Indole derivatives as serotonergic drugs useful in treating disorders related to serotonergic drugs

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

[0002] This application claims priority from the co-pending U.S. Provisional Patent Application 63 / 155,634, filed on 2 March 2021. The contents of this U.S. Provisional Patent Application are incorporated in their entirety by reference.

[0003] Mental health disorders, or psychiatric disorders, refer to a broad 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; some individuals experience debilitating illnesses that render normal social functioning impossible, while others suffer from intermittent, recurring episodes throughout their lives. While symptoms and diagnostic criteria are partially distinct among the various psychiatric states, there are notable intermediate traits common to these disorders, and comorbidities are often present. Specifically, there are intermediate phenotypic traits associated with changes in mood, cognition, and behavior. Interestingly, many of these intermediate traits extend to neurotic states. For example, attention deficit has been reported in patients with attention deficit disorder, attention deficit hyperactivity disorder, eating disorders, drug misuse disorder, 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 can partially explain the common intermediate traits and comorbidities among various neuropsychiatric and neurological disorders. Many therapeutic agents that modulate serotonergic function are commercially available, including serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, antidepressants, and monoamine oxidase inhibitors. While these agents were primarily developed for depressive disorders, many are used in a variety of 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 disorders, and smoking cessation. However, in many cases, over-the-counter medications offer only limited benefits compared to placebo, may take up to six weeks to work for some patients, and come with several side effects, including sleep disturbances, drowsiness, fatigue, weakness, changes in blood pressure, memory impairment, digestive problems, weight gain, and sexual problems.

[0005] The field of hallucinogenic neuroscience has experienced a recent renaissance after a period of limited research due to its legal status. Hallucinogens are among the oldest known classes of psychopharmacological agents and cannot be fully understood without referencing various fields of study, including anthropology, ethnopharmacology, psychiatry, psychology, sociology, and others. Hallucinogens (serotonergic hallucinogens) are potent psychostimulants that alter perception and mood and affect many cognitive processes. Hallucinogens are generally considered physiologically safe and do not lead to dependence or addiction. The origins of hallucinogens predate documented history, and they were used in early cultures in many sociocultural and ritualistic contexts. Following the discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD, 5, scheme 1) and the identification of serotonin in the brain, which occurred almost simultaneously, early research placed a strong emphasis on the possibility that LSD and other hallucinogens have a serotonergic basis for their effects. Today, the consensus is that hallucinogens are agonists or partial agonists of serotonin 5-hydroxytryptamine 2A (5-HT2A) receptors in the brain, particularly those expressed on the apical dendrites of neocortical pyramidal cells in layer V, but they also bind to other receptors, such as sigma-1 receptors, with lower affinity. Several useful rodent models have been developed over the years to help elucidate the neurochemical correlations 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] Hallucinogens possess both rapid onset of action and effects that persist long after their acute impact, including changes in mood and brain function. These long-lasting effects may be due to the hallucinogen's unique receptor affinity, which affects neurotransmission through neural modulation systems that regulate brain activity—that is, neuroplasticity—and promotes cell survival, is neuroprotective, and modulates the brain-neuroimmune system. The mechanisms leading to these long-term neuromodulatory changes are linked to epigenetic modifications, altered gene expression, and the regulation of presynaptic and postsynaptic receptor density. These previously understudied hallucinogens have the potential to offer a new generation of neurotherapeutics, potentially treating treatment-resistant psychiatric and neurological disorders, such as depression, post-traumatic stress disorder, dementia, and addiction, with a reduced pharmacological risk profile.

[0007] While there is a general perception that hallucinogens are dangerous, from a physiological safety standpoint, they are among the safest known classes of central nervous system (CNS) drugs. Hallucinogens do not cause addiction, and death from overdose has not occurred after the ingestion of typical doses of classic psychotic agents such as LSD, psilocybin, or mescaline (1, scheme 1). Preliminary data show that the 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, in essence, psychological rather than physiological. Physical effects, while varied, are relatively insignificant, even at doses that produce strong psychological effects. When administered in a controlled setting, psilocybin has often been reported to cause transient, delayed headaches, with onset, duration, and severity increasing in dose-dependent manner [Johnson et al., Drug Alcohol Depend (2012), 123(1-3):132-140]. Repeated administration of hallucinogens has been found to lead to the development of very rapid tolerance known as tachyphylaxis, a phenomenon thought to be partly mediated by the 5-HT2A receptor. In fact, several studies have shown that rapid tolerance to hallucinogens correlates with downregulation of the 5-HT2A receptor. For example, daily administration of LSD selectively reduced 5-HT2 receptor density in rat brains [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 possess rapidly initiating antidepressant and antiaddictive effects, unlike any other treatment currently available. 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 role as an NMDA antagonist. Ibogaine has shown potent antiaddictive potential in preclinical trials and is in the early stages of clinical trials to determine its efficacy in robust human trials [Barsuglia et al., Prog Brain Res, 2018, 242:121-158; Corkery, Prog Brain Res, 2018, 242:217-257].

[0009] Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine (5, scheme 1)) is C 12 H 17It has the chemical formula N2O4P. It is a tryptamine and one of the major psychoactive components in the mushroom species Psilocybe. Psilocybin was first isolated from Psilocybe mushroom by Hofmann in 1957 and subsequently synthesized by Hofmann in 1958 [Passie et al. Addict Biol., 2002, 7(4):357-364]. From the early to mid-1960s, it was used in psychiatric and psychological research and psychotherapy until it was listed on the regulated drug schedule in the United States in 1970 and in Germany in the 1980s [Passie 2005; Passie et al. Addict Biol., 2002, 7(4):357-364]. Research exploring the effects of psilocybin resumed in the mid-1990s, and psilocybin is now a 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 shorter 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 emotional instability.

[0010] In humans and other mammals, psilocybin is converted to its active metabolites, psilocine or 4-hydroxy-N,N-dimethyltryptamine (6, scheme 1). Psilocine is likely responsible for most, or entirely, of the subjective and psychological effects of psilocybin in humans and non-human animals. Recent studies of psilocybin in humans have confirmed the 5-HT2A activity of psilocybin and psilocine, 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 regarding the involvement of other receptors in the action of hallucinogens is the 5-HT1A receptor. This is especially true for tryptamine and LSD, which generally exhibit remarkable affinity and functional potency at this receptor. 5-HT1A receptors are known to colocalize with 5-HT2A receptors on cortical pyramidal cells [Martin-Ruiz et al. J Neurosci. 2001, 21(24):9856-986]. There, these two types of receptors have opposite functional effects [Araneda et al. Neuroscience 1991, 40(2):399-412].

[0011] Although the precise roles of the 5-HT2A receptor and other members of the 5-HT2 receptor family are not well understood in the amygdala, it is clear that the 5-HT2A receptor plays a crucial role in emotional responses and is an important target to consider in the action of 5-HT2A agonist hallucinogens. In fact, most known 5HT2A agonists produce hallucinogenic effects in humans, and rodents generalize from one 5HT2A agonist to another, as in the case of psilocybin-LSD [Aghajanian et al., Eur J Pharmacol., 1999, 367(2-3):197-206; Nichols et al., J Neurochem., 2004, 90(3):576-584]. Psilocybin has a stronger affinity for human 5HT2A receptors than for rat receptors and has a lower Ki than LSD for both 5HT2A and 5HT2C receptors. Furthermore, results from a series of drug identification tests in rats showed that 5HT2A antagonists, rather than 5HT1A antagonists, prevented rats from recognizing psilocybin [Winter et al., Pharmacol Biochem Behav., 2007, 87(4):472-480]. Daily administration of LSD and psilocybin reduced 5HT2 receptor density in rat brains.

[0012] Clinical trials in the 1960s and 1970s showed that psilocybin produced altered states of consciousness with subjective symptoms such as “noticeable changes in perception, mood, and thought, and changes in time, space, and one’s own experience.” Psilocybin was used in experimental studies to understand the pathogenesis of selective psychological disorders and demonstrated therapeutic potential [Rucker et al., Psychopharmacol., 2016, 30(12):1220-1229]. Psilocybin gradually gained popularity as a recreational drug that produced hallucinations and was eventually classified as a Schedule 1 controlled substance in 1970. Fear of hallucinogen abuse led to a significant decline in research conducted in this area, which remained true until the 1990s. In the 1990s, conditions for safe administration were established and human studies of psilocybin resumed [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 the subject. Recent studies have shown varying degrees of success in neurotic disorders, alcohol dependence, depression in terminally ill 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 psychotic model for the development of new treatments for mental disorders [Dubovyk and Monahan-Vaughn, ACS Chem. Neurosci., 2018, 9(9):2241-2251].

[0013] Recent exciting developments in this field have occurred in clinical research, where several double-blind, placebo-controlled phase 2 trials of psilocybin adjunctive psychotherapy in patients with treatment-resistant major depressive disorder and cancer-related psychosocial distress have shown unprecedented positive reductions in anxiety and depression. Two recent small pilot trials of psilocybin adjunctive psychotherapy have also shown positive benefits in treating both alcohol and nicotine addiction. More recently, blood oxygen level-dependent functional magnetic resonance imaging and magnetoencephalography have been used for in vivo brain imaging in humans after hallucinogen administration, and the results have shown that intravenously administered psilocybin and LSD produced a reduction in oscillatory power in areas 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 intake (15 or 20 mg orally) increased the absolute rate of glucose metabolism in the frontal lobe in healthy participants, and to a lesser extent in other cortical regions, as well as in the striatum and limbic subcortical structures, suggesting that some of the key behavioral effects of psilocybin involve the prefrontal cortex [Gouzoulis-Mayfrank et al., Neuropsychopharmacology, 1999, 20(6):565-581; Vollenweider et al., Brain Res. Bull. 2001, 56(5):495-507]. While 5HT2A agonism is widely recognized as the primary mechanism of action of classic hallucinogens, psilocybin has weaker affinity for a wide range of other presynaptic and postsynaptic serotonin and dopamine receptors, as well as for serotonin reuptake transporters [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 state characterized by episodes of mood disorders and other symptoms, such as anhedonia, psychomotor complaints, feelings of guilt, attention deficit, and suicidal tendencies, all of which vary in severity. According to the World Health Organization, the discovery of mainstream antidepressants has revolutionized the management of depression, yet up to 60% of patients remain untreated. This is often due to delayed therapeutic effects of medication (generally 6 weeks after the start of treatment), side effects leading to non-adherence to medication, or simply being unresponsive to such medications in the first place. 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 illness is the only anxiety subtype studied in terms of adjunctive therapy with hallucinogens. This form of anxiety affects up to 40% of individuals diagnosed with life-threatening illnesses such as cancer. This manifests as anxiety about future dangers or misfortunes, often accompanied by physical symptoms such as unpleasant sensations or tension, and frequently coexisting with depression. This is accompanied by a reduced quality of life, decreased treatment adherence, prolonged hospitalization, increased disability, and hopelessness, all of which contribute to a reduced overall survival rate. 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 hallucinogenic adjunct therapy may represent a promising alternative for patients with depression and anxiety that are inefficiently addressed by conventional methods.

[0016] Generally, the hallucinogen therapy model involves administering an active drug orally to induce a mystical experience lasting 4 to 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 studied as promising candidates. In one trial using classic hallucinogens for the treatment of depression and anxiety associated with life-threatening illness, psilocybin and LSD consistently produced significant and sustained antidepressant and anxiolytic effects in a supportive setting.

[0017] Hallucinogen therapy is generally well-tolerated and has no lasting adverse effects. Regarding its mechanism of action, it mediates its primary therapeutic effect biochemically through serotonin receptor agonism and psychologically by producing meaningful psychospiritual experiences that contribute to psychological flexibility. Given the limited success rates of current treatments for anxiety and mood disorders, and the high prevalence associated with these conditions, hallucinogens may offer symptom relief in patients who have not been adequately addressed by conventional methods.

[0018] Further emerging clinical research and evidence suggest that adjunctive hallucinogen therapy has potential as an alternative treatment for refractory substance use disorders and mental health conditions, and could be a crucial tool in crises where existing methods have yielded limited success. A recent systematic review of clinical trials published in the last 25 years outlines some of the antidepressant, anxiolytic, and antiaddictive effects of classic hallucinogens. Among these, the findings from a meta-analysis of randomized controlled trials of LSD therapy and a recent pilot trial of adjunctive psilocybin therapy for treating alcohol use disorder were encouraging [dos Santos et al., Ther Adv Psychopharmacol., 2016, 6(3):193-213]. Equally encouraging are the findings from a recent pilot study on adjunctive psilocybin therapy for tobacco use disorder, which showed an 80% smoking cessation rate at 6 months and a 67% smoking cessation rate at 12 months [Johnson et al., J Drug Alcohol Abuse 2017, 43(1):55-60; Johnson et al., 2014, Psychopharmacol. 2014, 28(11):983-992], significantly higher than any reported in the tobacco smoking cessation literature. Notably, the mystical type of experience produced from psilocybin sessions was significantly correlated with positive treatment outcomes. These results are also consistent with the growing evidence from recent trials supporting the effectiveness of adjunctive psilocybin therapy for treatment-resistant depression and end-of-life anxiety [Carhart-Harris et al. Neuropsychopharmacology, 2017 42(11):2105-2113]. Research is beginning to emerge on the potential benefits of adjunctive hallucinogenic therapy for opioid use disorder (OUD), and accumulating evidence supports the need to continue investigation in this area.Evidence available from previous randomized trials suggests a promising role for the treatment of OUD: participants receiving high-dose LSD adjunct therapy for heroin addiction and high-dose ketamine adjunct therapy showed a higher rate of drug withdrawal in long-term follow-up compared to controls. More recently, a large population study in the United States involving 44,000 individuals found that hallucinogen use was associated with a 40% reduction in opioid abuse risk and a 27% reduction in opioid dependence risk, according to DSM-IV criteria, in the following year [Pisano et al., J Psychopharmacol., 2017, 31(5):606-613]. Similarly, a protective mitigating effect of hallucinogen use has been observed in the relationship between prescription opioid use and suicide risk among socially marginalized women [Argento et al., J. Psychopharmacol., 2018, 32(12):1385-1391]. Despite the expectations arising from these preliminary findings regarding the use of classic hallucinogens, the potential toxicity of hallucinogens justifies further research to determine what contribution they may make to opioid crisis responses. Meanwhile, the growing evidence regarding the safety and efficacy of psilocybin in the treatment of psychological disorders and substance use disorders will help motivate further clinical research on the use of psilocybin as a novel intervention for OUD.

[0019] Typical doses of hallucinogens also improve sleep disorders. Sleep disorders are highly prevalent in depressed patients, with over 80% reporting poor sleep quality. Sleep symptoms often fail to resolve with first-line treatment and carry a greater risk of relapse and recurrence. Interestingly, sleep problems often precede other depressive symptoms, with subjective sleep quality deteriorating before the onset of episodes in relapsing depression. Brain regions with increased functional connectivity to poor sleep scores and higher depressive symptom scores included the prefrontal cortex and limbic system, areas involved in emotion processing. Sleep disturbance in healthy participants demonstrated that sleep is indeed involved in mood, the emotion evaluation process, and the brain's responsiveness to emotional stimuli. Increased negative mood and mislabeling of neutral stimuli as negative, occurring independently of mood, were shown in one study, for example, while other studies showed amplified responsiveness in limbic system brain regions in response to both negative and positive stimuli. Two other studies evaluating brain activity on electroencephalogram (EEG) recordings during sleep have shown that hallucinogens such as LSD have a positive effect on sleep patterns. In addition, partial or complete sleep deprivation for one night has been shown to alleviate symptoms of depression, suggesting that this is due to resetting the circadian rhythm through alteration of clock gene expression. A single dose of hallucinogens is further suggested to cause a reset of the biological clock underlying the sleep / wake cycle, thereby enhancing cognitive-emotional processes in depressed individuals, and improving well-being and mood in healthy individuals [Kuypers, Medical Hypotheses, 2019, 125:21-24].

[0020] A systematic meta-analysis of clinical trials from 1960 to 2018 that studied the therapeutic use of hallucinogens in patients with serious or terminal illness and associated mental disorders found that hallucinogen therapy (mostly LSD) could improve cancer-related depression, anxiety, and fear of death. Between 2011 and 2016, four randomized controlled trials were published, most using psilocybin, demonstrating that adjunctive hallucinogen therapy could produce rapid, robust, and persistent improvements in cancer-related psychological and existential distress [Ross, Int. Rev. Psychiatry, 2018, 30(4):317-330]. Therefore, the use of hallucinogens in the fields of oncology and palliative care is intriguing for several reasons. Firstly, many patients facing cancer or other life-threatening illnesses experience significant existential distress related to the loss of meaning or purpose in life, which may include feelings of despair, despair, helplessness, perceived burdensomeness, and a desire for premature death. These characteristics often lie at the core of clinically significant anxiety and depression and can greatly reduce the quality of life in this patient population. Alleviating these forms of distress should be a central goal of palliative care. Therefore, several standardized psychotherapies for cancer-related existential distress have been developed in recent years, with emphasis on the formation of dignity and meaning. However, there are currently no pharmacological interventions for existential distress itself, and available pharmacological treatments for depressive symptoms in cancer patients have not demonstrated superiority over placebo. There is still a need for more effective treatments for these conditions [Rosenbaum et al., Curr. Oncol., 2019, 26(4): 225-226].

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

[0022] 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT; 3, scheme 1) is C 13 H 18 N,N-dimethyltryptamine (DMT; 2, scheme 1) is a natural compound with the chemical formula N2O, most commonly identified as the major psychoactive component in the parotid gland secretions of the Colorado River toad (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 15Tryptamine is a natural compound with the chemical formula N2, most commonly identified as the major psychoactive component of various natural plants and vines, including 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 in the central nervous system, and has approximately 300 times greater selectivity for the human 5-HT1A (3±0.2nM) receptor subtype compared to the 5-HT2A (907±170nM) receptor subtype [Halberstadt et al., Psychopharmacology, 2012, 221(4):709-718]. DMT has more than three times the binding affinity for 5-HT1A (0.075nM) compared to 5-HT2A (0.237nM). The data suggest that, in a synergistic manner with 5HT2A activation, it 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 (an active metabolite of psilocybin) is approximately five times more selective for the human 5-HT2A receptor (107 nM) than for 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 lead to the absence of vivid geometric hallucinations typically associated with other hallucinogens such as DMT. Furthermore, both 5-MeO-DMT and DMT have been suggested to be potentially 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 comparable or greater intensity than those produced by psilocybin, but their effects are shorter in duration, lasting from 10 to 60 minutes depending on the route of administration.

[0025] Therefore, 5-MeO-DMT and DMT appear to be pharmacodynamically unique compared to previously clinically studied hallucinogens, particularly psilocybin and LSD, and can provide a useful comparative standard in comparative clinical trials using modern hallucinogens, thereby allowing for a better understanding of their modes 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 compared to the 5-8 hour duration of effect produced by psilocybin, typically less than 1 hour.

[0026] 5-MeO-DMT and DMT have unique pharmacodynamic properties and drug-dynamic propriety compared to other clinically tested hallucinogens due to their short duration of action and perhaps significant 5-HT2A receptor selectivity. These features may correlate with more positive treatment outcomes in comparative clinical trials in humans, and the shorter duration of action helps reduce the time patients spend in the hospital during hallucinogen-assisted psychotherapy. To test this hypothesis and better understand the psychotherapeutic utility of 5-MeO-DMT and DMT, appropriate controls are required to ensure potency, purity, and strength during the preparation of the active pharmaceutical ingredient (API). This application reports novel analogs of both compounds, aiming to pharmacologically optimize the next generation of short-acting hallucinogenic pharmaceuticals related to 5-MeO-DMT and DMT.

Summary of the Invention

Means for Solving the Problems

[0027] This application encompasses compounds having the general structural formula (I-A) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

Chemical Formula

[0028] In some embodiments, the compounds of formula (I-A) and their pharmaceutically acceptable salts, solvates, and / or prodrugs are isotopically enriched with deuterium. In aspects of these embodiments, A, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R[[ID=十七]] 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 18 、R 19 、R 19a and R 20 one or more of are optionally deuterium-containing

[0029] In some embodiments, the present application encompasses compounds of formula (I-A) or their pharmaceutically acceptable salts, solvates, and / or prodrugs. <00...1191><00...1192>

Chemical formula

[0030] In a further embodiment, the compound of the present application is used as a pharmaceutical. Therefore, the present application also includes the compound of the present application for use as a pharmaceutical.

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

[0032] The present invention also includes a method for treating psychosis or psychotic symptoms, which involves administering one or more of the compounds of the present invention in a therapeutically effective amount to a subject requiring treatment for psychosis or psychotic symptoms.

[0033] The present invention also includes a method for treating mental illness, which involves administering one or more of the compounds of the present invention in a therapeutically effective amount to a subject in need of treatment for mental illness.

[0034] This application further provides a process for preparing the compounds of this application. The general and specific processes are described in more detail below and are also described in the examples below.

[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, while illustrating embodiments of the present application, are provided only as examples, and the scope of the claims is not limited by these embodiments, and the broadest interpretation consistent with the entire disclosure should be given. [Brief explanation of the drawing]

[0036] This application will be described in more detail hereafter with reference to the attached drawings and tables. Here,

[0037] [Figure 1]Figure 1 is a graph showing the effect of various doses of the exemplary compound IA-6 of formula IA on the hematologic response (HTR) in male mice. Mice were treated with compound IA-6 (0.3, 1, 3, 10 mg / kg) in saline via subcutaneous injection (SC), and the total number of hematologic seizures was recorded. Data are expressed as mean ± mean standard error (SEM). [Modes for carrying out the invention]

[0038] I. Definition Unless otherwise stated, the definitions and embodiments set forth in this section and other sections are intended to be applicable to all embodiments and aspects of the present application described in this disclosure to which they are applicable. This will be understood by those skilled in the art.

[0039] The terms “compounds of the application” (single or multiple) as used in this disclosure refer to the compounds of formula (IA), (I-A1), (I-A2), (I-A3), (I-A4), and also include their pharmaceutically acceptable salts, solvates, and / or prodrugs.

[0040] The terms "composition of the application" (one or more) or "composition of the application" (one or more) as used in this disclosure refer to a composition comprising one or more of the compounds of the application, such as a pharmaceutical composition.

[0041] As used in this disclosure, the terms "and / or" mean that the listed items exist or are used individually or in combination. Substantively, the terms mean that "at least one" or "one or more" of the listed items are used or exist. With respect to pharmaceutically acceptable salts and / or solvates, the terms "and / or" mean that the compounds of the Application exist as individual salts and solvates, as well as as combinations of the compounds of the Application, such as salts of solvates.

[0042] As used in this application, the singular forms "a," "an," and "the" also include multiple objects unless the context clearly indicates otherwise. For example, an embodiment including "a compound" should be understood to present a configuration having one compound, or a configuration having two or more additional compounds.

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

[0044] The terms “consisting of” and their derivatives as used in this disclosure are intended to be closed terms that identify the presence of described features, elements, components, groups, integers, and / or steps, and exclude the presence of other features, elements, components, groups, integers, and / or steps that are not described.

[0045] As used in this disclosure, the term "essentially" is intended to identify the presence of any feature, element, component, group, integer, and / or step described, as well as any fundamental and novel properties (one or more) of these features, elements, components, group, integer, and / or step.

[0046] In embodiments including an “additional” or “second” component, for example, an additional or second compound, the second component as used in this disclosure is chemically different from the other components or the first component. The “third” component is different from the other first and second components, and any further listed or “additional” components are similarly different.

[0047] As used in this disclosure, the term “suitable” (or “preferred”) means that the selection of a particular compound or conditions depends on the specific synthetic operation to be performed, what the molecule(s) to be converted is, and / or the specific use for the compound, but that the selection is well within the skill of a person skilled in the art. All process / method steps described in this disclosure shall be carried out under conditions sufficient to provide the indicated product. A person skilled in the art will understand, and doing so is within the skill of a person skilled in the art, that all reaction conditions, such as the reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio, and whether the reaction should be carried out in an anhydrous or inert atmosphere, can be varied to maximize the yield of the desired product.

[0048] As used in this disclosure, the terms “about,” “substantially,” and “approximately” mean a reasonable amount of deviation of the modified word such that the final result is not significantly changed. These terms relating to degree should be interpreted as including a deviation of at least ±5% from the modified word, unless the deviation does not negate the meaning of the word it modifies or implies a different meaning to a person skilled in the art.

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

[0050] As used in this disclosure, the term "solvate" means a compound, a salt of a compound, or a prodrug in which molecules of a suitable solvent are incorporated into the crystal lattice. The suitable solvent is physiologically acceptable at the administered dose.

[0051] As used in this disclosure, the term "prodrug" means a compound or a salt of a compound that is converted into an active drug after administration.

[0052] As used in this disclosure, the term "alkyl" means a linear or branched saturated alkyl group, whether used alone or as part of another group. The number of carbon atoms possible in the alkyl group of interest is indicated by the prefix "C n1~Cn2 It is represented by ". Therefore, for example, the term "C 1~6 Alkyl (or "C1-C6 alkyl") refers to alkyl groups having one, two, three, four, five, or c carbon atoms, including, for example, any isotopes of hexylalkyl and pentylalkyl, as well as n-, iso-, sec-, and ter-butyl, n- and iso-propyl, ethyl, and methyl. Another example is "C4 alkyl," which 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 linear or branched saturated alkylene group, that is, a saturated carbon chain with substituents on two of its ends. The number of possible carbon atoms in the alkylene group of interest is indicated by the prefix "C". n1~n2 It is represented by ". Therefore, for example, the term "C 2~6 "Alkylene" refers to an alkylene group having 2, 3, 4, 5, or 6 carbon atoms.

[0054] As used in this disclosure, the term "alkynyl" means a linear or branched unsaturated alkynyl group containing at least one triple bond, whether used alone or as part of another group. The number of carbon atoms possible in the alkyl group of interest is determined by the prefix "C". n1~n2 It is represented by ". For example, term C 2~6Alkynyl refers to an alkynyl group having two, three, four, five, or six carbon atoms.

[0055] As used in this disclosure, the term "cycloalkyl" means a saturated carbocyclic group containing 3 to 20 carbon atoms and one or more rings, whether used alone or as part of another group. The number of carbon atoms possible in the cycloalkyl group of interest is determined by the prefix "C n1~n2 It is represented by ". For example, term C3~ 10 A cycloalkyl group refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0056] As used in this disclosure, the term "aryl," whether used alone or as part of another group, refers to a carbocyclic group containing at least one aromatic ring and comprising 6 to 20 carbon atoms.

[0057] In the terms "available hydrogen atom" or "available atom," the term "available" refers to an atom that would be known to those skilled in the art to be replaceable by a substituent / substituent.

[0058] As used in this disclosure, the term "heterocycloalkyl" refers to a cyclic group comprising at least one non-aromatic ring containing 3 to 20 atoms, where one or more of the atoms are heteromolets selected from O, S, S(O), SO2, and N, and the remaining atoms are C. The heterocycloalkyl group may be saturated or unsaturated (i.e., containing one or more double bonds). The prefix C is used for heterocycloalkyl groups. n1~n2Or, when it includes "n1~n2", this prefix represents the number of carbon atoms in the corresponding carbocyclic group, where one or more of the ring atoms, preferably 1 to 5, are replaced by heteromoto selected from O, S, S(O), SO2, and N, and the remaining atoms are C. The heterocycloalkyl group is optionally benzo-fused.

[0059] As used in this disclosure, the term "heteroaryl" refers to a cyclic group comprising at least one heteroaromatic ring containing 5 to 20 atoms, where one or more of the atoms are heteroatoms selected from O, S, and N, and the remaining atoms are C. n1~n2 When this prefix is ​​included, it 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 the heteroatoms defined above. The heteroaryl group is optionally benzo-fused.

[0060] All cyclic groups, including aryl groups, heteroaryl groups, heterocycloalkyl groups, and cycloalkyl groups, contain one or more rings (i.e., polycyclic). If a cyclic group contains multiple rings, those rings may be fused, bridged, spirofused, or linked by bonds.

[0061] As used in this disclosure, the term "benzo-fused ring" refers to a polycyclic group in which a benzene ring is fused with another ring.

[0062] The first ring is said to be "fused" with the second ring to mean that the first and second rings share two adjacent atoms between them.

[0063] The statement that the first ring "bridges" the second ring means that the first and second rings share two non-adjacent atoms between them.

[0064] The first ring is said to be "spirofused" with the second ring, meaning that the first and second rings share one atom with each other.

[0065] The term "halogen" (or "halo") refers to a halogen atom, whether used alone or as part of another group, and includes fluoro, chloro, bromo, and iodine atoms.

[0066] As used in this disclosure, the term "haloalkyl" refers to an alkyl group as defined above, wherein one or more of the available hydrogen atoms are replaced by a halogen. Therefore, for example, "C 1~6 A "haloalkyl" (or "C1-C6 haloalkyl") refers to a linear or branched alkyl group of C1-C6 as defined above, having one or more halogen substituents.

[0067] As used in this disclosure, the term "haloalkenyl" refers to an alkenyl group as defined above, in which one or more of the available hydrogen atoms are replaced by a halogen. Therefore, for example, "C 1~6 A "haloalkenyl" (or "C1-C6 haloalkenyl") refers to a linear or branched alkenyl group of C1-C6 as defined above, having one or more halogen substituents.

[0068] As used in this disclosure, the term "haloalkynyl" refers to an alkynyl group as defined above, in which one or more of the available hydrogen atoms are replaced by halogens. Therefore, for example, "C 1~6 A "haloalkynyl" (or "C1-C6 haloalkynyl") refers to a linear or branched alkynyl group of C1-C6 as defined above, having one or more halogen substituents.

[0069] As used in this disclosure, the term "alkoxy" includes alkyl groups linked to an oxygen-linked atom, either alone or in combination.

[0070] As used in this disclosure, the term “one or more” includes a single item selected from the list, as well as a mixture of two or more items selected from the list.

[0071] As used in this disclosure, the term "substituted" refers to groups where the referenced group is halogen, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, SO2CH3, unless otherwise specified. 3、 This means that the rings are substituted with one or more substituents independently selected from SOCH3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, and 3-6 membered heterocycles containing one or two ring members selected from O, S, S(O), SO2, N, NH and NCH3.

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

[0073] In compounds of general formula (IA) and their pharmaceutically acceptable salts, solvates, and / or prodrugs, atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with specific isotopes having the same atomic number but different atomic masses or mass numbers from those predominantly found in nature. This disclosure is intended to encompass all appropriate isotopic variations of compounds of general formula (IA) and their pharmaceutically acceptable salts, solvates, and / or prodrugs. For example, different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H), and tritium (3H). Protium is the primary hydrogen isotope found in nature.

[0074] As used in this disclosure, “all available atoms are optionally replaced by alternative isotopes” means that available atoms are optionally replaced by isotopes of the atom that have the same atomic number but have an atomic mass or mass number different from the atomic mass or mass number that is primarily found in nature.

[0075] The term “compound” means the compound, and in some embodiments, any hydrate or solvate thereof, to the extent that they are stable. A hydrate is a compound compound combined with water, and a solvate is a compound compound combined with a solvent, which may be an organic solvent or an inorganic solvent. A “stable” compound is one that can be prepared and isolated and whose structure and properties remain essentially unchanged, or can be made essentially unchanged, for a period of time sufficient to enable the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject). The compounds of this application are limited to stable compounds encompassed by general formula (IA), or their pharmaceutically acceptable salts, solvates, and / or prodrugs.

[0076] The term "medically acceptable" means suitable for treating the subject.

[0077] The term "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant, or other material that is mixed with an active ingredient to enable the formation of a pharmaceutical composition, i.e., a drug form that can be administered to a subject.

[0078] The term "medically acceptable salt" means an acid addition salt or base addition salt that is suitable or appropriate for treating the subject.

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

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

[0081] As used in this disclosure, the terms “protecting group” or “PG” refer to a chemical part that protects or masks the reactive part of a molecule to prevent side reactions in those reactive parts of the molecule while different parts of the molecule are being manipulated or reacted. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not destroy or decompose the rest of the molecule. The selection of an appropriate protecting group can be made by those skilled in the art. Many conventional protecting groups are known in the art, for example, “Protective Groups in Organic Chemistry” McOmie, JFW Ed., Plenum Press, 1973, in Greene, TW and Wuts, PGM, “Protective Groups in Organic Synthesis”, John Wiley & Sons, 3 rd This is mentioned in the 1999 edition 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. Therefore, the method of this application is applicable to both therapeutic and veterinary uses in humans.

[0083] As used in this disclosure, the terms “to treat” or “treatment” mean a method for obtaining beneficial or desired outcomes, such as clinical outcomes, as is well known in the art. Beneficial or desired clinical outcomes include, but are not limited to, reduction or improvement of one or more symptoms or conditions, a decrease in the severity of the disease, a stabilized (i.e., non-worsening) state of the disease, prevention of disease spread, delay or slowing of disease progression, improvement or mitigation of the disease state, reduction of disease recurrence, and remission (whether partial or complete), and may be detectable or undetectable. “To treat” and “treatment” may also mean an extended survival time compared to the expected survival time without treatment. In this disclosure, “to treat” and “treatment” also include preventive measures. For example, a subject with early-stage cancer may be treated to prevent progression, or a subject in remission may be treated with the compound or composition of the application to prevent recurrence. The treatment method comprises administering one or more of the compounds of this application in a therapeutically effective amount, which may optionally consist of a single dose or a series of multiple doses.

[0084] As used in this disclosure, the terms “effective dose” or “therapeutic effective dose” mean the amount of one or more compounds of the Application that is effective in the dosage and duration required to achieve the 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, the effective dose is, for example, the amount that increases the activation compared to the activation without administration of the one or more compounds.

[0085] To “palliate” a disease, disability, or condition means that the severity and / or undesirable clinical findings of the disease, disability, or condition are reduced and / or the time course of progression is slowed or prolonged compared to when the disability is left untreated.

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

[0087] As used in this disclosure, the terms “prevention” or “prevention,” or their synonyms, mean a reduction in the risk or probability that a patient will suffer from a disease, disability, or condition, or that will exhibit symptoms associated with a disease, disability, or condition.

[0088] In this disclosure, “disease, disorder, or condition” means serotonin receptors, e.g., 5-HT 2A , refers to a disease, disorder, or condition that is treated or treatable by activation of, in particular, with a serotonin receptor agonist such as one or more of the compounds described herein.

[0089] As used in this disclosure, “treating a disease, disorder, or condition by activation of serotonin receptors” means that the disease, disorder, or condition being treated is influenced, modulated, and / or has some biological basis involving serotonergic activity, particularly an increase in serotonergic activity, whether directly or indirectly. These diseases respond well when the serotonergic activity associated with the disease, disorder, or condition is stimulated (agonized) by one or more of the compounds or compositions of the Application.

[0090] As used in this disclosure, the term "activation" encompasses serotonin receptor agonism, partial agonism, and positive allosteric regulation.

[0091] The term "5-HT" is used in this disclosure. 1A " and "5-HT 2A " refers to the 5-HT2 serotonin receptor, specifically the 5-HT2 serotonin receptor. 2A Receptor subtype and 5-HT 2A This refers to receptor subtypes.

[0092] As used in this disclosure, the term "therapeutic agent" refers to any drug or activator that has a pharmacological effect when administered to a subject.

[0093] II. Compounds This application includes compounds of general formula (IA), or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] During the ceremony R 1 These are hydrogen, deuterium, C1-C3 alkyl, and C 1~6 Alkilen P(O)(OR) 6 )2, C 1~6 Alkilen OP(O)(OR 6 )2, C(O)R 6 CO2R 6 , C(O)N(R 6 )2, S(O)R 6 and SO2R 6 Selected from; R 2 , R 7 , R 8 , R 9 and R 10 This is independently selected from hydrogen, deuterium, halogens, and C1-C6 alkyl groups; R 3 These are hydrogen, deuterium, CN, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, CO2R 18 , C(O)N(R 18 )2, C2-C6 alkenyls, C2-C6 alkynyls, C2-C6 haloalkynyls, C3-C7 cycloalkyls, as well as O, S, S(O), SO2, N and NR 18 Independently selected from a 3- to 7-membered heterocycle containing one or two heteromolets selected from, where the C1-C6 alkyl group, C1-C6 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, C3-C7 cycloalkyl group and 3- to 7-membered heterocyclic group are CN, OR 18 , N(R 18)2 and SR 18 They are optionally substituted by one or more substituents independently selected from, where the C3-C7 cycloalkyl and 3-7 membered heterocycles are, respectively, halogens, CO2R 18 , C(O)N(R 18 )2, SO2R 18 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, as well as O, S, S(O), SO2, N, and NR 18 Optionally further substituted by substituents selected from a 3- to 6-membered heterocycle containing one or two ring heteromolets selected from; R 4 and R 5 These are hydrogen, deuterium, halogens, CN, OR 18 , N(R 18 )2, SR 18 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, CO2R 18 , C(O)N(R 18 )2, S(O)R 18 SO2R 18 , C2-C6 alkenyls, C2-C6 alkynyls, C2-C6 haloalkynyls, C3-C7 cycloalkyls, as well as O, S, S(O), SO2, N and NR 18 Independently selected from a 3- to 7-membered heterocycle containing one or two heteromolets selected from, where the C1-C6 alkyl group, C1-C6 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, C3-C7 cycloalkyl group and 3- to 7-membered heterocyclic group are CN, OR 18 , N(R 18 )2 and SR 18 They are optionally substituted by one or more substituents independently selected from, where the C3-C7 cycloalkyl and 3-7 membered heterocycles are, respectively, halogens, CO2R 18 , C(O)N(R 18 )2, SO2R18 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, as well as O, S, S(O), SO2, N, and NR 18 Optionally further substituted by substituents selected from a 3- to 6-membered heterocycle containing one or two ring heteromolets selected from; A is hydrogen, deuterium, halogen, OR 19 , N(R 19 )(R 19a ), SR 19 , S(O)R 19 and S(O2)R 19 Selected from; each R 18 These include hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl, as well as O, S, S(O), SO2, N, and NR. 20 Independently selected from a 3-7 membered heterocycle containing one or two ring heteromolets selected from, where the C1-C6 alkyl group, C1-C6 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, C3-C7 cycloalkyl group and 3-7 membered heterocyclic group are CN, OR 20 , N(R 20 )2 and SR 20 They are optionally substituted by one or more substituents independently selected from, where the C3-C7 cycloalkyl and 3-7 membered heterocycles are, respectively, halogens, CO2R 20 , C(O)N(R 20 )2, SO2R 20 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, as well as O, S, S(O), SO2, N and NR 20Optionally further substituted by substituents selected from a 3-6 member heterocycle containing one or two ring heteromolets selected from; R 6 These are independently selected from hydrogen, deuterium, and C1-C6 alkyl groups; R 11 and R 12 These are independently selected from hydrogen, deuterium, and C1-C6 alkyl groups; R 19 , R 19a and each R 20 This is independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and, Here, all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0094] This application encompasses compounds of formula (I) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [ka] During the ceremony, R 1 These are hydrogen, deuterium, C1-C3 alkyl, CH2P(O)(OR 6 )2;C(O)R 6 CO2R 6 , C(O)N(R 6 )2, S(O)R 6 and SO2R 6 Selected from; Q is, [ka] And; R 2 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 This is independently selected from hydrogen, deuterium, halogens, and C1-C6 alkyl groups; R 3 , R 4 and R 5 These are hydrogen, deuterium, halogens, CN, OR 18 , N(R 18 )2, SR 18 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, CO2R 18 , C(O)N(R 18 )2, S(O)R 18 SO2R 18 , C2-C6 alkenyls, C2-C6 alkynyls, C2-C6 haloalkynyls, C3-C7 cycloalkyls, as well as O, S, S(O), SO2, N and NR 18 Independently selected from a 3- to 7-membered heterocycle containing one or two heteromolets selected from, where the C1-C6 alkyl group, C1-C6 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, C3-C7 cycloalkyl group and 3- to 7-membered heterocyclic group are CN, OR 18 , N(R 18 )2 and SR 18 They are optionally substituted by one or more substituents independently selected from, where the C3-C7 cycloalkyl and 3-7 membered heterocycles are, respectively, halogens, CO2R 18 , C(O)N(R 18 )2, SO2R 18 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, as well as O, S, S(O), SO2, N, and NR 18Optionally further substituted by substituents selected from a 3- to 6-membered heterocycle containing one or two ring heteromolets selected from; A is hydrogen, deuterium, halogen, OR 19 , NR 19 , SR 19 , S(O)R 19 and S(O2)R 19 Selected from; Each R 18 These include hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl, as well as O, S, S(O), SO2, N, and NR. 20 Independently selected from a 3-7 membered heterocycle containing one or two ring heteromolets selected from, where the C1-C6 alkyl group, C1-C6 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, C3-C7 cycloalkyl group and 3-7 membered heterocyclic group are CN, OR 20 , N(R 20 )2 and SR 20 They are optionally substituted by one or more substituents independently selected from, where the C3-C7 cycloalkyl and 3-7 membered heterocycles are, respectively, halogens, CO2R 20 , C(O)N(R 20 )2, SO2R 20 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, as well as O, S, S(O), SO2, N and NR 20 Optionally further substituted by substituents selected from a 3-6 member heterocycle containing one or two ring heteromolets selected from; R 19 and R 20These are independently selected from hydrogen, deuterium, halogens, substituted or unsubstituted C1-C6 alkyls, substituted or unsubstituted C2-C6 alkenyls, substituted or unsubstituted C2-C6 alkynyls, substituted or unsubstituted C1-C6 haloalkyls, substituted or unsubstituted C3-C7 cycloalkyls, substituted or unsubstituted C3-C7 heterocycloalkyls, substituted or unsubstituted aryls, and substituted or unsubstituted heteroaryls; and, Here, all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0095] In some embodiments, if all available hydrogen atoms in the base are optionally replaced by halogen atoms, the halogen atoms are F, Cl, or Br. In some embodiments, if all available hydrogen atoms in the base are optionally replaced by halogen atoms, the halogen atoms are F or Br. In some embodiments, if all available hydrogen atoms are replaced by halogen atoms, the halogen atoms are F or Cl. In some embodiments, if all available hydrogen atoms in the base are optionally replaced by halogen atoms, the halogen atoms are F.

[0096] Therefore, in some embodiments, all available hydrogen atoms are optionally replaced independently by fluorine atoms, chlorine atoms, 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 atoms 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 by fluorine atoms 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 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 atoms 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 with their alternative isotopes. In some embodiments, the alternative isotope of hydrogen is deuterium. Thus, in some embodiments, the compounds of the present application are isotopically enriched with deuterium. 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 these contain one or more deuterium, or 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 these are deuterium.

[0099] In some embodiments, R 1 S(O)R 6 and SO2R 6 Selected from, where all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0100] In some embodiments, R 1 This is hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkylene P(O)(OR 6 )2, C1~C3 Alkilen OP(O)(OR 6 )2, C(O)R 6 CO2R 6 and C(O)N(R 6 ) Selected from 2, where 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, R 1 These are hydrogen, deuterium, C1-C3 alkyl, CH2P(O)(OR 6 )2, CH2CH2P(O)(OR 6 )2, CH2CH(CH3)P(O)(OR 6 )2, CH(CH3)CH2P(O)(OR 6 )2, CH(CH3)P(O)(OR 6 )2, CH(CH2CH3)P(O)(OR6 )2, (CH2)OP(O)(OR 6 )2, C(O)R 6 and CO2R 6 Selected from, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, R 1 is hydrogen, deuterium, CH3, CH2CH3, CH2P(O)(OR 6 )2, CH(CH3)P(O)(OR 6 )2, and (CH2)OP(O)(OR 6 ) Selected from 2, where 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, R 1 is hydrogen, deuterium, CH3, CH2CH3, CH2P(O)(OR 6 )2, CH(CH3)P(O)(OR 6 )2 and (CH2)OP(O)(OR 6 ) Selected from 2, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, R 1 is hydrogen, deuterium, CH3, CH2CH3, CH2P(O)(OR 6 )2 and (CH2)OP(O)(OR 6 ) Selected from 2. In some embodiments, R 1 is hydrogen, CH3, CH2CH3, CH2P(O)(OR 6 )2, (CH2)OP(O)(OR 6 )2, C(O)R 6 and CO2R 6Selected from, where 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, R 1 R is selected from hydrogen, deuterium, CH3, and CH2CH3, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, R 1 R is selected from hydrogen and deuterium. In some embodiments, R 1 It is hydrogen.

[0101] In some embodiments, R 2 , R 7 , R 8 , R 9 and R 10 These are hydrogen, deuterium, C1-C4 alkyl and C 1~4 Independently selected from fluoroalkyls, where 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, R 2 , R 7 , R 8 , R 9 and R 10 These are hydrogen, deuterium, F, Br, Cl, CH3, CD2H, CDH2, and CD 3、 Independently selected from CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 2 , R 7 , R 8 , R 9 and R 10 R is independently selected from hydrogen, deuterium, F, Br, CH3, CD2H, CDH2, and CD3. In some embodiments, R 2 , R 7 , R 8 , R 9 and R10 This is independently selected from hydrogen, deuterium, CH3, and CD3.

[0102] In some embodiments, R 2 R is selected from hydrogen, deuterium, CH3, and CD3. In some embodiments, R 2 It is selected from hydrogen and deuterium.

[0103] In some embodiments, R 6 These are hydrogen, deuterium, C1-C4 alkyl and C 1~4 Selected from fluoroalkyls, where 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, R 6 R is selected from hydrogen, deuterium, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 6 R is selected from hydrogen, deuterium, CH3, CF3, CHF2, CD2H, CDH2, and CD3. In some embodiments, R 6 This is selected from CH3 and CD3.

[0104] In some embodiments, R 7 , R 8 , R 9 and R 10 At least one of them is deuterium, or R 7 , R 8 , R 9 and R 10 At least one of them contains deuterium. In some embodiments, R 7 , R 8 , R 9 and R 10 These are hydrogen, deuterium, F, Br, CH3, CF3, CHF2, CD2H, CDH2, and CD 3、 Independently selected from CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R7 , R 8 , R 9 and R 10 R is independently selected from hydrogen, deuterium, F, Br, CH3, CD2H, CDH2, and CD3. In some embodiments, R 7 , R 8 , R 9 and R 10 R is independently selected from hydrogen, deuterium, F, Br, CH3, and CD3. In some embodiments, R 7 , R 8 , R 9 and R 10 is 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 these are deuterium. In some embodiments, R 7 , R 8 , R 9 and R 10 all are hydrogen. In some embodiments, R 7 , R 8 , R 9 and R 10 All of them are deuterium. In some embodiments, R 7 and R 8 Both are deuterium, and also R 9 and R 10 Both are hydrogen.

[0105] In some embodiments, R 11 and R 12 R is independently selected from hydrogen, deuterium, and C1-C4 alkyl, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, R 11 and R 12R is independently selected from hydrogen, deuterium, CH3, CH2CH3, CH(CH3)2, and C(CH3)3, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, R 11 and R 12 These are hydrogen, deuterium, CH3, CD2H, CDH2, and CD 3、 Independently selected from CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 11 and R 12 R is independently selected from hydrogen, deuterium, CH3, and CD3. In some embodiments, R 11 and R 12 Both are either CD3 or CH3.

[0106] In some embodiments, R 7 , R 8 , R 9 , R 10 , R 11 and R 12 At least one of them is deuterium, or R 7 , R 8 , R 9 , R 10 , R 11 and R 12 At least one of them contains deuterium. In some embodiments, R 7 , R 8 , R 9 and R 10 These are hydrogen, deuterium, F, Br, CH3, CF3, CHF2, CD2H, CDH2, and CD 3、 Independently selected from CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3, and also R 11 and R 12 These are hydrogen, deuterium, CH3, CD2H, CDH2, and CD 3、 Selected from CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 7 , R 8 , R 9 and R10 It is all hydrogen, and also R 11 and R 12 R is selected from deuterium and CD3. In some embodiments, R 7 , R 8 , R 9 and R 10 All of them are deuterium, and also R 11 and R 12 R is selected from hydrogen and CH3. In some embodiments, R 7 , R 8 , R 9 and R 10 All of them are deuterium, and also R 11 and R 12 R is selected from deuterium and CD3. In some embodiments, R 7 and R 8 It is deuterium, and also R 9 and R 10 is hydrogen, and R 11 and R 12 The element is selected from hydrogen, deuterium, CH3, and CD3.

[0107] In some embodiments, R 3 These are hydrogen, deuterium, CN, C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 18 , C(O)N(R 18 )2, C2-C6 alkenyls, C2-C6 alkynyls, C2-C6 haloalkynyls, C3-C7 cycloalkyls, as well as O, S, S(O), SO2, N and NR 18 Selected from a 3-7 membered heterocycle containing one or two ring heteromolets selected from, where the C1-C4 alkyl group, C1-C4 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, C3-C7 cycloalkyl group and 3-7 membered heterocyclic group are CN, OR 18 , N(R 18 )2 and SR 18They are optionally substituted by one or more substituents independently selected from, where the C3-C7 cycloalkyl and 3-7 membered heterocycles are, respectively, halogens, CO2R 18 , C(O)N(R 18 )2, SO2R 18 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, as well as O, S, S(O), SO2, N and NR 18 The ring is optionally further substituted by substituents selected from a 3-6 membered heterocycle containing one or two ring heteromolets selected from; where all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0108] In some embodiments, R 3 These are hydrogen, deuterium, CN, C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 18 , C(O)N(R 18 )2, selected from C2-C6 alkenyl, C2-C6 alkynyl and C2-C6 haloalkynyl, where the C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group and C2-C6 haloalkynyl group are CN, OR 18 , N(R 18 )2 and SR 18 R is optionally substituted by one or more substituents independently selected from, where all available hydrogen atoms are optionally replaced by fluorine, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, R 3 These are hydrogen, deuterium, CN, C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R18 , C(O)N(R 18 )2, selected from C2-C6 alkenyl, C2-C6 alkynyl and C2-C6 haloalkynyl, where the C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group and C2-C6 haloalkynyl group are CN, OR 18 , N(R 18 )2 and SR 18 R is optionally substituted by one to three substituents independently selected from, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, R 3 These are hydrogen, deuterium, CN, and SR. 18 CH3, CH2CH3, CH(CH3)2, C(CH3)3, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 18 , C(O)N(R 18 )2, selected from C2-C6 alkenyl and C2-C6 alkynyl groups, where the C1-C4 alkyl group, C1-C4 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group and C2-C6 alkynyl group are CN, OR 18 , N(R 18 )2 and SR 18 R is optionally substituted by one or two substituents independently selected from, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, R 3 These are hydrogen, deuterium, CN, CH3, CH2CH3, CH(CH3)2, C(CH3)3, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 18, and selected from C2-C6 alkenyls, where all available hydrogen atoms are optionally replaced by fluorine atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, R 3 R is selected from hydrogen and deuterium. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 It is deuterium.

[0109] In some embodiments, R 4 and R 5 These are hydrogen, deuterium, halogens, CN, OR 18 , N(R 18 )2, SR 18 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 18 , C(O)N(R 18 )2, S(O)R 18 SO2R 18 , C2-C6 alkenyls, C2-C6 alkynyls, C2-C6 haloalkynyls, C3-C7 cycloalkyls, as well as O, S, S(O), SO2, N and NR 18 Independently selected from a 3-7 membered heterocycle containing one or two ring heteromolets selected from, where the C1-C4 alkyl group, C1-C4 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, C3-C7 cycloalkyl group and 3-7 membered heterocyclic group are CN, OR 18 , N(R 18 )2 and SR 18 They are optionally substituted by one or more substituents independently selected from, where the C3-C7 cycloalkyl and 3-7 membered heterocycles are, respectively, halogens, CO2R 18 , C(O)N(R 18 )2, SO2R 18, C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, as well as O, S, S(O), SO2, N and NR 18 The ring is optionally further substituted by substituents selected from a 3-6 membered heterocycle containing one or two ring heteromolets selected from; where all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0110] In some embodiments, R 4 and R 5 These are hydrogen, deuterium, halogens, CN, OR 18 , N(R 18 )2, SR 18 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 18 , C(O)N(R 18 )2, S(O)R 18 SO2R 18 Independently selected from C2-C6 alkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl groups, where the C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl groups are CN, OR 18 , N(R 18 )2 and SR 18 R is optionally substituted by one or more substituents independently selected from, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, R 4 and R 5 These are hydrogen, deuterium, F, Cl, Br, CN, OR 18 , N(R 18 )2, SR 18, C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 18 , C(O)N(R 18 )2, S(O)R 118 SO2R 18 Independently selected from C2-C6 alkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl groups, where the C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl groups are CN, OR 18 , N(R 18 )2 and SR 18 R is optionally substituted by one to three substituents independently selected from, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, R 4 and R 5 These are hydrogen, deuterium, F, Cl, Br, CN, OR 18 , N(R 18 )2, SR 18 CH3, CH2CH3, CH(CH3)2, C(CH3)3, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 18 , S(O)R 18 SO2R 18 , C(O)N(R 18 )2, independently selected from C2-C6 alkenyl and C2-C6 alkynyl groups, where the C1-C4 alkyl group, C1-C4 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group and C2-C6 alkynyl group are CN, OR 18 , N(R 18 )2 and SR 18 R is optionally substituted by one or two substituents independently selected from, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, R4 and R 5 These are hydrogen, deuterium, F, Cl, Br, CN, OR 18 , N(R 18 )2, SR 18 CH3, CH2CH3, CH(CH3)2, C(CH3)3, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 18 , S(O)R 18 SO2R 18 and are independently selected from C2-C6 alkenyls, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, R 4 and R 5 R is independently selected from hydrogen, deuterium, F, Cl, and Br, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, R 4 and R 5 R is independently selected from hydrogen, deuterium, F, Cl, and Br. In some embodiments, R 4 and R 5 R is independently selected from hydrogen and deuterium. In some embodiments, R 4 and R 5 Both are hydrogen. In some embodiments, R 4 and R 5 Both are deuterium.

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

[0112] In some embodiments, R 3 , R 4 and R 5 The C3-C7 cycloalkyl groups in the above are independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, where all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0113] In some embodiments, R 3 , R 4 and R 5 The 3- to 7-membered heterorings within are independently substituted or unsubstituted heterorings. In some embodiments, R 3 , R 4 and R 5 The 3- to 7-membered heterocycles within are independently 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, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0114] In some embodiments, R 3 , R 4 and R 5 The 3- to 7-membered heterorings within are independently substituted or unsubstituted heterorings. In some embodiments, R 3 , R 4 and R 5The 3- to 7-membered heterocycles within are independently 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, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0115] In some embodiments, R 3 , R 4 and R 5 The aforementioned 3-7 member heterocycles include azilidinyl, oxylanil, thyranil, oxaxiridinyl, dioxylanil, azetidinyl, oxetanil, thietanyl, diazetidinyl, dioxetanil, dithietanyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxythiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil, dithiolanil, triazoli Independently selected from 1, 2, 3, 3, 4, 3

[0116] Several embodiments, each R 18These include hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl, as well as O, S, S(O), SO2, N, and NR. 20 Independently selected from a 3-7 membered heterocycle containing one or two ring heteromolets selected from, where the C1-C4 alkyl group, C1-C4 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, C3-C7 cycloalkyl group and 3-7 membered heterocyclic group are CN, OR 20 , N(R 20 )2 and SR 20 They are optionally substituted with one to three substituents independently selected from, where the C3-C7 cycloalkyl and 3-7 membered heterocycles are halogens, CO2R 20 , C(O)N(R 20 )2, SO2R 20 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, as well as O, S, S(O), SO2, N and NR 20 It is optionally further substituted by substituents selected from a 3- to 6-membered heterocycle containing one or two ring heteromolets selected from the above.

[0117] Several embodiments, each R 18 This is independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl, where the C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl are CN, OR 20 , N(R 20 )2 and SR 20They are optionally substituted by one to three substituents independently selected from R. In some embodiments, each R 18 This is independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, and C2-C6 alkynyl, where the C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, and C2-C6 alkynyl are CN, OR 20 , N(R 20 )2 and SR 20 R is optionally substituted by one to three substituents independently selected from, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, each R 18 This is independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, and C2-C6 alkynyl, where the C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, and C2-C6 alkynyl are CN, OR 20 and N(R 20 ) is optionally substituted by one or two substituents independently selected from 2, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, each R 18 This is independently selected from hydrogen, deuterium, F, Cl, CH3, CH2CH3, CH(CH3)2, C(CH3)3, C1-C4 haloalkyl, C2-C4 alkenyl, and C2-C4 haloalkenyl, where CH3, CH2CH3, CH(CH3)2, C(CH3)3, C1-C4 haloalkyl, C2-C6 alkenyl, and C2-C6 haloalkenyl are CN, OR 20 and N(R 20) are optionally substituted by one to three substituents independently selected from ), where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, each R 18 R is independently selected from hydrogen, deuterium, F, Cl, CH3, CH2CH3, CH(CH3)2, C(CH3)3, C1-C4 haloalkyl, C2-C4 alkenyl and C2-C4 haloalkenyl, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, each R 18 R is independently selected from hydrogen, deuterium, F, Cl, CH3, CH2CH3, CH(CH3)2, C(CH3)3 and C1-C4 haloalkyl, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, each R 18 These are hydrogen, deuterium, F, Cl, CH3, CH2CH3, CH(CH3)2, C(CH3)3CF3, CHF2, CD2H, CDH2, and CD 3、 CH2CH3 and CD2CD3 are selected independently. In some embodiments, each R 18 These are hydrogen, deuterium, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3, CHF2, CD2H, CDH2, and CD 3、 It is selected independently from CH2CH3 and CD2CD3.

[0118] In one embodiment, each R 18 These include C3-C7 cycloalkyl groups, as well as O, S, S(O), SO2, N, and NR. 20 Independently selected from a 3-7 membered heterocycle containing one or two ring heteromolets selected from, where the C3-C7 cycloalkyl group and the 3-7 membered heterocyclic group are CN, OR, respectively.20 , N(R 20 )2 and SR 20 It is optionally substituted by one to three substituents independently selected from, and halogens, CO2R 20 , C(O)N(R 20 )2, SO2R 20 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, as well as O, S, S(O), SO2, N and NR 20 It is optionally further substituted by substituents selected from a 3- to 6-membered heterocycle containing one or two ring heteromolets selected from the above.

[0119] In one embodiment, each R 18 These include C3-C7 cycloalkyl groups, as well as O, S, N, and NR. 20 Independently selected from a 3-7 membered heterocycle containing one or two ring heteromolets selected from, where the C3-C7 cycloalkyl group and the 3-7 membered heterocyclic group are CN, OR, respectively. 20 , N(R 20 )2 and SR 20 It is optionally substituted by one to three substituents independently selected from, and halogens, CO2R 20 , C(O)N(R 20 )2, SO2R 20 The R is optionally further substituted with substituents selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl. In one embodiment, each R 18 These include C3-C7 cycloalkyl groups, as well as O, S, N, and NR. 20 Independently selected from a 3-7 membered heterocycle containing one or two ring heteromolets selected from, where the C3-C7 cycloalkyl group and the 3-7 membered heterocyclic group are, respectively, OR 20 , N(R 20 )2 and SR 20They are optionally substituted with one or two substituents independently selected from, and optionally further substituted with substituents selected from halogens, C1-C4 alkyls, and C1-C4 haloalkyls.

[0120] In one embodiment, each R 18 These include C3-C7 cycloalkyl groups, as well as O, S, N, and NR. 20 Independently selected from a 3-7 membered heterocycle containing one or two ring heteromolets selected from, where the C3-C7 cycloalkyl group and the 3-7 membered heterocyclic group are CN, OR, respectively. 20 , N(R 20 )2 and SR 20 They are optionally substituted with one to three substituents independently selected from C3-C6 cycloalkyl groups as well as O, S, S(O), SO2, N, and NR. 20 The rings are optionally further substituted by substituents selected from a 3-6 member heterocycle containing one- or two ring heteromolets selected from the above. In some embodiments, each R 18 These are C3-C7 cycloalkyls and O, S, N and NR 20 Independently selected from a 3-7 membered heterocycle containing one or two ring heteromolets selected from, where the C3-C7 cycloalkyl group and the 3-7 membered heterocyclic group are, respectively, OR 20 , N(R 20 )2 and SR 20 They are optionally substituted with one to three substituents independently selected from, and are C3-C6 cycloalkyl and O, S, N and NR. 20 It is optionally further substituted by substituents selected from a 3- to 6-membered heterocycle containing one or two ring heteromolets selected from the above.

[0121] In some embodiments, R 18Each C3-C7 cycloalkyl or C3-C6 cycloalkyl in the compound is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, where all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0122] In some embodiments, R 18 The heterocycles, each consisting of 3 to 7 members, are azilidinyl, oxylanil, thyranil, oxaxiridinyl, dioxylanil, azetidinyl, oxetanil, thietanyl, diazetidinyl, dioxetanil, dithietanyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxythiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil, dithiolanil, triazoli Independently selected from 1, 2, 3, 3, 4, 3

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

[0124] In some embodiments, R 18 Each of the 3-6 member heterocycles inside is: azilidinyl, oxyranil, thyranil, oxaxiridinyl, dioxyranil, azetidinyl, oxetanil, thietanyl, diazetidinyl, dioxetanil, dithietanyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxythiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil Independently selected from dithiolanyl, triazolyl, flazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, dioxanyl, and dithianyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0125] In some embodiments, R 18 The 3-6 member heteroring within is independently selected from substituted or unsubstituted heterorings. In some embodiments, R 18The 3- to 7-membered heteroring in the ring is independently selected from substituted or unsubstituted bridged bicyclic heterorings. In some embodiments, the substituted or unsubstituted bridged bicyclic heteroring is independently 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 alternative isotopes.

[0126] In some embodiments, R 19 , R 19a and each R 20 This is independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0127] In some embodiments, R 19 , R 19a and each R 20This is independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0128] In some embodiments, R 19 , R 19a and each R 20 This is independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0129] In some embodiments, R 19 , R 19a and each R 20 The C3-C7 cycloalkyl groups in the above are independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, where all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0130] In some embodiments, R 19 , R 19a and each R 20The aforementioned 3-7 member heterocycles include azilidinyl, oxylanil, thyranil, oxaxiridinyl, dioxylanil, azetidinyl, oxetanil, thietanyl, diazetidinyl, dioxetanil, dithietanyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxythiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil, dithiolanil, triazoli Independently selected from 1, 2, 3, 3, 4, 3

[0131] In some embodiments, R 19 , R 19a and each R 20 The 3- to 7-membered heteroring within is independently selected from substituted or unsubstituted heterorings. In some embodiments, ring R 19 , R 19a and each R 20 The 3- to 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, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0132] In some embodiments, R19 , R 19a and each R 20 The heteroaryls in the above include azepinyl, benzoisoxazolyl, benzoflazanil, benzopyranil, benzothiopyranil, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanil, sinnolinil, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranil, dihydrobenzothiopyranylsulfone, 1,3-dioxolanil, furyl, imidazolidinyl, imidazolinil, imidazolyl, indolinyl, indolyl, isochromanil, isoindolinil, isoquinolinil, isothiazolidinil, isothiazolyl, isothiazolidinil, morpholinil, naphthilidinil, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdi Independently selected from nyl(2-oxopiperdinyl), 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridadinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothenyl, triazolyl, and thienyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0133] In some embodiments, R 19 , R 19a and each R 20R is independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyls, substituted or unsubstituted C2-C6 alkenyls, substituted or unsubstituted C2-C6 alkynyls, and substituted or unsubstituted C1-C4 haloalkyls, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, R 19 , R 19a and each R 20 R is independently selected from hydrogen, deuterium, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C4 haloalkyl, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, R 19 , R 19a and each R 20 R is independently selected from hydrogen, deuterium, C1-C4 alkyl and C2-C6 alkenyl atoms, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, R 19 , R 19a and each R 20 R is independently selected from hydrogen, deuterium, and C1-C4 alkyl, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, R 19 , R 19a and each R 20 These are hydrogen, deuterium, CH3, CF3, CHF2, CD2H, CDH2, and CD 3、 CH2CH3 and CD2CD3 are selected independently. In some embodiments, R 19 , R 19a and R 20This is independently selected from hydrogen, deuterium, CH3, CF3, CHF2, and CD3.

[0134] R 19 , R 19a and each R 20 If substituted, in some embodiments, the substituent is independently selected from one or more of the 3-6 membered heterocycles containing one or two ring heteromolets selected from Cl, F, Br, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, SO2CH3, C1-C4 alkyl, C1-C4 fluoroalkyl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, C2-C6 alkynyl, C2-C6 fluoroalkynyl, C3-C6 cycloalkyl, and O, S, S(O), SO2, N, NH, and NCH3. In some embodiments, R 19 , R 19a and each R 20 The substituents mentioned above are independently selected from one to three of the following: Cl, F, C1-C4 alkyl, C1-C4 fluoroalkyl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, C2-C6 alkynyl, and C2-C6 fluoroalkynyl. In some embodiments, R 19 , R 19a and each R 20 The substituents mentioned above are independently selected from one or two of Cl, F, Br, CH3, and CF3.

[0135] In some embodiments, A is selected from C3-C7 cycloalkyl, C4-C7 cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl atoms, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0136] In some embodiments, A is hydrogen, deuterium, C 1~6 Alkyl, OR 19 NHR 19 and SR 19Selected from, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, A is hydrogen, deuterium, C 1~6 Alkyl, or OR 19 Selected from, where all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, A is hydrogen, deuterium, and OR 19 A is selected from hydrogen, deuterium, OCH3, OCD3, OCHD2, OCDH2, OCF3, OCFH2, and OCHF2. In some embodiments, A is selected from hydrogen, deuterium, OCH3, OCD3, OCF3, and OCHF2. In some embodiments, A is selected from hydrogen, deuterium, OCH3, and OCD3.

[0137] In some embodiments, A is OC 1~6 Selected from alkyl, O-C3~C7 cycloalkyl, O-C4~C7 cycloalkenyl, O-heterocycloalkyl, O-aryl, and O-heteroaryl, where 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, A is O 1~6 Selected from alkyl, O-C3~C7 cycloalkyl, O-C4~C7 cycloalkenyl, O-heterocycloalkyl, O-aryl, and O-heteroaryl, where 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 C3-C7 cycloalkyl group in A is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0139] In some embodiments, the C4-C7 cycloalkenyl in A is selected from cyclobutenyl, cyclopentenyl, and cyclohexenyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0140] In some embodiments, the 3- to 7-membered heterocycle in A is azilidinyl, oxylanil, thyranil, oxaxiridinyl, dioxylanil, azetidinyl, oxetanil, theitanyl, diazetidinyl, dioxetanil, dithietanyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil, dithiolanyl A halogen is independently selected from 1, 2, 3, 4

[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 alternative isotopes.

[0142] In some embodiments, the heteroaryl in A is azepinyl, benzoisoxazolyl, benzoflazanil, benzopyranil, benzothiopyranil, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanil, sinnolinil, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranil, dihydrobenzothiopyranylsulfone, 1,3-dioxolanil, furyl, imidazolidinyl, imidazolinil, imidazolyl, indolinyl, indolyl, isochromanil, isoindolinil, isoquinolinil, isothiazolidinil, isothiazolyl, isothiazolidinil, morpholinil, naphthilidinil, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinil, 2 - Selected from oxopiperdinyl (2-oxopiperdinyl), 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridadinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothenyl, triazolyl, and thienyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0143] In some embodiments, A is hydrogen or OR 19 And the compound of formula (IA) is the compound of formula (I-A1) or formula (I-A2). Therefore, in some embodiments, the present application includes the compound of formula (I-A1) or formula (I-A2) or its pharmaceutically acceptable salts, solvates, and / or prodrugs: [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 This is as defined in equation (IA); and, R 19 C 1~6 It is alkyl, Here, 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 All of them are H, and A is either H or OC. 1~6 A compound of formula (IA) is alkyl, and is a compound of formula (I-A3) or formula (I-A4). Therefore, in some embodiments, the present application encompasses compounds of formula (I-A3) or formula (I-A4) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [ka] During the ceremony: R 7 , R 8 , R 9 , R 10 , R 11 and R 12 This is as defined in equation (IA); and, R 19 C 1~6 It is alkyl, Here, 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 them contains deuterium, or at least one 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 At least one of them is deuterium, or contains 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 R is independently selected from hydrogen and deuterium. In some embodiments, in compounds of formulas (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 7 , R 8 , R 9 and R 10 At least one of them is deuterium. In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 7 and R 8 , or R 9and R 10 Both are hydrogen, or both are deuterium. In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 7 and R 8 Both are deuterium, and also R 9 and R 10 Both are hydrogen. In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 7 and R 8 Both are hydrogen, and R 9 and R 10 Both are 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 all are deuterium. In some embodiments, in the compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 7 , R 8 , R 9 and R 10 It is 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 Both are deuterium, and R 11 and R 12 It contains deuterium. In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3) and (I-A4), R 11 and R 12 It contains deuterium. 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, CH3, CD2H, CDH2, CD 3、These are CH2CH3, CH2CH2D, CH2CD2H, or CD2CD3. In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3), and (I-A4), R 11 and R 12 Both are deuterium, CH3, CD2H, CDH2, CD 3、 These are CH2CH3, CH2CH2D, CH2CD2H, or CD2CD3. In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3), and (I-A4), R 11 and R 12 Both are CH3, CD2H, CDH2, CD 3、 These are CH2CH3, CH2CH2D, CH2CD2H, or CD2CD3. In some embodiments, in compounds of formula (IA), (I-A1), (I-A2), (I-A3), and (I-A4), R 11 and R 12 Both are CH3 or both are CD3. 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, CH3, CD2H, CDH2, CD 3、 Selected from CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. 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, CH3, CD2H, CDH2, CD 3、 Selected from CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. 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 CH3, CD2H, CDH2, CD 3、Selected from CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. 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 selected from CH3 and CD3.

[0147] In some embodiments, this application encompasses compounds of formula (IA) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [ka] During the ceremony R 1 This includes hydrogen, deuterium, C1-C3 alkyl, C1-C3 deuterated alkyl (deuteroalkyl), C1-C3 fluoroalkyl, and C1-C6 alkylene P(O)(OR 6 )2, C1~C6 Alkilen OP(O)(OR 6 )2, C(O)R 6 CO2R 6 , C(O)N(R 6 )2, S(O)R 6 and SO2R 6 Selected from; R 2 , R 3 , R 4 and R 5 It is independently selected from hydrogen and deuterium; R 7 , R 8 , R 9 and R 10 This is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl (deuteroalkyl), and C1-C6 fluoroalkyl; A is hydrogen, deuterium and OR 19 Selected from; R 6 These are selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl (deuteroalkyl), and C1-C6 fluoroalkyl; R 11and R 12 This is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl (deuteroalkyl), and C1-C6 fluoroalkyl; and, R 19 These are selected from C1-C6 alkyl, C1-C6 deuteroalkyl, and C1-C6 fluoroalkyl; however (3)R 2 , R 3 , R 4 and R 5 All are D, and A, R 1 , R 6 ~R 12 and R 19 Whether that is as defined above this disclaimer; or, (4) A is OR 19 And here R 19 The C1-C6 deuteroalkyl and C1-C6 fluoroalkyl groups are selected, and R 1 ~R 12 This is as defined above this disclaimer.

[0148] In some embodiments, R 1 This includes hydrogen, deuterium, C1-C3 deuterated alkyl, C1-C3 fluoroalkyl, fluorosubstituted C1-C3 alkyl, and C1-C3 alkylene P(O)(OR 6 )2, C1~C3 Alkilen OP(O)(OR 6 )2, C(O)R 6 CO2R 6 and C(O)N(R 6 ) is selected from. In some embodiments, R 1 is hydrogen, deuterium, CH3, CF3, CD3, CH2CH3, CF2CF3, CD2CD3, CH2P(O)(OR 6 )2, CH(CH3)P(O)(OR 6 )2 and (CH2)OP(O)(OR 6 ) Selected from 2.

[0149] In some embodiments, R 6 R is selected from hydrogen, deuterium, CH3, CF3, CHF2, CD2H, CDH2, and CD3. In some embodiments, R 6 This is selected from CH3 and CD3.

[0150] In some embodiments, R 1 R is selected from hydrogen, deuterium, CH3, CF3, CD3, CH2CH3, CF2CF3, and CD2CD3. In some embodiments, R 1 It is hydrogen or deuterium.

[0151] In some embodiments, R 7 , R 8 , R 9 and R 10 R is independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 deuterated alkyl (deuteroalkyl), and C1-C4 fluoroalkyl. In some embodiments, R 7 , R 8 , R 9 and R 10 These are hydrogen, deuterium, CH3, CD2H, CDH2, and CD 3、 Independently selected from CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 7 , R 8 , R 9 and R 10 These are hydrogen, deuterium, CH3, CF3, CHF2, CD2H, CDH2, and CD 3、 It is independently selected from CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3.

[0152] In some embodiments, R 7 , R 8 , R 9 and R 10 At least one of them is deuterium, or R 7 , R 8 , R 9 and R 10 At least one of them contains deuterium. In some embodiments, R 7, R 8 , R 9 and R 10 at least one or at least two of which are deuterium. In some embodiments, 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 are independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 deuteroalkyl, and C1-C4 fluoroalkyl.

[0154] In some embodiments, R 11 and R 12 are independently selected from hydrogen, deuterium, CH3, CD2H, CDH2, CD 3、 CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3.

[0155] In some embodiments, R 7 , R 8 , R 9 and R 10 are all hydrogen, and also R 11 and R<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​All of them are deuterium, and also R 11 and R 12 It is selected from deuterium and CD3.

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

[0159] In some embodiments, R 19 These are CF3, CHF2, CD2H, CDH2, CD 3、 And selected from CD2CD3. In some embodiments, R 19 These are CHF2 and CD3.

[0160] In some embodiments, A is selected from hydrogen, deuterium, OCH3, OCD3, OCF3, and OCHF2.

[0161] In some embodiments, the compound of formula (IA) is 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4; 2-(1H-indole-3-yl-2,4,5,6,7-d5)-N,N-dimethylethane-1-amine; 2-(1H-indole-3-yl-2,4,5,6,7-d5)-N,N-dimethylethane-1-amine-1,1,2,2-d4; 2-(1H-indole-3-yl-2,4,5,6,7-d5)-N,N-dimethylethane-1-amine-2,2-d2; 2-(1H-indole-3-yl-2,4,5,6,7-d5)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4; 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4; 2-(5-methoxy-1H-indole-3-yl-2,4,6,7-d4)-N,N-dimethylethane-1-amine; 2-(5-(methoxy-d3)-1H-indole-3-yl-2,4,6,7-d4)-N,N-dimethylethane-1-amine; 2-(5-methoxy-1H-indole-3-yl-2,4,6,7-d4)-N,N-bis(methyl-d3)ethane-1-amine; 2-(5-(methoxy-d3)-1H-indole-3-yl-2,4,6,7-d4)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4; 2-(5-(difluoromethoxy)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4; and 2-(5-(difluoromethoxy)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1,2,2-d4; Or selected from pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

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

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

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

[0165] An acid addition salt suitable for the treatment of the target is any non-toxic organic or inorganic acid addition salt of any basic compound. Basic compounds that produce acid addition salts include, for example, compounds containing an amine group. Exemplary inorganic acids that produce suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acidic metal salts such as sodium orthophosphate and potassium bisulfate. Exemplary organic acids that produce suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids. Examples of such organic acids include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, as well as 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 so on. In some embodiments, monoacid salts or diacid salts are formed, and such acids exist in either a hydrated, solvated, or substantially anhydrous form. Generally, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base form. The criteria for selecting a suitable salt will be known to those skilled in the art.Other pharmaceutically acceptable salts, such as oxalates, but not limited to them, may be used, for example, in the isolation of the compounds of the present invention for experimental purposes or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0166] A base addition salt suitable for the treatment of the target is any non-toxic organic or inorganic base addition salt of any acidic compound. Examples of acidic compounds that produce base addition salts include compounds containing a carboxylic acid group. Exemplary inorganic bases that produce suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide, as well as ammonia. Exemplary organic bases that produce 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, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The selection of an appropriate salt may be useful, for example, in preventing the hydrolysis of ester functional groups, if present, in other parts of the compound. The criteria for selecting an appropriate salt will be known to those skilled in the art. In some embodiments, salts with exemplary 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, and choline; and salts with amino acids such as arginine and lysine, etc.Basic nitrogen-containing groups may be quartenized using 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), and aralkyl halides (e.g., benzyl bromide and phenethyl bromide). Compounds having an acidic moiety can be mixed with a suitable pharmaceutically acceptable salt to obtain, 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 a suitable organic ligand, such as quaternary ammonium salts. Furthermore, if an acidic group (-COOH) or alcohol group is present, a pharmaceutically acceptable ester 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 pharmaceutically 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, if the compounds of this application contain both a basic moiety (e.g., aliphatic primary, secondary, tertiary, or cyclic amines, aromatic amines, or heteroarylamines, pyridines, or imidazoles) and an acidic moiety (e.g., tetrazoles or carboxylic acids), zwitterions ("intramolecular salts") may be formed, which are also 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 having both an anionic and a cationic center within the same compound and having a net neutral charge. Such zwitterions are within the scope of this application.

[0168] Examples of solvates of the compound of this application include those formed with a pharmaceutically acceptable solvent. Examples of such solvents include water (the resulting solvate is called a hydrate) and ethanol, etc. A suitable solvent is physiologically tolerable at the administered dose.

[0169] In some embodiments, the compounds of the Application may have at least one chiral center and may therefore exist as enantiomers and / or diastereomers. It should be understood that all such isomers and mixtures thereof in any proportion are included within the scope of the Application. The stereochemistry of the compounds may be as shown in a given compound enumerated in this disclosure, but it should also be understood that such compounds may contain a specific amount (e.g., less than 20%, preferably less than 10%, more preferably less than 5%) of the compounds of the Application having alternative stereochemistry. Any optical isomers as separated, pure, or partially purified optical isomers, or racemic mixtures thereof, are intended to be included within the scope of the Application.

[0170] In some embodiments, the compounds of the present application may include tautomer forms such as keto-enol tautomers. The tautomer forms may be in equilibrium or sterically locked into one form by appropriate substitution. Any tautomer forms formed by the compounds, as well as mixtures thereof, are intended to be within the scope of the present application.

[0171] The compounds of this application may further exist in various amorphous forms and polymorphic phases, and any amorphous forms, polymorphs, or mixtures thereof shall fall within the scope of this 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 included in the scope of the application. Here, the compounds of the present application also include compounds in which one or more radioactive atoms are introduced into their structure.

[0173] III. Composition The compounds of the present application are appropriately formulated into compositions using one or more carriers in a conventional manner. Accordingly, the present application also encompasses compositions comprising one or more of the compounds of the present application and carriers. The compounds of the present application are appropriately formulated into pharmaceutical compositions for administration to a subject in a biocompatible form suitable for in vivo administration. Accordingly, the present application further encompasses pharmaceutical compositions comprising one or more of the compounds of the present application and pharmaceutically acceptable carriers. In certain embodiments of the present application, the pharmaceutical composition is used to treat any of the diseases, disorders, or conditions described in the present disclosure.

[0174] The compounds of this application are administered to subjects in various forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, the compounds of this application are administered orally, by inhalation, parenterally, buccally, sublingually, by insulation, epidurally, nasally, rectally, vaginally, by patch, pump, minipump, topically, or transdermally, and the pharmaceutical compositions are formulated accordingly. In some embodiments, administration is carried out by pump for periodic or continuous delivery. Conventional procedures and raw materials for selecting and preparing 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, such as intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (e.g., by aerosol), intrathecal, rectal, and topical (including the use of patches or other transdermal delivery devices). Parenteral administration may also be by continuous infusion over a selected period.

[0176] In some embodiments, the compounds of the present application are administered orally, for example, with an inert diluent or an assimilated edible carrier, or encapsulated in a hard or soft shell gelatin capsule, or compressed into a tablet, or taken directly with food in a diet. In some embodiments, the compounds are incorporated with a pharmaceutical excipient and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions, aqueous suspensions, etc. In the case of tablets, carriers used include lactose, corn starch, sodium citrate, and phosphoric acid salts. pharmaceutically acceptable excipients include binders (e.g., pre-gelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); 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, or water). In some embodiments, tablets are coated in methods well known in the art. For tablets, capsules, caplets, pellets, or granules for oral administration, pH-sensitive enteric coatings such as Eudragits®, designed to control the release of the active ingredient, are optionally used. Oral dosage forms also include modified-release formulations, such as immediate-release and timed-release formulations.Examples of modified release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), and are used, for example, in the form of coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, aggregated particles (e.g., aggregated particles of molecular sieve-type particles), or fine hollow permeable fiber bundles, or chopped hollow permeable fiber groups that are aggregated or held in fibrous packets. Timed-release compositions are formulated, for example, as liposomes, or as formulations in which the active compound is protected by a coating that allows for differential degradation (by microencapsulation, multilayer coating, etc.). Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. In some embodiments, liposomes are formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. For oral administration in capsule form, useful carriers, solvents, or diluents include lactose, medium-chain triglycerides, ethanol, and dried corn starch.

[0177] In some embodiments, liquid preparations for oral administration may take the form of, for example, a solution, syrup, or suspension, or may be appropriately presented as a dry product to be prepared using water or other suitable solvent (vehicle) before use. When aqueous suspensions and / or emulsions are administered orally, the compounds of the present application are suitably suspended or dissolved in an oil phase combined with emulsifiers and / or suspending agents. Specific sweeteners and / or flavoring agents and / or colorants may be added as desired. Such liquid preparations for oral administration are prepared by conventional methods using pharmaceutically acceptable additives. pharmaceutically acceptable additives include, for example, suspending agents (e.g., sorbitol syrup, methylcellulose, or edible hydrogenated fat); emulsifiers (e.g., lecithin or acacia); non-aqueous solvents (vehicle) (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 glycol.

[0178] For example, it is possible to freeze-dry the compound of the present invention and use the resulting freeze-dried product for the preparation of an injection product.

[0179] In some embodiments, the compounds of the present application are administered parenterally. For example, a solution of the compounds of the present application in water, appropriately mixed with a surfactant such as hydroxypropylcellulose, is prepared. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof (with or without alcohol), and in oil. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth. Those skilled in the art know how to prepare suitable formulations. For parenteral administration, a sterile solution of the compounds of the present application is usually prepared and buffered by appropriately adjusting the pH of the solution. For intravenous use, the total concentration of the solute should be controlled so that the preparation is isotonic. For ocular administration, an ointment or an instillable liquid is delivered, which is done by an ocular delivery system known in the art, such as an applicator or dropper. In some embodiments, such compositions include mucosal mimics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose, or polyvinyl alcohol, preservatives such as sorbic acid, EDTA, or benzyl chromium chloride, and a typical amount of diluent or carrier. For pulmonary administration, the diluent or carrier will be selected to be suitable for enabling aerosol formation.

[0180] In some embodiments, the compounds of the present application are formulated for parenteral administration by infusion, which includes conventional catheter insertion techniques or infusions. The formulations for infusion are given, for example, in unit dose 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 solvent (vehicle) and include formulation agents such as suspending agents, stabilizers, and / or dispersants. In all cases, the form must be sterile and fluid enough to be easily injected. Alternatively, the compounds of the present application are preferably in a sterile powder form for reconstitution before use using a suitable solvent (vehicle), such as sterile water free of pyrogens.

[0181] In some embodiments, compositions for nasal administration are formulated as aerosols, drops, gels, and powders for convenience. For example, for intranasal or inhalation administration, the compounds of the present application are conveniently delivered in the form of a solution, dry powder formulation, or suspension from a pump spray container squeezed or pumped by the patient, or as an aerosol spray from a pressurized container or nebulizer. Aerosol formulations typically comprise a solution or microsuspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually provided in sterile form as a single dose or multiple dose in a sealed container. The container may take the form of a cartridge or refill for use with a spray device, for example. Alternatively, the sealed container may be a unit dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser fitted with a metering valve intended to be discarded after use. If the dosage form includes an aerosol dispenser, it will also include a propellant. The propellant is a compressed gas, such as compressed air or an organic propellant such as a fluorochloro hydrocarbon. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkane, carbon dioxide, or other suitable gases. In the case of pressurized aerosols, the dosage unit is appropriately determined by providing a valve for dispensing the measured 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 inhalers or inhalers are formulated, for example, containing a powder mixture of the compound of the present application and a suitable powder base such as lactose or starch. The aerosol dosage form may also take the form of a pump atomizer.

[0182] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and troches, in which 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 this application in suppository form are suitable for vaginal, urethral, ​​and rectal administration. Such suppositories generally consist of a mixture of substances that are solid at room temperature but melt at body temperature. Substances commonly used to make such vehicles include, but are not limited to, cocoa butter (also known as cocoa oil), glycerin-gelatinized, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. For further explanation of suppository administration 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 bound to soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl aspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, the compounds of the present application are bound to a class of biodegradable polymers useful for achieving controlled release of drugs, such biodegradable polymers include, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0185] The compounds of this application, including their pharmaceutically acceptable salts and / or solvates, are appropriately used alone, but are generally administered in the form of a pharmaceutical composition in which one or more of the compounds of this application (active ingredients) are accompanied by a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition contains 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 a pharmaceutically acceptable carrier, where all weight percentage values ​​are based on the entire composition.

[0186] In some embodiments, the compounds of the Application are used and administered in a composition comprising additional therapeutic agents, including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. Accordingly, the Application also encompasses pharmaceutical compositions comprising one or more of the compounds of the Application, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, as well as additional therapeutic agents, and optionally one or more pharmaceutically acceptable excipients. In some embodiments, the additional therapeutic agents are other known agents useful for treating diseases, disorders, or conditions by activation of serotonin receptors, such as those listed below in the "Methods and Uses" section. In some embodiments, the additional therapeutic agents are psychostimulants.

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

[0188] IV. Method and Use of the Present Application The compound of this application is a serotonergic conjugate that acts as an agonist or partial agonist at serotonin receptors.

[0189] Accordingly, the present application encompasses a method for activating intracellular serotonin receptors, whether in a biological sample or in a patient, comprising administering an effective amount of one or more of the compounds of the present application to said cells. The present application also encompasses the use of one or more of the compounds of the present application for activating intracellular serotonin receptors, and the use of one or more of the compounds of the present application for the preparation of a pharmacopoeia for activating intracellular serotonin receptors. The present application further encompasses one or more of the compounds of the present application for use in the activation of intracellular serotonin receptors.

[0190] Since the compounds of this application can activate serotonin receptors, they are useful for treating diseases, disorders, or conditions by activating serotonin receptors. Therefore, the compounds of this application are useful as pharmaceuticals. Accordingly, this application also includes the compounds of this application for use as pharmaceuticals.

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

[0192] This application also includes the use of one or more of the compounds of this application for the treatment of diseases, disorders, or conditions caused by the activation of serotonin receptors, and the use of one or more of the compounds of this application for the preparation of pharmaceuticals for the treatment of diseases, disorders, or conditions caused by the activation of serotonin receptors. This application further includes the use of one or more of the compounds of this application for use in the treatment of diseases, disorders, or conditions caused by the activation of serotonin receptors.

[0193] In some embodiments, the serotonin receptor is 5-HT 2A Therefore, this application relates to the intracellular 5-HT, whether in a biological sample or in a patient. 2A A method for activating 5-HT in cells, comprising administering an effective amount of one or more of the compounds of the present application to the cells. The present application relates to the intracellular 5-HT 2AUse of one or more of the compounds of this application to activate 5-HT in cells, and the use of one or more of the compounds of this application to activate 5-HT in cells. 2A This also includes the use of one or more of the compounds of this application for the preparation of pharmaceuticals for activating 5-HT in cells. 2A The present invention further includes one or more compounds of the present invention for use in the activation of [unclear].

[0194] This application relates to administering a therapeutically effective amount of one or more of the compounds of this application to a subject in need of treatment, including 5-HT 2A This also includes methods of treating diseases, disorders, or conditions by activating 5-HT. 2A Use of one or more of the compounds of this application for the treatment of diseases, disorders, or conditions by activation of 5-HT 2A The application also includes the use of one or more of the compounds of this application for the preparation of pharmaceuticals for the treatment of diseases, disorders, or conditions by activation of 5-HT. 2A This invention includes one or more compounds of the present application for use in the treatment of diseases, disorders, or conditions by activation.

[0195] In some embodiments, the compounds of the Application are useful in preventing, treating, and / or reducing the severity of mental disorders and / or conditions in a subject. Therefore, in some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is a mental disorder. Accordingly, the Application also encompasses a method for treating a mental disorder, comprising administering a therapeutically effective amount of one or more of the Compounds of the Application to a subject in need of treatment. The Application also encompasses the use of one or more of the Compounds of the Application for the treatment of mental disorders, and the use of one or more of the Compounds of the Application for the preparation of a medicament for the treatment of mental disorders. The Application further encompasses one or more of the Compounds of the Application for use in the treatment of mental disorders.

[0196] In some embodiments, the mental disorders include: anxiety disorders such as generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobias; depression such as hopelessness, loss of pleasure, fatigue, and suicidal thoughts; mood disorders such as depression, bipolar disorder, cancer-related depression, anxiety, and cyclothymic disorder; mental disorders such as hallucinations, delusions, and schizophrenia; impulse control and addiction disorders such as pyromania, kleptomania, 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 an object to perform a specific ritual or routine; post-traumatic stress disorder (PTSD); stress response syndrome (formerly called adjustment disorder); dissociative disorders, which were formerly called multiple personality disorder, or "split personality" (split personality). Selected from: personality disorder; depersonalization disorder; depersonalization disorder; sexual dysfunction, gender identity disorder, and sexual perversion; somatic symptom disorder, which was formerly known as psychosomatic disorder or somatoform disorder; and combinations thereof.

[0197] In some embodiments, the diseases, disorders, or conditions treated by activation of serotonin receptors include cognitive impairment; ischemia including stroke; neurodegeneration; refractory drug use disorders; sleep disorders; distress such as social distress, 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 paroxysmal disorders; neuronal cell death; excitotoxic cell death; or combinations thereof.

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

[0199] In some embodiments, hallucinations are selected from visual, auditory, olfactory, gustatory, tactile, proprioceptive, equilibrium, nociceptive, thermal, and temporal hallucinations, as well as combinations thereof.

[0200] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is psychosis or psychotic symptoms. Accordingly, the application also encompasses methods for treating psychosis or psychotic symptoms, which include administering a therapeutically effective amount of one or more of the compounds of the Application to a subject in need of treatment.

[0201] This application also includes the use of one or more of the compounds of this application for the treatment of psychosis or psychotic symptoms, and the use of one or more of the compounds of this application for the preparation of pharmaceuticals for the treatment of psychosis or psychotic symptoms. This application further includes one or more of the compounds of this application for use in the treatment of psychosis or psychotic symptoms.

[0202] In some embodiments, administration of a therapeutically effective amount of the compound of the Application to the subject requiring treatment does not result in exacerbation of psychosis or psychotic symptoms, including but not limited to hallucinations and delusions. In some embodiments, administration of a therapeutically effective amount of the compound of the Application to the subject requiring treatment results in improvement of psychosis or psychotic symptoms, including but not limited to hallucinations and delusions. In some embodiments, administration of a therapeutically effective amount of the compound of the Application to the subject requiring treatment results in improvement of psychosis or psychotic symptoms.

[0203] In some embodiments, the compounds of the present application are useful for treating central nervous system (CNS) disorders in subjects requiring treatment, the treatment comprising administering a therapeutically effective amount of the compound of general formula (IA) or a pharmaceutically acceptable salt thereof to the subject.

[0204] Accordingly, in some embodiments, the diseases, disorders, or conditions treated by serotonin receptor activation are diseases, disorders, or conditions of the central nervous system (CNS) and / or neurological diseases, disorders, or conditions. Accordingly, the Application also encompasses methods for treating diseases, disorders, or conditions of the CNS and / or neurological diseases, disorders, or conditions, including administering a therapeutically effective amount of one or more of the Compounds of the Application to a subject in need of treatment. The Application also encompasses the use of one or more of the Compounds of the Application for the treatment of diseases, disorders, or conditions of the CNS and / or neurological diseases, disorders, or conditions, as well as the use of one or more of the Compounds of the Application for the preparation of pharmaceuticals for the treatment of diseases, disorders, or conditions of the CNS and / or neurological diseases, disorders, or conditions. The Application further encompasses one or more of the Compounds of the Application for use in the treatment of diseases, disorders, or conditions of the CNS and / or neurological diseases, disorders, or conditions. In some embodiments, the CNS disease, disorder, or condition and / or neurological disease, disorder, or condition is selected from neurological disorders including neurodevelopmental disorders and neurodegenerative diseases, 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, e.g., Parkinsonian dementia, 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 ataxia; neurootological disorders and oculomotor disorders; neurodegenerative diseases of the retina; amyotrophic lateral sclerosis; tardive dyskinesia; hyperactivity disorder; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette syndrome; schizophrenia; autism spectrum disorder; Examples include tuberous sclerosis; Rett syndrome; cerebral palsy; reward system disorders such as anorexia nervosa (AN) and bulimia nervosa (BN); and bulimia nervosa (BED), trichotillomania, self-injurious dermatitis, nail biting; migraines; fibromyalgia; and peripheral neuropathy of any etiology, as well as 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. Therefore, the compounds, methods, and uses of this application address diseases, disorders, and conditions in both humans and veterinary medicine.

[0206] In some embodiments, the compounds of the present invention are useful for treating behavioral problems in subjects that are cats or dogs.

[0207] Accordingly, in some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is a behavioral problem in a subject that is a cat or a dog. Accordingly, the Application also encompasses a method for treating a behavioral problem, comprising administering a therapeutically effective amount of one or more of the Compounds of the Application to a non-human subject in need of treatment. The Application also encompasses the use of one or more of the Compounds of the Application for treating behavioral problems in non-human subjects, and the use of one or more of the Compounds of the Application for the preparation of a medicament for treating behavioral problems in non-human subjects. The Application further encompasses one or more of the Compounds of the Application for use in the treatment of behavioral problems in non-human subjects.

[0208] In some embodiments, the behavioral problems are selected from, but are not limited to, anxiety, fear, stress, sleep disturbances, cognitive impairment, aggression, excessive noise making, scratching, biting, and combinations thereof.

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

[0210] The present application also includes a method for treating a disease, disorder, or condition by activation of serotonin receptors, comprising administering one or more of the compounds of the present application in a therapeutically effective amount to a subject in need of treatment, together with other known agents useful for treating a disease, disorder, or condition by activation of serotonin receptors. The present application also includes the use of one or more of the compounds of the present application in combination with other known agents useful for treating a disease, disorder, or condition by activation of serotonin receptors for the treatment of a disease, disorder, or condition by activation of serotonin receptors, and the use of one or more of the compounds of the present application in combination with other known agents useful for treating a disease, disorder, or condition by activation of serotonin receptors for the preparation of a medicament for the treatment of a disease, disorder, or condition by activation of serotonin receptors. The present application further includes the use of one or more of the compounds of the present application in combination with other known agents useful for treating a disease, disorder, or condition by activation of serotonin receptors for use in the treatment of a disease, disorder, or condition by activation of serotonin receptors.

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

[0212] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is a mental disorder, and one or more compounds of the present application are administered in combination with one or more additional treatments for the mental disorder. In some embodiments, the additional treatments for the mental disorder are 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 treated by serotonin receptor activation is selected from attention deficit hyperactivity disorder and attention deficit disorder and combinations thereof. In some embodiments, the disease, disorder, or condition treated by serotonin receptor activation 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 muscarinic antagonists, and nicotine agonists.

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

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

[0217] In some embodiments, the nicotine agonist is nicotine, nicotinic acid, a nicotinic α7 agonist, an α2β4 agonist, or a combination thereof.

[0218] In some embodiments, the muscarinic agonist is a muscarinic M1 agonist, 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 psychotic symptoms, and one or more compounds of the present application are administered in combination with one or more additional treatments for psychosis or psychotic symptoms. In some embodiments, the additional treatments for psychosis or psychotic symptoms are selected from typical antipsychotics and atypical antipsychotics.

[0221] In some embodiments, the typical antipsychotic is acepromazine, acetophenazine, bemperidol, bromperidol, butaperazine, carfenazine, chlorproetazine, chlorpromazine, chlorprothixen, clopentixol, siamemazine, dixylazine, droperidol, fluanison, flupentixol, fluphenazine, fluspirylene, haloperidol, levomepromazine, lenperone, roxapine, mesolidazine, metitepine, morindone, moperone Selected from oxypertine, oxyprotepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipemperone, piperacetazine, pipothiazine, prochlorperazine, promazine, protipendyl, spiperone, sulforidazine, thiopropazate, thioproperazine, thioridazine, thiothixen, thymiperone, trifluoperazine, trifluperidol, triflupromazine, and zuclopentixol, as well as combinations thereof.

[0222] In some embodiments, the atypical antipsychotic is selected from amoxapine, amisulpride, aripiprazole, asenapine, blonanserin, brexpiprazole, caliprazine, carpipramine, clocapramine, chlorotepine, clotiapine, clozapine, iloperidone, levosulpiride, lurasidone, merperone, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxiprid, reserpine, risperidone, certindol, sulpiride, sultopride, tiapride, veraliprid, ziprasidone, and zotepine, as well as 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 psychosis. In some embodiments, the additional treatments for psychosis are selected from typical antipsychotics and atypical antipsychotics.

[0224] In some embodiments, the effective dose varies depending on factors such as the disease state, age, sex, and / or weight of the subject or species. In some embodiments, the amount of one or more compounds that constitutes an effective dose will vary depending on factors such as a given one or more drugs or compounds, pharmaceutical formulation, route of administration, condition, type of disease or disorder, and the identity of the subject being treated, but can be determined by routine methods by those skilled in the art.

[0225] In some embodiments, the compound of the present application is administered once, twice, three times, or four times per year. In some embodiments, the compound of the present application is administered once or more times per week. However, in other embodiments, the compound is administered to the subject approximately once every two weeks, approximately once every three weeks, or approximately once per month. In other embodiments, the compound is administered approximately once per week to approximately 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, disability, 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 treatment may be increased or decreased during a particular treatment regimen. Changes in dosage can be made and made apparent 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 sufficient to treat the subject.

[0226] In some embodiments, the compound of the present application may be administered in a hallucinogenic or psychotropic dose, taken in conjunction with psychotherapy or treatment, and administered once, twice, three times, or four times per year. However, in some embodiments, the compound may be administered to a subject once daily, once every two days, once every three days, once a week, once every two weeks, once a month, once every two months, or once every three months, in a dose that is not hallucinogenic or psychotropic.

[0227] A compound of the present application may be used alone or in combination with other known agents (e.g., a compound 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 one embodiment that the compound of the present application is administered concurrently with those agents. In this disclosure, “contemporary administration” of two substances to a subject means administering each of the two substances so that they are simultaneously active in the individual. The exact details of administration depend on the pharmacokinetics of the two substances in each other's presence, but may include administering the two substances with a time difference of no more than a few hours from each other, or even administering one substance within 24 hours of the administration of the other, provided the pharmacokinetics are suitable. Designing a suitable drug regimen is a routine technique for those skilled in the art. In certain embodiments, the two substances are administered substantially simultaneously, that is, with a time difference of no more than a few minutes from each other, or in a single composition containing both substances. A combination of agents administered to a subject non-simultaneously is a further embodiment of the present invention. In some embodiments, the compounds of the Application are administered with other therapeutic agents simultaneously or sequentially in separate unit dosing forms, or together in a single unit dosing form. Accordingly, the Application provides unit dosing forms comprising one or more of the Compounds of the Application, additional therapeutic agents, and pharmaceutically acceptable carriers.

[0228] The dosage of the compounds of this application varies depending on many factors, including, for example, the pharmacokinetic properties of the compounds, the mode of administration, the age, health, and weight of the recipient, the nature and severity of the symptoms, the frequency of treatment, and (if any) the type of concurrent treatment, as well as the clearance rate of the compounds within the patient receiving treatment. Those skilled in the art can determine an appropriate dosage based on the above factors. In some embodiments, one or more compounds of this application are initially administered in an appropriate dosage, and the dosage is adjusted as needed in response to the clinical response. The dosage is generally selected to maintain serum levels of one or more compounds of this application at approximately 0.01 μg / cc to approximately 1000 μg / cc or approximately 0.1 μg / cc to approximately 100 μg / cc. Typical examples of oral administration of one or more compounds of this application for adults include approximately 10 μg to 1000 mg per day, preferably approximately 10 μg to 500 mg per day, and more preferably approximately 10 μg to 200 mg per day. For parenteral administration, typical doses are approximately 0.0001 mg / kg to 10 mg / kg, approximately 0.0001 mg / kg to 1 mg / kg, approximately 0.01 mg / kg to 0.1 mg / kg, or approximately 0.0001 mg / kg to 0.01 mg / kg. For oral administration, typical doses are approximately 0.001 μg / kg to 10 mg / kg, approximately 0.1 μg / kg to 10 mg / kg, approximately 0.01 μg / kg to 1 mg / kg, or approximately 0.1 μg / kg to 1 mg / kg. When administered in suppository form, typical doses are approximately 0.1 mg / kg to 10 mg / kg or approximately 0.1 mg / kg to 1 mg / kg. In some embodiments of the present application, the composition is 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 of the compounds of the present application are administered in doses once daily, once weekly, or once monthly, or the total daily dose is divided into doses twice, three times, or four times daily.

[0229] In some embodiments, the compounds of the present application are used or administered in effective doses, including doses or dosage regimens that do not produce clinically significant hallucinogenic / psychotropic effects. In some embodiments, the compounds of the present application are used in amounts of 4 ng / mL or less of human plasma psilocin Cmax and / or 40% or less of human 5-HT. 2A Clinical effects expressed by human CNS receptor occupancy, or human plasma psilocin Cmax of 1 ng / mL or less and / or human 5-HT of 30% or less. 2A The compound is used or administered in an effective amount, including the administration of a dose or dosage regimen that produces a clinical effect similar to the clinical effect expressed by human CNS receptor occupancy. In some embodiments, the compound of the present application is used or administered in an effective amount, including the administration of a dose or dosage regimen that produces a clinical effect similar to the clinical effect expressed by human plasma psilosin Tmax for more than 60 minutes, more than 120 minutes, or more than 180 minutes.

[0230] To clarify, in the above, the term "a. compound" encompasses embodiments in which one or more compounds are referred to. Similarly, the expression "compounds of the present application" also encompasses embodiments in which only one compound is referred to.

[0231] V. Preparation of Compounds

[0232] The compounds of this application can be prepared by various synthetic processes. The selection of specific structural features and / or substituents may influence the preference for one process over another. Selecting a particular process for preparing a given compound of this application is within the scope of work of those skilled in the art. Some starting materials for preparing the compounds of this application are available from commercial chemical suppliers or can be extracted from cells, plants, animals, or fungi. Other starting materials, such as those described below, can be readily prepared from available precursors using simple transformations well known to those skilled in the art. In the following schemes illustrating some embodiments of the methods for preparing the compounds of this application, all symbols (variables) are as defined in Formula I unless otherwise noted.

[0233] In some embodiments, the compound of formula IA is prepared as shown in scheme I-II. [ka]

[0234] Therefore, in some embodiments, the compound of formula (IA) can be synthesized by treating an orthiodoaniline (A) derivative with a suitable unsaturated precursor (B). Through this route, the compound of formula (IA) is formed directly using a Pd catalyst [Fricke et al., Chem. Eur. J., 2019, 25(4):897-903]. Alternatively, the compound of formula (IA) can be synthesized by scheme II. [ka]

[0235] Therefore, in some embodiments, as shown in Scheme II, the compound of formula (IA) is obtained by first treating appropriately substituted indole (C) with oxalyl chloride, followed by amine NHR 11 R 12It can be synthesized by treating it with an intermediate indole (D). Subsequently, reduction based on Al, for example, in the presence of lithium aluminum hydride or lithium aluminum deuteride, yields the compound of formula IA.

[0236] A compound of formula IA, R 1 ~R 5 Compounds in which one or more of A are deuterium can be obtained, for example, by using hydrogen-deuterium exchange with a suitable starting substrate. This exchange reaction is catalyzed by Pd / C in D2O, as described in Esaki, H. et al. Tetrahedron, 2006, 62:10954-10961, and modified versions thereof are known to those skilled in the art.

[0237] Compounds of formula IA, wherein A is OCD3, can be obtained, for example, by the method described in Xu, YZ and Chen, CJ Label Compd. Radiopharm. (2006) 49:897-902, and modifications of said method known to those skilled in the art.

[0238] Those skilled in the art will understand that, in the scheme described above, the intermediates and final compounds can be subjected to further substituent manipulation using known chemical methods to obtain alternative compounds of the present invention.

[0239] For example, a person skilled in the art would know that R in compounds C and D above 1 If is H, then it is a compound of formula IA, and R 1 A compound is formed where H is then R 1 You will understand that further reactions of the compound of formula IA, where is H, can be used to prepare further compounds of formula I. For example, R 1 The compound of formula IA, in which 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 by methods known to those skilled in the art, for example, by reacting the compounds of the present application with a certain amount of acid or base, for example an equivalent amount of acid or base, in a medium such as a medium on which the salt precipitates or in an aqueous medium, followed by freeze-drying.

[0241] The formation of solvates will vary depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in a suitable solvent and cooling it, or by isolating the solvate using a poor solvent (antisolvent). Solvates are typically dried or azeotropically dried under environmental conditions. The selection of appropriate conditions for forming a particular solvate can be made by those skilled 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 this application will vary depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in a suitable solvent and cooling it, or by isolating the solvate using a poor solvent. Solvates are typically dried or azeotropically dried under environmental conditions. The selection of appropriate conditions for forming a particular solvate can be made by those skilled in the art.

[0242] The isotopically enriched compounds of this application and their pharmaceutically acceptable salts, solvates, and / or prodrugs can be prepared without excessive experimentation by means of the prior art well known to those skilled in the art or by processes similar to those described herein in schemes and examples, using appropriate isotopically enriched reagents and / or intermediates.

[0243] It should be understood that, throughout the processes described herein, where necessary, appropriate protecting groups are added to various reactants and intermediates in a manner readily understood by those skilled in the art, and subsequently removed from said reactants and intermediates. Conventional procedures for using such protecting groups and examples of appropriate protecting groups are described, for example, in “Protective Groups in Organic Synthesis”, TW Green, PGMWuts, Wiley-Interscience, New York, (1999). It should also be understood that chemical transformations from one group or substituent to another can be performed on any intermediate or final product in the synthetic pathway toward the final product, and the types of possible transformations are limited only by the inherent incompatibility of other functionalities of the molecule at that step with respect to the conditions or reagents used for the transformation. Such inherent incompatibility, and methods for avoiding such incompatible incompatibility by performing appropriate transformations and synthetic steps in the appropriate order, will be readily understood by those skilled in the art. Examples of transformations are given herein, and it should be understood that the transformations described are not limited to the generic groups or substituents for which the transformation is illustrated. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations - A Guide to Functional Group Preparations” RC Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are found in organic chemistry textbooks, e.g., “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-phase and reverse-phase chromatography on columns or on rotating plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, which will be readily apparent to those skilled in the art.

[0244] It should also be understood that any intermediate or final product in the synthetic pathway leading to the final product can be chemically converted to another group or substituent, and that the types of conversions possible are limited only by the fact that other functionalities of the molecule at that stage are inherently incompatible with the conditions or reagents used in the conversion. Such inherent incompatibility, and ways of avoiding it by performing appropriate conversion and synthesis steps in the appropriate order, will be readily understood by those skilled in the art. Examples of conversions are given in this disclosure, and it should also be understood that the conversions described are not limited to the generic groups or substituents exemplified. References and descriptions of other suitable conversions are given 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, for example, “Advanced Organic Chemistry”, March, 4th ed. McGraw Hill (1992) or “Organic Synthesis”, Smith, McGraw Hill, (1994).

[0245] Techniques for purifying intermediates and final products include, for example, normal-phase and reverse-phase chromatography on columns or rotating plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, which will be readily understood by those skilled in the art.

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

[0247] The prodrug of the compound of the present invention may be a conventional ester formed using, for example, an available hydroxyl group, thiol group, amino group, or carboxyl group. For example, the available hydroxyl group or amino group may be acylated with an activated acid (e.g., an acid chloride in pyridine) in the presence of a base and optionally in an inert solvent.

[0248] Those skilled in the art will understand that, when the reaction steps of the present application are carried out in various solvents or solvent systems, the reaction steps may also be carried out in a suitable solvent or a mixture of solvent systems. [Examples]

[0249] The following non-limiting embodiments illustrate the present invention. General method

[0250] All starting materials used in this disclosure are either commercially available or previously described in the literature. 1 H and 13 Unless otherwise specified, the 13C NMR spectrum was obtained using TMS or the residual solvent signal as an internal standard in deuterated chloroform as the solvent. 1 ¹H NMR was recorded using one of the following spectrophotometers operating at 300 MHz, 400 MHz, and 400 MHz respectively: Bruker 300, Bruker DPX400, or Varian +400. All reported chemical shifts are expressed in ppm on the delta scale, and fine splitting of signals observed during recording is generally represented as, for example, s: singlet, br s: broad singlet, d: doublet, t: triplet, q: quadruplet, m: multiplet. Unless otherwise noted, the following tables use the following notation. 1 ¹H NMR data were obtained at 400 MHz using CDCl3 as the solvent.

[0251] The products were purified 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 using 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 of the present invention Example 1: Synthesis of 2-(1H-indole-3-yl-2,4,5,6,7-d5)-N,N-bis(methyl-d3)ethane-1-amine (IA-1) [ka] Synthesis of 2-(1H-indole-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 product was allowed to rise to room temperature and stirred for 16 hours. The reaction product was cooled to 0°C and treated with bis(methyl-d3)amine hydrochloride (3.48 g, 39.788 mmol, liberated with Et3N in THF (80 mL)) for 5 minutes. The reaction product was allowed to rise to room temperature and stirred for 4 hours. The reaction was stopped with water (100 mL), and the product was extracted in ethyl acetate (2 × 75 mL). The combined ethyl acetate layer was washed with brine (25 mL) and dried (Na2SO4). The solvent was evaporated, and the crude product was purified by flash column chromatography on silica gel (MeOH:CH2Cl2=5:95) to obtain compound 2 (1.65 g, 63.9%) as a bright yellow solid. ESI-MS (m / z, %): 249 (M+Na, 100)

[0254] Synthesis of 2-(1H-indole-3-yl-2,4,5,6,7-d5)-N,N-bis(methyl-d3)ethane-1-amine: A suspension of lithium aluminum hydride (0.82 g, 21.820 mmol) in dry THF (10 mL) was treated with 2-(1H-indole-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 for 10 minutes. The reaction product was allowed to cool to room temperature and refluxed for 16 hours. The reaction product was cooled to 0°C and the reaction was stopped by sequentially adding water (0.82 mL), 2N NaOH solution (0.82 mL), and water (0.82 mL) over a period of 15 minutes. The reaction product was allowed to cool to room temperature and stirred for 30 minutes. The solid was filtered and washed with THF (2 × 50 mL). The combined THF layer was evaporated, and the crude product was purified by column chromatography on silica gel (2M NH3 in MeOH:CH2Cl2=5:95) to obtain 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-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(IA-6) [ka] Synthesis of 2-(5-(methoxy-d3)-1H-indole-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 product was allowed to rise to room temperature and stirred for 16 hours. The reaction product was cooled to 0°C and treated with bis(methyl-d3)amine hydrochloride (2.1 g, 24.235 mmol, liberated with Et3N in THF (50 mL)) for 5 minutes. The reaction product was allowed to rise to room temperature and stirred for 4 hours. The reaction was stopped with water (100 mL), and the compound was work-up and purified in the same manner as described for compound 2 to obtain 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-indole-3-yl)-N,N-bis(methyl-d3)ethane-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-indole-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 10 minutes. The reaction product was allowed to cool to room temperature and then refluxed for 16 hours. The reaction product was work-up and purified in the same manner as described for compound IA-1 to obtain compound IA-6 (0.59 g, 85.7%) 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-indole-3-yl-2,4,5,6,7-d5)-N,N-dimethylethane-1-amine (IA-2) [ka] Synthesis of 2-(1H-indole-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 product was allowed to rise to room temperature and stirred for 16 hours. The reaction product was cooled to 0°C and treated with dimethylamine solution (16.22 mL, 32.45 mmol, 2 M in THF) for 5 minutes. The reaction product was allowed to rise to room temperature and stirred for 4 hours. The reaction product was work-up and purified in the same manner as described for compound 2 to obtain compound 26 (1.1 g, 76.5%) as a light brown solid. 1H NMR (CDCl3)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-indole-3-yl-2,4,5,6,7-d5)-N,N-dimethylethane-1-amine: A suspension of lithium aluminum hydride (1.34 g, 35.431 mmol) in dry THF (20 mL) was treated with 2-(1H-indole-3-yl-2,4,5,6,7-d5)-N,N-dimethyl-2-oxoacetamide (26 g, 0.98 g, 4.428 mmol) in dry THF (30 mL) at 0°C for 10 minutes. The reaction product was allowed to cool to room temperature and then refluxed for 16 hours. The reaction product was work-up and purified in the same manner as described for compound IA-1 to obtain compound IA-2 (0.75 g, 87.6%) 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. Biology Test Example 4: FLIPR assay: Human 5-HT2A I. Evaluation of the activated effects of exemplary formula IA compounds targeting the human 5-HT2A (h5-HT2A) receptor in agonist mode: Controls for compound preparation and assays [Table 1-4] [Table 1-5]

[0259] Ic experimental method and procedure: 1. Cells were cultured in cell culture medium (10% FBS, G418 containing 1× penicillin-streptomycin 300 μg / ml, and DMEM containing 100 μg / ml hygromycin B) at 37°C and 5% (vol / vol) CO2.

[0260] 2. One day prior to the assay, cells were detached using TrypLE® Express and counted using a cell counter. Only cells with a viability of over 85% were used in the assay.

[0261] 20,000 cells / well in 3.30 μl / well of culture medium were seeded into a 384-well cell plate, and the cells were incubated overnight at 37°C with 5% (vol / vol) CO2.

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

[0263] 5. The culture medium was separated from the cell plate by gently tapping it 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. The cell plate was placed on a plate shaker and the plate was agitated at 600 rpm for 2 minutes. The plate was incubated at 37°C for 2 hours, followed by incubation at 25°C for a further 15 minutes.

[0266] 8. Preparation of 3× compounds in assay buffer: a. Dilution of the reference compound with DMSO to the required concentration. Add the compound to a 384-well compound plate; b. Serial dilution was performed; c. 10 mM of the test compound was added to the compound plate, and then 3-fold serial dilution was performed. d. 60 nl / well of the compound was transferred from the source plate to a 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 on a plate shaker for 2 minutes;

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

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

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

number

[0270] iii. Using XLfit, the EC is calculated by applying the activation % relative to the log of the compound concentration to the Hill equation. 50 I calculated it.

[0271] The compound in this study was found to be a 5-HT2A agonist. The results for representative compounds are shown in Table 1 (EC). 50 The letters "A" indicate that the EC50 is less than 1,000 nM, "B" indicate that the EC50 is greater than 1,000 nM but less than 10,000 nM, and "C" indicate that the EC50 is greater than 10,000 nM. [Table 1-6]

[0272] Results and Discussion Exemplary compounds of formula IA were functionally evaluated using the FLIPR assay to assess their effects on the h5-HT2A receptor in agonist mode. 50 The (nM) concentrations are shown in Table 5. This assay confirmed that the compound of this invention is an effective inhibitor of the target 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. Assay buffers were prepared according to the following table; [Table 1-9]

[0273] ii. Preparation of eight doses of the reference compound and test compound, starting from a 10 mM stock solution required for 5-fold serial dilution at 100%;

[0274] iii. (Voltage / volt) DMSO was prepared: a. 50 μl / well of 0.5% (Voltage / volt) 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 three times with ice-cold washing buffer (50 mM Tris, pH 7.4);

[0275] iv. Preparation of assay plates: a. Dilute the cell membrane with assay buffer and add 330 μl / well to a 96-round deep-bottom plate to reach a concentration of 20 μg / well; b. Prepare eight concentrations of the reference compound or test compound and add 110 μl / well to a 96-round deep-bottom plate; c. Dilute [3H]-ketanserin with assay buffer to 5 nM (5 × final concentration) and add 110 μl / well to a 96-round deep-bottom plate.

[0276] v. The plate was centrifuged at 1000 rpm for 30 seconds, and then stirred 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 stopped by vacuum filtration onto a GF / B filter plate, and then washed four times with ice-cold washing buffer (50 mM Tris, pH 7.4).

[0279] viii. The plate was dried at 37°C for 45 minutes.

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

[0281] The plate was read using the x.Microbeta2 microplate counter.

[0282] Data analysis: For the reference compound and the test compound, the results were normalized using the following formula: N = 100 - 100 × (U - C2) / (C1 - C2) The inhibition was expressed as a percentage using the formula. Here, U is an unknown value, C1 is the mean of the high control, and C2 is the mean of the low control. IC50 is determined by fitting the inhibition percentage as a function of compound concentration to the Hill equation using XLfit.

[0283] Results and Discussion: Table 2 summarizes the results of the potential competitive binding properties of representative compounds targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A). The results for representative compounds are listed in Table 2. 50 It is shown as follows. The symbol "#" is IC 50 This indicates that it is less than 500nM, and "##" is IC 50 This indicates that the value is greater than 500 nM and less than 5,000 nM, and "###" indicates IC 50 This indicates that it is greater than 5,000 nM. [Table 2]

[0284] Results and Discussion Exemplary compounds of formula IA were evaluated using a radioligand binding assay to the human 5-HT2A receptor. 50 The (nM) concentrations are shown in Table 2. This assay confirms that the compound is an effective ligand for the target human 5-HT2A receptor.

[0285] Example 5: Stability of human, rat, and mouse liver microsomes the purpose The purpose of this study was to estimate the in vitro metabolic stability of representative compounds of the present invention in pooled human and male mouse liver microsomes. The concentrations of the parent compounds in the reaction system were evaluated by LC-MS / MS to estimate their stability in pooled human and male mouse liver microsomes. The in vitro intrinsic clearance of the test compounds was also determined.

[0286] Protocol A master solution in an incubation plate containing phosphate buffer, ultrapure H2O, MgCl2 solution, and liver microsomes was prepared according to Table 3. This mixture was preheated 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. A negative control sample was prepared by replacing the NADPH with 40 μL of ultrapure H2O. Samples were prepared in two sets. The negative control was prepared in one set.

[0288] The reaction was initiated by adding 4 μL of either the 200 μM test compound or the control compound to each master solution to a final concentration of 2 μM. This test was performed in two series.

[0289] At 0, 15, 30, 45, and 60 minutes, 50 μL aliquots were taken from the reaction solution. 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). The samples were centrifuged at 3,220 g for 40 minutes. A 90 μL aliquot of the supernatant was mixed with 90 μL of ultrapure H2O and then used for LC-MS / MS analysis.

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

[0291] All calculations were performed using Microsoft Excel. The peak area ratio of the test compound to the internal standard (listed in the table below) was determined from the extracted ion chromatograms.

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

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

[0294] In vitro t1 / 2 (min) in vitro specific clearance (in vitro CL int The conversion to units (μL / min / mg protein) was performed using the following formula (average of two sets of measurements):

number

[0295] For compounds or control compounds that exhibited rapid initial disappearance followed by slow subsequent disappearance, 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 diverse range of drug-metabolizing enzymes and are commonly used to support in vitro ADME (absorption, distribution, metabolism, and excretion) studies. These microsomes are used to investigate possible first-pass metabolic byproducts of orally administered drugs. Representative compounds of the present invention were evaluated for their stability in human, rat, and mouse liver microsomes. In the liver microsomes of the three species—human, rat, and mouse—the majority of the compounds of the present invention were recovered within a 60-minute period, indicating that these compounds are not rapidly removed (see Table 4 for representative compounds of exemplary formula IA). [Table 4]

[0297] Example 6: Hallucinogenic effect of compound of formula IA The effects of representative compounds of exemplary formula IA at various doses were evaluated based on the head convulsion response (HTR) as a behavioral model of hallucinogenic activity.

[0298] Protocol Mouse head spasms Male C57BL / 6J mice (body weight range 20g-30g) were administered an appropriate dose of the test substance and placed in individual observation chambers after a 1-minute pre-treatment time. Animals were continuously visually assessed for head convulsions over a 1-hour period. Head convulsions were defined as rapid spasms of the head not caused by external tactile stimuli (Corne and Pickering, Psychopharmacologia, 1967, 11(1):65-78). Each head convulsion was counted individually by a trained observer, and data were expressed as the mean ± mean standard error (SEM) of 6-10 mice per group. Mice were used in only one experiment.

[0299] Rat behavioral tests Male Sprague-Dawley rats (body weight range 250g–400g) were administered an appropriate dose of the test substance. After a 1-minute pretreatment time, the rats were placed in a spontaneous motility activation box (dimensions: 17 inches wide × 17 inches long × 12 inches high) and continuously monitored for 1 hour. Data were collected in 10-minute intervals in a bin. The animals were visually evaluated for overt behavioral signs, including behavioral characteristics of 5-HT2A receptor activation (violent tremors (wet dog shakes), spinal muscle contraction), 5-HT2A receptor activation (yawning, penile grooming), and 5-HT1A behavior (forelimb stomping, hindlimb abduction) (Halberzettl et al, Behav Brain Res. 256:328-345, 2013). Additional behavioral and physical signs characteristic of 5-HT syndrome (e.g., tremors, salivation, prone flat posture, core body temperature changes) were also measured. Simultaneously, the spontaneous behavior of the rats was measured using an automated tracking system (Med Associates, Vermont, USA). Collected activity data included total distance traveled, number of times the rat stood up, and ambulatory episodes. All data were expressed as mean ± mean standard error (SEM) for 6–10 rats per group.

[0300] Drug identification in rats Male Sprague-Dawley rats were initially subjected to food restriction by being presented with 18-20g of food at the end of the day (single housing). After 7 days of adaptation to the food restriction procedure, these rats were trained daily for one week in a standard two-lever operant conditioning chamber controlled by Med-PC software to press the lever for food (45mg Bioserve pellet) (Med. Associates Ins., St. Albans, Vermont, USA). These rats were trained to press the lever for food up to an FR10 value (i.e., 10 lever presses for one food reward). Once a stable food response was achieved for both response levers, discrimination training was initiated. Over a period of 20–50 training sessions, rats were trained to associate one lever with a training dose of psilocybin administered subcutaneously at 1 mg / kg and a second lever with a neutral stimulus (saline, administered subcutaneously) (Winter et al, Pharmacol Biochem Behav. 87(4):472-480, 2007). Training sessions lasted 30 minutes, or until 50 pellets were distributed, and continued until the animals achieved appropriate stimulus control (defined as six consecutive sessions in which the animal presses the lever 16 times or less before the distribution of the first reward, and 95% or more of the total responses being for the correct lever). At the end of the day, the rats continued to receive their daily food distribution in their home cages.

[0301] Once trained, substitution tests were conducted. On the day of the test, both levers were made operational, meaning that food pellets were dispensed on the 10th response with either lever. Test sessions continued until 50 pellets were obtained, or until 30 minutes had elapsed. Response speed was also measured during these sessions.

[0302] Results and Discussion: Dose-response (0.3–3 mg / kg subcutaneous injection) – signs of 5-HT2A, such as severe tremors / back muscle contractions (WDS / BMC), were measured over a 1-hour period. Spontaneous movement and other 5-HT receptor signs were also measured. The effect of various doses of the formula IA exemplary compound IA-6 on cerebral convulsion response (HTR) in male C57BL6 mice was tested. Mice were treated with compound IA-6 (0.3, 1, 3, 10 mg / kg) via subcutaneous injection (SC) in saline, and the total number of cerebral convulsions was recorded over a 1-hour period. Data are expressed as mean ± mean standard error (SEM).

[0303] To evaluate the involvement of the 5-HT2A receptor in HTR induced by the exemplary compounds of formula IA, mice were pre-treated with the selective 5-HT2AR antagonist M100907 (also known as borinanserin) prior to administration of the compounds of formula IA. As expected, pre-treatment with this antagonist completely blocked the effect of the exemplary compounds of formula IA on HTR.

[0304] Although this application has been described with reference to examples, it should be understood that the claims are not limited to the embodiments described in the examples, and should be given the broadest interpretation consistent with the entire disclosure.

[0305] All patents, patent applications, and publications cited herein are incorporated in their entirety by reference. The disclosures of those publications are incorporated in their entirety by reference to more completely describe the state of the art known to those skilled in the art as of the date of the application described and claimed herein. The aspects relating to this disclosure also include the following aspects: <1> Compounds of formula (IA) or pharmaceutically acceptable salts, solvates, and / or prodrugs 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 Alkilen P(O)(OR) 6 ) 2 、C 1 ~C 6 Alkilen OP(O)(OR 6 ) 2 , C(O)R 6 CO 2 R 6 , C(O)N(R 6 ) 2 , S(O)R 6 and SO 2 R 6 Selected from; R 2 、R 3 、R 4 and R 5 It is 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 groups; 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 Selected from fluoroalkyl; R 11 and R 12 is hydrogen, deuterium, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl and C 1 ~C 6 Independently selected from fluoroalkyls; and, R 19 C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl and C 1 ~C 6 Selected from fluoroalkyl; however, (1)R 2 、R 3 、R 4 and R 5 All are D, and A, R 1 、R 6 ~R 12 and R 19 as defined above this disclaimer; or (2) A is OR 19 And here R 19 C 1 ~C 6 Deuteroalkyl and C 1 ~C 6 Selected from fluoroalkyl, and also R 1 ~R 12 This is as defined above this disclaimer. <2> R 1 is hydrogen, deuterium, C 1 ~C 3 Deuteroalkyl, C 1 ~C 3 Fluoroalkyl, fluorosubstituted C 1 ~C 3 Alkyl, C 1 ~C 3 Alkilen P(O)(OR) 6 ) 2 、C 1 ~C 3 Alkilen OP(O)(OR 6 ) 2 , C(O)R6 CO 2 R 6 and C(O)N(R 6 ) to be selected from, <1> The compounds described above. <3> R 1 Hydrogen, deuterium, CH 3 , CF 3 CD 3 CH 2 CH 3 , CF 2 CF 3 CD 2 CD 3 CH 2 P(O)(OR 6 ) 2 CH(CH 3 )P(O)(OR 6 ) 2 and (CH 2 )OP(O)(OR 6 ) 2 Selected from, <2> The compounds described above. <4> R 6 is hydrogen, deuterium, CH 3 , CF 3 CHF 2 CD 2 H, CDH 2 , and CD 3 Selected from, <1> ~ <3> A compound listed in any one of the following. <5> R 6 CH 3 and CD 3 Selected from, <4> The compounds described above. <6> R 1 is hydrogen, deuterium, CH 3 , CF 3 CD 3 CH 2 CH 3 , CF 2 CF 3 and CD 2 CD 3 Selected from, <3> The compounds described above. <7> R 1 It is hydrogen or deuterium. <6> The compounds described above. <8> 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 Independently selected from fluoroalkyls, <1> ~ <7> A compound listed in any one of the following. <9> R 7 、R 8 、R 9 and R 10 is hydrogen, deuterium, CH 3 CD 2 H, CDH 2 CD 3、 CH 2 CH 3 CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 Selected independently from, <8> The compounds described above. <10> R 7 、R 8 、R 9 and R 10 is hydrogen, deuterium, CH 3 , CF 3 CHF 2 CD 2 H, CDH 2 CD 3、 CH 2 CH 3 CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 Selected independently from, <8> The compounds described above. <11> R7 、R 8 、R 9 and R 10 At least one of them is deuterium, or R 7 、R 8 、R 9 and R 10 At least one of them contains deuterium, <8> The compounds described above. <12> R 7 、R 8 、R 9 and R 10 At least one or at least two of them are deuterium. <11> The compounds described above. <13> R 7 、R 8 、R 9 and R 10 Is it all hydrogen, or R 7 、R 8 、R 9 and R 10 They are all deuterium. <8> The compounds described above. <14> R 11 and R 12 is hydrogen, deuterium, C 1 ~C 4 Alkyl, C 1 ~C 4 Deuteroalkyl and C 1 ~C 4 Independently selected from fluoroalkyls, <1> ~ <13> A compound listed in any one of the following. <15> R 11 and R 12 is hydrogen, deuterium, CH 3 CD 2 H, CDH 2 CD 3、 CH 2 CH 3 CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 Selected independently from, <14> The compounds described above. <16> R 7 、R 8 、R 9 and R 10 It is all hydrogen, and also R 11 and R 12 Deuterium and CD 3 Selected independently from, <1> ~ <7> A compound listed in any one of the following. <17> R 7 、R 8 、R 9 and R 10 All of them are deuterium, and also R 11 and R 12 is hydrogen and CH 3 Selected independently from, <1> ~ <7> A compound listed in any one of the following. <18> R 7 、R 8 、R 9 and R 10 All of them are deuterium, and also R 11 and R 12 Deuterium and CD 3 Selected from, <1> ~ <7> A compound listed in any one of the following. <19> A, R 2 、R 3 、R 4 and R 5 They are all deuterium. <1> ~ <18> A compound listed in any one of the following. <20> R 19 , CF 3 CHF 2 CD 2 H, CDH 2 CD 3、 and CD 2 CD 3 Selected from, <1> ~ <18> A compound listed in any one of the following. <21> R 19 is CHF 2 and CD 3 That is, <20> The compounds described above. <22> A is hydrogen, deuterium, OCH 3 OCD 3 OCF 3 , and OCHF 2 Selected from, <1> ~ <18> A compound listed in any one of the following. <23> A is deuterium, OCD 3 and OCHF 2 Selected from, <22> The compounds described above. <24> The compound of formula (IA) is selected from the compounds listed below or their pharmaceutically acceptable salts, solvates, and / or prodrugs. <1> The compounds listed: Table 5 Table 6 。 <25> <1> ~ <24> A composition comprising one or more compounds and carriers as described in any one of the following. <26> <1> ~ <24> A pharmaceutical composition comprising one or more compounds described in any one of the above and a pharmaceutically acceptable carrier. <27> A method for activating intracellular serotonin receptors in a biological sample or in a patient, wherein an effective amount <1> ~ <24> The method comprising administering one or more compounds described in any one of the above to the cells. <28> Therapeutic effective dose <1> ~ <24> A method for treating a disease, disorder, or condition by activating serotonin receptors, comprising administering one or more compounds described in any one of the above to a subject in need of treatment. <29> Intracellular 5-HT in biological samples or in patients 1A and a method for activating 5-HT2A, wherein an effective amount <1> ~ <24> The method comprising administering one or more compounds described in any one of the above to the cells. <30> Therapeutic effective dose <1> ~ <24> A method for treating a mental disorder, comprising administering one or more compounds described in any one of the above to a subject in need of treatment. <31> The aforementioned mental disorders are selected from hallucinations, delusions, and combinations thereof. <30> Methods used. <32> The aforementioned mental disorders include anxiety disorders; depression; mood disorders; mental disorders; impulse control and addiction disorders; substance addiction; obsessive-compulsive disorder (OCD); post-traumatic stress disorder (PTSD); stress response syndromes; dissociative disorders; depersonalization disorders; deviance disorders; sexual and gender disorders; and somatic symptom disorders; and combinations thereof, selected from these. <31> Methods used. <33> Therapeutic effective dose <1> ~ <24> A method for treating psychosis or psychotic symptoms, comprising administering one or more compounds described in any one of the above to a subject in need of treatment. <34> Therapeutic effective dose <1> ~ <24> A method for treating a disease, disorder, or condition of the central nervous system (CNS) and / or a disease, disorder, or condition of the nerves, comprising administering one or more compounds described in any one of the above to a subject in need of treatment. <35> The aforementioned CNS diseases, disorders, or conditions, and / or neurological diseases, disorders, or conditions include neurological disorders, including neurodevelopmental and neurodegenerative diseases, such as Alzheimer's disease; presenile dementia; senile dementia; vascular dementia; Lewy body dementia; cognitive impairment; Parkinson's disease, Parkinson's disease-related disorders, such as Parkinsonian dementia, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disease; fragile X syndrome; Angelman syndrome; hereditary ataxia; Neuro-otological disorders and oculomotor disorders; neurodegenerative diseases of the retina, amyotrophic lateral sclerosis; tardive dyskinesia; hyperactivity disorder; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette syndrome; schizophrenia; autism spectrum disorder; tuberous sclerosis; Rett syndrome; cerebral palsy; reward system disorders such as anorexia nervosa (AN) and bulimia nervosa (BN); and bulimia nervosa (BED), trichotillomania, self-injurious dermatitis, nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology, and combinations thereof, selected from: <34> Methods used. <36> Therapeutic effective dose <1> ~ <24> A method for treating behavioral disorders, comprising administering one or more compounds described in any one of the above to a non-human subject in need of treatment. <37> The aforementioned non-human subjects are dogs or cats suffering from neurological disorders, behavioral problems, trainability issues, and / or a combination thereof. <36> Methods used. <38> The aforementioned neurological disorders, behavioral problems, and trainability problems include, but are not limited to, anxiety, fear and stress, sleep disorders, cognitive impairments, aggression, and / or combinations thereof. <37> Methods used. <39> In combination with other known agents useful for treating diseases, disorders, or conditions caused by serotonin receptor activation, in a therapeutically effective dose <1> ~ <24> A method for treating a disease, disorder, or condition by activating serotonin receptors, comprising administering one or more compounds described in any one of the above to a subject in need of treatment. <40> <1> ~ <24> A pharmaceutical composition comprising any one of the compounds described in one of the above and an additional therapeutic agent. <41> The aforementioned additional therapeutic agent is a psychostimulant. <40> The composition described above.

Claims

1. Compounds of formula (I-A) or pharmaceutically acceptable salts thereof, and / or solvates: 【Chemistry 1】 During the ceremony R ６ , ６ , ６ , ６ , ２ , ２ is selected from 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<00000​​​​​​​​​​ R ２ , R ３ , R ４ , and R ５ It is 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 Deuterated alkyl, and C １ ~C ６ Independently selected from fluoroalkyls; A is hydrogen, deuterium, and OR １９ Selected from; R ６ is hydrogen, deuterium, C １ ~C ６ Alkyl, C １ ~C ６ Deuterated alkyl, and C １ ~C ６ Selected from fluoroalkyl; R １１ and R １２ is hydrogen, deuterium, C １ ~C ６ Alkyl, C １ ~C ６ Deuterated alkyl, and C １ ~C ６ Independently selected from fluoroalkyls; and, R １９ C １ ~C ６ Alkyl, C １ ~C ６ Deuterated alkyl, and C １ ~C ６ Selected from fluoroalkyl; however, (1) R ２ , R ３ , R ４ , and R ５ All are deuterium, and R11 and R12 are independently selected from deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl (deuteroalkyl), and C1-C6 fluoroalkyl, and A, R １ , R ６ ~R 10, and R １９ as defined above this disclaimer; or (2) A is OR １９ And here R １９ C １ ~C ６ Deuterated alkyl and C １ ~C ６ Selected from fluoroalkyls, where R7, R8, R9, and R10 are all deuterium, and R １ R6, R11, and R12 are defined above this disclaimer.

2. R １ is hydrogen, deuterium, C １ to C ３ deuterated alkyl (deuteroalkyl), C １ to C ３ fluoroalkyl, fluorine-substituted C １ to C ３ alkyl, C １ to C ３ alkylene P(O)(OR ６ ), C ２ to C １ to C ３ alkylene OP(O)(OR ６ ), C(O)R ２ , CO ６ R ２ R ６ , and C(O)N(R ６ ) selected from the compound according to claim 1.

3. R １ is hydrogen, deuterium, CH ３ , CF ３ , CD ３ , CH ２ CH ３ , CF ２ CF ３ , CD ２ CD[[ID=I19]] ３ , CH ２ P(O)(OR ６ ) ２ , CH(CH ３ )P(O)(OR ６ ) ２ , and (CH ２ )OP(O)(OR ６ ) ２ The compound according to claim 2, selected from

4. R ６ is hydrogen, deuterium, CH ３ CF ３ CHF ２ CD ２ H, CDH ２ , and CD ３ A compound according to any one of claims 1 to 3, selected from the above.

5. In the case of (1) above, R ７ , R ８ , R ９ , and R １０ is hydrogen, deuterium, C １ ~C ４ Alkyl, C １ ~C ４ Deuterated alkyl, and C １ ~C ４ A compound according to any one of claims 1 to 4, independently selected from fluoroalkyls.

6. R ７ , R ８ , R ９ , and R １０ At least one of them is deuterium, or R ７ , R ８ , R ９ , and R １０ The compound according to claim 5, wherein at least one of them contains deuterium.

7. In the case of (1), R11 and R12 are independently selected from deuterium, C1-C4 alkyl, C1-C4 deuterated alkyl, and C1-C4 fluoroalkyl, or in the case of (2), R １１ and R １２ is hydrogen, deuterium, C １ ~C ４ Alkyl, C １ ~C ４ Deuterated alkyl, and C １ ~C ４ A compound according to any one of claims 1 to 6, independently selected from fluoroalkyls.

8. In the case of (1) above, R ７ , R ８ , R ９ , and R １０ All of them are hydrogen, and R １１ and R １２ Deuterium and CD ３ A compound according to any one of claims 1 to 4, independently selected from the above.

9. In the case of (1) above, R ７ , R ８ , R ９ , and R １０ All are deuterium, and R11 and R12 are CH3, or in the case of (2) above, R １１ and R １２ is hydrogen and CH ３ A compound according to any one of claims 1 to 4, independently selected from the above.

10. In the case of (1) above, R ７ , R ８ , R ９ , and R １０ All of them are deuterium, and R １１ and R １２ Deuterium and CD ３ A compound according to any one of claims 1 to 4, selected from or, in the case of (2) above, R 11 and R 12 are selected from deuterium and CD 3.

11. The compound according to any one of claims 1 to 10, in the case of (1) above, wherein A is deuterium.

12. R １９ CF ３ CHF ２ CD ２ H, CDH ２ CD ３ , and CD ２ CD ３ A compound according to any one of claims 1 to 10, selected from the above.

13. In the case of (1) above, A is hydrogen, deuterium, OCH ３ OCD ３ OCF ３ , and OCHF ２ A compound according to any one of claims 1 to 10, selected from or in the case of (2) above, wherein A is selected from OCD3, OCF3, and OCHF2.

14. The compound according to claim 1, wherein the compound of formula (I-A) is selected from the compounds listed below or their pharmaceutically acceptable salts and / or solvates: Table 1 Table 2 。

15. A pharmaceutical composition comprising one or more compounds described in any one of claims 1 to 14 and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition according to claim 15 for use in a method of treating a mental disorder, comprising administering one or more of the compounds to a subject in need of treatment.

17. The pharmaceutical composition according to claim 16, wherein the mental disorder is selected from anxiety disorders, depression, mood disorders, impulse control and addiction disorders, drug addiction, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), stress response syndrome, dissociative disorders, depersonalization disorders, compulsive disorders, sexual disorders and gender disorders, and somatic symptom disorders, and combinations thereof.

18. The pharmaceutical composition according to claim 15, for use in 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 one or more of the compounds to a subject in need of treatment.

19. The aforementioned CNS diseases, disorders, or conditions, and / or neurological diseases, disorders, or conditions include neurological diseases, including neurodevelopmental and neurodegenerative diseases, such as Alzheimer's disease, presenile dementia, senile dementia, vascular dementia, Lewy body dementia, cognitive impairment, Parkinson's disease, Parkinson's disease-related disorders, such as Parkinsonian dementia, corticobasal degeneration, and supranuclear palsy, epilepsy, CNS trauma, CNS infection, CNS inflammation, stroke, multiple sclerosis, Huntington's disease, mitochondrial disease, fragile X syndrome, Angelman syndrome, hereditary ataxia, and neuro-otology. The pharmaceutical composition according to claim 18, selected from eye disorders and oculomotor disorders, neurodegenerative diseases of the retina, amyotrophic lateral sclerosis, tardive dyskinesia, hyperactivity disorder, attention deficit hyperactivity disorder and attention deficit disorder, restless legs syndrome, Tourette syndrome, schizophrenia, autism spectrum disorder, tuberous sclerosis, Rett syndrome, cerebral palsy, eating disorders such as anorexia nervosa (AN) and bulimia nervosa (BN), and bulimia nervosa (BED), trichotillomania, self-injurious dermatitis, nail biting, migraine, fibromyalgia, peripheral neuropathy of any etiology, and combinations thereof.

20. A pharmaceutical composition comprising the compound described in any one of claims 1 to 14 and an additional therapeutic agent.

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