Psilosine derivatives as serotonergic hallucinogens for the treatment of central nervous system disorders

Abstract

The present invention provides compounds and pharmaceutical compositions for treating conditions that are treated by activation of serotonin receptors, such as neurological diseases, disorders, and conditions including mental illnesses. [Solution] The psilocine derivative of formula (I) can be used for the activation of serotonin receptors in cells, and for the treatment of diseases, disorders, or symptoms caused by the activation of serotonin receptors in cells. JPEG2026053405000073.jpg79118

Description

[Technical Field]

[0001] This application relates to novel psilocine derivatives of formula (I) for the treatment of various conditions treated by activation of serotonin receptors, such as mental disorders and other neurological diseases, disorders, and conditions, in the fields of psychiatry, neurobiology, and pharmacotherapy. This application further includes methods for preparing compounds of formula (I) and corresponding intermediates. [Background technology]

[0002] This application claims priority from the co-pending U.S. Provisional Patent Application 62 / 969,934, filed on 4 February 2020. 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 wide range 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, commercially available medications offer only limited benefit compared to placebo, and some patients require up to six weeks to return to work. They also 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 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 their use in early cultures in many sociocultural and ritualistic contexts. Following the discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD) 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 long-lasting effects following their acute impact, including changes in mood and brain function. These prolonged effects may stem from the hallucinogen's unique receptor affinity, which influences 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 common 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 does not occur after taking typical doses of classic hallucinogens such as LSD, psilocybin, or mescaline (Scheme 1). Preliminary data show that administration of hallucinogens in humans produced a unique profile of effects and potential adverse reactions that need to be appropriately addressed to maximize safety. The primary safety concerns are primarily psychological rather than physiological. 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-HT2A 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 (i), LSD (ii), psilocybin (iii), and psilocin (iv)

[0008] Classical and dissociative hallucinogens are known to possess rapidly onset antidepressant and antiaddictive effects, unlike any other treatment currently available. Randomized controlled clinical studies 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 studies and is in the early stages of clinical trials to determine its efficacy in robust human trials [Barsuglia et al., Prog Brain Res, 2018, 242:121-158; Corkery, Prog Brain Res, 2018, 242:217-257].

[0009] Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine (iii, scheme 1)) is 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 the study of 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 metabolite, psilocine, or 4-hydroxy-N,N-dimethyltryptamine (iv, scheme 1). Psilocine likely accounts for most, or partially, 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 investigate 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 K(i) 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 studies 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 psychotherapeutic 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 studies 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 is still strong research and therapeutic potential for psilocybin. Psilocybin is also useful as a psychosis model for the development of new treatments for mental disorders [Dubovyk and Monahan-Vaughn, ACS Chem. Neurosci., 2018, 9(9):2241-2251].

[0013] Recent developments in this field have occurred in clinical research, where several double-blind, placebo-controlled phase 2 trials of psilocybin 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-dependent functional magnetic resonance imaging and magnetoencephalography have been used for in vivo brain imaging in humans after hallucinogen administration, and 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 that depend 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 efficacy is mixed and limited, often failing 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 poorly addressed by conventional methods.

[0016] Generally, the hallucinogenic therapy model involves administering an orally effective drug 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 over the past 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., Psychopharmacol. 2014, 28(11):983-992], significantly higher than any reported in the tobacco smoking cessation literature. Notably, the mystical kind of experience generated from psilocybin sessions was significantly correlated with positive treatment outcomes. These results are also consistent with the surge of 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 withdrawal during long-term follow-up compared to controls. More recently, a large US population study of 44,000 participants 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 these preliminary findings regarding the use of classic hallucinogens, given the potential toxicity of hallucinogens, further research is warranted 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 consideration of its use 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 recurrent depression. Brain regions with increased functional connectivity to poor sleep scores and higher depressive symptom scores include the prefrontal cortex and limbic system, areas involved in emotion processing. Sleep disturbance in healthy participants has shown 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 brain regions to 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 depressive symptoms, suggesting that this is achieved by 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, improving well-being, and improving 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 therapy, demonstrating that adjunctive hallucinogen therapy could produce rapid, robust, and persistent improvements in cancer-related psychological and existential distress [Ross S, 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 suffering should be a central goal of palliative care. Therefore, several standardized psychotherapies for cancer-related existential distress have been developed in recent years, emphasizing 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 remains a need for more effective treatments for these conditions [Rosenbaum et al., Curr. Oncol., 2019, 26(4): 225-226].

[0021] In recent years, there has been growing interest in a new 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 are 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] Psychosis is often described as an abnormal state of mind characterized by hallucinatory experiences, paranoid thinking, and disjointed thinking. Furthermore, this state is accompanied by impaired social cognition, inappropriate expression of emotions, and bizarre behavior. In most cases, psychosis arises as part of a mental disorder, and among these, psychosis represents an integral part of schizophrenia. Psychosis corresponds to the most florid phase of the disease. The very first manifestation of psychosis in a patient is called first-episode psychosis. This reflects a crucial transitional stage toward the chronic establishment of the disorder, likely mediated by progressive structural and functional abnormalities observed in diagnosed patients [ACS Chem. Neurosci. 2018, 9, 2241-2251]. Case evidence suggests that low, non-hallucinogenic doses of hallucinogens (microdosing), administered regularly, can reduce the symptoms of schizophrenia and psychosis. [Overview of the project] [Means for solving the problem]

[0023] This application includes a compound having the general structural formula (I) or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof. [Chemical formula] Here, R 1 is selected from hydrogen, C1-C3 alkyl, C1-C6 alkylene P(O)(OR 12 )2, C(O)R 12 , CO2R 12 , C(O)N(R 12 )2, S(O)R 12 , and SO2R 12 ; R 2 ~R 6 are independently selected from hydrogen and C1-C6 alkyl; R 7 and R 8 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or R 7 and R 8 together with the nitrogen atom existing between them, optionally form a 3- to 7-membered heterocycle containing 1 to 2 additional ring hetero moieties selected from O, S, S(O), SO2, N, and NR 13 , wherein the C3-C7 cycloalkyl and the 3- to 7-membered heterocycle each further optionally contains halogen, CO2R 13 , C(O)N(R 13 )2, SO2R 13 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, and O, S, N, S(O), SO2, and NR 13Substituted with substituents selected from 3- to 6-membered heterocycles containing 1-2 ring heteromolets selected from; R 9 , R 10 , and R 11 is hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, CO2R 13 , C(O)N(R 13 )2, SOR 13 SO2R 13 , C2-C6 alkenyls, C2-C6 alkynyls, C2-C6 haloalkynyls, C3-C7 cycloalkyls, as well as O, S, S(O), SO2, N, and NR 13 A 3- to 7-membered heterocycle containing 1 to 2 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- to 7-membered heterocycle group are optionally CN, OR 13 , N(R 13 )2, and SR 13 Substituting with one or more substituents independently selected from, and the C3-C7 cycloalkyl and 3- to 7-membered heterocycles are further optionally, halogens, CO2R 13 , C(O)N(R 13 )2, SO2R 13 , 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 13 Substituted with substituents selected from 3- to 6-membered heterocycles containing 1-2 ring heteromolets selected from; Y is selected from halogen and XA; X is O, NR 13 Selected from S, S(O), and SO2; A is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C6 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, P(O)(OR 12 )2, C1~C6 alkylene P(O)(OR 12 )2, selected from C1-C6 alkylene, C3-C7 cycloalkyl, C1-C6 alkylene, C4-C6 cycloalkenyl, C1-C6 alkylene heterocycloalkyl, C1-C3 alkylene aryl, C1-C6 alkylene heteroaryl, C(O)Q', CO2Q', C(O)N(Q')2, S(O)Q', and SO2Q'. Here, Q' is C1-C20 alkyl, C1-C20 haloalkyl, C2-C20 alkenyl, C2-C20 haloalkenyl, C2-C20 alkynyl, C2-C20 haloalkynyl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, as well as O, S, S(O), SO2, N, and NR 13 Selected from a 3- to 7-membered heterocycle containing 1 to 2 ring heteromolets selected from, where the C1-C20 alkyl group, C2-C20 haloalkyl group, C2-C20 alkenyl group, C2-C20 haloalkenyl group, C3-C7 cycloalkyl group, C4-C7 cycloalkenyl group, and 3- to 7-membered heterocyclic group are optionally CN, OR 13 , N(R 13 )2, CO2R 13 , SR 13 , substituted with one or more substituents independently selected from C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3-membered-7-membered heterorings, and / or disubstituted on the same carbon atom by C1-C6 alkyl or by C2-C6 alkylene to form a C3-C7 cycloalkyl ring, and each of the C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3-membered-7-membered heterorings is further optionally substituted with substituents selected from C1-C3 alkyl and C1-C3 haloalkyl; Each R 12This is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C6 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C6 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C6 alkylene aryl, and substituted or unsubstituted C1-C6 alkylene heteroaryl; Each R 13 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. 14 Independently selected from a 3- to 7-membered heterocycle containing 1 to 2 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- to 7-membered heterocyclic group are CN, OR 14 , N(R 14 )2, and SR 14 Optionally substituted with one or more substituents independently selected from, where the C3-C7 cycloalkyl and 3-7 membered heterocycles are, respectively, halogens, CO2R 14 , C(O)N(R 14 )2, SO2R 14 , 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 14 It is further optionally substituted with substituents selected from 3- to 6-membered heterocycles containing 1 to 2 ring heteromolets selected from the above, R 14This is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, 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. However, R 1 is C1~C6P(O)(OR 12 )2 and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 Q', X, Y, and A are as defined above for equation (I); or Y is XA, where A is C1~C6 alkylene P(O)(OR 12 )2, selected from C1-C6 alkylene, C3-C7 cycloalkyl, C1-C6 alkylene, C4-C6 cycloalkenyl, C1-C6 alkylene heterocycloalkyl, C1-C3 alkylene aryl, C1-C6 alkylene heteroaryl, C(O)Q', CO2Q', C(O)N(Q')2, S(O)Q', and SO2Q', and 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 13 , and R 14, Q’, and X are as defined above for formula (I).

[0024] In some embodiments, the compounds of formula (I) and their pharmaceutically acceptable salts, solvates, and / or prodrugs are isotopically enriched with deuterium. In some embodiments, one or more of A, X, Q’, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 contains one or more deuteriums, or one or more of A, X, Q’, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is deuterium.

[0025] In a further embodiment, the compounds of the present application are used as medicaments. Accordingly, the present application also includes the compounds of the present application for use as medicaments.

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

[0027] The present application also includes a method for treating a mental disorder, comprising administering to a subject in need of treatment for a mental disorder a therapeutically effective amount of one or more compounds of the present application.

[0028] 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 requiring treatment for mental illness.

[0029] The present invention also includes a method for treating a central nervous system disorder, disorder, or condition, and / or a neurological disorder, disorder, or condition, comprising administering a therapeutically effective amount of one or more compounds of the present invention to a subject requiring such treatment.

[0030] This application further provides a method for preparing the compound. The general and specific processes are described in more detail below and in the examples described later.

[0031] Other features and advantages of the present application will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while 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]

[0032] Embodiments of the present invention will be described in more detail hereafter with reference to the attached drawings. Here,

[0033] [Figure 1] Figure 1 is a graph showing the effects of various doses of compound I-28, an example compound of formula I, on the head-twitch response (HTR) in male C57BL6 mice. Mice were treated orally (PO) with compound I-28 (1-100 mg / kg) (N=6 mice per dose), and the total number of head twitches was recorded over a 1-hour period. Data are expressed as mean ± mean standard error (SEM). The induction of head twitches by 5-HT2A receptor agonists is thought to represent a behavioral proxy for their hallucinogenic effects.

[0034] [Figure 2] Figure 2 is a graph showing the effect of various doses of the metabolite (MSP=1007) of I-45, an example compound of formula I, on the head-twitch response (HTR) in male C57BL6 mice. Mice were treated with compound MSP-1007 (0.03-10 mg / kg) via subcutaneous injection (SC) (N=6 mice per dose), and the total number of head twitches was recorded over a 1-hour period. Data are expressed as mean ± mean standard error (SEM). The induction of head twitches by 5-HT2A receptor agonists is thought to represent a behavioral proxy for their hallucinogenic effects. [Modes for carrying out the invention]

[0035] I. Definition Unless otherwise stated, the definitions and embodiments set forth in this section and other sections are intended to be applicable to all embodiments and aspects of the present application described in this disclosure to which they are applicable. This will be understood by those skilled in the art.

[0036] As described herein, “the Compounds of this Application” (single or multiple) refers to the Compounds of Formula (I) and the Compounds of Formulas (IA) to (II), as well as their pharmaceutically acceptable salts, solvates, and / or prodrugs.

[0037] 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.

[0038] As used in this disclosure, the term "and / or" means that the listed items exist or are used individually or in combination. Substantively, the term means that "at least one" or "one or more" of the listed items are used or exist. With respect to pharmaceutically acceptable salts, solvates, and / or prodrugs, the term "and / or" means that the compounds of the Application exist as individual salts, solvates, and prodrugs, as well as in combinations such as salts of solvates of the compounds of the Application.

[0039] 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.

[0040] As used in this application and claims, the words “comprising” (and any form of “comprising,” e.g., “comprising” (with or without the third-person singular s)), “having” (and any form of “having,” e.g., “having” (with or without the third-person singular s)), “including” (and any form of “including,” e.g., “including” (with or without the third-person singular s)), and “containing” (and any form of “containing,” e.g., “containing” (with or without the third-person singular s)) are inclusive and open, and do not exclude additional, undescribed elements or process steps.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] As used in this disclosure, the term “suitable” (“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 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 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.

[0045] 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 does not change significantly. These terms relating to degree should be interpreted as including a deviation of at least ±5% from the modified word, unless the context suggests otherwise, provided that the deviation does not negate the meaning of the word modified by the term.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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 “Cn1-Cn2”. Thus, for example, the term “C1-C6 alkyl” (or “C1-C6 alkyl”) means an alkyl group having 1, 2, 3, 4, 5, or c carbon atoms, and includes, for example, any isotopes of hexylalkyl and pentylalkyl, as well as n-, iso-, sec-, and ter-butyl, n- and isopropyl, ethyl, and methyl. Another example is “C4 alkyl,” which refers to n-, iso-, sec-, and tert-butyl, n- and isopropyl, ethyl, and methyl.

[0050] 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 carbon atoms possible in the alkylene group of interest is indicated by the prefix "Cn1~n2". Therefore, for example, the term "C2~6 alkylene" refers to an alkylene group having 2, 3, 4, 5, or 6 carbon atoms.

[0051] As used in this disclosure, the term "alkynyl," whether used alone or as part of another group, means a linear or branched unsaturated alkynyl group containing at least one triple bond. The number of carbon atoms possible in the alkyl group of interest is indicated by the prefix "Cn1~n2." For example, the term C2~6 alkynyl means an alkynyl group having two, three, four, five, or six carbon atoms.

[0052] As used in this disclosure, the term "cycloalkyl," whether used alone or as part of another group, means a saturated carbocyclic group containing 3 to 20 carbon atoms and one or more rings. The number of carbon atoms possible in the cycloalkyl group of interest is indicated by the prefix "Cn1-n2." For example, the term C3-10 cycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0053] 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.

[0054] 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 substituents.

[0055] 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, wherein 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). When the heterocycloalkyl group includes the prefix Cn1~n2 or “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 heteromolets selected from O, S, S(O), SO2, and N, and the remaining atoms are C. The heterocycloalkyl group is optionally benzo-fused.

[0056] 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. When the heteroaryl group is prefixed with the prefixes Cn1 to n2, the prefix represents the number of carbon atoms in the corresponding carbocyclic group, where one or more, preferably 1 to 5, of the ring atoms are replaced by the heteroatoms defined above. The heteroaryl group is optionally benzo-fused.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] The statement that the first ring "bridges" the second ring means that the first and second rings share two non-adjacent atoms between them.

[0061] The first ring is said to be "spiro-fused" with the second ring, meaning that the first and second rings share one atom with each other.

[0062] 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.

[0063] 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, "C1-6 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.

[0064] 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, "C1-C6 haloalkenyl" (or "C1-C6 haloalkenyl") refers to a linear or branched C1-C6 alkenyl group as defined above, having one or more halogen substituents.

[0065] 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 a halogen. Therefore, for example, "C1-C6 haloalkynyl" (or "C1-C6 haloalkynyl") refers to a linear or branched C1-C6 alkynyl group as defined above, having one or more halogen substituents.

[0066] As used in this disclosure, the term "alkoxy" includes alkyl groups linked to an oxygen-linked atom, either alone or in combination.

[0067] 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.

[0068] As used in this disclosure, the term "substituted" means that the group of interest is substituted with one or more substituents independently selected from halogens, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, SO2CH3, SOCH3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocycles containing one or two ring heteromolets selected from O, S, S(O), SO2, N, NH, and NCH3.

[0069] As used in this disclosure, the term "alternative isotope" refers to an isotope of an element other than the isotope that is most abundant in nature.

[0070] In compounds of general formula (I) and their pharmaceutically acceptable salts, solvates, and / or prodrugs, atoms may exhibit their natural isotopic abundance, or one or more 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 (I) and their pharmaceutically acceptable salts, solvates, and / or prodrugs. For example, different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H), and tritium (3H). Protium is the primary hydrogen isotope found in nature.

[0071] As used in this disclosure, “all available atoms are optionally replaced by alternative isotopes” means that any available atom is optionally replaced by an isotope of the atom having the same atomic number but having an atomic mass or mass number different from that which is primarily found in nature.

[0072] 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 the Application are limited to stable compounds encompassed by general formula (I), or their pharmaceutically acceptable salts, solvates, and / or prodrugs.

[0073] The term "medically acceptable" means suitable for treating the subject.

[0074] 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.

[0075] The term "medically acceptable salt" means an acid addition salt or base addition salt that is suitable or appropriate for treating the subject.

[0076] 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.

[0077] A suitable or appropriate base addition salt for treating the target is any non-toxic organic or inorganic base addition salt of any acidic compound. 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, e.g., “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).

[0078] 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.

[0079] As is well known in this disclosure and in the art, the terms “to treat” or “treatment” mean a method for obtaining beneficial or desired outcomes, such as clinical outcomes. 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 disease conditions, reduction of disease recurrence and remission (whether partial or complete), and may be detectable or undetectable. “To treat” and “treatment” may also mean extended survival time compared to 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 includes administering therapeutically effective doses of one or more of the compounds of the present application to a target, which may optionally consist of a single dose or a series of multiple doses.

[0080] As used in this disclosure, the terms “effective dose” or “therapeutic effective dose” mean the effective amount of one or more compounds of the Application in the dosage and duration required to achieve the desired outcome. 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.

[0081] To “reduce” 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.

[0082] As used in this disclosure, the term “administered” means administering a therapeutically effective dose of one or more of the compounds or compositions of this application to a cell, tissue, organ, or subject.

[0083] 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 the risk or probability that will exhibit symptoms associated with a disease, disability, or condition.

[0084] 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, particularly by using a serotonin receptor agonist such as one or more of the compounds described herein.

[0085] 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 favorably to stimulation of disease, disorder, or condition-related serotonergic activity by one or more of the compounds or compositions of the Application.

[0086] As used in this disclosure, the term "activation" encompasses serotonin receptor agonism, partial agonism, and positive allosteric regulation.

[0087] The term "5-HT" is used in this disclosure.2A " refers to the 5-HT2 serotonin receptor, specifically the 5-HT2 serotonin receptor. 2A This refers to receptor subtypes.

[0088] 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.

[0089] II. Compounds This application includes compounds of formula (I) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [ka] In the formula, R 1 This is hydrogen, C1-C3 alkyl, C1-C6 alkylene P(O)(OR 12 )2, C(O)R 12 CO2R 12 , C(O)N(R 12 )2, S(O)R 12 , and SO2R 12 Selected from; R 2 ~R 6 It is independently selected from hydrogen and C1-C6 alkyl groups; R 7 and R 8 These are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or R 7 and R 8 Along with the nitrogen atoms present between them, O, S, S(O), SO2, N, and NR 13 It forms a 3- to 7-membered heteroring that optionally includes 1 to 2 additional ring heterostructures selected from the above. Here, the C3-C7 cycloalkyl and 3- to 7-membered heterocycles are, respectively, halogens and CO2R. 13 , C(O)N(R 13 )2, SO2R 13 , 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, N, S(O), SO2, and NR 13 It may be further optionally substituted by substituents selected from a 3- to 6-membered heterocycle containing 1 to 2 ring heteromolets selected from; R 9 , R 10 , and R 11 is hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, CO2R 13 , C(O)N(R 13 )2, SOR 13 SO2R 13 , C2-C6 alkenyls, C2-C6 alkynyls, C2-C6 haloalkynyls, C3-C7 cycloalkyls, as well as O, S, S(O), SO2, N, and NR 13 A 3- to 7-membered heterocycle containing 1 to 2 ring heterostructures selected from the following, 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 heterocycle group are optionally CN, OR 13 , N(R 13 )2, and SR 13 Substituted by one or more substituents independently selected from, and the C3-C7 cycloalkyl and 3- to 7-membered heterocycles are, respectively, halogens, CO2R 13 , C(O)N(R 13 )2, SO2R 13, 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 13 A 3- to 6-membered heteroring containing 1 to 2 ring heteromolets selected from, further optionally substituted by substituents selected from; Y is selected from halogen and XA; X is O, NR 13 Selected from S, S(O), and SO2; A is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C6 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, P(O)(OR 12 )2, C1~C6 alkylene P(O)(OR 12 )2, selected from C1-C6 alkylene, C3-C7 cycloalkyl, C1-C6 alkylene, C4-C6 cycloalkenyl, C1-C6 alkylene heterocycloalkyl, C1-C3 alkylene aryl, C1-C6 alkylene heteroaryl, C(O)Q', CO2Q', C(O)N(Q')2, S(O)Q', and SO2Q', Here, Q' is C1-C20 alkyl, C1-C20 haloalkyl, C2-C20 alkenyl, C2-C20 haloalkenyl, C2-C20 alkynyl, C2-C20 haloalkynyl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, as well as O, S, S(O), SO2, N, and NR 13 A 3- to 7-membered heterocycle containing 1 to 2 ring heteromolets selected from, where the C1-C20 alkyl group, C2-C20 haloalkyl group, C2-C20 alkenyl group, C2-C20 haloalkenyl group, C3-C7 cycloalkyl group, C4-C7 cycloalkenyl group, and 3- to 7-membered heterocyclic group are optionally CN, OR 13 , N(R 13 )2, CO2R 13 , SR 13, substituted with one or more substituents independently selected from C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3-membered-7-membered heterorings, and / or disubstituted on the same carbon atom with C1-C6 alkyl or with C2-C6 alkylene to form a C3-C7 cycloalkyl ring, each of the C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3-membered-7-membered heterorings, each further optionally substituted with substituents selected from C1-C3 alkyl and C1-C3 haloalkyl; Each R 12 This is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C6 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C6 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C6 alkylene aryl, and substituted or unsubstituted C1-C6 alkylene heteroaryl; Each R 13 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. 14 A 3- to 7-membered heterocycle containing 1 to 2 ring heteromolets is independently selected from the following, 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 optionally CN, OR 14 , N(R 14 )2 and SR 14Substituting with one or more substituents independently selected from, and the C3-C7 cycloalkyl and 3- to 7-membered heterocycles are further optionally, halogens, CO2R 14 , C(O)N(R 14 )2, SO2R 14 , 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 14 Substituting with substituents selected from 3- to 6-membered heterocycles containing 1 to 2 ring heteromolets selected from, R 14 This is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and, All available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes. However, R 1 is C1~C6P(O)(OR 12 )2, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 Q', X, Y, and A are as defined above for equation (I); or, Y is XA, and A is C1~C6 alkylene P(O)(OR 12)2, selected from C1-C6 alkylene, C3-C7 cycloalkyl, C1-C6 alkylene, C4-C6 cycloalkenyl, C1-C6 alkylene heterocycloalkyl, C1-C3 alkylene aryl, C1-C6 alkylene heteroaryl, C(O)Q', CO2Q', C(O)N(Q')2, S(O)Q', and SO2Q', and 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 13 , and R 14 Q' and X are defined above for equation (I).

[0090] This application includes compounds of formula (I), or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [ka] During the ceremony: R 1 This is hydrogen, C1-C3 alkyl, -(CH2)P(O)(OR 12 ); CO(R 12 ), COO(R 12 ), C(O)N(R 12 )2, SO(R 12 ), and SO2(R 12 Selected from the group consisting of; R 2 ~R 6 It is independently selected from the group consisting of hydrogen and lower alkyl groups; R 7 and R 8R is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. 7 and R 8 Along with the atoms to which they bond, O, S, SO2, N, and NR 13 A 3- to 7-membered heteroring is formed, comprising 1 to 2 ring members selected from the group consisting of the following, where the C3-C7 cycloalkyl and the 3- to 7-membered heteroring are each optionally further comprising C1-C3 alkyl and C1-C3 haloalkyl, halogen, CN, OR 13 , N(R 13 )2, COOR 13 , C(O)N(R 13 )2, SR6, SO2R 13 , 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, N, and N(R) 13 Substituted by a member of a group consisting of a 3- to 6-membered heterocycle containing 1 to 2 ring members selected from the group consisting of ), where C1-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl; R 9 , R 10 , and R 11 is hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-C6 alkyl, C1-C6 haloalkyl, OR 13 C1-C6 alkyl groups substituted with SR 13 C1-C6 alkyl, N(R) substituted 13 )2-substituted C1-C6 alkyl, C2-C6 haloalkyl, COOR 13 , C(O)N(R 13 )2, SO2R 13 COOR 13 , C(O)N(R 13)2, SO2R 13 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl, as well as O, S, N, and N(R) 13 A group consisting of 3- to 67-membered heterocycles containing 1 to 2 ring members selected from the group consisting of ), 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 optionally CN, OR 13 , N(R 13 )2, and SR 13 The C3-C7 cycloalkyl and 3- to 7-membered heterorings are substituted with one or more substituents independently selected from the group consisting of the following, and the C3-C7 cycloalkyl and 3- to 7-membered heterorings are further optionally substituted with C1-C3 alkyl and C1-C3 haloalkyl, halogen, CN, OR 13 , N(R 13 )2, COOR 13 , C(O)N(R 13 )2, SR 13 SO2R 13 , 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, N, and N(R) 13 Substituted by a member of a group consisting of a 3- to 6-membered heterocycle containing 1 to 2 ring members selected from the group consisting of ), where C1-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl; X is O, NR 13 Selected from S, SO, and SO2; Here, R 12This is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 13 C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl, OR 13 C1-C6 alkyl groups substituted with SR 13 C1-C6 alkyl, N(HR) substituted 13 ) N(R 13 )2-substituted C1-C6 alkyl, C2-C6 haloalkyl, COOR 13 , C(O)N(R 13 )2, SO2R 13 COOR 13 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C7 cycloalkyl, as well as O, S, N, and N(R) 13 Selected from the group consisting of 3- to 7-membered heterocycles containing 1 to 2 ring members selected from the group consisting of ), 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 heterocycle group are optionally CN, OR 13 , N(R 13 )2, and SR 13 The C3-C7 cycloalkyl and 3- to 7-membered heterorings are substituted with one or more substituents independently selected from the group consisting of the following, and the C3-C7 cycloalkyl and 3- to 7-membered heterorings are further optionally substituted with C1-C3 alkyl and C1-C3 haloalkyl, halogen, CN, OR 13 , N(R 13 )2, COOR 13 , C(O)N(R 13 )2, SR 13 SO2R13 , 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, N, and N(R) 13 Substituted by a member of a group consisting of a 3- to 6-membered heterocycle containing 1 to 2 ring members selected from the group consisting of ), where C1-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl; and A is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heterocycloalkynylaryl, heteroaryl, C0~C1P(O)(OR 12 )2, CO(Q'), COO(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), where Q' is selected from hydrogen, C1-C20 alkyl, C1-C20 haloalkyl, C2-C20 alkenyl, C2-C20 haloalkenyl, C2-C20 alkynyl, C2-C20 haloalkynyl, C3-C7 cycloalkyl, as well as O, S, N, and N(R) 13 A 3- to 7-membered heterocycle containing 1 to 2 ring members selected from the group consisting of ), where the C1-C20 alkyl group, C2-C20 haloalkyl group, C2-C6 alkenyl group, C2-C20 haloalkenyl group, C3-C7 cycloalkyl group, and 3- to 7-membered heterocyclic group are optionally CN, OR 13 , N(R 13 )2, and SR 13 The C3-C7 cycloalkyl and 3- to 7-membered heterorings are each optionally substituted with members of the group consisting of C1-C3 alkyl and C1-C3 haloalkyl; and R 12 and R 13 These are defined independently as described above.

[0091] In some embodiments, if all available hydrogen atoms in the group of the compound of formula I are optionally replaced by halogen atoms, the halogen atoms are F, Cl, or Br. In some embodiments, if all available hydrogen atoms in the group are optionally replaced by halogen atoms, the halogen atoms are F or Br. In some embodiments, if all available hydrogen atoms in the group are optionally replaced by halogen atoms, the halogen atoms are F.

[0092] Therefore, in some embodiments, all available hydrogen atoms are optionally replaced with fluorine, chlorine, or bromine atoms, and / or all available atoms are optionally replaced with their alternative isotopes. In some embodiments, all available hydrogen atoms are optionally replaced with halogen or bromine atoms, and / or all available atoms are optionally replaced with their alternative isotopes. In some embodiments, all available hydrogen atoms are optionally replaced with halogen or chlorine atoms, and / or all available atoms are optionally replaced with their alternative isotopes. In some embodiments, all available hydrogen atoms are optionally replaced with halogen atoms, and / or all available atoms are optionally replaced with their alternative isotopes. In some embodiments, all available hydrogen atoms are optionally replaced with halogen atoms, and / or all available hydrogen atoms are optionally replaced with deuterium. In some embodiments, all available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by deuterium.

[0093] In some embodiments, all available hydrogen atoms are optionally replaced with their alternative isotopes. In some embodiments, the alternative isotope for hydrogen is deuterium. Thus, in some embodiments, the compounds of the present application are isotopeally enriched with deuterium. In some embodiments, A, X, Q', R 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 One or more of these contain one or more deuterium atoms, or A, X, Q', 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 13 , and R 14 One or more of them are deuterium.

[0094] In some embodiments, R 1 This is hydrogen, C1-C3 alkyl, C1-C3 alkylene P(O)(OR 12 )2, C(O)R 12 CO2R 12 , C(O)N(R 12 )2, S(O)R 12 and SO2R 12 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. In some embodiments, R 1 S(O)R 12 , and SO2R 12 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. In some embodiments, R 1 These are hydrogen, C1-C3 alkyl, CH2P(O)(OR 12 )2, CH2CH2P(O)(OR 12)2, CH2CH(CH3)P(O)(OR 12 )2, CH(CH3)CH2P(O)(OR 12 )2, CH(CH3)P(O)(OR 12 )2, CH(CH2CH3)P(O)(OR 12 )2, C(O)R 12 CO2R 12 , and C(O)N(R 9 ) 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, C1-C3 alkyl, CH2P(O)(OR 12 )2, CH2CH2P(O)(OR 12 )2, CH2CH(CH3)P(O)(OR 12 )2, CH(CH3)CH2P(O)(OR 12 )2, CH(CH3)P(O)(OR 12 )2, CH(CH2CH3)P(O)(OR 12 )2, C(O)R 12 , and CO2R 12 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. In some embodiments, R 1 is hydrogen, CH3, CH2CH3, CH(CH3)2, CH2P(O)(OR 12 )2, and CH(CH3)P(O)(OR 12 ) 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 1is selected from hydrogen, deuterium, F, CH3, CF3, CD3, CH2CH3, CD2CD3, CF2CF3, CH(CH3)2, CD(CD3)2, CF(CF3)2, C(CD3)3, C(CF3)3, and C(CH3)2. In some embodiments, R 1 R is selected from hydrogen, deuterium, CH3, CF3, and CD3. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is CH2P(O)(OR 12 )2 and CH(CH3)P(O)(OR 12 ) 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 CH(CH3)P(O)(OR 12 )2. In some embodiments, R 1 is CH2P(O)(OR 12 )2.

[0095] In some embodiments, R 2 ~R 6 R is independently selected from hydrogen and C1-C4 alkyl groups, 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 is selected from hydrogen, CH3, CH2CH3, CH(CH3)2, and C(CH3)3, 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 2R is selected from hydrogen, 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 2 R is selected from hydrogen and deuterium, Br, F, CH3, CF3, CH2CH3, CD2CD3, CF2CF3, CH(CH3)2, CD(CD3)2, CF(CF3)2, C(CD3)3, C(CF3)3, and C(CH3)3. In some embodiments, R 2 R is selected from hydrogen and deuterium. In some embodiments, R 2 It is hydrogen.

[0096] In some embodiments, R 3 , R 4 , R 5 , and R 6 R is independently selected from hydrogen, CH3, CH2CH3, CH(CH3)2, and C(CH3)3, 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 3 , R 4 , R 5 , and R 6 R is independently selected from hydrogen, CH3, CH2CH3, CH(CH3)2, and C(CH3)3, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, R 3 , R 4 , R 5 , and R 6 At least one of them is deuterium, or R 3 , R 4 , R 5 , and R 6At least one of them contains deuterium. In some embodiments, R 3 and R 4 at least one of or R 5 and R 6 At least one of them is deuterium, or R 3 and R 4 at least one of or R 5 and R 6 At least one of them contains deuterium. In some embodiments, R 3 , R 4 , R 5 , and R 6 R is independently selected from hydrogen, deuterium, Br, F, CH3, CD2H, CDH2, CD3, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 3 , R 4 , R 5 , and R 6 R 4 R is independently selected from hydrogen, deuterium, F, CH3, CD2H, CDH2, and CD3. In some embodiments, R 3 , R 4 , R 5 , and R 6 R is independently selected from hydrogen, deuterium, F, CH3, and CD3. In some embodiments, R 3 , R 4 , R 5 , and R 6 is independently selected from hydrogen, deuterium, and F. In some embodiments, R 3 , R 4 , R 5 , and R 6 At least one of them is F. In some embodiments, R 3 and R 4 At least one of the following, or R 5 and R 6 At least one of them is deuterium. In some embodiments, R 3 , R 4 , R 5 , and R 6 At least one of them is deuterium. In some embodiments, R 3, R 4 , R 5 , and R 6 all are hydrogen. In some embodiments, R 3 , R 4 , R 5 , and R 6 They are all deuterium.

[0097] In some embodiments, R 7 and R 8 This is independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0098] In some embodiments, R 7 and R 8 The C3-C7 cycloalkyl group in 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.

[0099] In some embodiments, R 7 and R 8 In the above, the heterocycloalkyl is independently a substituted or unsubstituted heterocycle. In some embodiments, R 7 and R 8The heterocycloalkyl in is independently a substituted or unsubstituted bridged bicyclic heterocycle. In some embodiments, the substituted or unsubstituted bridged bicyclic heterocycle is independently selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl, and oxobicycloheptanenyl (heptanenyl), 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 7 and R 8 In the above, the heterocycloalkyl is independently a substituted or unsubstituted heterocycle. In some embodiments, R 7 and R 8 The heterocycloalkyl in is independently a substituted or unsubstituted bridged bicyclic heterocycle. In some embodiments, the substituted or unsubstituted bridged bicyclic heterocycle is independently selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl, and oxobicycloheptanenyl (heptanenyl), where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0101] In some embodiments, R 7 and R 8The heterocycloalkyls in this context are azilidinyl, oxylanil, thyranil, oxaxiridinyl, dioxylanil, azetidinyl, oxetanil, theitanyl, diazetidinyl, dioxetanil, dithietanyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil, dithiolanil, piperidinyl, triazolyl, and flazani. Independently selected from oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, diazinyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, and diazepanyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0102] In some embodiments, R 7 and R 8The heteroaryls in this context are azepinyl, benzoisoxazolyl, benzoflazanyl, benzopyranil, benzothiopyranil, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanil, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranil, dihydrobenzothiopyranil Sulfone, 1,3-dioxolanil, furyl, imidazolidinyl, imidazolinil, imidazolyl, indolinil, indolyl, isochromanil, isoindolinil, isoquinolinil, isothiazolidinil, isothiazolyl, isothiazolidinil, morpholinil, naphthilidinil, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, piperidyl, piperazinil, pyridyl, pyrazinil, pyrazolidinil, pyrazolyl, pyridadinil, pyrimidinil, pyrrolidinil, pyrrolyl, quinazolinil, quinolinil, quinoxalinil, tetrahydrofuryl, tetrahydroisoquinolinil, tetrahydroquinolinil, thiamorpholinil, thiamorpholinil A sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothenyl, triazolyl, and thienyl are independently selected, where all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0103] In some embodiments, R 7 and R 8 R is independently selected from hydrogen, C1-C4 alkyl, and C2-C6 alkenyl, 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 7 and R 8R is independently selected from hydrogen and C1-C4 alkyl groups, 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 7 and R 8 R is independently selected from hydrogen and C1-C4 alkyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, R 7 and R 8 R is independently selected from hydrogen, deuterium, Br, F, CH3, CF3, CD2H, CDH2, CD3, CH2CH3, CF2CF3, and CD2CD3. In some embodiments, R 7 and R 8 R is independently selected from hydrogen, deuterium, CH3, CD2H, CDH2, CD3, CH2CH3, and CD2CD3. In some embodiments, R 7 and R 8 R is independently selected from hydrogen, deuterium, CH3, CD3, CH2CH3, and CD2CD3. In some embodiments, R 7 and R 8 R is independently selected from CH3, CD3, CH2CH3, and CD2CD3. In some embodiments, R 7 and R 8 Both are CH3, CD3, CH2CH3, or CD2CD3. In some embodiments, R 7 and R 8 Both are CH3. In some embodiments, R 7 and R 8 Both are CD3. In some embodiments, R 7 and R 8 Both are CH2CH3. In some embodiments, R 7 and R 8 Both are CD2CD3.

[0104] In some embodiments, R 7 and R 8 These atoms, along with the nitrogen atoms present between them, form 3- to 7-membered heterorings, which optionally consist of O, S, S(O), SO2, N, and NR. 13 It comprises one or two additional 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. In some embodiments, R 7 and R 8 These atoms, along with the nitrogen atoms present between them, form a 4- to 7-membered heteroring, and this heteroring can optionally consist of O, S, S(O), SO2, N, and NR. 13 It comprises one or two additional 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. In some embodiments, R 7 and R 8 These, together with the nitrogen atoms present between them, form an azetidinyl ring, diazetidinyl ring, pyrrolidinyl ring, imidazolidinyl ring, pyrazolidinyl ring, thiazolidinyl ring, isothiozolidinyl ring, piperidinyl ring, diazinyl ring (e.g., piperazinyl), morpholinyl ring, or azepanyl ring, 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 7 and R 8These, together with the nitrogen atoms present between them, form pyrrolidinyl, piperidinyl, or diazinyl, 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 7 and R 8 These, together with the nitrogen atoms present between them, form pyrrolidinyl, piperidinyl, or diazinyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, R 7 and R 8 These atoms, together with the nitrogen atoms present between them, form pyrrolidinyl, piperidinyl, or diazinyl compounds, where all available hydrogen atoms are optionally replaced by deuterium.

[0105] R 7 and R 8 If R is substituted, in some embodiments the substituent is independently selected from one or more 3- to 6-membered heterocycles containing one or two ring heteromolets selected from Br, Cl, F, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, SO2CH3, C1-C4 alkyl, C1-C4 fluoroalkyl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, C2-C6 alkynyl, C2-C6 fluoroalkynyl, C3-C6 cycloalkyl, and O, S, S(O), SO2, N, NH, and NCH3. In some embodiments, R 7 and R 8 The substituents mentioned above are independently selected from one to three of Br, Cl, F, C1-C4 alkyl, C1-C4 fluoroalkyl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, C2-C6 alkynyl, and C2-C6 fluoroalkynyl. In some embodiments, R 7 and R 8The substituents mentioned above are independently selected from one or two of Br, Cl, F, CH3, and CF3.

[0106] In some embodiments, R 9 , R 10 and R 11 is hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 13 , C(O)N(R 13 )2, S(O)R 13 SO2R 13 , C2-C6 alkenyls, C2-C6 alkynyls, C2-C6 haloalkynyls, C3-C7 cycloalkyls, as well as O, S, S(O), SO2, N, and NR 13 A 3- to 7-membered heterocycle containing 1 to 2 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- to 7-membered heterocycle group are optionally CN, OR 13 , N(R 13 )2, and SR 13 The C3-C7 cycloalkyl and 3- to 7-membered heterocycles are substituted with one or more substituents independently selected from the C3-C7 cycloalkyl and CO2R cycloalkyl groups, respectively, which are further optionally substituted with halogens, CO2R cycloalkyl groups 13 , C(O)N(R 13 )2, SO2R 13 , 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 13The substituents are selected from a 3- to 6-membered heterocycle containing 1-2 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.

[0107] In some embodiments, R 9 , R 10 , and R 11 is hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 13 , C(O)N(R 13 )2, S(O)R 13 SO2R 13 A C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C2-C6 haloalkynyl group are independently selected, where the C1-C4 alkyl group, C1-C4 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, and C2-C6 haloalkynyl group are optionally CN, OR 13 , N(R 13 )2, and SR 13 Substituting with one or more substituents independently 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. In some embodiments, R 9 , R 10 , and R 11 These are hydrogen, F, Cl, Br, CN, OR 13 , N(R 13 )2, SR 13 , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 13 , C(O)N(R 13 )2, S(O)R 13 SO2R 13A C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C2-C6 haloalkynyl group are independently selected, where the C1-C4 alkyl group, C1-C4 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, and C2-C6 haloalkynyl group are optionally CN, OR 13 , N(R 13 )2, and SR 13 R is substituted with 1 to 3 substituents independently 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. In some embodiments, R 9 , R 10 , and R 11 These are hydrogen, F, Cl, Br, CN, OR 13 , N(R 13 )2, SR 13 CH3, CH2CH3, CH(CH3)2, C(CH3)3, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 13 , S(O)R 13 SO2R 13 , C(O)N(R 13 )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 optionally CN, OR 13 , N(R 13 )2, and SR 13 R is substituted with one or two substituents independently 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. In some embodiments, R 9 , R 10 , and R 11 These are hydrogen, F, Cl, Br, CN, OR 13 , N(R 13)2, SR 13 CH3, CH2CH3, CH(CH3)2, C(CH3)3, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 13 , S(O)R 13 SO2R 13 , and C2-C6 alkenyls are independently selected, 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 9 , R 10 , and R 11 R is independently selected from hydrogen, F, Cl, Br, and CN, 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 9 , R 10 , and R 11 R is independently selected from hydrogen, deuterium, F, Cl, Br, and CN. In some embodiments, R 9 , R 10 , and R 11 R is independently selected from hydrogen and deuterium. In some embodiments, R 9 , R 10 , and R 11 all are hydrogen. In some embodiments, R 9 , R 10 , and R 11 All of them are deuterium. In some embodiments, R 10 R is selected from hydrogen, deuterium, F, Cl, Br, and CN, 9 and R 11 R is selected from hydrogen and deuterium. In some embodiments, R 10 R is selected from hydrogen, deuterium, F, and CN, 9 and R 11 R is selected from hydrogen and deuterium. In some embodiments, R 10 R is selected from hydrogen, F, and CN, 9 and R11 R is selected from hydrogen and deuterium. In some embodiments, R 10 R is selected from hydrogen, F, and CN, 9 and R 11 Both are hydrogen.

[0108] In some embodiments, R 9 , R 10 , and R 11 The C3-C7 cycloalkyl group in 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.

[0109] In some embodiments, R 9 , R 10 , and R 11 The 3- to 7-membered heterorings in are independently substituted or unsubstituted heterorings. In some embodiments, R 9 , R 10 , and R 11 The 3- to 7-membered heterocycles in 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 (heptanenyl), 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 9 , R 10 , and R 11 The 3- to 7-membered heterorings in are independently substituted or unsubstituted heterorings. In some embodiments, R 9 , R10 , and R 11 The 3- to 7-membered heterocycles in 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 (heptanenyl), where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0111] In some embodiments, R 9 , R 10 , and R 11 The 3- to 7-membered heterocycles in the above are independently azilidinyl, oxylanil, thyranil, oxaxiridinyl, dioxylanil, azetidinyl, oxetanil, theitanyl, diazetidinyl, dioxetanil, dithietanyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil, dithiolanil, piperidinyl, triazolyl, Selected from fluzanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, diazinyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, and diazepanyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0112] Several embodiments, each R 12This is independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C4 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C4 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C4 alkylene aryl, and substituted or unsubstituted C1-C4 alkylene heteroaryl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0113] Several embodiments, each R 12 The C3-C7 cycloalkyl group 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.

[0114] Several embodiments, each R 12 The heterocycloalkyl group is independently a substituted or unsubstituted heterocycle. In some embodiments, R 12 The heterocycloalkyl in is a substituted or unsubstituted bridged bicyclic heterocycle. In some embodiments, the substituted or unsubstituted bridged bicyclic heterocycle is independently selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl, and oxobicycloheptanenyl (heptanenyl), where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0115] Several embodiments, each R 12 The aforementioned heterocycloalkyls are independently azilidinyl, oxylanil, thyranil, oxaxiridinyl, dioxylanil, azetidinyl, oxetanil, theitanyl, diazetidinyl, dioxetanil, dithietanyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil, dithiolanil, piperidinyl, triazolyl, and fura. Selected from zanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, diazinyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, and diazepanyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0116] Several embodiments, each R 12The aforementioned heteroaryls are independently azepinyl, benzoisoxazolyl, benzoflazanyl, benzopyranil, benzothiopyranil, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanil, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranil, dihydrobenzothiopyranil Sulfone, 1,3-dioxolanil, furyl, imidazolidinyl, imidazolinil, imidazolyl, indolinil, indolyl, isochromanil, isoindolinil, isoquinolinil, isothiazolidinil, isothiazolyl, isothiazolidinil, morpholinil, naphthilidinil, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, piperidyl, piperazinil, pyridyl, pyrazinil, pyrazolidinil, pyrazolyl, pyridadinil, pyrimidinil, pyrrolidinil, pyrrolyl, quinazolinil, quinolinil, quinoxalinil, tetrahydrofuryl, tetrahydroisoquinolinil, tetrahydroquinolinil, thiamorpholinil, thiamorpholinil Selected from sulfoxides, thiazolyls, thiazolinyls, thienofuryls, thienothenyls, triazolyls, and thienyls, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0117] Several embodiments, each R 12 R is independently selected from hydrogen, C1-C4 alkyl, and C2-C6 alkenyl, 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, each R 12R is independently selected from hydrogen and C1-C4 alkyl, 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, each R 12 R is independently selected from hydrogen 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, each R 12 R is independently selected from hydrogen, deuterium, CH3, CD2H, CDH2, CD3, CH2CH3, and CD2CD3. In some embodiments, each R 12 R is independently selected from hydrogen, deuterium, CH3, CD3, CH2CH3, and CD2CD3. In some embodiments, each R 12 R is independently selected from hydrogen, CH3, CD3, CH2CH3, and CD2CD3. In some embodiments, R 12 is CH3. In some embodiments, R 12 is CD3. In some embodiments, each R 12 Independently, R is CH2CH3. In some embodiments, R 12 It is CD2CD3.

[0118] Several embodiments, each R 12 R is independently selected from substituted or unsubstituted C1-C4 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C4 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C4 alkylene aryl, and substituted or unsubstituted C1-C4 alkylene 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, each R 12R is independently selected from substituted or unsubstituted C1-C4 alkylenearyls and substituted or unsubstituted C1-C4 alkylene heteroaryls, 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, each R 12 R is independently a substituted or unsubstituted C1-C4 alkylenearyl, 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, each R 12 R is independently a substituted or unsubstituted CH2 aryl, 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, each R 12 These are independently substituted or unsubstituted CH2 phenyl compounds.

[0119] R 12 If R is substituted, in some embodiments the substituent is independently selected from one or more 3- to 6-membered heterocycles containing one or two ring heteromolets selected from Br, Cl, F, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, SO2CH3, C1-C4 alkyl, C1-C4 fluoroalkyl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, C2-C6 alkynyl, C2-C6 fluoroalkynyl, C3-C6 cycloalkyl, and O, S, S(O), SO2, N, NH, and NCH3. In some embodiments, R 12 The substituents mentioned above are independently selected from one to three of Br, Cl, F, C1-C4 alkyl, C1-C4 fluoroalkyl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, C2-C6 alkynyl, and C2-C6 fluoroalkynyl. In some embodiments, R 12The substituents mentioned above are independently selected from one or two of Br, Cl, F, CH3, and CF3.

[0120] In some embodiments, Y is a halogen. In some embodiments, the halogen in Y is selected from F, Cl, and Br. In some embodiments, the halogen in Y is selected from F and Cl. In some embodiments, the halogen in Y is F.

[0121] In some embodiments, Y is XA.

[0122] In some embodiments, X is selected from S, S(O), and SO2. In some embodiments, X is O, NR 13 Selected from , and S, 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, X is NR 13 X is selected from and O. In some embodiments, X is O.

[0123] In some embodiments, A is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, P(O)(OR 12 )2, C1~C3 alkylene P(O)(OR 12 Selected from )2, C1-C3 alkylene C3-C7 cycloalkyl, C1-C3 alkylene C4-C6 cycloalkenyl, C1-C3 alkylene heterocycloalkyl, C1-C3 alkylene aryl, C1-C3 alkylene heteroaryl, C(O)Q′, CO2Q′, C(O)N(Q′)2, S(O)Q′, and SO2Q', 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, A is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, C1-C3 alkylene C3-C7 cycloalkyl, C1-C3 alkylene C4-C6 cycloalkenyl, C1-C3 alkylene heterocycloalkyl, C1-C3 alkylene aryl, and C1-C3 alkylene heteroaryl, 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, A is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, heterocycloalkyl, C1-C3 alkylene C3-C7 cycloalkyl, C1-C3 alkylene C4-C6 cycloalkenyl, C1-C3 alkylene heterocycloalkyl, C1-C3 alkylene aryl, and C1-C3 alkylene 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 selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and heterocycloalkyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, A is selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl, 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 selected from hydrogen and C1-C4 alkyl, 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 selected from hydrogen and C1-C4 alkyl groups, 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 selected from hydrogen, CH3, CF3, CH2CH3, CD2CD3, CF2CF3, CH(CH3)2, CD(CD3)2, CF(CF3)2, C(CD3)3, C(CF3)3, and C(CH3)3.

[0126] In some embodiments, A is selected from C1-C3 alkylene C3-C7 cycloalkyl, C1-C3 alkylene C4-C6 cycloalkenyl, C1-C3 alkylene heterocycloalkyl, C1-C3 alkylene aryl, and C1-C3 alkylene 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 selected from CH2C3-C7 cycloalkyl, CH2C4-C6 cycloalkenyl, CH2 heterocycloalkyl, CH2 aryl, and CH2 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 selected from CH2C3-C7 cycloalkyl, CH2 aryl, and CH2 heteroaryl groups, 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 CH2 aryl, 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 CH2 phenyl.

[0127] In some embodiments, A is hydrogen, P(O)(OR 12 )2, CH2P(O)(OR 12 )2, CH2CH2P(O)(OR 12 )2, CH2CH(CH3)P(O)(OR 12 )2, CH(CH3)CH2P(O)(OR 12 )2, CH(CH3)P(O)(OR 12 )2, CH(CH2CH3)P(O)(OR 12 A is selected from )2, C(O)Q', CO2Q', C(O)N(Q')2, S(O)Q', and SO2Q', where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, A is hydrogen, P(O)(OR 12 )2, CH2P(O)(OR 12 )2, CH(CH3)P(O)(OR 12 A is selected from )2, C(O)N(Q')2, C(O)Q', S(O)Q', and SO2Q', where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, A is selected from S(O)Q' and SO2Q', where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, A is hydrogen, P(O)(OR 12 )2, CH2P(O)(OR 12 )2, CH(CH3)P(O)(OR 12 )2, C(O)N(Q′)2, and C(O)Q′ are selected. In some embodiments, A is hydrogen, P(O)(OR 12)2, and C(O)Q' are selected. In some embodiments, A is hydrogen. In some embodiments, A is C(O)N(Q')2, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, A is P(O)(OR 11 )2, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, A is C(O)Q′, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0128] In some embodiments, Q' is selected from C1-C20 alkyl, C1-C20 haloalkyl, C2-C20 alkenyl, C2-C20 haloalkenyl, C2-C20 alkynyl, and C2-C20 haloalkynyl, where the C1-C20 alkyl, C2-C20 haloalkyl, C2-C6 alkenyl, C2-C20 haloalkenyl, C2-C20 alkynyl, and C2-C20 haloalkynyl groups are optionally CN, OR 13 , N(R 13 )2, CO2R 13 , SR 13The rings are substituted with 1 to 3 substituents independently selected from C3-C7 cycloalkyl groups, C4-C7 cycloalkenyl groups, and 3- to 7-membered heterorings, and / or disubstituted on the same carbon atom by C1-C6 alkyl groups or by C2-C6 alkylene groups to form a C3-C7 cycloalkyl ring, and each of the C3-C7 cycloalkyl groups, C4-C7 cycloalkenyl groups, and 3- to 7-membered heterorings is further optionally substituted with substituents selected from C1-C3 alkyl groups and C1-C3 haloalkyl groups, 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, Q' is selected from C1-C20 alkyl, C2-C20 alkenyl, and C2-C20 alkynyl, where the C1-C20 alkyl, C2-C6 alkenyl, and C2-C20 alkynyl are optionally CN, OR 13 , N(R 13 )2, CO2R 13 , and SR 13 They are substituted with 1 to 3 substituents independently selected from and / or disubstituted on the same carbon atom by C1-C6 alkyls or by C2-C6 alkylenes to form a C3-C7 cycloalkyl ring, and each of the C3-C7 cycloalkyls, C4-C7 cycloalkenyls, and 3- to 7-membered heterocycles is further optionally substituted with substituents selected from C1-C3 alkyls and C1-C3 haloalkyls, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0129] In some embodiments, Q' is selected from C1-C20 alkyl, C2-C20 alkenyl, and C2-C20 alkynyl, where the C1-C20 alkyl, C2-C6 alkenyl, and C2-C20 alkynyl are optionally N(R) 13 )2 and CO2R 13 Substituted by 1 to 3 substituents independently selected from and / or disubstituted on the same carbon atom by C1-C6 alkyl or by C2-C6 alkylene to form a C3-C7 cycloalkyl ring, where the C3-C7 cycloalkyl is further optionally substituted by substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, 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, Q' is N(R 13 )2 and CO2R 13 Selected from C1-C20 alkyl, C2-C20 alkenyl, and C2-C20 alkynyl compounds, which are optionally substituted with one or two substituents independently selected from and / or optionally disubstituted on the same carbon atom by C1-C6 alkyl or by C2-C6 alkylene to form a C3-C7 cycloalkyl ring, wherein the C3-C7 cycloalkyl ring is further optionally substituted with substituents selected from C1-C3 alkyl and C1-C3 haloalkyl compounds, wherein 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, Q' is N(R 13A C1-C20 alkyl or C2-C20 alkenyl which is substituted with )2 and / or disubstituted on the same carbon atom with a C2-C6 alkylene to form a C3-C7 cycloalkyl ring, wherein the C3-C7 cycloalkyl ring is further optionally substituted with substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0131] In some embodiments, Q' is N(R 13 A C1-C20 alkyl or C2-C20 alkenyl substituted with )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, Q' is N(R 13 A C1-C20 alkyl group substituted with )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, Q' is N(R 13 A C1-C10 alkyl group substituted with )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, Q' is N(R 13 A C1-C10 alkyl group substituted with )2, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium.

[0132] In some embodiments, Q' is N(R13 A C1-C20 alkyl or C2-C20 alkenyl which is substituted with )2 and disubstituted on the same carbon atom with a C2-C6 alkylene to form a C3-C7 cycloalkyl ring, wherein the C3-C7 cycloalkyl ring is further optionally substituted with substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes. In some embodiments, Q' is N(R 13 A C1-C20 alkyl group is substituted with 2 and disubstituted on the same carbon atom with a C2-C6 alkylene to form a C3-C7 cycloalkyl ring, where the C3-C7 cycloalkyl ring is further optionally substituted with substituents selected from C1-C3 alkyl groups, 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, Q' is N(R 13 A C1-C10 alkyl group substituted with )2 and disubstituted on the same carbon atom with a C2-C6 alkylene to form a C3-C7 cycloalkyl ring, wherein the C3-C7 cycloalkyl ring is further optionally substituted with substituents selected from C1-C3 alkyl groups, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, Q' is N(R 13A C1-C10 alkyl group substituted with )2 and disubstituted on the same carbon atom with a C2-C6 alkylene to form a C5-C6 cycloalkyl ring, wherein the C3-C7 cycloalkyl ring is further optionally substituted with substituents selected from C1-C3 alkyl groups, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, Q' is N(R 13 A C1-C10 alkyl group which is substituted with )2 and disubstituted on the same carbon atom with a C2-C6 alkylene to form a spirocyclohexanyl ring, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium.

[0133] In some embodiments, Q' is a C1-C20 alkyl or C2-C20 alkenyl, and optionally CO2R 13 Substituted with, 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, Q′ is CO2R 13 A C1-C20 alkyl or C2-C20 alkenyl substituted with, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, Q' is CO2R 13A C1-C10 alkyl or C2-C10 alkenyl substituted with, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, Q' is CO2R 13 A C1-C6 alkyl or C2-C6 alkenyl substituted with a halogen atom, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium.

[0134] In some embodiments, Q' is a C1-C20 alkyl or C2-C20 alkenyl, 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, Q' is a C1-C20 alkyl or C2-C20 alkenyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, when Q' is a C1-C20 alkyl, Q' is a saturated fatty acid derivative, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, when Q' is a C2-C20 alkenyl, Q' is an unsaturated fatty acid derivative, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium.

[0135] In some embodiments, Q' is a C1-C10 alkyl or C2-C10 alkenyl, 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, Q' is a C1-C6 alkyl or C2-C6 alkenyl, 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, Q' is a C1-C4 alkyl or C2-C4 alkenyl, 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, Q' is a C1-C4 alkyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes. In one embodiment, Q' is selected from CH3, CF3, CD2H, CDH2, CD3, CH2CH3, CF2CF3, and CD2CD3.

[0136] In some embodiments, Q' is a C3-C7 cycloalkyl, a C4-C7 cycloalkenyl, and O, S, S(O), SO2, N, and NR 13 Selected from a 3- to 7-membered heterocycle containing 1-2 ring heteromolets, where the C3-C7 cycloalkyl group, C4-C7 cycloalkenyl group, and 3- to 7-membered heterocyclic group are optionally CN, OR 13 , N(R 13 )2, CO2R 13 , SR 13The rings are substituted with 1 to 3 substituents independently selected from C3-C7 cycloalkyl groups, C4-C7 cycloalkenyl groups, and 3- to 7-membered heterocycles, and each of the C3-C7 cycloalkyl groups, C4-C7 cycloalkenyl groups, and 3- to 7-membered heterocycles is further optionally substituted with substituents selected from C1-C3 alkyl groups, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0137] In some embodiments, Q' is a C3-C7 cycloalkyl, a C4-C7 cycloalkenyl, as well as O, S, N, S(O), SO2, and NR 13 Selected from a 3- to 7-membered heterocycle containing 1 to 2 ring heteromolets, where the C3-C7 cycloalkyl group, C4-C7 cycloalkenyl group, and 3- to 7-membered heterocyclic group are optionally N(R) 13 )2 and CO2R 13 The C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterocycles are each optionally substituted with substituents selected from C1-C3 alkyl groups, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0138] In some embodiments, Q' is a C3-C7 cycloalkyl, a C4-C7 cycloalkenyl, and N and NR. 13 Selected from a 3- to 7-membered heterocycle containing 1-2 ring heteromolets, where the C3-C7 cycloalkyl group, C4-C7 cycloalkenyl group, and 3- to 7-membered heterocyclic group are optionally CN, OR 13 , N(R 13 )2, CO2R13 , SR 13 , and are substituted with 1 to 3 substituents independently selected from 3- to 7-membered heterocycles, and each of the C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterocycles is further optionally substituted with substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, 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, Q' is N and NR 13 A 3- to 7-membered heteroring containing 1 to 2 ring heteromolets selected from, where the 3- to 7-membered heteroring groups are optionally CN, OR 13 , N(R 13 )2, CO2R 13 , SR 13 , and are substituted with 1 to 3 substituents independently selected from 3- to 7-membered heterorings, and each of the 3- to 7-membered heterorings is further optionally substituted with substituents selected from C1-C3 alkyl groups, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with their alternative isotopes. In some embodiments, Q' is N and NR 13 A 3- to 7-membered heterocycle comprising 1 to 2 ring heteromolets selected from, where the 3- to 7-membered heterocyclic group is optionally substituted by a 3- to 7-membered heterocycle, and each of the 3- to 7-membered heterocycles is further optionally substituted by a substituent selected from C1-C3 alkyl groups, 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, Q' is N and NR 13A 5- to 6-membered heterocycle comprising one ring heterostructure selected from, where the 5- to 6-membered heterocycle group is optionally substituted by a 5- to 6-membered heterocycle, where all available hydrogen atoms are optionally substituted by halogen atoms, and / or all available atoms are optionally substituted by their alternative isotopes. In some embodiments, Q' is piperidinyl or pyrrolidinyl substituted with piperidinyl or pyrrolidinyl, where all available hydrogen atoms are optionally substituted by halogen atoms, and / or all available atoms are optionally substituted by their alternative isotopes. In some embodiments, Q' is piperidinyl substituted with piperidinyl, where all available hydrogen atoms are optionally substituted by halogen atoms, and / or all available atoms are optionally substituted by their alternative isotopes.

[0139] In some embodiments, the C3-C7 cycloalkyl group in Q' 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.

[0140] In some embodiments, the C4-C7 cycloalkenyl in Q' 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.

[0141] In some embodiments, the 3- to 7-membered heterocycle in Q′ is azilidinyl, oxylanil, thyranil, oxaxiridinyl, dioxylanil, azetidinyl, oxetanil, theitanyl, diazetidinyl, dioxetanil, dithietanyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil, dithiolanil, piperidinyl, tri Selected from azolyl, flazanil, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranil, diazinyl (e.g., piperazinil), morpholinyl, thiomorpholinyl, dioxanil, dithianil, azepanil, oxepanil, thiepanil, and diazepanil, 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 3- to 7-membered heterocycle in Q′ is a substituted or unsubstituted heterocycle. In some embodiments, the 3- to 7-membered heterocycle in Q′ is a substituted or unsubstituted bridged bicyclic heterocycle. In some embodiments, the substituted or unsubstituted bridged bicyclic heterocycle is selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl, and oxobicycloheptanenyl (heptanenyl), 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, the heteroaryl in Q' is azepinyl, benzoisoxazolyl, benzoflazanyl, benzopyranil, benzothiopyranil, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanil, sinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranil, dihydrobenzothiopyranil Sulfone, 1,3-dioxolanil, furyl, imidazolidinyl, imidazolinil, imidazolyl, indolinil, indolyl, isochromanil, isoindolinil, isoquinolinil, isothiazolidinil, isothiazolyl, isothiazolidinil, morpholinil, naphthilidinil, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, piperidyl, piperazinil, pyridyl, pyrazinil, pyrazolidinil, pyrazolyl, pyridadinil, pyrimidinil, pyrrolidinil, pyrrolyl, quinazolinil, quinolinil, quinoxalinil, tetrahydrofuryl, tetrahydroisoquinolinil, tetrahydroquinolinil, thiamorpholinil, thiamorpholinil Selected from sulfoxides, thiazolyls, thiazolinyls, thienofuryls, thienothenyls, triazolyls, and thienyls, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0144] In some embodiments, Q' is selected from the following bases: [ka] Here: [ka] This indicates a covalent bond point.

[0145] In some embodiments, A is C(O)Q', and Q' is selected from the groups listed above.

[0146] In some embodiments, A is C(O)N(Q')2, where each Q' is a C1-C4 alkyl or C2-C4 alkenyl, 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, each Q' is a C1-C4 alkyl, 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, Q' is selected from CH3, CF3, CD2H, CDH2, CD3, CH2CH3, CF2CF3, and CD2CD3. In some embodiments, A is C(O)N(Q')2, where each Q' is CH3 or CD3.

[0147] Several embodiments, each R 13 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 N(R) 14 ) independently selected from a 3- to 7-membered heterocycle containing 1 to 2 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- to 7-membered heterocyclic group are optionally CN, OR 14 , N(R 14 )2, and SR 14 Substituting with one or more substituents independently selected from, and the C3-C7 cycloalkyl and 3- to 7-membered heterocycles are further optionally, halogens, CO2R 14 , C(O)N(R14 )2, SO2R 14 The atoms are substituted with substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl atoms, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0148] Several embodiments, each R 13 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 N(R) 14 Independently selected from 3- to 7-membered heterorings containing 1-2 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.

[0149] Several embodiments, each R 13 These include hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, as well as O, S, S(O), SO2, N, and N(R) 14 Independently selected from 3- to 7-membered heterorings containing 1-2 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. In some embodiments, each R 13R is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, 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, each R 13 R is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, each R 13 R is independently selected from hydrogen and C1-C6 alkyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In one embodiment, each R 13 R is independently selected from hydrogen, deuterium, F, CH3, CF3, CD2H, CDH2, CD3, CH2CH3, CF2CF3, and CD2CD3. In one embodiment, each R 13 R is independently selected from hydrogen, deuterium, CH3, CD2H, CDH2, CD3, CH2CH3, and CD2CD3. In one embodiment, each R 13 is hydrogen. In one embodiment, each R 13 These are independently CH3 or CD3.

[0150] In some embodiments, R 14This is selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

[0151] In some embodiments, R 14 R is selected from hydrogen, C1-C4 alkyl, and C2-C6 alkenyl, 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 14 R is selected from hydrogen and C1-C4 alkyl groups, 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 14 R is selected from hydrogen and C1-C4 alkyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, R 14 R is selected from hydrogen, deuterium, F, CH3, CF3, CD2H, CDH2, CD3, CH2CH3, CF2CF3, and CD2CD3. In some embodiments, R 14 R is selected from hydrogen, deuterium, CH3, CD2H, CDH2, CD3, CH2CH3, and CD2CD3. In some embodiments, R 14 R is selected from hydrogen, deuterium, CH3, and CD3. In some embodiments, R 14It is hydrogen.

[0152] R 14 If R is substituted, in some embodiments, the substituent is independently selected from one or more 3- to 6-membered heterocycles containing one or two ring heteromolets selected from Br, Cl, F, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, SO2CH3, C1-C4 alkyl, C1-C4 fluoroalkyl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, C2-C6 alkynyl, C2-C6 fluoroalkynyl, C3-C6 cycloalkyl, and O, S, S(O), SO2, N, NH, and NCH3. In some embodiments, R 14 The substituents mentioned above are independently selected from one to three of Br, Cl, F, C1-C4 alkyl, C1-C4 fluoroalkyl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, C2-C6 alkynyl, and C2-C6 fluoroalkynyl. In some embodiments, R 14 The substituents mentioned above are independently selected from one or two of Br, Cl, F, CH3, and CF3.

[0153] In some embodiments, when Y is XA and X is O, the compound of formula (I) is the compound of formula (IA). Accordingly, the present application also includes the compound of formula (IA) or its pharmaceutically acceptable salts, solvates, and / or prodrugs. [ka] Here, A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 This is defined in equation (I), and, All available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes. However, R 1 is C1~C6P(O)(OR 12 )2 and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 Furthermore, is A as defined by formula (I); or is A C1~C6 alkylene P(O)(OR 12 )2, selected from C1-C6 alkylene, C3-C7 cycloalkyl, C1-C6 alkylene, C4-C6 cycloalkenyl, C1-C6 alkylene heterocycloalkyl, C1-C3 alkylene aryl, C1-C6 alkylene heteroaryl, C(O)Q', CO2Q', C(O)N(Q')2, S(O)Q', and SO2Q' and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Furthermore, Q' is defined as shown in equation (I).

[0154] In some embodiments, Y is XA, X is O, and A is P(O)(OR 12 )2, R 9 and R 11 If both are H, then the compound of formula (I) is the compound of formula (IB). Therefore, this application also includes the compound of formula (IB) or its pharmaceutically acceptable salts, solvates, and / or prodrugs: [ka] During the ceremony: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , and R 12 This is defined in equation (I), and All available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes. However, R 1 C1~C6 alkylene P(O)(OR 12 )2.

[0155] In some embodiments, Y is XA, X is O, A is C(O)Q′, and R 9 and R 11 If both are H, then the compound of formula (I) is the compound of formula (IC). Therefore, in some embodiments, the present application also includes formula (IC) or its pharmaceutically acceptable salts, solvates, and / or prodrugs: [ka] During the ceremony Q', R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 10 This is defined in equation (I), and All available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0156] In some embodiments, Y is XA, X is O, and A is CH2P(O)(OR 12 )2, R 2 is hydrogen, R 9 and R 11 Both are hydrogen, and R 1 When is hydrogen, the compound of formula (I) is the compound of formula (IE). Therefore, this application also includes the compound of formula (IE) or its pharmaceutically acceptable salts, solvates, and / or prodrugs: [ka] During the ceremony: R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 10 This is defined in equation (I), and All available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0157] In some embodiments, Y is XA, X is O, A is hydrogen, and R 9 and R 11 Both are hydrogen, and R 1 If is CH2P(O)(OH)2, then the compound of formula (I) is the compound of formula (IF). Therefore, this application also includes the compound of (IF) or its pharmaceutically acceptable salts, solvates, and / or prodrugs: [ka] During the ceremony: R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 10 This is defined in equation (I), and All available hydrogen atoms are optionally replaced by fluorine atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0158] In some embodiments, Y is XA, X is O, A is C(O)Q′, and R 9 and R 11 Both are H and R 1 When is H, the compound of formula (I) is the compound of formula (IG). Therefore, this application also includes the compound of formula (IG) or its pharmaceutically acceptable salts, solvates, and / or prodrugs: [ka] During the ceremony: R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 10 This is defined in equation (I), and All available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0159] In some embodiments, when Y is XA, the compound of formula (I) is the compound of formula (IH). Therefore, in some embodiments, the present application encompasses the compound of formula (IH) or its pharmaceutically acceptable salts, solvates, and / or prodrugs: [ka] During the ceremony: A, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 This is defined in equation (I), and All available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes. However, R 1 is C1~C6P(O)(OR 12 )2 and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Are X, A, and X as defined in equation (I)? Y is XA, where A is C1~C6 alkylene P(O)(OR 12 )2, selected from C1-C6 alkylene, C3-C7 cycloalkyl, C1-C6 alkylene, C4-C6 cycloalkenyl, C1-C6 alkylene heterocycloalkyl, C1-C3 alkylene aryl, C1-C6 alkylene heteroaryl, C(O)Q', CO2Q', C(O)N(Q')2, S(O)Q', and SO2Q', and R1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Q' and X are defined as shown in equation (I).

[0160] In some embodiments, Y is a halogen, and the compound of formula (I) is the compound of formula (II). Therefore, in some embodiments, the present application encompasses the compound of formula (II) or its pharmaceutically acceptable salts, solvates, and / or prodrugs: [ka] During the ceremony: Y is a halogen; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 This is defined in equation (I), and All available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes. However, R 1 C1~C6 alkylene P(O)(OR 12 )2 and R 12 This is defined in equation (I).

[0161] In some embodiments, in the compound of formula (II), Y is selected from F, Cl, and Br. In some embodiments, in the compound of formula (II), Y is selected from F and Br. In some embodiments, in the compound of formula (II), Y is F.

[0162] In some embodiments, Y is XA, A is a C1-C6 alkyl, and the compound of formula (I) is the compound of formula (IJ). Therefore, in some embodiments, the present invention encompasses the compound of formula (IH) or its pharmaceutically acceptable salts, solvates, and / or prodrugs: [ka] During the ceremony: A is a C1-C6 alkyl group; R 1 C1~C6 alkylene P(O)(OR 12 ) and X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 This is defined in equation (I), and All available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

[0163] In some embodiments, A in the compound of formula (IJ) is selected from CH3, CD2H, CDH2, CD3, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, A in the compound of formula (IJ) is selected from CH3, CD3, CH2CH3, and CD2CD3. In some embodiments, A in the compound of formula (IJ) is selected from CH3 and CD3.

[0164] In some embodiments, R in compounds of formulas (IA) to (IC) and (IH) to (IJ) 1 This is hydrogen, C1-C3 alkyl, C1-C3 alkylene P(O)(OR 12 )2, C(O)R 12 CO2OR 12 , C(O)N(R 12 )2, S(O)R 12 , and SO2R 12 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. In some embodiments, R in compounds of formulas (IA)~(IC) and (IH)~(IJ) 1 These are hydrogen, C1-C3 alkyl, CH2P(O)(OR 12 )2, CH2CH2P(O)(OR 12 )2, CH2CH(CH3)P(O)(OR 12 )2, CH(CH3)CH2P(O)(OR 12 )2, CH(CH3)P(O)(OR 12 )2, CH(CH2CH3)P(O)(OR 12 )2, C(O)R 12 , and CO2R 12 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. In some embodiments, R in compounds of formulas (IA)~(IC) and (IH)~(IJ)1 The halogen atom is selected from hydrogen, CH3, CH2CH3, and CH(CH3)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 in compounds of formulas (IA)~(IC) and (IH)~(IJ) 1 R is selected from hydrogen, deuterium, Br, F, CH3, CF3, CD3, CH2CH3, CD2CD3, CF2CF3, CH(CH3)2, CD(CD3)2, CF(CF3)2, C(CD3)3, C(CF3)3, and C(CH3)2. In some embodiments, R is in compounds of formulas (IA) to (IC) and (IH) to (IJ). 1 R is selected from hydrogen, deuterium, CH3, CF3, and CD3. In some embodiments, R in compounds of formulas (IA) to (IC) and (IH) to (IJ) is selected. 1 R is hydrogen. In some embodiments, R in compounds of formulas (IA)~(IC) and (IH)~(IJ) 1 is CH2P(O)(OR 12 )2 and CH(CH3)P(O)(OR 12 )2 is selected, 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 in compounds of formulas (IA)~(IC) and (IH)~(IJ) 1 is CH(CH3)P(O)(OR 12 )2. In some embodiments, R in compounds of formulas (IA) to (IC) and (IH) 1 is CH2P(O)(OR 12 )

[0165] In some embodiments, in compounds of formulas (IA) to (IC) and (IE) to (IJ), R 2 ~R 6is independently selected from hydrogen and C1-C4 alkyl, 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, in the compounds of formulas (I-A)-(I-C) and (I-E)-(I-J), R 3 R 4 R 5 and R 6 at least one of is deuterium, or R 3 R 4 R 5 and R 6 at least one of contains deuterium. In some embodiments, in the compounds of formulas (I-A)-(I-C) and (I-E)-(I-J), R 3 and R 4 at least one of or R 5 R 6 at least one of is deuterium, or R 3 R 4 at least one of or R 5 R 6 at least one of contains deuterium. In some embodiments, in the compounds of formulas (I-A)-(I-C) and (I-E)-(I-J), R 3 R 4 R 5 and R 6 are independently selected from hydrogen, deuterium, Br, F, CH3, CD2H, CDH2, CD3, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, in the compounds of formulas (I-A)-(I-C) and (I-E)-(I-J), R 3 R 4 R 5 and R 6 and R 4 are independently selected from hydrogen, deuterium, F, CH3, CD2H, CDH2, and CD3. In some embodiments, in the compounds of formulas (I-A)-(I-C) and (I-E)-(I-J), R 3 R 4 R5 , and R 6 R is independently selected from hydrogen, deuterium, F, CH3, and CD3. In some embodiments, in compounds of formulas (IA) to (IC) and (IE) to (IJ), 3 , R 4 , R 5 , and R 6 R is independently selected from hydrogen, deuterium, and F. In some embodiments, in compounds of formulas (IC) and (IE) to (IJ), R 3 , R 4 , R 5 , and R 6 At least one of them is F. In some embodiments, in compounds of formulas (IA) to (IC) and (IE) to (IJ), R 3 and R 4 At least one of or R 5 and R 6 At least one of them is deuterium. In some embodiments, in compounds of formulas (IA) to (IC) and (IE) to (IJ), R 3 , R 4 , R 5 , and R 6 All are hydrogen. In some embodiments, in compounds of formulas (IA) to (IC) and (IE) to (IJ), R 3 , R 4 , R 5 , and R 6 It is all deuterium.

[0166] In some embodiments, in compounds of formulas (IA) to (IC) and (IE) to (IJ), R 7 and R 8 R is independently selected from hydrogen, deuterium, Br, F, CH3, CF3, CD2H, CDH2, CD3, CH2CH3, CF2CF3, and CD2CD3. In some embodiments, in compounds of formulas (IA) to (IC) and (IE) to (IJ), R 7 and R 8is independently selected from hydrogen, deuterium, CH3, CD3, CH2CH3, and CD2CD3. In some embodiments, in the compounds of formulae (I-A)-(I-C) and (I-E)-(I-J), R 7 and R 8 are each hydrogen, deuterium, CH3, CD3, CH2CH3, or CD2CD3. In some embodiments, in the compounds of formulae (I-A)-(I-C) and (I-E)-(I-J), R 7 and R 8 are both hydrogen. In some embodiments, in the compounds of formulae (I-A)-(I-C) and (I-E)-(I-J), R 7 and R 8 are both CH3. In some embodiments, in the compounds of formulae (I-A)-(I-C) and (I-E)-(I-J), R 7 and R 8 are both CD3. In some embodiments, in the compounds of formulae (I-A)-(I-C) and (I-E)-(I-J), R 7 and R 8 are both CH2CH3. In some embodiments, in the compounds of formulae (I-A)-(I-C) and (I-E)-(I-J), R 7 and R 8 are both CD2CD3.

[0167] In some embodiments, in the compounds of formulae (I-A)-(I-C) and (I-E)-(I-J), at least one of R 3 , R 4 , R 5 , and R 6 is deuterium, or at least one of R 3 , R 4 , R 5 , and R 6 contains deuterium, and R 7 and R 8 are independently selected from hydrogen, deuterium, CH3, CD3, CH2CH3, and CD2CD3. In some embodiments, in the compounds of formulae (I-A)-(I-C) and (I-E)-(I-J), R 3 and R4 At least one of the above or R 5 and R 6 At least one of them is deuterium and R 7 and R 8 Both are hydrogen, deuterium, CH3, CD3, CH2CH3, or CD2CD3. In some embodiments, in compounds of formulas (IA) to (IC) and (IE) to (IJ), R 3 , R 4 , R 5 , and R 6 All of them are hydrogen, or R 3 , R 4 , R 5 , and R 6 They are all deuterium, and R 7 and R 8 Both are hydrogen, deuterium, CH3, CD3, CH2CH3, or CD2CD3.

[0168] In some embodiments, in compounds of formulas (IA) to (IC) and (IE) to (IJ), R 7 and R 8 Together with the nitrogen atoms present between them, they form pyrrolidinyl, piperidinyl, or diazinanyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, in compounds of formulas (IA) to (IC) and (IE) to (IJ), R 3 , R 4 , R 5 , and R 6 All of them are hydrogen, or R 3 , R 4 , R 5 , and R 6 They are all deuterium, and R 7 and R 8These atoms, together with the nitrogen atoms present between them, form pyrrolidinyl, piperidinyl, or diazinanyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium.

[0169] In some embodiments, in the compounds of formulas (IA), (IH) to (IJ), R 9 , R 10 , and R 11 These are hydrogen, F, Cl, Br, CN, OR 13 , N(R 13 )2, SR 13 CH3, CH2CH3, CH(CH3)2, C(CH3)3, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO2R 13 , S(O)R 13 SO2R 13 , and C2-C6 alkenyls are independently selected, 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, in the compounds of formula (IA), (IH)-(IJ), R 9 , R 10 , and R 11 R is independently selected from hydrogen, F, Cl, Br, and CN, where all available atoms are optionally replaced by their alternative isotopes. In some embodiments, in the compounds of formulas (IA), (IH) to (IJ), R 9 , R 10 , and R 11 R is independently selected from hydrogen, deuterium, F, Cl, Br, and CN. In some embodiments, in the compounds of formulas (IA), (IH) to (IJ), R 9 , R 10 , and R 11 R is independently selected from hydrogen and deuterium. In some embodiments, in the compounds of formulas (IA), (IH) to (IJ), R9 , R 10 , and R 11 all are hydrogen. In some embodiments, in the compounds of the above formulas (IA), (IH) to (IJ), R 9 , R 10 , and R 11 All of them are deuterium. In some embodiments, in the compounds of formula (IA), (IH) to (IJ), R 10 is selected from hydrogen, deuterium, F, Cl, Br, and CN, and R 9 and R 11 R is selected from hydrogen and deuterium. In some embodiments, in the compounds of formulas (IA), (IH) to (IJ), R 10 is selected from hydrogen, deuterium, F, and CN, and R 9 and R 11 R is selected from hydrogen and deuterium. In some embodiments, in the compounds of formula (IA), (IH) to (IJ), R 10 is selected from hydrogen, F, and CN, and R 9 and R 11 R is selected from hydrogen and deuterium. In some embodiments, in the compounds of formula (IA), (IH) to (IJ), R 10 is selected from hydrogen, F, and CN, and R 9 and R 11 Both are hydrogen. In some embodiments, in the compounds of the above formulas (IA), (IH) to (IJ), R 10 The element is selected from hydrogen, deuterium, F, Cl, Br, and CN.

[0170] In some embodiments, in compounds of formula (IA) and (IH) where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), and in compounds of formula (IC) and (IG), Q' is selected from hydrogen, C1-C20 alkyl, C2-C20 alkenyl, and 3- to 7-membered heterocyclic groups, where the C1-C20 alkyl and C2-C6 alkenyl are optionally N(R) 13 )2 and CO2R13 Substituting with 1 to 3 substituents independently selected from, and all available hydrogen atoms optionally replaced by halogen atoms, and / or all available atoms optionally replaced by their alternative isotopes.

[0171] In some embodiments, in compounds of formula (IA) and (IH) where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), and in compounds of formula (IC) and (IG), Q' is CO2R 10 A C1-C10 alkyl or C2-C10 alkenyl substituted with, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, in compounds of formula (IA) and (IH) where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), and in compounds of formula (IC) and (IG), Q' is CO2R 10 A C1-C6 alkyl or C2-C6 alkenyl substituted with, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, in compounds of formula (IA) and (IH) where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), and in compounds of formula (IC) and (IG), Q' is [ka] Selected from, here, [ka] The symbol indicates a covalent bond point.

[0172] In some embodiments, in compounds of formula (IA) and (IH) where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), and in compounds of formula (IC) and (IG), Q' is C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and O, S, N, S(O), SO2, and NR 10 Selected from a 3- to 7-membered heterocycle containing 1 to 2 ring heteromolets, where the C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterocyclic groups are optionally N(R) 10 )2 and CO2R 10 Substituted by 1 to 3 substituents independently selected from, and the C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterocycles are each optionally substituted by substituents selected from C1-C3 alkyl; 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, compounds of formula (IA) and (IH) and compounds of formula (IC) and (IG) where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), Q' is, [ka] And here,: [ka] The symbol indicates a covalent bond point.

[0173] In some embodiments, in compounds of formulas (IA) and (IH) and (IC) and (IG), where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), Q' is a C1-C4 alkyl or C2-C4 alkenyl, 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, in the compounds of formulas (IA) and (IH) and (IC) and (IG) when A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), Q' is selected from CH3, CF3, CD2H, CDH2, CD3, CH2CH3, CF2CF3, and CD2CD3.

[0174] In some embodiments, in the compounds of formulas (IA) and (IH), and of formulas (IC) and (IG), where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), Q' is a C1-C20 alkyl or a C2-C20 alkenyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, in the compounds of formulas (IA) and (IH), and of formulas (IC) and (IG), where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), Q' is, [ka] Selected from, here, [ka] indicates a covalent bond point. In some embodiments, Q' is [ka] And here, [ka] The symbol indicates a covalent bond point.

[0175] In some embodiments, compounds of formulas (IA) and (IH) and compounds of formulas (IC) and (IG) are obtained when A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), and SO2(Q'), where Q' is N(R 10 A C1-C20 alkyl substituted with )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, compounds of formula (IA) and (IH) and compounds of formula (IC) and (IG) where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q') are used, and Q' is N(R 10 A C1-C10 alkyl substituted with )2, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, compounds of formula (IA) and (IH) and compounds of formula (IC) and (IG) are where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), and Q' is, [ka] Selected from, here, [ka] The symbol indicates a covalent bond point.

[0176] In some embodiments, compounds of formulas (IA) and (IH) and compounds of formulas (IC) and (IG) are obtained when A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), and SO2(Q'), where Q' is N(R 10 A C1-C20 alkyl group is substituted with )2 and disubstituted on the same carbon atom with a C2-C6 alkylene to form a C3-C7 cycloalkyl ring, where the C3-C7 cycloalkyl ring is further optionally substituted with substituents selected from C1-C3 alkyl groups, where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with their alternative isotopes. In some embodiments, compounds of formula (IA) and (IH) and compounds of formula (IC) and (IG) are where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), where Q' is N(R 10 A C1-C10 alkyl group is substituted with )2 and disubstituted on the same carbon atom with a C2-C6 alkylene to form a spirocyclohexanyl ring, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, compounds of formula (IA) and (IH) and compounds of formula (IC) and (IG) are where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), where Q' is [ka] And here, [ka] The symbol indicates a covalent bond point.

[0177] In some embodiments, compounds of formula (IA) and (IH) and compounds of formula (IC) and (IG) are obtained when A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), and SO2(Q'), where Q' is N and NR 10 A 3- to 7-membered heteroring containing 1 to 2 ring heteromolets selected from, where the 3- to 7-membered heteroring groups are optionally CN, OR 10 , N(R 10 )2, CO2R 10 , SR 10 , and are substituted with 1 to 3 substituents independently selected from 3- to 7-membered heterocycles, and each of the 3- to 7-membered heterocycles is further optionally substituted with substituents selected from C1-C3 alkyl groups; where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes, and available atoms are optionally replaced by their alternative isotopes. In some embodiments, compounds of formula (IA) and (IH) and compounds of formula (IC) and (IG) are where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), where Q' is N and NR 10A 5- to 6-membered heterocycle comprising one ring heteromove selected from, where the 5- to 6-membered heterocyclic group is optionally substituted by a 5- to 6-membered heterocycle, 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, compounds of formula (IA) and (IH) and compounds of formula (IC) and (IG) where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'), Q' is piperidinyl substituted with piperidinyl, 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, the compounds of formula (IA) and (IH) and the compounds of formula (IC) and (IG) are defined as follows, where A is C(O)Q', CO2(Q'), C(O)N(Q')2, SO(Q'), SO2(Q'). [ka] And here, [ka] This indicates a covalent bond point.

[0178] In some embodiments, the compound of formula (I) is: ((3-(2-(dimethylamino)ethyl)-4-(phosphonooxy)-1H-indole-1-yl)methyl)phosphonic acid; ((3-(2-(dimethylamino)ethyl)-4-hydroxy-1H-indole-1-yl)methyl)phosphonic acid; ((3-(2-(bis(methyl-d3)amino)ethyl)-4-(phosphonooxy)-1H-indole-1-yl)methyl)phosphonic acid; (1-((3-(2-(dimethylamino)ethyl)-1H-indole-4-yl)oxyethyl)phosphonic acid; (1-((3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl)oxyethyl)phosphonic acid; 3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl glycinate; 3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl D-alaninate; (Z)-4-((3(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl)oxy)-4-oxobuta-2-enoic acid; (E)-4-((3(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl)oxy)-4-oxobuta-2-enoic acid; 4-((3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl)oxy)-4-oxobutanoic acid; 3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl acetate; 3 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indole-4-yl acetate; ((4-acetoxy-3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-1-yl)methyl)phosphonic acid ((4-acetoxy-3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-1-yl)methyl)phosphonic acid; 3-(2-(dimethylamino)ethyl)-1H-indole-4-yl (9Z,12Z)-octadeca-9,12-dienoate; 3-(2-(d6-dimethylamino)ethyl)-1H-indole-4-yl(9Z,12Z)-octadeca-9,12-dienoate-11,11-d2; 3-(2-(dimethylamino)ethyl)-1H-indole-4-yl (9Z,12Z)-octadeca-9,12-dienoate-11,11-d2; 3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl (9Z,12Z)-octadeca-9,12-dienoate; 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indole-4-yl (9Z,12Z)-octadeca-9,12-dienoate; 3-(2-(bis(methyl-d6)amino)ethyl-1,1,2,2-d4)-1H- Indole-4-yl (9Z,12Z)-octadeca-9,12-dienoate-11,11-d2; 3-(2-(d10-diethylamino)ethyl-d4)-1H-indole-4-yl (9Z,12Z)-octadeca-9,12-dienoate; 3-(2-(d10-diethylamino)ethyl-d4)-1H-indole-4-yl (9Z,12Z)-octadeca-9,12-dienoate-11,11-d2; 3-(2-(diethylamino)ethyl-d4)-1H-indole-4-yl (9Z,12Z)-octadeca-9,12-dienoate; 3-(2-(diethylamino)ethyl-d4)-1H-indole-4-yl (9Z,12Z)-octadeca-9,12-dienoate-11,11-d2; 3-(2-(pyrroridine-1-yl)ethyl-1,1,2,2-d4)-1H-indole-4-yl (9Z,12Z)-octadeca-9,12-dienoate; 3-(2-(pyrroridine-1-yl)ethyl-1,1,2,2-d4)-1H-indole-4-yl (9Z,12Z)-octadeca-9,12-dienoate-11,11-d2; 3-(2-(dimethylamino)ethyl)-1H-indole-4-yl (S)-3-(aminomethyl)-5-methylhexanoate; 3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl (S)-3-(aminomethyl)-5-methylhexanoate; 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indole-4-yl (S)-3-(aminomethyl)-5-methylhexanoate; 3-(2-(dimethylamino)ethyl)-1H-indole-4-yl 2-(1-(aminomethyl)cyclohexyl)acetate; 3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl 2-(1-(aminomethyl)cyclohexyl)acetate; 3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl [1,4'-bipiperidine]-1'-carboxylate; 3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl dimethylcarbamate; 2-(4-(benzyloxy)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4; 2-(4-(benzyloxy)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine; and Dibenzyl (((1-((bis(benzyloxy)phosphoryl)methyl)-3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl)oxy)methyl)phosphonate, Or selected from pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0179] In some embodiments, the compound of formula (I) is selected from the compounds listed below: [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] Or, a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

[0180] 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.

[0181] The compounds of this application may also exist in various polymorphic phases, and any polymorph or mixture thereof shall fall within the scope of this application.

[0182] The compounds of this application may further be radiolabeled, and therefore all radiolabeled forms of the compounds of this application are included in the scope of this application. The compounds of this application also include compounds in which one or more radioactive atoms are introduced into their structure.

[0183] 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.

[0184] 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.

[0185] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, such as intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary (e.g., by the use of aerosols), 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.

[0186] 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 some embodiments, the compounds are incorporated with a pharmaceutical excipient and used in the form of orally 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 formulation additives 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 time-release formulations.Examples of modified release formulations include sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), and are used, for example, in the form of coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, aggregated particles (e.g., aggregated molecular sieve 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.). Examples of liposome delivery systems include small monolayer vesicles, large monolayer vesicles, and multilayer 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.

[0187] 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.

[0188] 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.

[0189] In some embodiments, the compounds of the present application are administered parenterally. For example, a solution of the compounds of the present application is prepared in water, appropriately mixed with a surfactant such as hydroxypropylcellulose. 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 instillable liquid is delivered by an ocular delivery system known in the art, such as an applicator or dropper. In some embodiments, such compositions include mucosal imitation substances 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.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] 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 soluble at body temperature. Substances commonly used to make such a vehicle 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 description of suppository administration forms, see, for example, Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530–1533.

[0194] 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, polyhydroxy-ethyl 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, polydihydroxypyran, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0195] The compounds of this application, including their pharmaceutically acceptable salts, solvates, and / or prodrugs, can be appropriately used alone, but generally, they are 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 whole composition.

[0196] In some embodiments, the compounds of the Application are used and administered in compositions 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 formulation additives. 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 in the "Methods and Uses" section below. In some embodiments, the additional therapeutic agents are psychostimulants.

[0197] In the above, the term "compound" also includes embodiments that refer to one or more types of compounds.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] The present invention also includes a method for treating a disease, disorder, or condition by activating serotonin receptors, which involves administering a therapeutically effective amount of one or more of the compounds of the present invention to a subject in need of treatment.

[0202] 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.

[0203] 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].

[0204] 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 for 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.

[0205] 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.

[0206] 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 (ignition), kleptomania (theft), and compulsive gambling; alcohol addiction; drug addiction such as opioid addiction; antisocial personality disorder, obsessive-compulsive personality disorder, and paranoid personality disorder. Personality disorders such as personality disorders; obsessive-compulsive disorder (OCD), such as thoughts or fears that compel an object to perform a specific ritual or routine; post-traumatic stress disorder (PTSD); stress response syndrome (formerly known as adjustment disorder); dissociative disorders, formerly known as multiple personality disorder or "multiple personality," and depersonalization; dysphagia; sexual and gender disorders, such as sexual dysfunction, gender identity disorder, and sexual perversion; somatic symptom disorders, formerly known as psychosomatic disorders or somatoform disorders; and combinations thereof.

[0207] In some embodiments, the disease, disorder, or condition treated by serotonin receptor activation is neurodegeneration. In some embodiments, the disease, disorder, or condition treated by serotonin receptor activation is a decrease in brain-derived neurotrophic factor (BDNF), which is the mammalian target of rapamycin (mTOR) activation, and / or inflammation.

[0208] In some embodiments, the diseases, disorders, or conditions treated by serotonin receptor activation 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. In some embodiments, mental disorders are selected from hallucinations and delusions and combinations thereof.

[0209] In some embodiments, hallucinations are selected from visual, auditory, olfactory, gustatory, tactile, proprioceptive, equilibrium, nociceptive, thermal, and temporal hallucinations, as well as combinations thereof.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] In some embodiments, the compounds of the present application are useful for treating central nervous system (CNS) diseases, disorders, or conditions and / or neurological diseases, disorders, or conditions in subjects requiring treatment, which involves administering a therapeutically effective amount of the compound of general formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] In some embodiments, the compounds of the present invention are useful for treating behavioral problems in subjects that are cats or dogs.

[0218] 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.

[0219] 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.

[0220] In some embodiments, the non-human subject is a dog. In some embodiments, the non-human subject is a cat.

[0221] 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.

[0222] In some embodiments, the disease, disorder, or condition treated by serotonin receptor activation is a mental disorder. In some embodiments, the disease, disorder, or condition treated by serotonin receptor activation is a disease, disorder, or condition of the central nervous system (CNS) and / or a neurological disease, disorder, or condition. 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.

[0223] 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.

[0224] 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.

[0225] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is dementia or Alzheimer's disease, and one or more compounds of the present application are administered in combination with one or more additional therapies for the treatment of dementia or Alzheimer's disease. In some embodiments, the additional therapy for dementia or Alzheimer's disease is selected from selected acetylcholinesterase inhibitors, NMDA antagonists, and nicotine agonists.

[0226] In some embodiments, the acetylcholinesterase inhibitor is selected from donepezil, galantamine, rivastigmine, and fencerin, as well as combinations thereof.

[0227] In some embodiments, the NMDA antagonist is selected from MK-801, ketamine, phencyclidine, and memantine, as well as combinations thereof.

[0228] In some embodiments, the nicotine agonist is nicotine, nicotinic acid, a nicotinic α7 agonist, a nicotinic α2β4 agonist, or a combination thereof.

[0229] In some embodiments, the muscarinic agonist is a muscarinic M1 agonist, a muscarinic M4 agonist, or a combination thereof.

[0230] In some embodiments, the muscarinic antagonist is a muscarinic M2 antagonist.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] In some embodiments, the effective dose varies depending on factors such as the disease state, age, sex, and / or weight, or species of the subject. 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 identity of the subject being treated, but can be determined by routine methods by those skilled in the art.

[0235] 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 combinations 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.

[0236] In some embodiments, the compound of the present application may be administered in a hallucinogenic and 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.

[0237] 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 if the pharmacokinetics are suitable, this may include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of the other. Designing a suitable drug regimen is a routine practice for those skilled in the art. In certain embodiments, the two substances are administered substantially simultaneously, i.e., within a few minutes of each other, or in a single composition containing both substances. Non-contemporary administration of a combination of agents is a further embodiment of the present invention. In some embodiments, the compounds of the present application are administered simultaneously or sequentially with other therapeutic agents in separate unit dosing forms, or together in a single unit dosing form. Accordingly, the present application provides unit dosing forms comprising one or more compounds of the present application, additional therapeutic agents, and pharmaceutically acceptable carriers.

[0238] 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 recipient's age, health, and weight, the nature and severity of symptoms, the frequency of treatment, and (if any) the type of concurrent treatment, as well as the clearance rate of the compounds within the treated subject. 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 of the 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.

[0239] 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.

[0240] V. Preparation of Compounds The compounds of this application can be prepared by various synthetic processes. The selection of specific structural features and / or substituents may influence the choice of 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.

[0241] In some embodiments of the present application, the compounds of the present application are generally prepared according to the processes illustrated in Schemes II to IV.

[0242] In some embodiments, the compound of formula (I) is prepared as shown in scheme II. Thus, using known methods, for example, the Pd-catalyzed method described in Chem. Eur. J. 2019, 25, 897-903, the ortho-iodoaniline compound of formula (A) is coupled with a suitable unsaturated precursor, such as the disubstituted alkyne compound of formula (B), in the presence of a catalyst such as a Pd catalyst, to give the compound of formula (I). [ka]

[0243] In some embodiments, the compound of formula (I) is synthesized according to scheme III. Thus, the substituted indole compound of formula (C) is coupled with a suitable amino compound of formula (E) in the presence of a suitable coupling reagent such as oxalyl chloride to give the compound of formula (D). The compound of formula (D) is reduced with a suitable reducing agent such as an Al-based reducing agent to give the compound of general formula (I). [ka]

[0244] 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.

[0245] Salts of the compounds of the present application may be formed by methods known to those skilled in the art, for example, by reacting a certain amount of acid or base, such as an equivalent amount, with the compounds of the present application in a medium such as a medium on which the salt precipitates, or in an aqueous medium, and then freeze-drying.

[0246] 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 then isolating the solvate by cooling or using a reverse solvent. Solvates are typically dried or azeotrope-dried under ambient conditions. The selection of appropriate conditions for forming a particular solvate can be made by those skilled in the art. Examples of suitable solvents include ethanol, water, etc. When water is the solvent, the molecule is referred to as 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 then isolating the solvate by cooling or using a reverse solvent. Solvates are typically dried or azeotrope-dried under ambient conditions. The selection of appropriate conditions for forming a particular solvate can be made by those skilled in the art.

[0247] Isotope-enriched compounds of the present invention, as well as 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 analogous to those described in the schemes and examples of the present disclosure, using appropriate isotope-enriched reagents and / or intermediates.

[0248] It should be understood that, where appropriate, suitable protecting groups are added to and subsequently removed from various reactants and intermediates in a manner readily understood by those skilled in the art throughout the processes described herein. Conventional methods for using such protecting groups, and examples of suitable protecting groups, are described, for example, in “Protective Groups in Organic Synthesis”, TW Green, PGM Wuts, Wiley-Interscience, New York (1999). It should also be understood that a group or substituent can be chemically converted to another group or substituent on intermediates or final products in the synthetic pathway toward the final product, and that the types of conversions possible are limited only by other functionalities of the molecule at that stage that 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 herein, and it should be understood that the conversions described are not limited to the generic groups or substituents exemplified. 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 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). 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 apparent to those skilled in the art.

[0249] Examples The following non-restrictive examples illustrate the present application. A: Synthesis of the exemplary compound of the present invention General method

[0250] All starting materials used here are either commercially available or have been previously described in the literature. 1 H and 13 Unless otherwise specified, the 13C NMR spectra were obtained in deuterated chloroform as the solvent, using TMS or residual solvent signal as an internal reference. 1 ¹H NMR was recorded using Bruker300, BrukerDPX400, or Varian+400 spectrometers operating at 300 MHz, 400 MHz, and 400 MHz, respectively. 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 product was purified using Chem Elut Extraction columns (Varian, cat numbers 1219-8002), Mega BE-SI (Bond Elut Silica) SPE columns (Varian, cat numbers 12256018; 12256026; 12256034), or flash chromatography in silica-packed glass columns.

[0252] The following compounds were prepared using one or more of the synthetic methods outlined in Schemes II to IV.A. A. Synthesis of exemplary compounds of the present invention Example 1: 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indole-4-yl(9Z,12Z)-octadeca-9,12-dienoate(I-28): [ka] Synthesis of 2-(4-(benzyloxy)-1H-indole-3-yl)-N,N-bis(methyl-d3)-2-oxoacetamide (41):

[0253] A solution of 4-(benzyloxy)-1H-indole (2.27 g, 10.16 mmol) in dry ether (50 mL) was treated dropwise with oxalyl chloride (0.86 mL, 10.16 mmol) at 0°C. The reaction product was allowed to rise to room temperature and stirred overnight (18 hours). The reaction product was cooled to 0°C and treated with bis(methyl-d3)amine hydrochloride (2.22 g, 25.41 mmol, liberated and based with K2CO3 in THF) 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 × 100 mL). The combined ethyl acetate layer was washed with brine (50 mL) and dried (Na2SO4). The solvent was evaporated, and the crude product was purified by flash column chromatography (MeOH:CH2Cl2=5:95) on silica gel to obtain the compound described in the heading (2.13 g, 63.7%) as a light brown foam. 1H NMR (CDCl3): δ 10.20 (s, 1H), 7.56-7.53 (m, 3H), 7.42-7.30 (m, 3H), 7.05 (t, 1H, J =6.0 Hz), 6.90 (d, 1H, J = 6.0 Hz), 6.65 (d, 1H, J = 6.0 Hz), 5.26 (s, 2H); ESI-MS (m / z, %): 351 (M+Na, 100), 329 (MH + ) Synthesis of 2-(4-(benzyloxy)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-46):

[0254] A suspension of lithium aluminum deuteride (1.94 g, 46.28 mmol) in dry THF (20 mL) was treated with 2-(4-(benzyloxy)-1H-indole-3-yl)-N,N-bis(methyl-d3)-2-oxoacetamide (1.9 g, 5.78 mmol) in dry THF (40 mL) at 0°C for 10 minutes. The reaction product was allowed to cool to room temperature and then refluxed for a further 16 hours. The reaction product was cooled to 0°C and the reaction was stopped by sequentially adding water (1.94 mL), 2N NaOH solution (1.94 mL), and water (1.94 mL). 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 the compound described in the heading (0.91 g, 51.7%) as a yellowish-brown (tan) solid. 1 H NMR (CDCl3): δ 8.16 (s, 1H), 7.54-7.52 (m, 2H), 7.43-7.33 (m, 2H), 7.08 (t, 1H, J = 6.0 Hz), 6.98 (d, 1H, J = 6.0 Hz), 6.90 (d, 1H, J = 3.0 Hz), 6.57 (d, 1H, J = 6.0 Hz), 5.24-5.20 (m, 2H); ESI-MS (m / z, %): 305 (MH + ,100) Synthesis of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indole-4-ol(I-45):

[0255] A solution of 2-(4-(benzyloxy)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4 (0.88 g, 2.89 mmol) in methanol (25 mL) was treated with Pd-C (0.2 g) and hydrogenated under a hydrogen atmosphere for 2 hours. The reaction product was filtered through a Celite pad and washed with methanol (2 × 25 mL). The combined methanol layer was evaporated, and the crude product was purified by flash column chromatography on silica gel (2 M NH3 in MeOH:CH2Cl2=5:95) to obtain the compound described in the heading (0.53 g, 85.6%) as an off-white solid. 1 H NMR (DMSO-d6): δ 10.81 (s, 1H), 9.55 (s, 1H), 9.38 (s, 1H), 7.06 (d, 1H, J = 1.5 Hz), 6.88-6.80 (m, 2H), 6.38-6.36 (m, 1H); ESI-MS (m / z, %): 215 (MH + , 100) Synthesis of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indole-4-yl (9Z,12Z)-octadeca-9,12-dienoate(I-28):

[0256] A solution of linoleic acid (0.23 g, 0.84 mmol) in dry CH2Cl2 (10 mL) was treated with oxalyl chloride (0.1 mL, 1.12 mmol), followed by treatment with one drop of dry DMF at room temperature, and stirring for a further 2 hours. The solvent was evaporated, and the crude product was dried under high vacuum to obtain the corresponding acid chloride. A solution of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indole-4-ol (0.12 g, 0.55 mmol) in dry CH2Cl2 (10 mL) and triethylamine (0.23 mL, 1.68 mmol) was treated with the crude acid chloride in dry CH2Cl2 (10 mL) at 0°C. The reaction product was allowed to come to room temperature and stirred for a further 2 hours. The reaction was stopped with water (50 mL), and the product was extracted to CH2Cl2 (2 × 50 mL). The combined CH2Cl2 layer was washed with brine (25 mL) and dried (Na2SO4). The solvent was evaporated, and the crude product was purified by column chromatography on silica gel (2M NH3 in MeOH:CH2Cl2=5:95) to obtain the compound described in the heading (0.22 g, 82.7%) as a pale yellow oil. 1 H NMR (DMSO-d6): δ 11.28(s, 1H), 9.58 (brs, 1H), 7.30-7.28 (m, 2H), 7.11-7.06 (m, 1H), 6.72 (d, 1H, J =6.0 Hz), 5.41-5.29 (m, 4H), 2.78-2.70 (m, 4H), 2.08-2.01 (m, 4H), 1.73-1.66 (m,2H), 1.43-1.24 (m, 14H), 0.87 (t, 3H, J = 6.0 Hz); ESI-MS (m / z, %): 477 (MH + , 100) Example 2: 2-(4-(benzyloxy)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine(I-47): [ka] Synthesis of 2-(4-(benzyloxy)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine(I-47)

[0257] Similar to the preparation for compound I-46, compound I-47 (0.24 g, 53%) described in the heading was prepared using LiAlH4 from 2-(4-(benzyloxy)-1H-indole-3-yl)-N,N-bis(methyl-d3)-2-oxoacetamide (0.5 g, 1.52 mmol), and compound I-47 was obtained as a pale yellow semi-solid. 1 H NMR (CDCl3): δ 8.10 (s, 1H), 7.54-7.52 (m, 2H), 7.43-7.29 (m, 2H), 7.11-7.03 (m, 1H), 6.91 (s, 1H), 6.57 (d, 1H, J = 6.0 Hz), 5.19 (s, 2H), 3.10-3.06 (m, 2H), 2.64-2.60 (m, 2H); ESI-MS (m / z, %): 301 (MH + , 100) Examples 3 and 4 [ka] Example 3 (I-48) Synthesis of dibenzyl(((1-((bis(benzyloxy)phosphoryl)methyl)-3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl)oxy)methyl)phosphonate 3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl dihydrogen phosphate (54):

[0258] A solution of 3-(2-(bis(methyl-d3)amino)ethyl-1H-indole-4-ol (0.31 g, 1.47 mmol) in dry THF (10 mL) was treated with n-butyllithium (2.36 mL, 5.90 mmol) at -78 °C. After stirring at the same temperature for 10 minutes, the reaction product was treated with tetrabenzyl pyrophosphate (1.03 g, 1.9 mmol) in dry THF (8 mL). The reaction product was then subjected to a period of 1 hour. The mixture was cooled to 0°C and stirred at the same temperature for a further 1 hour. The reaction product was treated with aminopropyl silica gel (1.3 g) and diluted with ethyl acetate (50 mL). The reaction product was filtered through a Celite pad and washed with ethyl acetate (2 × 20 mL). The combined organic layers were evaporated and vacuum-dried to obtain crude dibenzyl (3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indole-4-yl) phosphate as a light brown semi-solid. Synthesis of dibenzyl(((1-((bis(benzyloxy)phosphoryl)methyl)-3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl)oxy)methyl)phosphonate (I-48)

[0259] To a solution of dibenzyl (3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indole-4-yl) phosphate in acetonitrile, 2 equivalents of potassium carbonate and 1.1 equivalents of dibenzyl(chloromethyl)phosphonate were added dropwise. The reaction mixture was heated at 100°C for 2 hours. After work-up, evaporation of the solvent, and subsequent crystallization, the target compound I-48 was obtained as a light brown solid. Example 4 ((3-(2-(bis(methyl-d3)amino)ethyl)-4-(phosphonooxy)-1H-indole-1-yl)methyl)phosphonic acid (I-13)

[0260] A solution of dibenzyl(((1-((bis(benzyloxy)phosphoryl)methyl)-3-(2-(bis(methyl-d3)amino)ethyl)-1H-indole-4-yl)oxy)methyl)phosphonate in dry methanol was treated with PdC and hydrogenated under a hydrogen atmosphere. The reaction product was filtered through a Celite pad and washed with methanol. The combined methanol layer was evaporated, and the crude product was purified by flash column chromatography on silica gel to obtain compound I-13 as described in the heading. B. Biological Tests Example 5: FLIPR assay: Human 5-HT2A I. Evaluation of the activated effects of exemplary compounds of formula I targeting the human 5-HT2A (h5-HT2A) receptor in agonist mode: Controls for compound preparation and assays [Table 10] [Table 11] Ic Experimental Methods and Procedures:

[0261] 1. Cells are cultured in cell culture medium (DMEM containing 10% FBS, 1× penicillin-streptomycin, 300 μg / ml G418, and 100 μg / ml hygromycin B) at 37°C and 5% (v / v) CO2.

[0262] 2. One day before the assay, detach the cells using TrypLE® Express and count them using a cell counter. Only cells with a viability of more than 85% should be used in the assay.

[0263] Seed 20,000 cells / well from 3.30 μl / well of culture medium into a 384-well cell plate, and incubated the cells overnight at 37°C in 5% (v / v) CO2.

[0264] 4. On the day of the assay, prepare the 2× dye solution according to the manual for the FLIPR® Calcium 6 assay kit: i. Dilute the dye with assay buffer (20 mM HEPES in 1× HBSS, pH 7.4); ii. Add probenecid to a final concentration of 5 mM; iii. Vortex vigorously for 1-2 minutes.

[0265] 5. Gently tap the cell plate on a paper towel to separate the culture medium from the cell plate.

[0266] Add 6.10 μl of assay buffer and 10 μl of 2× dye solution to each well of the cell plate.

[0267] 7. Place the cell plate on a plate shaker and agitate the plate at 600 rpm for 2 minutes. Incubate the plate at 37°C for 2 hours, then incubate at 25°C for a further 15 minutes.

[0268] 8. Prepare the 3× compound in the assay buffer: a. Dilute the reference compound with DMSO to the required concentration. Add the compound to a 384-well compound plate; b. Perform serial dilutions; c. Add 10 mM of the test compound to the compound plate and perform 3-fold serial dilutions. d. Transfer 60 nl / well of the compound from the source plate to the 384-well compound plate (Corning, 3657) using echo; e. Add 20 μl / well of assay buffer to the compound plate; f. Mix the plate on a plate shaker for 2 minutes;

[0269] 9. Place the cell plate, compound plate, and tip into the FLIPR and transfer 10 μl of 3× compound per well to the cell plate using the FLIPR. Id Data Analysis

[0270] i. Calculate the normalized fluorescence reading (RFU) as follows: Here, Fmax and Fmin represent the maximum and minimum calcium signals within a specified time window: RFU = Fmax - Fmin

[0271] ii. Calculate the activation percentage using the following formula:

[0272]

number

[0273] iii. Using XLfit, calculate EC50 by applying the percentage activation relative to the log value of the compound concentration to the Hill equation.

[0274] Exemplary compounds in this application were found to be 5-HT2A agonists. The results for representative compounds are shown as EC50 in Table 1. [Table 12] II. Results and Discussion

[0275] The exemplary compounds of formula I, I-46, I-28, and the metabolite of I-28 (I-45), were functionally evaluated using the FLIPR assay for their effects on the h5-HT2A receptor in agonist mode. 50 The (nM) concentrations are shown in Table 1. This assay confirms that the compound of the present invention and / or its major metabolites are effective agonists of the target human 5-HT2A receptor. In particular, in this example, the metabolite of the I-28 prodrug is an active agonist of the target human 5-HT2A receptor. Example 6: Human 5-HT2A: Radioligand Binding Assay: [Table 13] [Table 14] II.3 Experimental Procedure:

[0276] i. Prepare the assay buffer according to the following table; [Table 15]

[0277] 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%;

[0278] iii. Preparation of (v / v)DMSO: a. Add 50 μl / well of 0.5% (v / v)PEI to a UniFilter-96 GF / B plate. Seal the plate and incubate at 4°C for 3 hours; b. After incubation, wash the plate three times with ice-cold water buffer (50 mM Tris, pH 7.4);

[0279] 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 a concentration of 20 μg / well; b. Prepare eight concentrations of the reference compound and the 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.

[0280] v. Centrifuge the plate at 1000 rpm for 30 seconds, then stir at 600 rpm for 5 minutes at room temperature.

[0281] vi. Incubate the plate at 27°C for 90 minutes.

[0282] vii. Stop the incubation by vacuum filtration onto a GF / B filter plate, and then wash four times with ice-cold water buffer (50mM Tris, pH 7.4).

[0283] viii. Dry the plate at 37°C for 45 minutes.

[0284] ix. Seal the filter plate and add 40 μl / well of the scintillation cocktail.

[0285] The plate is read using the X.Microbeta2 microplate counter. Data analysis:

[0286] For the reference compound and the exemplary test compound of this application, 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, where U is an unknown value, C1 is the mean of the high control, and C2 is the mean of the low control. The IC50 was determined by fitting the percentage of inhibition as a function of compound concentration to the Hill formula using XLfit. Results and Discussion

[0287] Table 2 summarizes the results of the potential competitive binding properties of the exemplary prodrug compounds (I-28) and their metabolite (I-45) of this application, targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A). The results for the exemplary compounds of this application are shown in Table 2. 50 It is shown as follows. [Table 16]

[0288] The exemplary compounds of Formula I were evaluated using a radioligand binding assay on the human 5-HT2A receptor. 50The (nM) concentrations are shown in Table 2. This assay confirms that the compounds or metabolites of this invention are effective ligands for the target human 5-HT2A receptor. In particular, the metabolite of example compound (I-28) has demonstrated greater binding affinity to the target receptor. Example 7: Stability of human, rat, and mouse liver microsomes the purpose

[0289] The objective of this study was to estimate the in vitro metabolic stability of I-12 in pooled human, male rat, and male mouse liver microsomes. The concentration of the parent compound in the reaction system was assessed by LC-MS / MS to estimate its stability in pooled human, male rat, and male mouse liver microsomes. The in vitro intrinsic clearance of the test compound was also determined. Protocol

[0290] 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 17]

[0291] 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.

[0292] The reaction was initiated by adding 4 μL of either the exemplary test compound or the control compound (200 μM) to each master solution to a final concentration of 2 μM. This test was performed in two series.

[0293] At 0, 15, 30, 45, and 60 minutes, 50 μL aliquots were taken from the reaction solution. The reaction solution was stopped by adding four 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.

[0294] All samples in this test were subjected to LC / MS analysis using a Shimadzu liquid chromatography separation system equipped with a DGU-20A5R degasser, LC-30AD solvent transport unit, SIL-30AC system controller, CTO-30A column oven, and HTC PAL CTC analyzer. Mass spectrometry analysis was performed using a Triple Quad™ 5500 instrument.

[0295] 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.

[0296] 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.

[0297] The in vitro half-time (in vitro t1 / 2) was determined from the slope value: In Vitro T 1 / 2 =-(0.693 / k)

[0298] The conversion of in vitro t1 / 2 (min) to in vitro specific clearance (in vitro CLInt, in units of μL / min / mg protein) was performed using the following formula (average of two sets of measurements):

number

[0299] Human, rat, and mouse liver microsomes contain diverse drug-metabolizing enzymes and are commonly used to support in vitro ADME (absorption, distribution, metabolism, and excretion) studies. These microsomes are used to investigate possible first-pass metabolic byproducts of orally administered drugs. Exemplary compounds of the present invention were evaluated for their stability in human, rat, and mouse liver microsomes. In liver microsomes of the three species—human, rat, and mouse—the majority of the exemplary compounds of the present invention were recovered within a 60-minute period. This indicates that these compounds are not rapidly removed (see Table 4 for the exemplary compound of Formula I). [Table 18] Results: These results demonstrate that the exemplary compounds (I-46 and I-28) are rapidly metabolized, and that the metabolite of I-28 is comparable to psilocine as a reference. Example 8: In vitro evaluation of the pharmacokinetics of exemplary compound I-28 and its metabolite I-45 in mice. 1. Preparation and storage of pharmaceutical products [Table 19] 2. Sample collection [Table 20] 3. Exam Details animal:

[0300] Male C57BL / 6 mice (25-30g) obtained from the Charles River lab were acclimatized for at least 5 days before drug administration. Body weight was recorded on the day of administration. Dietary restrictions:

[0301] Animals administered orally were fasted overnight and fed approximately two hours after administration. Clinical findings:

[0302] The animals were observed at the time of medication administration and at the time of each sample collection. Any abnormalities were recorded. dosage

[0303] The preparation was administered intravenously (IV) via the tail vein or orally (PO) via gastric tube feeding through a disposable feeding needle. Sample collection:

[0304] Sequential blood samples were collected via tail snip. The final blood sample was collected by cardiac puncture under isoflavone anesthesia. Sample processing / storage:

[0305] All blood samples were transferred to K2EDTA tubes on wet ice and centrifuged for 5 minutes (3200×g for 5 minutes at 4°C) to obtain plasma. The plasma was stored at -80°C until analysis. Sample retention: 4. Improvement of biological analysis methods and sample analysis

[0306] Matrix: Mouse plasma

[0307] Equipment: AB Sciex QTRAP4000 or 6500 MS / MS system equipped with a liquid chromatography system featuring a binary pump, solvent degasser, thermostat-equipped column compartment, and multi-plate automated sampler. 5. Improvement of the method:

[0308] i. Selection of ionic transitions for the test compound (i.e., identification of parent and product ions)

[0309] ii. Optimization of mass spectrometry operation parameters

[0310] iii. Establishment of chromatography conditions

[0311] iv. (One or more) appropriate internal standards (IS)

[0312] V. Sample purification method using protein precipitation 6. Determining the suitability of the method:

[0313] i. Determination of the eligibility dynamic range using a series of non-zero calibration standards (STDs). The STDs consist of a blank matrix sample (without internal standard), a zero sample (with internal standard), and six or more non-zero STDs covering the predicted range and including the lower limit of quantification (LLOQ).

[0314] ii. Three injections of system-suitability samples (solvent-free solutions containing the analyte and internal standards) before and after the batch. 7. Criteria for accepting the method:

[0315] i. More than 75% of non-zero STDs are included in the calibration curve, and all recalculated concentrations are within ±20% of the nominal concentration (within ±25% for the lower limit of quantification (LLOQ)).

[0316] II. The correlation coefficient (r) of the calibration curve must be 0.99 or greater.

[0317] III. The variation in the area ratio of system suitability sample injection before and after the run is within ±25%. 8. Sample analysis batch:

[0318] i. Injection of three system suitability samples before and after batching.

[0319] ii. Ascending order of (multiple) STDs

[0320] iii. The test sample and drug composition are diluted in a blank matrix (plasma) as three independent dilutions.

[0321] iv. If there were more than 40 test samples in a batch, two sets of STDs were used, one before and one after the sample group.

[0322] v. Samples that were 25% higher than the highest calibration standard were diluted and re-asserted with the corresponding diluted quality control standard. Diluted standards are acceptable if their accuracy is within 25% of the target concentration. 9.PK analysis

[0323] i. Analysis software: Phoenix® WinNonlin® 8.2 (Pharsight, Certara, Mountainview, CA)

[0324] ii. Analysis methods: Non-compartmental analysis, linear up / log down trapezoidal method

[0325] iii. PK parameters: C0, t as appropriate. 1 / 2 AUC 0-tlast AUC 0-∞ CL, V ss , MRT, t max(po) , C max(po) F 10. Results and Discussion [Table 21] (a) The dosage is equivalent to 1 mg / kg of the metabolite. (b) Characteristics of metabolites after administration of example prodrug I-28 [Table 22] (a) The dosage is equimolar to 10 mg / kg of the metabolite. (b) nc indicates that the calculation is not possible because the terminal phase was not defined. (c) Characteristics of metabolites after administration of exemplary prodrug I-28 (d) Ratio of AUC to metabolite after administration in Example 1 (I-28) [Table 23] (a) The I-28 formulation was diluted in plasma for analysis. The concentrations of metabolites (Example No. 1, I-45) in the I-28 formulation were analyzed against the solvent-free (neat) metabolite curve in solvent-free (neat) solution (DMSO). [Table 24] Example 7: Hallucinogenic effect of exemplary compounds of formula I

[0326] The effects of various doses of the example compound I-28 of formula I and its active metabolites were evaluated based on the head convulsion response (HTR) as a behavioral model of hallucinogenic activity. 1. Protocol Mouse head spasms

[0327] Male C57BL / 6J mice (body weight range 20-30g) 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 mean ± mean standard error (SEM) of 6-10 mice per group. Mice were used in only one experiment. Rat behavioral tests

[0328] Male Sprague-Dawley rats (body weight range 250–400 g) were administered an appropriate dose of the test substance. After a 1-minute pre-treatment 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 bottle. 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, penis 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 rats' spontaneous behavior was measured using an automated tracking system (Med Associates, VT, USA). Collected activity data included total distance traveled, stand-up counts, and ambulatory episodes. All data were expressed as mean ± mean standard error (SEM) for 6–10 rats per group. Drug identification in rats

[0329] Male Sprague-Dawley rats were initially subjected to food restriction by being presented with 18-20 g 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 (45 mg Bioserve pellet) (Med. Associates Ins., St. Albans, VT). These rats were trained to press the lever for food up to the 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. Once trained, the machines underwent substitution testing. On the day of testing, both levers were deemed operational, meaning that food pellets would be dispensed on the 10th response with either lever. Test sessions continued until 50 pellets were obtained, or until 30 minutes had elapsed. Response rates were also measured during these sessions. Results and Discussion

[0330] Figure 1 is a graph showing the effect of various doses of I-28, an exemplary compound of formula I, on the hematologic response (HTR) in male C57BL6 mice. The mice were treated with compound I-28 via subcutaneous injection (N=6 mice per dose), and the total number of hematologic seizures was recorded over a 1-hour period. Data are expressed as mean ± mean standard error (SEM). The induction of hematologic seizures by 5-HT2A receptor agonists is considered to represent a behavioral proxy for the hallucinogenic effect of those 5-HT2A receptor agonists. Spontaneous motor activity and other 5-HT receptor signs were also measured (Figure 1). A metabolite of I-28 (I-45) showed a higher hematologic seizure induction efficiency than the exemplary prodrug I-28 (Figure 2).

[0331] While 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 interpreted in the broadest way consistent with the entire disclosure.

[0332] All patents, patent applications, and publications cited in this disclosure are incorporated in their entirety by reference. The disclosures of these 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 filing date of the applications described and claimed in this disclosure.

Claims

1. Compounds of formula (I) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: 【Chemistry 1】 wherein, R ２ is selected from hydrogen, C1-C3 alkyl, C1-C6 alkylene P(O)(OR １２ ), C(O)R ２ , CO １２ R ２ , C(O)N(R １２ ), S(O)R １２ , and SO ２ R １２ , and SO ２ R １２ ; R ２ ~R ６ is independently selected from hydrogen and C1-C6 alkyl groups; R ７ and R ８ These are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or R ７ and R ８ Together with the nitrogen atoms present between them, they are O, S, S(O), SO ２ , N, and NR １３ It forms a 3- to 7-membered heteroring that optionally includes 1 to 2 additional ring heteromotors selected from the above. Here, the C3-C7 cycloalkyl and 3- to 7-membered heterorings can each be optionally a halogen, CO ２ R １３ , C(O)N(R １３ ) ２ SO ２ R １３ , 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, N, S(O), SO ２ , and NR １３ Substituted by substituents selected from a 3- to 6-membered heterocycle containing 1 to 2 ring heteromolets selected from; R ９ , R １０ , and R １１ is hydrogen, halogen, CN, OR １３ , N(R １３ ) ２ , SR １３ , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, CO ２ R １３ , C(O)N(R １３ ) ２ , SOR １３ SO ２ R １３ , C2-C6 alkenyls, C2-C6 alkynyls, C2-C6 haloalkynyls, C3-C7 cycloalkyls, as well as O, S, S(O), SO ２ , N, and NR １３ A 3- to 7-membered heterocycle containing one or two ring heteromolets selected from, and 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 １３ , N(R １３ ) ２ , and SR １３ The C3-C7 cycloalkyl and 3-7 membered heterorings are optionally substituted with one or more substituents independently selected from the C3-C7 cycloalkyl and 3-7 membered heterorings, respectively, and each is optionally substituted with a halogen, CO ２ R １３ , C(O)N(R １３ ) ２ SO ２ R １３ , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, as well as O, S, S(O), SO ２ , N, and NR １３ Substituted by substituents selected from a 3- to 6-membered heterocycle containing 1 to 2 ring heteromolets selected from; Y is selected from halogen and X-A; X is O, NR １３ , S, S(O), and SO ２ Selected from; A is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C6 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, P(O)(OR １２ ) ２ , C1-C6 alkylene P(O)(OR １２ ) ２ , C1-C6 alkylene, C3-C7 cycloalkyl, C1-C6 alkylene, C4-C6 cycloalkenyl, C1-C6 alkylene heterocycloalkyl, C1-C3 alkylene aryl, C1-C6 alkylene heteroaryl, C(O)Q', CO ２ Q', C(O)N(Q') ２ , S(O)Q', and SO ２ Selected from Q', Here, Q' is C1-C20 alkyl, C1-C20 haloalkyl, C2-C20 alkenyl, C2-C20 haloalkenyl, C2-C20 alkynyl, C2-C20 haloalkynyl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, as well as O, S, S(O), SO ２ , N, and NR １３ Selected from a 3- to 7-membered heterocycle containing 1 to 2 ring heteromolets selected from, and the C1-C20 alkyl group, C2-C20 haloalkyl group, C2-C20 alkenyl group, C2-C20 haloalkenyl group, C3-C7 cycloalkyl group, C4-C7 cycloalkenyl group, and 3- to 7-membered heterocyclic group optionally, CN, OR １３ , N(R １３ ) ２ CO ２ R １３ , SR １３ , substituted with one or more substituents independently selected from C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterorings, and / or disubstituted on the same carbon atom by C1-C6 alkyl or by C2-C6 alkylene to form a C3-C7 cycloalkyl ring, and each of the C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterorings is further optionally substituted with substituents selected from C1-C3 alkyl and C1-C3 haloalkyl; Each R １２ This is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C6 alkylene C3-C7 cycloalkyl, substituted or unsubstituted C1-C6 alkylene C3-C7 heterocycloalkyl, substituted or unsubstituted C1-C6 alkylenearyl, and substituted or unsubstituted C1-C6 alkylene heteroaryl; Each R １３ 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), SO ２ , N, and NR １４ A 3- to 7-membered heterocycle containing one or two ring heteromolets selected from the above, 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 heterocycle group are optionally CN, OR １４ , N(R １４ ) ２ , and SR １４ Substituted with one or more substituents independently selected from, and the C3-C7 cycloalkyl and 3-7 membered heterorings are each further optionally, halogens, CO ２ R １４ , C(O)N(R １４ ) ２ SO ２ R １４ , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, as well as O, S, S(O), SO ２ , N, and NR １４ Substituted by substituents selected from a 3- to 6-membered heterocycle containing 1 to 2 ring heteromolets selected from, R １４ is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and further All available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes. However, R １ is C1-C6P(O)(OR １２ ), ２ and R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ and R １４ , Q', X, Y, and A are as defined above for formula (I); or, Y is X - A, where A is C1-C6 alkylene P(O)(OR １２ ) ２ , C1-C6 alkylene, C3-C7 cycloalkyl, C1-C6 alkylene, C4-C6 cycloalkenyl, C1-C6 alkylene heterocycloalkyl, C1-C3 alkylene aryl, C1-C6 alkylene heteroaryl, C(O)Q', CO ２ Q', C(O)N(Q') ２ , S(O)Q', and SO ２ Selected from Q', and then 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 １３ and R １４ Q' and X are as defined above for equation (I).

2. R １ is hydrogen, C1-C3 alkyl, C1-C3 alkylene P(O)(OR １２ ) ２ , C(O)R １２ CO ２ R １２ , C(O)N(R １２ ) ２ S(O)R １２ , and SO ２ R １２ The compound according to claim 1, wherein all available hydrogen atoms are 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.

3. R １ ga S(O)R １２ and SO ２ R １２ The compound according to claim 2, wherein 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.

4. R １ is hydrogen, C1-C3 alkyl, C1-C3P(O)(OR １２ ) ２ , C(O)R １２ CO ２ R １２ , and C(O)N(R ９ ) ２ The compound according to claim 2, wherein 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.

5. R １ Hydrogen, CH ３ ,CH ２ CH ３ , CH (CH ３ ) ２ ,CH ２ P(O)(OR １２ ) ２ , and CH(CH ３ )P(O)(OR １２ ) ２ The compound according to claim 4, wherein 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.

6. R １ ga CH ２ P(O)(OR １２ ) ２ and CH(CH ３ )P(O)(OR １２ ) ２ A compound according to claim 5, selected from the above.

7. R １ Hydrogen, deuterium, CH ３ CF ３ , and CD ３ A compound according to claim 5, selected from the above.

8. R ２ The compound according to any one of claims 1 to 7, wherein is independently selected from hydrogen and C1-C4 alkyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

9. R ２ Hydrogen, CH ３ ,CH ２ CH ３ , CH (CH ３ ) ２ , and C(CH ３ ) ３ The compound according to claim 8, wherein 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.

10. R ２ hydrogen and deuterium, F, CH ３ CF ３ ,CH ２ CH ３ CD ２ CD ３ CF ２ CF ３ , CH (CH ３ ) ２ CD (CD ３ ) ２ , CF (CF ３ ) ２ , C (CD ３ ) ３ , C (CF ３ ) ３ , and C(CH ３ ) ３ A compound according to claim 9, selected from the above.

11. R ２ The compound according to claim 10, wherein is selected from hydrogen and deuterium.

12. R ３ , R ４ , R ５ , and R ６ The compound according to any one of claims 1 to 11, wherein is independently selected from hydrogen and C1-C4 alkyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

13. R ３ , R ４ , R ５ , and R ６ Hydrogen, CH ３ ,CH ２ CH ３ , CH (CH ３ ) ２ , and C(CH ３ ) ３ The compound according to claim 12, wherein a hydrogen atom is independently 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.

14. R ３ , R ４ , R ５ , and R ６ These are hydrogen and deuterium, Br, F, CH ３ CF ３ ,CH ２ CH ３ CD ２ CD ３ CF ２ CF ３ , CH (CH ３ ) ２ CD (CD ３ ) ２ , CF (CF ３ ) ２ , C (CD ３ ) ３ , C (CF ３ ) ３ , and C(CH ３ ) ３ A compound according to claim 13, independently selected from the above.

15. R ３ , R ４ , R ５ , and R ６ These are hydrogen, deuterium, Br, F, and CH ３ CD ２ H, CDH ２ , and CD ３ A compound according to claim 14, independently selected from the above.

16. R ３ , R ４ , R ５ , and R ６ At least one of them is deuterium, or R ３ , R ４ , R ５ , and R ６ The compound according to any one of claims 1 to 15, wherein at least one of the compounds contains deuterium.

17. R ３ , R ４ , R ５ , and R ６ All of them are hydrogen, or R ３ , R ４ , R ５ , and R ６ The compound according to any one of claims 1 to 15, wherein all of the atoms are deuterium.

18. R ７ and R ８ The compound according to any one of claims 1 to 17, wherein is independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

19. R ７ and R ８ The compound according to claim 18, wherein is independently selected from hydrogen, C1-C4 alkyl, and C2-C6 alkenyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

20. R ７ and R ８ The compound according to claim 19, wherein is independently selected from hydrogen and C1-C4 alkyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

21. R ７ and R ８ is hydrogen, deuterium, CH ３ CD ２ H, CDH ２ CD ３ ,CH ２ CH ３ , and CD ２ CD ３ A compound according to claim 20, independently selected from the above.

22. R ７ and R ８ Both are CH ３ CD ３ ,CH ２ CH ３ , or CD ２ CD ３ The compound according to claim 20.

23. R ７ and R ８ These atoms, together with the nitrogen atoms present between them, form a 4- to 7-membered heteroring, which can optionally consist of O, S, S(O), SO₂. ２ , N, and NR １３ The compound according to any one of claims 1 to 17, comprising one or two additional ring heteromolets selected from, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

24. R ７ and R ８ The compound according to claim 23, wherein the atoms, together with the nitrogen atoms present between them, form pyrrolidinyl, piperidinyl, or diazinanyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

25. R ７ and R ８ The compound according to claim 23, wherein the atoms, together with the nitrogen atoms present between them, form pyrrolidinyl, piperidinyl, or diazinanyl, where all available hydrogens are optionally replaced by deuterium.

26. R ９ , R １０ , and R １１ is hydrogen, halogen, CN, OR １３ , N(R １３ ) ２ , SR １３ , C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 haloalkenyl, CO ２ R １３ , C(O)N(R １３ ) ２ S(O)R １３ SO ２ R １３ A C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C2-C6 haloalkynyl group are independently selected, where the C1-C4 alkyl group, C1-C4 haloalkyl group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, and C2-C6 haloalkynyl group are optionally CN, OR １３ , N(R １３ ) ２ , and SR １３ The compound according to any one of claims 1 to 25, wherein it is substituted with one or more substituents independently selected from, and all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

27. R ９ , R １０ , and R １１ is hydrogen, F, Cl, Br, CN, OR １３ , N(R １３ ) ２ , SR １３ ,CH ３ ,CH ２ CH ３ , CH (CH ３ ) ２ , C (CH ３ ) ３ , C1-C4 haloalkyl, C2-C6 haloalkenyl, CO ２ R １３ S(O)R １３ SO ２ R １３ , C(O)N(R １３ ) 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 optionally CN, OR １３ , N(R １３ ) ２ , and SR １３ The compound according to claim 26, wherein it is substituted with one or two substituents independently 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.

28. R ９ , R １０ , and R １１ is hydrogen, F, Cl, Br, CN, OR １３ , N(R １３ ) ２ , SR １３ ,CH ３ ,CH ２ CH ３ , CH (CH ３ ) ２ , C (CH ３ ) ３ , C1-C4 haloalkyl, C2-C6 haloalkenyl, CO ２ R １３ S(O)R １３ SO ２ R １３ The compound according to claim 27, which is independently selected from C2-C6 alkenyls, where all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

29. R ９ , R １０ , and R １１ The compound according to claim 28, wherein is independently selected from hydrogen, deuterium, F, Cl, Br, and CN.

30. R １０ is selected from hydrogen, deuterium, F, Cl, Br, and CN, R ９ and R １１ The compound according to claim 29, wherein is selected from hydrogen and deuterium.

31. R １０ is selected from hydrogen, F, and CN, R ９ and R １１ The compound according to claim 30, wherein both are hydrogen.

32. Each R １２ The compound according to any one of claims 1 to 30, wherein is independently selected from hydrogen, C1-C4 alkyl, and C2-C6 alkenyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

33. Each R １２ is hydrogen, deuterium, CH ３ CD ２ H, CDH ２ CD ３ ,CH ２ CH ３ , and CD ２ CD ３ A compound according to claim 33, independently selected from the above.

34. The compound according to any one of claims 1 to 33, wherein Y is a halogen, and the halogen in Y is selected from F, Cl, and Br.

35. A compound according to any one of claims 1 to 33, wherein Y is X-A.

36. X is S, S(O), and SO ２ A compound according to claim 35, selected from the above.

37. X is O, NR １３ The compound according to claim 35, selected from , and S, wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

38. The compound according to claim 35, wherein X is O.

39. A is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C7 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, P(O)(OR １１ ) ２ , C1-C3 alkylene P(O)(OR １１ ) ２ , C1-C3 alkylene C3-C7 cycloalkyl, C1-C3 alkylene C4-C6 cycloalkenyl, C1-C3 alkylene heterocycloalkyl, C1-C3 alkylene aryl, C1-C3 alkylene heteroaryl, C(O)Q', CO ２ Q', C(O)N(Q') ２ , S(O)Q', and SO ２ A compound according to any one of claims 1 to 38, selected from Q', where all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

40. A is hydrogen, P(O)(OR １２ ) ２ ,CH ２ P(O)(OR １２ ) ２ ,CH ２ CH ２ P(O)(OR １２ ) ２ ,CH ２ CH (CH ３ )P(O)(OR １２ ) ２ , CH (CH ３ )CH ２ P(O)(OR １２ ) ２ , CH (CH ３ )P(O)(OR １２ ) ２ , CH (CH ２ CH ３ )P(O)(OR １２ ) ２ ,C(O)Q',CO ２ Q', C(O)N(Q') ２ , S(O)Q', and SO ２ The compound according to claim 39, selected from Q', where all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

41. A is hydrogen, P(O)(OR １１ ) ２ ,CH ２ P(O)(OR １１ ) ２ , CH (CH ３ )P(O)(OR １１ ) ２ ,C(O)N(Q') ２ The compound according to claim 40, selected from , and C(O)Q.

42. A is C(O)N(Q') ２ The compound according to claim 41, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

43. The compound according to claim 42, wherein A is C(O)Q', where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

44. R １１ The compound according to claim 41, wherein is selected from hydrogen, C1-C4 alkyl, and C2-C6 alkenyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

45. The compound according to claim 39, wherein A is selected from hydrogen and C1-C4 alkyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

46. A is CH ２ C3-C7 cycloalkyl, CH ２ C4-C6 cycloalkenyls, CH ２ Heterocycloalkyl, CH ２ Aryl, and CH ２ The compound according to claim 39, selected from heteroaryls, wherein all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

47. The compound according to claim 39, wherein A is selected from C3-C7 cycloalkyl, C4-C7 cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

48. Q' is selected from C1-C20 alkyl, C1-C20 haloalkyl, C2-C20 alkenyl, C2-C20 haloalkenyl, C2-C20 alkynyl, and C2-C20 haloalkynyl, where the C1-C20 alkyl, C2-C20 haloalkyl, C2-C6 alkenyl group, C2-C20 haloalkenyl group, C2-C20 alkynyl group, and C2-C20 haloalkynyl group are optionally CN, OR １３ , N(R １３ ) ２ CO ２ R １３ , SR １３ The compound according to any one of claims 1 to 43, wherein the carbon atom is substituted with 1 to 3 substituents independently selected from C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterorings, and / or disubstituted on the same carbon atom by C1-C6 alkyl or by C2-C6 alkylene to form a C3-C7 cycloalkyl ring, where each of the C3-C7 cycloalkyl, C4-C7 cycloalkenyl, and 3- to 7-membered heterorings is further optionally substituted with substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, where all available hydrogen atoms are optionally replaced by halogen atoms, and / or all available atoms are optionally replaced by their alternative isotopes.

49. Q' is N(R １３ ) ２ and CO ２ R １３ The compound according to claim 48, which is optionally substituted with one or two substituents independently selected from and / or optionally disubstituted on the same carbon atom by C1-C6 alkyl or by C2-C6 alkylene to form a C3-C7 cycloalkyl ring, selected from C1-C20 alkyl, C2-C20 alkenyl, and C2-C20 alkynyl, wherein the C3-C7 cycloalkyl ring is further optionally substituted with substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

50. Q' is N(R １３ ) ２ The compound according to claim 44, which is a C1-C20 alkyl or C2-C20 alkenyl substituted with, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

51. Q' is N(R １３ ) ２ The compound according to claim 49, wherein a C1-C10 alkyl group is substituted with a halogen atom, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium.

52. Q' is N(R １３ ) ２ The compound according to claim 49, which is a C1-C20 alkyl or C2-C20 alkenyl which is substituted with and disubstituted on the same carbon atom with a C2-C6 alkylene to form a C3-C7 cycloalkyl ring, wherein the C3-C7 cycloalkyl ring is further optionally substituted with substituents selected from C1-C3 alkyl and C1-C3 haloalkyl, wherein all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with their alternative isotopes.

53. Q' is N(R １３ ) ２ The compound according to claim 52, wherein the C1-C10 alkyl group is substituted with and disubstituted on the same carbon atom with a C2-C6 alkylene to form a C5-C6 cycloalkyl ring, where the C3-C7 cycloalkyl ring is further optionally substituted with substituents selected from C1-C3 alkyl groups, and all available hydrogen atoms are optionally replaced with halogen atoms and / or all available hydrogen atoms are optionally replaced with deuterium.

54. Q' is optionally CO ２ R １３ The compound according to claim 49, which is a C1-C20 alkyl or C2-C20 alkenyl substituted with, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

55. Q' is CO ２ R １３ The compound according to claim 54, which is a C1-C6 alkyl or C2-C6 alkenyl substituted with a, wherein all available hydrogen atoms are optionally replaced by halogen atoms and / or all available hydrogen atoms are optionally replaced by deuterium.

56. The compound according to claim 49, wherein Q' is a C1-C20 alkyl or C2-C20 alkenyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

57. The compound according to claim 56, wherein Q' is a C1-C6 alkyl or C2-C6 alkenyl, where all available hydrogen atoms are optionally replaced by halogen atoms and / or all available atoms are optionally replaced by their alternative isotopes.

58. Q' is a C3-C7 cycloalkyl, C4-C7 cycloalkenyl, as well as O, S, S(O), SO ２ , N, and NR １３ A 3- to 7-membered heterocycle containing one or two ring heteromolets selected from, where the C3-C7 cycloalkyl group, C4-C7 cycloalkenyl group, and 3- to 7-membered heterocyclic group are optionally CN, OR １３ , N(R １３ ) ２ CO ２ R １３ , SR １３ The compound according to any one of claims 1 to 48, wherein the C3-C7 cycloalkyl group, the C4-C7 cycloalkenyl group, and the 3-membered to 7-membered heterocycle are substituted with 1 to 3 substituents independently selected from C3-C7 cycloalkyl groups, and the 3-membered to 7-membered heterocycle, each of which is further optionally substituted with substituents selected from C1-C3 alkyl groups; where all available hydrogen atoms are optionally replaced with halogen atoms and / or all available atoms are optionally replaced with their alternative isotopes.

59. Q' is N and NR １３ The compound according to claim 58, selected from a 5- to 6-membered heteroring comprising one ring heteromoon selected from, wherein the 5- to 6-membered heteroring group is optionally substituted by a 5- to 6-membered heteroring, wherein all available hydrogen atoms are optionally substituted by halogen atoms and / or all available atoms are optionally substituted by their alternative isotopes.

60. Q' is selected from the following groups, and is the compound according to any one of claims 1 to 48: 【Chemistry 2】 【Transformation 3】 During the ceremony 【Chemistry 4】 This indicates a covalent bond point.

61. The compound according to claim 1, wherein the compound of formula (I) is selected from the compounds listed below, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 。

62. A composition comprising one or more compounds according to any one of claims 1 to 61, and a carrier.

63. A pharmaceutical composition comprising one or more compounds described in any one of claims 1 to 61, and a pharmaceutically acceptable carrier.

64. A method for activating intracellular serotonin receptors in a biological sample or in a patient, comprising administering an effective amount of one or more compounds described in any one of claims 1 to 61 to the cells.

65. A method for treating a disease, disorder, or condition by activating serotonin receptors, comprising administering a therapeutically effective amount of one or more compounds described in any one of claims 1 to 61 to a subject in need of treatment.

66. Intracellular 5-HT in biological samples or in patients ２Ａ A method for activating a cell, comprising administering an effective amount of one or more compounds described in any one of claims 1 to 61 to the cell.

67. A method for treating a mental disorder, comprising administering a therapeutically effective amount of one or more compounds described in any one of claims 1 to 61 to a subject in need of treatment.

68. The method according to claim 67, wherein the mental disorder is selected from hallucinations, delusions, and combinations thereof.

69. The method according to claim 67, wherein the mental disorder is selected from anxiety disorders; depression; mood disorders; psychiatric disorders; impulse control and addiction disorders; drug addiction; obsessive-compulsive disorder (OCD); post-traumatic stress disorder (PTSD); stress response syndromes; dissociative disorders; depersonalization disorders; dysphonia; sexual and gender disorders; somatic symptom disorders; and combinations thereof.

70. A method for treating psychosis or psychotic symptoms, comprising administering a therapeutically effective amount of one or more compounds described in any one of claims 1 to 61 to a subject in need of treatment.

71. A method for treating a disease, disorder, or condition of the central nervous system (CNS) and / or a neurological disease, disorder, or condition, comprising administering a therapeutically effective amount of one or more compounds described in any one of claims 1 to 61 to a subject in need of treatment.

72. The aforementioned CNS diseases, disorders, or conditions and / or neurological diseases, disorders, or conditions include neurological disorders, such as neurodevelopmental disorders and neurodegenerative diseases, e.g., 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; 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; The method according to claim 71, selected from tuberous sclerosis; Rett syndrome; cerebral palsy; reward system disorders such as eating disorders including 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.

73. A method for treating behavioral problems, comprising administering a therapeutically effective amount of one or more compounds described in any one of claims 1 to 61 to a non-human subject in need of treatment.

74. The method according to claim 73, wherein the non-human subject is a dog or cat suffering from a neurological disorder, behavioral problems, trainability problems, and / or a combination thereof.

75. The method according to claim 74, wherein the neurological disorder, behavioral problem, and trainability problem include, but are not limited to, anxiety, fear and stress, sleep disorders, cognitive impairment, aggression, and / or combinations thereof.

76. A method for treating a disease, disorder, or condition by activation of serotonin receptors, comprising administering a therapeutically effective amount of one or more compounds described in any one of claims 1 to 61 to a subject in need of treatment, in combination with other known agents useful for treating diseases, disorders, or conditions by activation of serotonin receptors.

77. A pharmaceutical composition comprising a compound according to any one of claims 1 to 61 and an additional therapeutic agent.

78. The composition according to claim 77, wherein the additional therapeutic agent is a psychostimulant.

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