1 to 10, wherein all of are deuterium.

12. R １９ CF ３ , C.H.F. ２ , C.D. ２ H, C.D.H. ２ , C.D. ３、 and CDs ２ CDs ３ The compound according to any one of claims 1 to 10, selected from:

13. A is hydrogen, deuterium, OCH ３ , O.C.D. ３ , O.C.F. ３ , and O.C.H.F. ２ The compound according to any one of claims 1 to 10, selected from:

14. The compound of claim 1, wherein the compound of formula (IA) is selected from the compounds listed below or pharma- ceutically acceptable salts, solvates, and / or prodrugs thereof: 【Table 1】 【Table 2】 。

15. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 14 and a pharma- ceutically acceptable carrier.

16. A method of treating a psychiatric disorder comprising administering to a subject in need of treatment a therapeutically effective amount of one or more compounds according to any one of claims 1 to 14.

17. 17. The method of claim 16, wherein the psychiatric disorder is selected from anxiety disorders, depression, mood disorders, impulse control and addictive disorders, drug addiction, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), stress response syndromes, dissociative disorders, depersonalization disorders, factitious disorder, sexual and gender disorders, and somatic symptom disorders, and combinations thereof.

18. A method of treating a disease, disorder or condition of the central nervous system (CNS) and / or a neurological disease, disorder or condition comprising administering to a subject in need of such treatment a therapeutically effective amount of one or more compounds according to any one of claims 1 to 14.

19. The CNS disease, disorder or condition and / or neurological disease, disorder or condition may be a neurological disease, including neurodevelopmental and neurodegenerative diseases, such as Alzheimer's disease, presenile dementia, senile dementia, vascular dementia, dementia with Lewy bodies, cognitive impairment, Parkinson's disease, 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 diseases, fragile X syndrome, Angelman syndrome, hereditary ataxias, neuro-otological disorders, 19. The method of claim 18, wherein the condition is selected from disorders of the reward system such as cognitive and ocular movement 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 disorder, tuberous sclerosis, Rett's syndrome, cerebral palsy, eating disorders such as anorexia nervosa (AN) and bulimia nervosa (BN), and binge eating disorder (BED), trichotillomania, self-injurious dermatosis, nail biting, migraine, fibromyalgia, peripheral neuropathy of any etiology, and combinations thereof.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and an additional therapeutic agent.

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