Indole derivatives useful as serotonergic agents for the treatment of conditions associated therewith

Abstract

This disclosure relates to indole derivatives of general formula (I), methods for their preparation, compositions comprising indole derivatives of general formula (I), and their use in activating serotonin receptors in cells, as well as to treating diseases, conditions, or ailments by activating serotonin receptors in cells. The diseases, conditions, or ailments include, for example, psychosis, mental illness, and CNS disorders. Formula (I).

Description

[0001] Cross-reference and priority statement of related applications This application claims priority to U.S. Provisional Application No. 63 / 598,683, filed November 14, 2023, with the invention entitled “INDOLE DERIVATIVES AS SEROTONERGICAGENTS USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO”, and U.S. Provisional Application No. 63 / 598,703, filed November 14, 2023, with the same invention title, the full disclosures of which are incorporated herein by reference and each claim priority. Technical Field

[0002] This disclosure relates to indole derivatives of general formula I for use in the fields of psychiatry, neurobiology, and pharmacological therapy to treat various conditions (e.g., mental illnesses and neurological disorders) treated by activating serotonin receptors. This disclosure further includes methods for preparing compounds of formula (I) and corresponding intermediates. Background Technology

[0003] Mental health disorders or mental illnesses refer to a wide range of conditions, including but not limited to depression, anxiety and panic disorders, schizophrenia, eating disorders, substance abuse disorders, post-traumatic stress disorder, attention deficit hyperactivity disorder, and obsessive-compulsive disorder. Many mental health disorders, as well as neurological disorders, are affected by alterations, dysfunctions, degeneration, and / or damage to the brain's serotonergic system, which may partially explain the common endophenotypes and comorbidities in neuropsychiatric and neurological disorders.

[0004] Due to the constantly changing legal status of psychedelics, the field of psychedelic neuroscience has recently experienced a resurgence after decades of restricted research. Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect many cognitive processes. There is now a consensus that psychedelics are serotonin 2A (5-HT). 2A )Agonists or partial agonists of receptors.

[0005] Psychedelics exhibit rapid onset and sustained effects long after their acute effects, including changes in mood and brain function. These long-term effects are likely due to their unique receptor affinity, which influences neurotransmission (i.e., neuroplasticity) via neuromodulatory systems that regulate brain activity, promotes cell survival, has neuroprotective effects, and modulates the brain's neuroimmune system. The mechanisms leading to these long-term neuromodulatory changes may involve epigenetic modifications, alterations in gene expression, and regulation of presynaptic and postsynaptic receptor density. These previously poorly studied psychedelic drugs have the potential to provide next-generation neuropathic therapies, where treatment-resistant psychiatric and neurological disorders such as depression, post-traumatic stress disorder, dementia, and addiction may become treatable with a reduced pharmacological risk profile.

[0006] Despite being generally considered dangerous, psychedelic drugs are among the safest known classes of central nervous system (CNS) drugs from a physiological safety perspective. Preliminary data suggest that administration of psychedelic drugs to the human body produces uniquely characteristic effects and potential adverse reactions that require appropriate addressing to maximize safety. The main safety concerns are primarily psychological rather than physiological. Somatic effects vary but are relatively insignificant, even at doses that elicit strong psychological effects. Psilocybin has been frequently reported to cause transient delayed headaches when administered in a controlled environment, with the incidence, duration, and severity increasing in a dose-related manner [Johnson et al., Drug Alcohol Depend (2012) 123(1-3):132–140]. Repeated administration of psychedelic drugs has been found to lead to the rapid development of tolerance, known as rapid resistance, a condition believed to be partly caused by 5-HT. 2A Receptor-mediated phenomena. In fact, several studies have shown that rapid tolerance to psychedelics is related to 5-HT. 2A Downregulation of receptors is associated. For example, daily administration of LSD selectively reduces the density of 5-HT2 receptors in the rat brain [Buckholtz et al., Eur. J. Pharmacol. 1990, 109:421–425. 1985; Buckholtz et al., Life Sci. 1985, 42:2439–2445].

[0007] Unlike any currently available treatment, classic psychedelics and dissociative psychedelics are known to have rapid-acting antidepressant and anti-addictive effects. Randomized controlled clinical trials have confirmed the antidepressant and anti-anxiety effects of classic psychedelics in humans.

[0008] The chemical formula of serocepin (4-phosphoryloxy-N,N-dimethyltryptamine) is C12 H 17 N2O4P. Selocillin is a tryptophan-based prodrug and one of the main psychoactive components of Psilocybean mushrooms. Selocillin was first isolated from Psilocybean mushrooms by Hofmann in 1957 and later synthesized by him in 1958 [Passie et al., AddictBiol., 2002, 7(4):357-364]. It was used in psychiatric, psychological research and psychotherapy in the early to mid-1960s until it was listed as a controlled drug in the United States in 1970 and in Germany in the 1980s [Passie 2005; Passie et al., Addict Biol., 2002, 7(4):357-364]. Research on the effects of serozepine resumed in the mid-1990s, and it is currently the preferred compound for studies on 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], possibly because its effects are shorter-lasting and less notorious than LSD. Like other members of this class, serozepine can sometimes cause significant changes in perception, cognition, and mood, including mood instability.

[0009] In humans and other mammals, psilocin is converted into the active metabolite psilocin, or the parent compound of 4-hydroxy-N,N-dimethyltryptamine. Psilocin may partially or wholly produce most of the subjective and physiological effects of psilocin in humans and non-human animals. Recent studies on human psilocin have confirmed that psilocin, through the 5-HT pathway of the parent compound psilocin, contributes to the overall effects of psilocin. 2A Activity, and for 5-HT 2A The activity of serotonin receptors and other receptors may provide some support for the indirect effects of dopamine. In fact, the most consistent finding regarding the involvement of other receptors in psychedelic effects is 5-HT. 1A Receptors. This is especially true for tryptophan and LSD, which typically exhibit significant affinity and functional potency for these receptors. 5-HT is known to... 1A Receptors and 5-HT 2AThe receptors are colocalized on cortical pyramidal cells [Martín-Ruiz et al., JNeurosci. 2001, 21(24):9856–986], with two types of receptors having opposite functions [Araneda et al., Neuroscience 1991, 40(2):399–412].

[0010] Although we do not yet understand 5-HT 2A The exact role of receptors and other members of the 5-HT2 receptor family in the amygdala is unclear, but the role of 5-HT2 receptors is clearly unknown. 2A Receptors play an important role in emotional responses and are 5-HT receptors. 2A Important targets to consider in the action of agonists and psychedelics. In fact, most known 5-HT... 2A Agonists produce hallucinogenic effects in humans, derived from a 5-HT... 2A Agonists have been extrapolated to other agonists, such as selocillin and LSD, which produce hallucinogenic effects in rodents [Aghajanian et al., Eur J Pharmacol., 1999, 367(2-3):197–206; Nichols et al., J Neurochem., 2004,90(3):576–584]. Selocillin has an effect on human 5-HT. 2A The receptor affinity is stronger than that for rat receptors, and compared to LSD, it has a stronger affinity for 5-HT. 2A and 5-HT 2C Both receptors have lower K(i). Furthermore, a series of rat drug identification studies have found that 5-HT... 2A Antagonist rather than 5-HT 1A Antagonists prevent rats from recognizing serocillin [Winter et al., PharmacolBiochem Behav., 2007, 87(4):472–480]. Daily doses of LSD and serocillin reduced the density of 5-HT2 receptors in the rat brain.

[0011] Today, serocerabin is one of the most widely used psychedelics in human studies due to its relative safety, moderately long duration of activity, and good absorption in subjects. Serocerabin still holds significant research and therapeutic potential, as recent studies have shown varying degrees of success in neurotic disorders, alcoholism, depression associated with major depressive disorder, treatment-resistant depression, as well as in patients with advanced cancer, obsessive-compulsive disorder, addiction, anxiety disorders, post-traumatic stress disorder, and even cluster headaches.

[0012] Recent advances include several double-blind, placebo-controlled phase 2 studies of selocillin as an adjunct psychotherapy in patients with treatment-resistant depression, major depressive disorder, and cancer-related psychosocial distress, which have shown unprecedented positive remissions of anxiety and depression. Two recent small pilot studies of selocillin as an adjunct psychotherapy have also shown positive benefits in the treatment of alcohol and nicotine addiction. Recently, oxygen level-dependent functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) have been used for in vivo brain imaging in humans after psychedelic drug administration, with results showing that intravenous administration of selocillin and LSD reduces the oscillatory power of regions of the brain's default mode network [Nichols DE. Pharmacol Rev., 2016, 68(2):264–355].

[0013] Preliminary studies using positron emission tomography (PET) have shown that selocillin intake (15 or 20 mg orally) increased the absolute metabolic rate of glucose in the frontal lobe in healthy participants, and to a lesser extent increased the absolute metabolic rate of glucose in other cortical regions and in the striatum and limbic subcortical structures, suggesting that some key behavioral effects of selocillin involve the frontal cortex [Gouzoulis-Mayfrank et al., Neuropsychopharmacology, 1999, 20(6):565-581; Vollenweider et al., Brain Res. Bull. 2001, 56(5):495–507]. Although 5-HT 2A Stimulation is widely considered the primary effect of classic psychedelics, but serozepine has low affinity for many other presynaptic and postsynaptic serotonin and dopamine receptors, as well as serotonin reuptake transporters [Tyls et al., Eur. Neuropsychopharmacol., 2014, 24(3):342–356]. Serozepine activates 5-HT 1A Receptors, which may contribute to antidepressant / anti-anxiety effects.

[0014] Depression and anxiety disorders are two of the most common mental illnesses worldwide. Depression is a multifaceted condition characterized by mood disturbances and other symptoms such as anhedonia, psychomotor malaise, guilt, attention deficit, and suicidal tendencies, all of which can vary in severity. Similarly, anxiety disorders are a group of complex conditions characterized by intense psychological distress and other subtype-dependent symptoms. Anxiety disorders associated with life-threatening conditions are the only subtype of anxiety disorder that has been studied in conjunction with psychedelic therapy. Pharmacological and psychosocial interventions are commonly used to manage this type of anxiety, but their efficacy is mixed and limited, often failing to provide satisfactory mood relief. Recent interest in the use of psychedelic-assisted therapy may represent a promising alternative for patients with depression and anxiety disorders who do not respond to conventional approaches.

[0015] Typically, psychedelic therapy models consist of the administration of an oral active drug to induce a mystical experience lasting approximately 4–9 hours (depending on the psychedelic) [Halberstadt, Behav Brain Res., 2015, 277:99–120; Nichols, Pharmacol. Rev., 2016, 68(2): 264–355]. This allows participants to resolve and integrate difficult feelings and situations, resulting in lasting antidepressant and anti-anxiety effects. Classic psychedelics such as serocillin and LSD have been investigated as potential candidates. In a study of treating depression and anxiety associated with life-threatening conditions with classic psychedelics, serocillin and LSD were found to consistently produce significant and sustained antidepressant and anti-anxiety effects in a supportive setting.

[0016] Psychedelic therapy is generally well-tolerated with few or no lasting side effects. Regarding the mechanism of action, psychedelics work primarily through biochemical means via serotonin receptor agonism and by psychologically mediating the production of meaningful psycho-psychological experiences that contribute to mental flexibility. Given the limited success rate of current treatments for anxiety disorders and mood disorders, and considering the high morbidity associated with these conditions, psychedelics have the potential to provide symptom relief for patients whose symptoms are not adequately controlled by conventional methods.

[0017] Other emerging clinical research and evidence suggest that psychedelic adjunctive therapy also shows potential as an alternative treatment for treatment-resistant substance use disorders and mental health conditions, and could therefore be an important tool in a crisis where existing methods have achieved limited success [dos Santos et al., Ther Adv Psychopharmacol., 2016, 6(3):193-213]. Equally encouraging are the findings of a recent pilot study of serocibin adjunctive therapy for tobacco use disorder, which showed a withdrawal rate of 80% at six months of follow-up and 67% at 12 months of follow-up [Johnson et al., https: / / www.ncbi.nlm.nih.gov / pubmed / 27441452, J Drug Alcohol Abuse, 2017, 43(1):55-60; Johnson et al., Psychopharmacol. 2014, 28(11):983-992]; these rates are significantly higher than any rates documented in the smoking cessation literature. Notably, the mystical experiences generated by serocillin therapy were significantly associated with positive treatment outcomes. These results are consistent with emerging evidence from recent clinical trials, supporting the effectiveness of serocillin-assisted therapy for treatment-resistant depression and end-of-life anxiety [Carhart-Harris et al., Neuropsychopharmacology, 2017, 42(11):2105-2113]. Research on the potential benefits of psychedelic-assisted therapy for opioid use disorder (OUD) is beginning to emerge, and increasing evidence supports the necessity of advancing this research line. Available evidence from early randomized clinical trials suggests a promising role in the treatment of OUD: higher withdrawal rates were observed in participants receiving high-dose LSD and ketamine-assisted therapy for heroin addiction compared to long-term follow-up controls. A recent large U.S. population study of 44,000 people found that, according to the DSM-IV criteria, psychedelic use was associated with a 40% lower risk of opioid abuse and a 27% lower risk of opioid dependence the following year [Pisano et al., J Psychopharmacol., 2017, 31(5):606-613]. Similarly, in marginalized women, psychedelic use was found to have a protective moderating effect on the relationship between prescription opioid use and suicide risk [Argento et al., J Psychopharmacol.,2018, 32(12):1385-1391].While these preliminary findings on classic psychedelics are promising, further research is needed to determine how psychedelics can improve opioid crisis responses. Meanwhile, mounting evidence regarding the safety and efficacy of serocerabin in treating psychotic and substance use disorders should help drive further clinical research as a novel intervention for OUD.

[0018] Regular doses of psychedelics also improve sleep disorders, which are very common in people with depression, with over 80% of depressed patients complaining of poor sleep quality. Sleep symptoms are often not resolved with first-line treatment and are associated with a greater risk of relapse and recurrence. Interestingly, sleep problems often precede other symptoms of depression, and subjective sleep quality deteriorates before recurrent depressive episodes. Two other studies assessing brain activity via electroencephalography (EEG) during sleep have shown that psychedelics, such as LSD, have a positive effect on sleep patterns. Furthermore, it has been proposed that a single dose of psychedelics can cause a reset of the circadian rhythm during the sleep / wake cycle, thereby enhancing cognitive-emotional processes in people with depression, and also improving well-being and mood in healthy individuals [Kuypers, Medical Hypotheses, 2019, 125:21-24].

[0019] A systematic meta-analysis of clinical trials conducted between 1960 and 2018 investigated the therapeutic use of psychedelic therapy in patients with severe or advanced illness and related mental disorders, finding that psychedelic therapy (primarily LSD) could improve cancer-related depression, anxiety, and fear of death. Four randomized controlled clinical trials published between 2011 and 2016, primarily using serocillin, demonstrated that adjunctive psychedelic therapy could rapidly, strongly, and persistently improve cancer-related psychological and existential anguish [Ross S, Int Rev Psychiatry, 2018, 30(4):317-330]. Many patients facing cancer or other life-threatening illnesses experience significant existential anguish associated with a loss of meaning or purpose in life, which may be related to despair, depression, helplessness, feelings of burden, and a desire to hasten death. These characteristics are often central to clinically significant anxiety and depression, which can significantly reduce the quality of life of this patient population. Alleviating these core characteristics of existential anguish should be one of the central goals of palliative care. Therefore, several manual psychotherapies for cancer-related suffering have been developed in recent years, focusing on dignity and meaning creation. However, there are currently no pharmacological interventions for suffering itself, and available pharmacological treatments for depressive symptoms in cancer patients have not shown an advantage over placebo. Further effective treatments for these symptoms are still needed [Rosenbaum et al., Curr. Oncol., 2019, 26(4): 225-226].

[0020] Recently, there has been growing interest in a new dosing paradigm for psychedelics (such as serotonin and LSD), commonly known as microdose administration. In this paradigm, a subconscious dose of approximately 10% or less of the full dose of the serotonergic hallucinogen is administered once daily, every other day, every three days, or in the same sequence on a more consistent basis. This dosing paradigm not only better aligns with current standards of pharmacological care but may also be particularly beneficial for certain conditions (such as Alzheimer's disease, other neurodegenerative diseases, attention deficit disorder, and attention deficit hyperactivity disorder) and for certain patient populations (such as the elderly, adolescents, and patients who fear or oppose psychedelic adjunctive therapy). Furthermore, this approach may be particularly well-suited for managing cognitive deficits and preventing neurodegeneration. For example, at doses of selociline below the threshold used to elicit the classic wet dog shake behavioral response associated with hallucinogenic doses, subgroups of low-attention and low-motivation rats showed improved performance on five selection series reaction times and progressive ratio tasks, respectively (Blumstock et al., WO 2020 / 157569 A1). Similarly, with hallucinogenic doses of 5-HT... 2A Agonist treatment in patients was associated with increased activation of the BDNF and mTOR pathways, and these agonists are thought to promote neuroplasticity and are hypothesized as molecular targets for the treatment of dementia and other neurodegenerative diseases (Ly et al., Cell Rep., 2018, 23(11):3170-3182). Additionally, several groups have demonstrated that low-dose, non-hallucinogenic, and non-psychotic doses of 5-HT... 2A Agonists have also shown similar neuroprotective effects and increased neuroplasticity (neural remodeling agents) and reduced neuroinflammation, which may be beneficial for treating both neurodegenerative and neurodevelopmental disorders as well as chronic conditions (Manfrediet 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 repetitive, lower-dose paradigm could extend the utility of these compounds to other indications and could prove useful for health applications.

[0021] Psychosis generally refers to an abnormal mental state characterized by hallucinatory experiences, delusional thinking, and thought disorder. Furthermore, this state is accompanied by social cognitive impairment, inappropriate emotional expression, and bizarre behavior. Most commonly, psychosis develops as part of a mental disorder, in which it represents an integral part of schizophrenia. It corresponds to the most fully developed stage of the disease. The initial manifestation of psychosis (i.e., within the body) in a patient is called the first episode of psychosis. It reflects a critical transitional stage toward the chronic establishment of the disease, presumably mediated by progressive structural and functional abnormalities appearing in the diagnosed patient [ACS Chem. Neurosci., 2018, 9, 2241-2251]. Anecdotal evidence suggests that regular administration of low-dose, non-hallucinogenic (microdose) psychedelic agents can alleviate symptoms of schizophrenia and psychosis. Summary of the Invention

[0022] This summary is provided to introduce a series of representative concepts in a simplified form, which will be further described in the detailed embodiments below. This summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to limit the scope of the claimed subject matter.

[0023] This disclosure includes a compound of formula (I): Formula (I) Or its pharmaceutically acceptable salts, solvates and / or prodrugs, in X does not exist or is selected from O, S, S(O) and SO2; R 1 Selected from H, C 1- C6 alkyl, C 1- C6 alkylene P(O)(OR) 11 2. C 1- C6 alkylene OP(O)(OR) 11 2. C(O)R 11 CO2R 11 C(O)N(R) 11 2. S(O)R 11 and SO2R 11 ; R 2 Selected from H, halogens and C 1- C6 alkyl; R 3 R 4 and R 5 Independently selected from H, CN, halogens, C 1- C6 alkyl, C 2- C6 alkenyl and C 2- C6 ynyl group; R 6 Selected from H, C 1- C 10 Alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene ZR 12 C 2- C6 imenoyl ZR 12 C 2- C6-Isoynyl ZR 12 C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C6 alkylene C 3- C7 cycloalkyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 6- C 10 Aryl and C 1- C6 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 13 and C(O)R 13 ; R 7 and R 8 Independently selected from H, halogens and C 1- C6 alkyl; Each R 9 Independently selected from halogens, C 1- C6 alkyl, OH, OC 1- C6 alkyl, C 1- C6 alkylene OH and C 1- C6 alkylene OC 1- C6 alkyl; R 10 Selected from H, C 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene Z'R 14 C 2- C6 imene-Z'R 14 C 2- C6-Imyynyl Z'R 14 C3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C6 alkylene C 3- C7 cycloalkyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 6- C 10 Aryl and C 1- C6 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 15 and C(O)R 15 ; Z is selected from O, C(O), NR 16 C(O), NR 16 C(O)O、C(O)NR 16 OC(O)NR 16 and NR 16 ; Z' is selected from O, C(O), NR 17 C(O), NR 17 C(O)O、C(O)NR 17 OC(O)NR 17 and NR 17 ; n is an integer selected from 0, 1, 2, 3, and 4; R 11 R 13 R 15 R 16 and R 17 Independently selected from H and C 1- C6 alkyl; R 12 and R 14 Independently selected from H and C 1- C6 alkyl, C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl and C 5- C 10 Heteroaryl, the last four groups are optionally substituted by one to four independent substituents selected from the following: halogenated, C-shaped.1- C4 alkyl, OC 1- C4 alkyl and C(O)C 1- C4 alkyl, Hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes. The condition is that when X is O, R 1 R 2 R 3 R 4 R 5 R 7 and R 8 It is H or D, n is 0, and R 6 When it is H, CH3 or CD3, then R 10 It is not H, CH3, or CD3. The condition is that when X is O, R 1 R 2 R 3 R 4 R 5 R 7 and R 8 It is H or D, n is 0, and R 6 When it is CH3 or CHF2, then R 10 It is not H, CH3, or CD3. The condition is that X does not exist and R 6 When it is H, then n is not 0, or R. 10 Not H or C 1- C6 alkyl.

[0024] In some embodiments, the condition is (1) when X does not exist, then R 6 It is not H, D, or a halogen, and (2) when X is O, S, S(O), or SO2, then each R9 is not independently selected from H, D, a halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, and C1-C6 deuterated haloalkyl, and / or R 10 Not selected from H, D, halogens, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl and C1-C6 deuterated haloalkyl.

[0025] In some embodiments, the condition is that when X does not exist, then R 6 It is not H, D or halogen.

[0026] In some embodiments, including when X is O, S, S(O) or SO2, each R9 is not independently selected from H, D, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl and C1-C6 deuterated haloalkyl.

[0027] In some embodiments, including when X is O, S, S(O) or SO2, R 10 Not selected from H, D, halogens, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl and C1-C6 deuterated haloalkyl.

[0028] In some embodiments, the condition is (1) when X does not exist, then R 6 It is not H, D or halogen, and (2) when X is O, S, S(O) or SO2, then each R9 is not independently selected from H, D, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl and C1-C6 deuterated haloalkyl.

[0029] In some embodiments, the condition is (1) when X does not exist, then R 6 It is not H, D or halogen, and (2) when X is O, S, S(O) or SO2, then R 10 Not selected from H, D, halogens, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl and C1-C6 deuterated haloalkyl.

[0030] In another embodiment, the compounds of this disclosure are used as pharmaceuticals. Therefore, this disclosure also includes the use of the compounds of this disclosure as pharmaceuticals.

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

[0032] This disclosure also includes a method for treating psychosis or psychotic symptoms, the method comprising administering a therapeutically effective amount of one or more compounds of this disclosure to a subject in need.

[0033] This disclosure also includes a method for treating a mental illness, the method comprising administering a therapeutically effective amount of one or more compounds of this disclosure to a subject in need.

[0034] This disclosure also provides a method for preparing the compounds of this disclosure. General and specific methods will be discussed in more detail below and illustrated in the following examples.

[0035] This disclosure further provides intermediates for the compounds disclosed herein, methods for preparing intermediates, and methods for preparing compounds from intermediates.

[0036] Other features and advantages of this disclosure will become apparent from the following detailed description. However, it should be understood that while the detailed description and specific examples indicate embodiments of this disclosure, they are given by way of illustration only, and the scope of the claims should not be limited to these embodiments but should be given the broadest interpretation consistent with the entire specification. Attached Figure Description

[0037] Embodiments of this disclosure will be described in more detail with reference to the accompanying drawings, which are incorporated herein by reference and are shown in the drawings: Figure 1 This is a bar graph illustrating the effect of various doses of the exemplary compound (R)I-1 on the head twitching response (HTR) in male C57BL6 mice. Mice were treated with the exemplary compound (R)I-1 (3 mg / kg, 30 mg / kg, SC) via the SC route, and the total number of head twitches was recorded over 20 minutes. It is believed that the 5-HT... 2A The induction of head twitching induced by receptor agonists represents a behavioral proxy for their hallucinogenic effects. Data are presented as mean ± SEM using one-way ANOVA and Fisher post-hoc LSD analysis. *p<0.05, **p<0.01, *p<0.0001 # The acute effects of the test compound (20 minutes after SC administration); Figures 2 to 5 Bar graphs illustrating the effects of various doses of exemplary compound (I), particularly (R)I-98, (R)I-244, (R)I-245, and cis(R)I-248, on head twitching response (HTR) in male C57BL6 mice. Mice were treated with exemplary compounds (R)I-98, (R)I-244, (R)I-245, or cis(R)I-248 (3 mg / kg, 30 mg / kg, SC) via the SC route (N = 6 mice / dose), and the total number of head twitches was recorded over 1 hour. It is believed that 5-HT 2A The induction of head twitching induced by receptor agonists represents a behavioral proxy for their hallucinogenic effects. Data are presented as mean ± SEM using one-way ANOVA and Fisher post-hoc LSD analysis. *p<0.05, **p<0.01, *p<0.0001. # The acute effects of the test compound (20 minutes after SC administration). Detailed Implementation

[0038] I. Definition Unless otherwise stated, the definitions and embodiments described in this and other sections are intended to apply to all embodiments and aspects of this disclosure described herein as to which the definitions and embodiments will be understood by one of skill in the art.

[0039] As used herein, the terms “disclosed compound” and “compound of this disclosure” mean a compound of formula (I) (including formulas (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (IJ), (IK), (IL) and (IM) falling within the scope of formula (I), and include its pharmaceutically acceptable salts, solvates and / or prodrugs.

[0040] As used herein, the terms “disclosed compound” and “composition of the disclosure” mean a composition comprising one or more of the compounds of the disclosure, such as a pharmaceutical composition.

[0041] As used herein, the term “and / or” means the presence or use of the listed items, alone or in combination. In effect, the term means the use or presence of “at least one” or “one or more” of the listed items. The term “and / or” relating to pharmaceutically acceptable salts and / or solvates means that the compounds of this disclosure are present as individual salts and solvates, as well as in combinations of, for example, salts or solvates of the compounds of this disclosure. As used herein, the term “and / or” means (or any combination or expression of all terms referring to) any one or both of the following, for example, “A, B and / or C” covers A alone, B alone, C alone, A and B, A and C, B and C, and A, B and C.

[0042] As used in this disclosure, unless the context clearly indicates otherwise, the singular forms “a (a)”, “an (an)”, and “the” include plural indicators. For example, embodiments including “a compound” should be understood to represent certain aspects with one compound or two or more additional compounds. Those skilled in the art will further understand that if there is an intention to describe a particular number of introduced claim elements, such intention will be explicitly stated in the claims, and there is no such limitation in the absence of such a subject matter. For non-limiting instances, to aid understanding, the appended claims contain the use of the introductory phrases “at least one” and “one or more” to introduce claim elements. However, the use of such phrases should not be construed as implying that a claim element introduced by the indefinite article “a (a)” or “an (an)” limits any particular claim containing such an introduced claim element to embodiments containing only one such element, even when the same claim includes the introductory phrases “a plurality of” or “at least one” and indefinite articles such as “a (a)” or “an (an)”; the same applies to the use of definite articles in claims.

[0043] As used in this disclosure and claims, the terms “comprising” (and any form of inclusion, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of inclusion, such as “include” and “includes”), or “containing” (and any form of containing, such as “contain” and “contains”) are inclusive or open-ended and do not exclude additional unlisted elements or method steps.

[0044] As used herein, the term “consisting” and its derivatives are intended as closed terms to specify the presence of the stated feature, element, component, group, integer and / or step, and not including the presence of other unstated features, elements, components, groups, integers and / or steps.

[0045] As used herein, “consisting essentially of” is intended to specify the presence of the described features, elements, components, groups, integers and / or steps, as well as the presence of essential and novel properties that do not substantially affect these features, elements, components, groups, integers and / or steps.

[0046] As used herein, in embodiments containing an "additional" or "second" component, such as an additional or second compound, the second component is chemically different from the other components or the first component. A "third" component is different from the other components, and the first and second components, as well as other listed components or "additional" components, are similarly different. In this context, unless expressly indicated otherwise by the claims, "first," "second," "third," etc., do not imply any order or sequence other than the order in which the terms appear in the claims.

[0047] As used herein, the term “suitable” means that the selection of a particular compound or conditions will depend on the specific synthetic operation to be performed, the identity of the molecule to be transformed, and / or the specific use of the compound, but the selection is entirely within the skill of a person skilled in the art. All process / method steps described herein will be carried out under conditions sufficient to provide the product shown. Those skilled in the art will understand that all reaction conditions, including, for example, reaction solvents, reaction times, reaction temperatures, reaction pressures, reactant ratios, and whether the reaction should be carried out under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product, and doing so is within the skill of a person skilled in the art.

[0048] As used herein, the terms “about,” “substantially,” and “approximately” mean a reasonable amount of deviation of the modified term such that the final result is not significantly altered. These degree terms should be interpreted to include at least ±5% deviation of the modified term, provided that such deviation does not negate the meaning of the word it modifies, or unless the context otherwise implies to those skilled in the art.

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

[0050] As used herein, whether alone or as part of another group, the term "alkyl" refers to a straight-chain or branched saturated alkyl group. The number of carbon atoms that may be located in the cited alkyl group is prefixed with "C". n1- C n2 The term "C1-C6 alkyl" indicates this. Therefore, for example, the term "C1-C6 alkyl" (or "C... 1-6 "Alkyl" means an alkyl group having one, two, three, four, five, or six carbon atoms, including, for example, any hexylalkyl and pentylalkyl isomers, as well as n-butyl, isobutyl, sec-butyl and tert-butyl, n-propyl and isopropyl, ethyl and methyl. As another example, "C1-C4 alkyl" refers to n-butyl, isobutyl, sec-butyl and tert-butyl, n-propyl and isopropyl, ethyl and methyl.

[0051] As used herein, whether alone or as part of another group, the term "alkenyl" refers to a straight-chain or branched unsaturated alkyl group containing at least one double bond. The number of carbon atoms that may be located in the cited alkenyl group is prefixed with "C". n1- C n2 " indicates. For example, the term C" indicates... 2- C6 alkenyl (or C 2-6 Alkenyl refers to an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms.

[0052] As used herein, whether alone or as part of another group, the term "alkynyl" means a straight-chain or branched unsaturated alkyl group containing at least one triple bond. The number of carbon atoms that may be located in the cited alkynyl group is prefixed with "C". n1- C n2 " indicates. For example, the term C" indicates... 2- C6 ynyl group (or C) 2-6 The term "alkynyl group" refers to an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms.

[0053] As used herein, whether alone or as part of another group, the term "cycloalkyl" refers to a saturated carbocyclic group containing one or more rings. The number of carbon atoms that may be present in the cited cycloalkyl group is prefixed with the number "C". n1- C n2 " indicates. For example, the term C" indicates... 3-7 cycloalkyl (or C) 3-7 Cycloalkyl means a cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms.

[0054] As used herein, whether alone or as part of another group, the term "heterocyclic alkyl" refers to a cyclic group containing at least one non-aromatic ring, wherein one or more atoms are heteromeric moieties selected from O, S, and N, including oxidized or substituted versions thereof (e.g., S(O) and SO2), and the remaining atoms are C. Heterocyclic alkyl groups are saturated or unsaturated (i.e., containing one or more double bonds) and / or optionally contain one or more C=O groups (i.e., one or more carbon atoms in the ring are oxidized to C=O). When a heterocyclic alkyl group contains the prefix C... n1- C n2 In this case, the prefix indicates the number of carbon atoms in the corresponding carbocyclic group, wherein one or more, suitably one to five ring atoms are selected from O, S, and N, including heterocyclic portions of their oxidized or substituted versions, and the remaining atoms are C. The heterocyclic alkyl group may also be preceded by "n1- to n2-", which refers to the total number of atoms in the group. The heterocyclic alkyl group is optionally fused together.

[0055] As used herein, whether alone or as part of another group, the term "aryl" refers to a carbocyclic group containing at least one aromatic ring.

[0056] As used herein, whether alone or as part of another group, the term "heteroaryl" refers to a cyclic group containing at least one heteroaromatic ring, wherein one or more atoms are heteromeric portions selected from O, S, and N, including their oxidized or substituted versions (e.g., S(O) and SO2), and the remaining atoms are C. When a heteroaryl contains the prefix C... n1-n2 In this case, the prefix indicates the number of carbon atoms in the corresponding carbocyclic group, wherein one or more, suitably one to five ring atoms, are replaced by heteroatoms as defined above. The prefix "n1 to n2" can also be added before the heteroaryl group, referring to the total number of atoms in the group. The heteroaryl group is optionally benzofused.

[0057] All cyclic groups, including aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, contain one or more rings (i.e., polycyclic). When a cyclic group contains more than one ring, these rings can be bonded, bridged, spirofused, or linked.

[0058] As used herein, the term "benzo-fused" refers to a polycyclic group in which a benzene ring is fused with another ring.

[0059] The term "fusion" between the first and second rings means that the first and second rings share two adjacent atoms.

[0060] The term "bridge" between the first and second rings means that the first and second rings share two non-adjacent atoms.

[0061] The term "spiro-fused" means that the first and second rings share an atom between them.

[0062] Whether used alone or as part of another group, the term "halogen" (or "halogenated") refers to a halogen atom, including fluorine, chlorine, bromine, and iodine.

[0063] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more available hydrogen atoms have been independently replaced by a halogen, as defined above. Thus, for example, "C..." 1-6 "Halogenated alkyl" (or "C1-C6 halogenated alkyl") refers to a C1 to C6 straight-chain or branched alkyl group having one or more halogen substituents as defined above.

[0064] As used herein, the term "haloalkenyl" refers to an alkenyl group in which one or more of the available hydrogen atoms have been independently replaced by a halogen, as defined above. Thus, for example, "C..." 2-6"Haloalkenyl" (or "C2-C6 haloalkenyl") refers to a C2 to C6 straight-chain or branched alkenyl group having one or more halogen substituents as defined above.

[0065] As used herein, the term "haloalkynyl" refers to an alkynyl group in which one or more available hydrogen atoms have been independently replaced by a halogen, as defined above. Thus, for example, "C..." 2-6 "Haloalkynyl" (or "C2-C6 haloalkynyl") refers to a C2 to C6 straight-chain or branched alkynyl group having one or more halogen substituents as defined above.

[0066] As used herein, the term "deuterated alkyl" refers to an alkyl group in which one or more available hydrogen atoms have been independently replaced by deuterium, as defined above. Thus, for example, "C 1-6 "Deuterated alkyl" (or "C1-C6 deuterated alkyl") refers to a C1 to C6 straight-chain or branched alkyl group having one or more deuterated substituents as defined above.

[0067] As used herein, the term "deuterated alkenyl" refers to an alkenyl group in which one or more of the available hydrogen atoms have been independently replaced by deuterium, as defined above. Thus, for example, "C..." 2-6 "Deuterated alkenyl" (or "C2-C6 deuterated alkenyl") refers to a C2 to C6 straight-chain or branched alkenyl group having one or more deuterated substituents as defined above.

[0068] As used herein, the term "deuterated ynyl" refers to an ynyl group in which one or more available hydrogen atoms have been independently replaced by deuterium, as defined above. Thus, for example, "C 2-6 "Deuterated alkynyl" (or "C2-C6 deuterated alkynyl") refers to a C2 to C6 straight-chain or branched alkynyl group having one or more deuterated substituents as defined above.

[0069] As used herein, the term "fluoroalkyl" refers to an alkyl group in which one or more available hydrogen atoms have been independently replaced by fluorine, as defined above. Thus, for example, "C..." 1-6 "Fluoroalkyl" (or "C1-C6 fluoroalkyl") refers to a C1 to C6 straight-chain or branched alkyl group having one or more fluorine substituents as defined above.

[0070] As used herein, the term "fluoroalkenyl" refers to an alkenyl group in which one or more of the available hydrogen atoms have been independently replaced by fluorine, as defined above. Thus, for example, "C..." 2-6 "Fluoro-alkenyl" (or "C2-C6 fluoro-alkenyl") refers to a C2 to C6 straight-chain or branched alkenyl group having one or more fluorine substituents as defined above.

[0071] As used herein, the term "fluoroalkynyl" refers to an alkynyl group in which one or more of the available hydrogen atoms have been independently replaced by fluorine, as defined above. Thus, for example, "C..." 2-6 "Fluorynyl" (or "C2-C6 fluoroynyl") refers to a C2 to C6 straight-chain or branched ynyl group having one or more fluorine substituents as defined above.

[0072] As used herein, the term "deuterated haloalkyl" refers to an alkyl group in which one or more available hydrogen atoms have been independently substituted by deuterium and one or more available hydrogen atoms have been independently substituted by a halogen, as defined above. Thus, for example, "C 1-6 "Deuterated haloalkyl" (or "C1-C6 deuterated haloalkyl") refers to a C1 to C6 straight-chain or branched alkyl group having one or more deuterated substituents and one or more halogen substituents as defined above.

[0073] As used herein, the term "deuterated haloalkenyl" refers to an alkenyl group in which one or more available hydrogen atoms have been independently substituted by deuterium and one or more available hydrogen atoms have been independently substituted by a halogen, as defined above. Thus, for example, "C..." 2-6 "Deuterated haloalkenyl" (or "C2-C6 deuterated haloalkenyl") refers to a C2 to C6 straight-chain or branched alkenyl group having one or more deuterated substituents and one or more halogen substituents as defined above.

[0074] As used herein, the term "deuterated haloalkynyl" refers to an alkynyl group in which one or more available hydrogen atoms have been independently substituted by deuterium and one or more available hydrogen atoms have been independently substituted by a halogen, as defined above. Thus, for example, "C..." 2-6 "Deuterated haloalkynyl" (or "C2-C6 deuterated haloalkynyl") refers to a C2 to C6 straight-chain or branched alkynyl group having one or more deuterated substituents and one or more halogen substituents as defined above.

[0075] As used herein, the term "deuterated fluoroalkyl" refers to an alkyl group in which one or more available hydrogen atoms have been independently substituted with deuterium and one or more available hydrogen atoms have been independently substituted with fluorine, as defined above. Thus, for example, "C 1-6 "Deuterated fluoroalkyl" (or "C1-C6 deuterated fluoroalkyl") refers to a C1 to C6 straight-chain or branched alkyl group having one or more deuterated substituents and one or more fluorine substituents as defined above.

[0076] As used herein, the term "deuterated fluoroalkenyl" refers to an alkenyl group in which one or more available hydrogen atoms have been independently substituted with deuterium and one or more available hydrogen atoms have been independently substituted with fluorine, as defined above. Thus, for example, "C..." 2-6"Deuterated fluoroalkenyl" (or "C2-C6 deuterated fluoroalkenyl") refers to a C2 to C6 straight-chain or branched alkenyl group having one or more deuterated substituents and one or more fluorine substituents as defined above.

[0077] As used herein, the term "deuterated fluoroalkynyl" refers to an alkynyl group in which one or more available hydrogen atoms have been independently substituted by deuterium and one or more available hydrogen atoms have been independently substituted by fluorine, as defined above. Thus, for example, "C..." 2-6 "Deuterated fluoroalkynyl" (or "C2-C6 deuterated fluoroalkynyl") refers to a C2 to C6 straight-chain or branched alkynyl group having one or more deuterated substituents and one or more fluorine substituents as defined above.

[0078] The suffix "ene" at the end of a group (e.g., "alkylene" or "alkenylene") indicates that the group is divalent, meaning it is bonded to two variables, each located at a different end or position of the group.

[0079] As used herein, the term “optionally substituted” means that the subject group is unsubstituted or substituted, and the terms “optionally substituted” and “unsubstituted or substituted” are used interchangeably herein. As used herein, when referring to more than one item or “each” item, “optionally substituted” and “unsubstituted or substituted” mean that the item is unsubstituted or substituted relative to each other, for example, for item A and item B, both may be substituted, both may be unsubstituted, or one may be substituted and the other unsubstituted. Additionally, as used herein, when referring to more than one item, the term “optionally substituted” means that if more than one item is substituted, the substitutions may be independent of each other, for example, for items A and B, both of which are substituted, item A may have a first substitution, and item B may have a second substitution that is the same as or different from the first substitution of item A.

[0080] As used herein, the term "one or more" includes a single item selected from a list as well as two or more items selected from a list (e.g., a mixture).

[0081] Unless otherwise indicated, as used herein, the term “substituted” means that the referenced group is substituted by one or more substituents independently selected from: halogen, C1-C4 alkyl, OC1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 haloalkyl, CN, OH, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)(C1-C4 alkyl), SC1-C4 alkyl, S(O)C1-C4 alkyl, SO2C1-C4 alkyl, CO2H, CO2C1-C4 alkyl, C(O)NH2, C(O)NHC1-C4 alkyl, C(O)N(C1-C4 alkyl)(C1-C4 alkyl), C3-C6 cycloalkyl, and 3- to 6-membered heterocyclic rings including one or two heteroparts selected from: O, S, S(O), SO2, N, NH, and NC1-C4 alkyl.

[0082] When a group is substituted by more than one substituent selected from the list of substituents, each substituent is independently selected from the listed group of substituents.

[0083] In the context of “available hydrogen atoms” or “available atoms”, the term “available” means an atom that is known to those skilled in the art to be substituted by a substituent.

[0084] As used herein, the term "alternative isotopes" refers to isotopes of an element other than the most abundant isotopes in nature.

[0085] As used herein, the terms "all available atoms are optionally substituted with their substituted isotopes" or "available atoms are optionally substituted with their substituted isotopes" mean that available atoms, optionally individually and independently, are substituted with an isotope of the atom, the number of which is the same as the number of atoms predominantly found in nature, but the atomic mass or mass number is different from that predominantly found in nature. When a compound contains atoms that have been substituted with their substituted isotopes, the compound contains a larger amount of the substituted isotope than would otherwise be present in the compound if the substitution had not occurred.

[0086] As used herein, the terms “all available hydrogen atoms are optionally replaced by halogen atoms” or “available hydrogen atoms are optionally replaced by halogen atoms” mean that available hydrogen atoms, optionally individually and each available hydrogen atom is optionally and independently replaced by halogen atoms.

[0087] As used herein, the terms “all available hydrogen atoms are optionally replaced by fluorine and / or chlorine atoms” or “available hydrogen atoms are optionally replaced by fluorine and / or chlorine atoms” mean that available hydrogen atoms, optionally individually and each available hydrogen atom, are optionally and independently replaced by fluorine or chlorine atoms.

[0088] The term "pharmaceutically acceptable" means that it is compatible with the subject's treatment.

[0089] The term “pharmaceuticalally acceptable carrier” refers to a non-toxic solvent, dispersant, excipient, adjuvant, or other material that is mixed with the active ingredient to allow the formation of a pharmaceutical composition (i.e., a dosage form that can be administered to a subject).

[0090] The term "pharmaceutically acceptable salt" means an acid addition salt or base addition salt that is suitable for or compatible with the treatment of the subject.

[0091] An acid addition salt suitable for or compatible with the treatment of a subject is any non-toxic organic or inorganic acid addition salt of any basic compound.

[0092] A base addition salt suitable for or compatible with the treatment of a subject is any non-toxic organic or inorganic base addition salt of any acidic compound.

[0093] As used herein, the term "solvent" refers to a compound or a salt or prodrug of a compound in which molecules of a suitable solvent are incorporated into the crystal lattice. The suitable solvent is physiologically tolerable at the administered dose.

[0094] As used herein, the term "prodrug" refers to a compound or salt of a compound that is converted into an active drug after administration.

[0095] As used herein, the terms "protecting group" or "PG," etc., refer to a chemical moiety that protects or masks the reactive portion of a molecule to prevent side reactions within the reactive portion, while simultaneously controlling or enabling reactions in different parts of the molecule. After the control or reaction is complete, the protecting group is removed without degrading or breaking down the remaining portion of the molecule. Those skilled in the art can select suitable protecting groups. Many conventional protecting groups are known in the art, for example, as described below: McOmie, JFW, ed., "Protective Groups in Organic Chemistry", Plenum Press, 1973; Greene, TW and Wuts, PGM, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3rd ed., 1999; and Kocienski, P., "Protecting Groups", 3rd ed., 2003, Georg Thieme Verlag (Americas).

[0096] As used herein, the term "subject" includes all members of the animal kingdom, including mammals, and appropriately refers to humans. Therefore, the methods disclosed herein are applicable to both human therapeutics and veterinary applications.

[0097] As used herein and as is well understood in the art, the terms “treating” or “treatment” mean a method for obtaining a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes include, but are not limited to: reducing or improving one or more symptoms or ailments, reducing the severity of disease, stabilizing (i.e., not worsening) a disease state, preventing the spread of disease, delaying or slowing disease progression, improving or alleviating a disease state, reducing disease relapses, and remission (whether partial or complete), whether detectable or undetectable. “Treating” and “treatment” can also mean prolonged survival compared to expected survival without treatment. As used herein, “treating” and “treatment” also include preventative treatment. Treatment methods comprise administering a therapeutically effective amount of one or more compounds of this disclosure to a subject, and optionally consist of a single administration, or alternatively comprise a series of administrations.

[0098] As used herein, the term "effective amount" or "therapeutic effective amount" means the amount of one or more of the disclosed compounds that is effective at the dose and time period required to achieve the desired result. For example, in the context of treating a disease, condition, or symptom mediated or treated by agonistic action or activation of serotonergic receptors and downstream second messengers, an effective amount is, for example, an amount that increases said activation compared to the activation without the administration of said one or more compounds.

[0099] "Relief" of a disease, symptom, or condition means a reduction in the severity and / or undesirable clinical manifestations and a slower or longer progression of the disease, symptom, or condition compared to an untreated condition.

[0100] As used herein, the term “application” means the administration of a therapeutically effective amount of one or more of the compounds or compositions disclosed herein to a cell, tissue, organ, or subject.

[0101] As used herein, the terms “prevention” or “prophylaxis” or their synonyms refer to reducing the risk or probability of a patient suffering from a disease, condition, or symptom or exhibiting symptoms associated with a disease, condition, or symptom.

[0102] As used herein, the term "disease, symptom, or condition" refers to a condition caused by the activation and / or binding of any serotonin receptor (5HT1 to 5HT7) and its daughter receptors and subtypes (e.g., 5-HT1). 1A 5-HT 2A 5-HT 2B 5-HT 2C And particularly, to use one or more of the compounds described herein to treat or treatable diseases, conditions or symptoms.

[0103] As used herein, the term "treating a disease, condition, or symptom by activating serotonin receptors" means that the disease, condition, or symptom to be treated is directly or indirectly influenced, regulated, and / or has some biological basis, including serotonergic activity, specifically an increase in serotonergic activity. When serotonergic activity associated with a disease, condition, or symptom is stimulated by one or more compounds or compositions of this disclosure, these diseases respond well.

[0104] As used herein, the term “activation” includes agonist, partial agonist, and orthoallosteric regulation of the serotonin receptor.

[0105] As used in this article, the term "5-HT" 2A "This refers to the 5-HT2 serotonin receptor." 2A Receptor subtypes.

[0106] As used in this article, the term "5-HT" 1A "This refers to the 5-HT1 serotonin receptor." 1A Receptor subtypes.

[0107] As used in this article, the term "5-HT" 2B "This refers to the 5-HT2 serotonin receptor." 2B Receptor subtypes.

[0108] As used in this article, the term "5-HT" 2C "This refers to the 5-HT2 serotonin receptor." 2C Receptor subtypes.

[0109] As used herein, the term "therapeutic agent" means any drug or active agent that has a pharmacological effect when administered to a subject.

[0110] II.Compounds This disclosure includes a compound of formula (I): Formula (I) Or its pharmaceutically acceptable salts, solvates and / or prodrugs, in: X does not exist or is selected from O, S, S(O) and SO2; R 1 Selected from H, C 1- C6 alkyl, C 1- C6 alkylene P(O)(OR) 11 2. C 1- C6 alkylene OP(O)(OR) 11 2. C(O)R 11 CO2R 11 C(O)N(R) 11 2. S(O)R 11 and SO2R 11 ; R 2 Selected from H, halogens and C 1- C6 alkyl; R 3 R 4 and R 5 Independently selected from H, CN, halogens, C 1- C6 alkyl, C 2- C6 alkenyl and C 2- C6 ynyl group; R 6 Selected from H, C 1- C 10 Alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene ZR 12 C 2- C6 imenoyl ZR 12 C 2- C6-Isoynyl ZR 12 C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C6 alkylene C 3- C7 cycloalkyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 6- C 10 Aryl and C 1- C6 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR13 and C(O)R 13 ; R 7 and R 8 Independently selected from H, halogens and C 1- C6 alkyl; Each R 9 Independently selected from halogens, C 1- C6 alkyl, OH, OC 1- C6 alkyl, C 1- C6 alkylene OH and C 1- C6 alkylene OC 1- C6 alkyl; R 10 Selected from H, C 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene Z'R 14 C 2- C6 imene-Z'R 14 C 2- C6-Imyynyl Z'R 14 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C6 alkylene C 3- C7 cycloalkyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 6- C 10 Aryl and C 1- C6 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 15 and C(O)R 15 ; Z is selected from O, C(O), NR 16 C(O), NR 16 C(O)O、C(O)NR 16 OC(O)NR 16 and NR 16 ; Z' is selected from O, C(O), NR 17 C(O), NR17 C(O)O、C(O)NR 17 OC(O)NR 17 and NR 17 ; n is an integer selected from 0, 1, 2, 3, and 4; R 11 R 13 R 15 R 16 and R 17 Independently selected from H and C 1- C6 alkyl; R 12 and R 14 Independently selected from H and C 1- C6 alkyl, C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl and C 5- C 10 Heteroaryl, the last four groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C4 alkyl, OC 1- C4 alkyl and C(O)C 1- C4 alkyl, Hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes. The condition is that when X is O, R 1 R 2 R 3 R 4 R 5 R 7 and R 8 It is H or D, n is 0, and R 6 When it is H, CH3 or CD3, then R 10 Not H, CH3, or CD3; The condition is that when X is O, R 1 R 2 R 3 R 4 R 5 R 7 and R 8 It is H or D, n is 0, and R 6 When it is CH3 or CHF2, then R 10 Not H, CH3, or CD3; The condition is that X does not exist and R 6 When it is H, then n is not 0, or R. 10 Not H or C1- C6 alkyl.

[0111] According to one or more embodiments, this disclosure includes compounds of formula (I) as defined above, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, wherein: X is selected from O, S, S(O) and SO2; R 1 Selected from H, C 1- C6 alkyl, C 1- C6 alkylene P(O)(OR) 11 2. C 1- C6 alkylene OP(O)(OR) 11 2. C(O)R 11 CO2R 11 C(O)N(R) 11 2. S(O)R 11 and SO2R 11 ; R 2 Selected from H, halogens and C 1- C6 alkyl; R 3 R 4 and R 5 Independently selected from H, CN, halogens, C 1- C6 alkyl, C 2- C6 alkenyl and C 2- C6 ynyl group; R 6 Selected from H, C 1- C 10 Alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene ZR 12 C 2- C6 imenoyl ZR 12 C 2- C6-Isoynyl ZR 12 C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C6 alkylene C 3- C7 cycloalkyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 6- C 10 Aryl and C 1-C6 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 13 and C(O)R 13 ; R 7 and R 8 Independently selected from H, halogens and C 1- C6 alkyl; Each R 9 Independently selected from halogens, C 1- C6 alkyl, OH, OC 1- C6 alkyl, C 1- C6 alkylene OH and C 1- C6 alkylene OC 1- C6 alkyl; R 10 Selected from H, C 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene Z'R 14 C 2- C6 imene-Z'R 14 C 2- C6-Imyynyl Z'R 14 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C6 alkylene C 3- C7 cycloalkyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 6- C 10 Aryl and C 1- C6 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 15 and C(O)R 15 ; Z is selected from O, C(O), NR 16 C(O), NR 16 C(O)O、C(O)NR16 OC(O)NR 16 and NR 16 ; Z' is selected from O, C(O), NR 17 C(O), NR 17 C(O)O、C(O)NR 17 OC(O)NR 17 and NR 17 ; n is an integer selected from 0, 1, 2, 3, and 4; R 11 R 13 R 15 R 16 and R 17 Independently selected from H and C 1- C6 alkyl; R 12 and R 14 Independently selected from H and C 1- C6 alkyl, C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl and C 5- C 10 Heteroaryl, the last four groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C4 alkyl, OC 1- C4 alkyl and C(O)C 1- C4 alkyl, Hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes.

[0112] According to one or more embodiments, this disclosure includes compounds of formula (I) as defined above, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, wherein: X either does not exist or is 0; R 1 Selected from H, C 1- C6 alkyl, C 1- C6 alkylene P(O)(OR) 11 2. C 1- C6 alkylene OP(O)(OR) 11 2. C(O)R 11 CO2R 11 C(O)N(R) 11 2. S(O)R 11 and SO2R 11 ; R 2Selected from H, halogens and C 1- C6 alkyl; R 3 R 4 and R 5 Independently selected from H, CN, halogens, C 1- C6 alkyl, C 2- C6 alkenyl and C 2- C6 ynyl group; R 6 Selected from H, C 1- C 10 Alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene ZR 12 C 2- C6 imenoyl ZR 12 C 2- C6-Isoynyl ZR 12 C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C6 alkylene C 3- C7 cycloalkyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 6- C 10 Aryl and C 1- C6 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 13 and C(O)R 13 ; R 7 and R 8 Independently selected from H, halogens and C 1- C6 alkyl; Each R 9 Independently selected from halogens, C 1- C6 alkyl, OH, OC 1- C6 alkyl, C 1- C6 alkylene OH and C 1- C6 alkylene OC 1- C6 alkyl; R 10 Selected from H, C 1-C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene Z'R 14 C 2- C6 imene-Z'R 14 C 2- C6-Imyynyl Z'R 14 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C6 alkylene C 3- C7 cycloalkyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 6- C 10 Aryl and C 1- C6 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 15 and C(O)R 15 ; Z is selected from O, C(O), NR 16 C(O), NR 16 C(O)O、C(O)NR 16 OC(O)NR 16 and NR 16 ; Z' is selected from O, C(O), NR 17 C(O), NR 17 C(O)O、C(O)NR 17 OC(O)NR 17 and NR 17 ; n is an integer selected from 0, 1, 2, 3, and 4; R 11 R 13 R 15 R 16 and R 17 Independently selected from H and C 1- C6 alkyl; R 12 and R 14 Independently selected from H and C 1- C6 alkyl, C3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl and C 5- C 10 Heteroaryl, the last four groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C4 alkyl, OC 1- C4 alkyl and C(O)C 1- C4 alkyl, Hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes. The condition is that when X is O, R 1 R 2 R 3 R 4 R 5 R 7 and R 8 It is H or D, n is 0, and R 6 When it is H, CH3 or CD3, then R 10 Not H, CH3, or CD3; The condition is that when X is O, R 1 R 2 R 3 R 4 R 5 R 7 and R 8 It is H or D, n is 0, and R 6 When it is CH3 or CHF2, then R 10 Not H, CH3, or CD3; The condition is that X does not exist and R 6 When it is H, then n is not 0, or R. 10 Not H or C 1- C6 alkyl.

[0113] In some embodiments, especially but not necessarily, when X is 0, n is 0, 1, 2, 3, or 4, R 9 Selected from halogen or C 1- C6 alkyl, R 10 Is it H or C? 1- C6 alkyl, and R 6 It is H, or substituted or unsubstituted C. 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C10 Aryl or C 5- C 10 In the case of heteroaryl groups, hydrogen atoms can be optionally replaced by halogen atoms (i.e., H, C). 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl and C 5- C 10 All available hydrogen atoms in the heteroaryl group are optionally not substituted with deuterium. In some embodiments, when X is O and n is 0, 1, 2, 3, or 4, R 9 Is it halogen or C? 1- C6 alkyl, R 10 Is it H or C? 1- C6 alkyl, and R 6 It is H or substituted or unsubstituted C. 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl or C 5- C 10 When the compound is heteroaryl, the compound of formula (I) does not contain deuterium.

[0114] In some embodiments, when a hydrogen atom in a group is optionally replaced by a halogen atom, the halogen atom is selected from F, Cl, and Br. In some embodiments, when a hydrogen atom in a group is optionally replaced by a halogen atom, the halogen atom is selected from F and Br. In some embodiments, when a hydrogen atom in a group is optionally replaced by a halogen atom, the halogen atom is F.

[0115] In some embodiments, hydrogen atoms may optionally be independently substituted with their alternative isotopes. In some embodiments, the alternative isotope of hydrogen is deuterium.

[0116] Therefore, in some embodiments, hydrogen atoms may be optionally replaced by halogen atoms, and / or hydrogen atoms may be optionally replaced by deuterium. In some embodiments, particularly when X is S, S(O), or SO2, for other embodiments where X is O or absent, the halogen atom is selected from F, Cl, and I when hydrogen atoms in the group may be optionally replaced by halogen atoms. In some embodiments, particularly when X is S, S(O), or SO2, for other embodiments of X, the halogen atom is selected from F and I when hydrogen atoms in the group may be optionally replaced by halogen atoms. In some embodiments, hydrogen atoms may be optionally replaced by fluorine and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium. In some embodiments, hydrogen atoms may be optionally replaced by fluorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium. In some embodiments, hydrogen atoms may be optionally replaced by fluorine and / or chlorine atoms.

[0117] In some embodiments, the compounds of this disclosure are isotopically enriched with deuterium. In some embodiments, 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 R 14 R 15 R 16 and R 17 One or more of them independently contain one or more deuterium, or 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 R 14 R 15 R 16 and R 17 One or more of them are deuterium independently.

[0118] In some embodiments, particularly when X is selected from S, S(O), and SO2, but also when X is O or does not exist, when R 9 Is it halogen or C? 1- C6 alkyl, R10 Is it H or C? 1- C6 alkyl, n is 0, 1, 2, 3 or 4, and R 6 It is H, or substituted or unsubstituted C. 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl or C 5- C 10 In the case of heteroaryl groups, hydrogen atoms can be optionally replaced by halogen atoms (e.g., H, C). 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl and C 5- C 10 The available hydrogen atoms in the heteroaryl group are optionally not substituted with deuterium. In some embodiments, when R 9 Is it halogen or C? 1- C6 alkyl, R 10 Is it H or C? 1- C6 alkyl, n is 0, 1, 2, 3 or 4, and R 6 It is H, or substituted or unsubstituted C. 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl or C 5- C 10 When the compound is heteroaryl, the compound of formula (I) does not contain deuterium.

[0119] In some embodiments, particularly when X is absent or O, and when X is S, S(O) or SO2, when R 10 Selected from H and C 1- When C6 alkyl, R 10 H and C 1- Available hydrogen atoms in C6 alkyl groups are optionally replaced by halogen atoms (e.g., R...). 10 H and C 1- Available hydrogen atoms in the C6 alkyl group are optionally not substituted with deuterium. In some embodiments, when R 10 Selected from H and C 1-When C6 is alkyl, the compound of formula (I) does not contain deuterium.

[0120] In some embodiments, X is S(O), as shown in the following structure: .

[0121] In some embodiments, X is SO2, as shown in the following structure: .

[0122] In some embodiments, X is S, as shown in the following structure: .

[0123] In some embodiments, X does not exist (e.g., a direct key), as shown in the following structure: .

[0124] In some embodiments, X is O, as shown in the following structure: .

[0125] In some embodiments, R 1 Selected from S(O)R 11 and SO2R 11 .

[0126] In some embodiments, R 1 Selected from H, C 1- C4 alkyl, C 1- C3 alkylene P(O)(OR) 11 2. C 1- C4 alkylene OP(O)(OR) 11 2. C(O)R 11 CO2R 11 and C(O)N(R) 11 )2, wherein hydrogen atoms may optionally be replaced by iodine atoms, fluorine atoms, and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 1 Selected from H, C 1- C4 alkyl, C 1- C4 alkylene P(O)(OR) 11 2. C 1- C4 alkylene OP(O)(OR) 11 2. C(O)R 11 CO2R 11 and C(O)N(R) 11 )2, wherein hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 1Selected from H, C 1- C3 alkyl group, CH2P(O)(OR 11 )2、CH2CH2P(O)(OR 11 )2、CH2CH(CH3)P(O)(OR 11 )2、CH(CH3)CH2P(O)(OR 11 )2、CH(CH3)P(O)(OR 11 )2、CH(CH2CH3)P(O)(OR 11 2. (CH2)OP(O)(OR 11 2. C(O)R 11 and CO2R 11 In which hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 1 Selected from H, CH3, CH2CH3, CH2P(O)(OR) 11 )2、CH(CH3)P(O)(OR 11 )2 and (CH2)OP(O)(OR 11 )2, wherein hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 1 Selected from H, CH3, CH2CH3, CH2P(O)(OR) 11 )2、CH(CH3)P(O)(OR 11 )2 and (CH2)OP(O)(OR 11 )2, wherein hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 1 Selected from H, CH3, CH2CH3, CH2P(O)(OR) 11 )2 and (CH2)OP(O)(OR 11 )2, wherein hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 1 Selected from H, CH3, CH2CH3, CH2P(O)(OR) 11 2. (CH2)OP(O)(OR 11 2. C(O)R 11 and CO2R 11 In which hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 1Selected from H, CH3, and CH2CH3, wherein hydrogen atoms may optionally be replaced by fluorine and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 1 Selected from H and D. In some embodiments, R 1 It is H. In some embodiments, R 1 It is D. In some embodiments, R 1 It is CD3. In some embodiments, R 1 It is CH3.

[0127] In some embodiments, R 2 Selected from H, halogens and C 1- C4 alkyl, wherein the available hydrogen atoms are optionally replaced by halogen atoms, and / or the available atoms are optionally replaced by their substituted isotopes. In some embodiments, R 2 Selected from H, halogens and C 1- C4 alkyl, wherein hydrogen atoms may optionally be replaced by iodine, fluorine, and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 2 Selected from H, halogens and C 1- C4 alkyl, wherein all available hydrogen atoms are optionally replaced by fluorine and / or chlorine atoms, and / or all available hydrogen atoms are optionally replaced by deuterium. In some embodiments, R 2 Selected from H, D, F, Cl, Br, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 deuterated alkyl, and C1-C4 deuterated fluoroalkyl. In some embodiments, R 2 Selected from H, D, F, Br, Cl, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2F, CH2CH3, CH2CH2F, CF2CF3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 2 Selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2F, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 2 Selected from H, D, CH3, CF3, CHF2, CH2F, CD2H, CDH2, and CD3. In some embodiments, R 2 Selected from H, D, CH3, CF3, and CD3. In some embodiments, R 2 It is H. In some embodiments, R 2 It is D. In some embodiments, R 2 It is CD3. In some embodiments, R 2 It is CH3.

[0128] In some embodiments, R 3 Selected from H, halogens, CN, C 1- C4 alkyl, C 2- C4 alkenyl and C 2- C4 ynyl group, wherein the available hydrogen atoms may be optionally replaced by halogen atoms, and / or the available atoms may be optionally replaced by their substituted isotopes. In some embodiments, R 3 Selected from H, halogens, CN, C 1- C4 alkyl, C 2- C4 alkenyl and C 2- C4 alkynyl group, wherein the hydrogen atom may optionally be replaced by an iodine atom, a fluorine atom, and / or a chlorine atom, and / or the hydrogen atom may optionally be replaced by a deuterium atom. In some embodiments, R 3 Selected from H, halogens, CN, C 1- C4 alkyl, C 2- C4 alkenyl and C 2- C4 alkynyl group, wherein the hydrogen atom may optionally be replaced by a fluorine atom and / or a chlorine atom, and / or the hydrogen atom may optionally be replaced by a deuterium atom. In some embodiments, R 3 Selected from H, D, CN, halogens, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, C 2- C4 alkenyl, C 2- C4 fluoroolefin, C 2- C4 deuterated alkenyl, C 2- C4 deuterated fluoroolefin, C 2- C4 ynyl group, C 2- C4 deuterated ynyl group, C 2- C4 fluorokynyl and C 2- C4 deuterated fluoroalkynyl. In some embodiments, R 3 Selected from H, D, CN, halogens, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, C 2- C4 alkenyl and C 2- C4 fluoroolefin. In some embodiments, R 3 Selected from H, D, CN, F, Cl, Br, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl and C 1- C4 deuterated fluoroalkyl group. In some embodiments, R 3Selected from H, D, CN, F, Br, Cl, CH3, CD2H, CDH2, CD 3、 CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3, and CD2CD3. In some embodiments, R 3 Selected from H, D, CN, F, Cl, CH3, CD2H, CDH2, CD 3、 CF2H, CFH2, and CF3. In some embodiments, R 3 Selected from H, F, and D. In some embodiments, R 3 Selected from H, F, and Cl. In some embodiments, R 3 Selected from H and D. In some embodiments, R 3 It's H.

[0129] In some embodiments, R 3 Selected from H, CN, C 1- C4 alkyl, C 1- C4 haloalkyl, C 2- C4 alkenyl, C 2- C4 haloalkenyl, C 2- C4 acetylene and C 2- C4 haloacetylenic groups, wherein the available atoms may optionally be substituted with their substituted isotopes. In some embodiments, R 3 Selected from H, CN, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 2- C4 alkenyl, C 2- C4 fluoroolefin, C 2- C4 acetylene and C 2- C4 fluoroalkynyl group, wherein the hydrogen atom may optionally be replaced by deuterium. In some embodiments, R 3 Selected from H, D, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, C 2- C4 alkenyl, C 2- C4 fluoroolefin, C 2- C4 deuterated alkenyl, C 2- C4 deuterated fluoroolefin, C 2- C4 ynyl group, C 2- C4 deuterated ynyl group, C 2- C4 fluorokynyl and C 2- C4 deuterated fluoroalkynyl. In some embodiments, R 3 Selected from H, D, CN, C 1- C4 alkyl, C1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, C 2- C4 alkenyl, C 2- C4 fluoroolefin, C 2- C4 deuterated alkenyl and C 2- C4 deuterated fluoroolefin. In some embodiments, R 3 Selected from H, D, CN, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl and C 1- C4 deuterated fluoroalkyl group. In some embodiments, R 3 Selected from H, D, CN, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3, and CD2CD 3。 In some embodiments, R 3 It's H.

[0130] In some embodiments, R 4 and R 5 Independently selected from H, halogens, CN, C 1- C4 alkyl, C 2- C4 alkenyl and C 2- C4 ynyl group, wherein the available hydrogen atoms may be optionally replaced by halogen atoms, and / or the available atoms may be optionally replaced by their substituted isotopes. In some embodiments, R 4 and R 5 Independently selected from H, halogens, CN, C 1- C4 alkyl, C 2- C4 alkenyl and C 2- C4 alkynyl group, wherein the hydrogen atom may optionally be replaced by an iodine atom, a fluorine atom, and / or a chlorine atom, and / or the hydrogen atom may optionally be replaced by a deuterium atom. In some embodiments, R 4 and R 5 Independently selected from H, halogens, CN, C 1- C4 alkyl, C 2- C4 alkenyl and C 2- C4 alkynyl group, wherein the hydrogen atom may optionally be replaced by a fluorine atom and / or a chlorine atom, and / or the hydrogen atom may optionally be replaced by a deuterium atom. In some embodiments, R 4 and R 5 Independently selected from H, D, CN, halogens, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C1- C4 deuterated fluoroalkyl, C 2- C4 alkenyl, C 2- C4 fluoroolefin, C 2- C4 deuterated alkenyl, C 2- C4 deuterated fluoroolefin, C 2- C4 ynyl group, C 2- C4 deuterated ynyl group, C 2- C4 fluorokynyl and C 2- C4 deuterated fluoroalkynyl. In some embodiments, R 4 and R 5 Independently selected from H, D, CN, halogens, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, C 2- C4 alkenyl, C 2- C4 fluoroolefin, C 2- C4 acetylene and C 2- C4 fluoroynyl group. In some embodiments, R 4 and R 5 Independently selected from H, D, CN, F, Cl, Br, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl and C 1- C4 deuterated fluoroalkyl group. In some embodiments, R 4 and R 5 Independently selected from H, D, CN, F, Cl, Br, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3, and CD2CD 3。 In some embodiments, R 4 and R 5 Independently selected from H, D, CN, F, Cl, Br, CH3, CD2H, CDH2, CD3, CF2H, CFH2, and CF3. In some embodiments, R 4 and R 5 Independently selected from H, F, and D. In some embodiments, R 4 and R 5 Independently selected from H and D. In some embodiments, R 4 and R 5 Both are H.

[0131] In some embodiments, R 3 R 4 and R 5Each of them is H. In some embodiments, R 2 R 3 R 4 and R 5 Each of them is H. In some embodiments, R 3 R 4 and R 5 At least one of them is D. In some embodiments, R 2 R 3 R 4 and R 5 Each of them is D.

[0132] In some embodiments, R 6 Selected from H, C 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene ZR 12 C 2- C6 imenoyl ZR 12 C 2- C6-Isoynyl ZR 12 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C4 alkylene C 3- C7 cycloalkyl, C 1- C4 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C4 alkylene C 6- C 10 Aryl and C 1- C4 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 13 and C(O)R 13 In which hydrogen atoms may optionally be replaced by halogen atoms, and / or atoms may optionally be replaced by their substituted isotopes. In some embodiments, R 6 Selected from C 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene ZR 12 C 2-C6 imenoyl ZR 12 C 2- C6-Isoynyl ZR 12 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C4 alkylene C 3- C7 cycloalkyl, C 1- C4 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C4 alkylene C 6- C 10 Aryl and C 1- C4 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 13 and C(O)R 13 In which hydrogen atoms may optionally be replaced by iodine atoms, fluorine atoms, and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 6 Selected from C 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene ZR 12 C 2- C6 imenoyl ZR 12 C 2- C6-Isoynyl ZR 12 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C4 alkylene C 3- C7 cycloalkyl, C 1- C4 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C4 alkylene C 6- C 10 Aryl and C 1- C4 alkylene C 5- C 10Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 13 and C(O)R 13 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0133] In some embodiments, R 6 It is C 1- C6 alkyl, wherein hydrogen atoms may be optionally replaced by fluorine and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium. In some embodiments, particularly when X is S, S(O) or SO2, and when X is O or absent, R 6 Selected from C 1- C6 alkyl, C 1- C6 fluoroalkyl, C 1- C6 deuterated alkyl and C 1- C6 deuterated fluoroalkyl group. In some embodiments, R 6 Selected from C 1- C6 alkyl, C 1- C6 fluoroalkyl, C 1- C6 deuterated alkyl and C 1- C6 deuterated fluoroalkyl group. In some embodiments, R 6Select CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3, CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2, CH(CHD2)2, CH(CDH2)2, C(CH3)3, C(CF3)3, C(CHF2)3, C (CFH2)3, C(CD3)3, C(CHD2)3, C(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2CH(CH3)CH3, CH2CH(CH3)CF3, CH2CH(CH3)CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3 and CH2CH2C(CD3)3. In some embodiments, R 6 Select CH3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH(CH3)2, CH(CF3)2, C(CH3)3, C(CF3)3, CH2CH2CH 2CH3, CH2CH2CH2CF3, CH2CH2CH2CHF2, CH2CH(CH3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH2C(CH3)3, CH2C(CF3)3, CH2CH2C(CH3)3 sum CH2CH2C(CF3)3. Currently in practical use, R 6 Select CH3, CH2CH3, CH2CF 3、CH2CH2CH3, CH(CH3)2, CH2C(CH3)3, CH2CH2C(CH3)3, CD3, CF3, CHF2, CH2F, CH2CF2H, CH2CH2F, CH2CH2CHF2, CH2CH2CF3, and CH2CH2CH2CF3. In some embodiments, particularly when X is S, S(O), or SO2, for other embodiments where X is O or absent, R 6 Selected from CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CF2H, CH2CH2CF3, CH2CH2CH2CF 3、 CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2CH(CH3)2, CH(CH3)CH2CH3, and CH2C(CH3)3. In some embodiments, particularly when X is absent or oxygen is present, for other embodiments of X, R 6 Selected from H, D, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CF2H, CH2CH3, CH2CH2CH3, CH2CH2CF3, CH2CH2CH2CF3, CH(CH3)2, C(CH3)3, CH2CH(CH3)2, CH(CH3)CH2CH3, and CH2C(CH3)3. In some embodiments, R 6 Selected from CH3, CD3, CD2H, CDH2, CF2H, CH2CF2H, CFH2, and CF3. In some embodiments, R 6 Selected from CH3 and CD3. In some embodiments, R 6 It is CH3.

[0134] In some embodiments, R 6 Selected from C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene ZR 12 C 2- C6 imenoyl ZR 12 C 2- C6-Isoynyl ZR 12 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C4 alkylene C 3- C7 cycloalkyl, C 1- C4 alkylene C 3-C 10 Heterocyclic alkyl, C 1- C4 alkylene C 6- C 10 Aryl and C 1- C4 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 13 and C(O)R 13 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0135] In some embodiments, R 6 Selected from C 4- C6 alkenyl and C 2- C6 alkynyl group, wherein the hydrogen atom may optionally be replaced by a fluorine atom and / or a chlorine atom, and / or the hydrogen atom may optionally be replaced by a deuterium atom. In some embodiments, R 6 Selected from C 2- C6 alkenyl, C 2- C6 fluoroolefin, C 2- C6 deuterated alkenyl, C 2- C6 deuterated fluoroolefin, C 2- C6 ynyl group, C 2- C6 fluoroynyl group, C 2- C6 deuterated ynyl group and C 2- C6 deuterated fluoroalkynyl. In some embodiments, R 6 Selected from C 2- C4 alkenyl, C 2- C4 fluoroolefin, C 2- C6 deuterated alkenyl, C 2- C6 deuterated fluoroolefin, C 2- C4 ynyl group, C 2- C4 fluoroynyl group, C 2- C4 deuterated ynyl group and C 2- C4 deuterated fluoroalkynyl. In some embodiments, R 6Selected from CH=CH2, CH2CH=CH2, CF2CH=CH2, CD2CH=CH2, CH=CH2CH3, CH=CH2CF3, CH=CH2CHF2, CH=CH2CH2F, CH=CH2CD3, CH=CH2CHD2, CH=CH2CH2D, C≡CH, C≡CCH3, C≡CCF3, C≡CCHF2, C ≡CCFH2, C≡CCD3, C≡CCHD2, C≡CCDH2, CH2C≡CH, CF2C≡CH, CD2C≡CH, CH2C≡CCH3, CF2C≡CCH3, CD2C≡CCH3, CH2C≡CCD3, CF2C≡CCD3, CD2C≡CCD3, CH2C≡CCF3, CF2C≡CCF3, CD2C≡CCF 3、 CH2C≡CCHD2, CF2C≡CHD2, CD2C≡CHD2, CH2C≡CHF2, CF2C≡CHF2, and CD2C≡CHF2. In some embodiments, R 6 Selected from CH=CH2, CH2CH=CH2, C≡CH, C≡CCH3, CH2C≡CH and CH2C≡CCH3.

[0136] In some embodiments, R 6 Selected from C 1- C6 alkylene ZR 12 C 2- C6 imenoyl ZR 12 and C 2- C6-Isoynyl ZR 12 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0137] In some embodiments, R 6 Selected from C 1- C6 alkylene ZR 12 C 1- C6 fluoroalkyl ZR 12 C 1- C6 deuteride-based ZR 12 C 1- C6 deuterated fluorine-alkyl group ZR 12 C 2- C6 imenoyl ZR 12 C 2- C6 fluoroimide ZR 12 C 2- C6 deuterated alkenyl ZR 12 C 2- C 2- C6 deuterated fluorine-imide ZR 12 C6-acetylenic ZR 12 C2- C6-Fluoro-ynyl ZR 12 C 2- C6-deuterated ynylene ZR 12 and C 2- C6-deuterated fluoroynyl ZR 12 In some embodiments, R 6 Selected from C 1- C6 alkylene ZR 12 C 1- C6 fluoroalkyl ZR 12 C 1- C6 deuteride-based ZR 12 C 1- C6 deuterated fluorine-alkyl group ZR 12 C 2- C6 imenoyl ZR 12 and C 2- C6-Isoynyl ZR 12 In some embodiments, R 6 Selected from C 1- C4 alkylene ZR 12 C 1- C4 fluoroalkyl ZR 12 C 1- C4 deuteride-containing ZR 12 C 1- C4 deuterated fluorine-alkyl group ZR 12 C 2- C4 imenoyl ZR 12 C 2- C4 fluoroimide ZR 12 C 2- C4 deuterated imide ZR 12 C 2- C4 deuterated fluorine-imide ZR 12 C 2- C4-Imyynyl ZR 12 C 2- C4 fluoroynyne-ZR 12 C 2- C4-deuterated ynylene ZR 12 and C 2- C4-deuterated fluoroacetylenic ZR 12 In some embodiments, R 6 Selected from C 1- C4 alkylene ZR 12 C 1- C4 fluoroalkyl ZR 12 C 1- C4 deuteride-containing ZR 12 C 1- C4 deuterated fluorine-alkyl group ZR 12 C 2- C4 imenoyl ZR12 and C 2- C4 alkynyl ZR 12 .

[0138] In some embodiments, R 6 is selected from CH2ZR 12 、 CH2CH2ZR 12 CH2CH2CH2ZR 12 CH2CH2CH2CH2ZR 12 CH(CH3)CH2ZR 12 CH(CH3)CH2CH2ZR 12 CH2CH(CH3)ZR 12 CF2ZR 12 CFHZR 12 CH2CHFZR 12 CH2CF2ZR 12 CF2CF2ZR 12 CH2CH2CF2ZR 12 CH2CH2CFHZR 12 CH2CH2CF2ZR 12 CH(CH3)CF2ZR 12 CH(CH3)CHFZR 12 CH2CH2CH2CF2ZR 12 CH2CH2CHI2CHFZR 12 CH(CH3)CH2CF2ZR 12 CH(CH3)CH2CHFZR 12 CD2ZR 12 CDHZR 12 CH2CHDZR 12 CH2CD2ZR 12 CD2CD2ZR 12 CH2CH2CD2ZR 12 CH2CH2CDHZR 12 CH2CH2CD2ZR 12 CH(CH3)CD2ZR 12 CH(CH3)CHDZR 12 CH2CH2CH2CD2ZR 12 CH2CH2CH2CHDZR 12 CH(CH3)CH2CD2ZR 12 CH(CH3)CH2CHDZR 12 CH=CHZR 12CH2CH=CHZR 12 C≡CZR 12 C≡CCH2ZR 12 CH2C≡CZR 12 and CH2C≡CH2ZR 12 In some embodiments, R 6 Selected from CH2ZR 12 、 CH2CH2ZR 12 CH2CH2CH2ZR 12 CH2CH2CH2CH2ZR 12 CH(CH3)CH2ZR 12 CH(CH3)CH2CH2ZR 12 CH2CH(CH3)ZR 12 CH=CHZR 12 CH2CH=CHZR 12 CH=CH2CHZR 12 C≡CCH2ZR 12 CH2C≡CZR 12 and CH2C≡CH2ZR 12 .

[0139] In some embodiments, R 6 Selected from C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C4 alkylene C 3- C7 cycloalkyl, C 1- C4 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C4 alkylene C 6- C 10 Aryl and C 1- C4 alkylene C 5- C 10 Heteroaryl groups, each of which may optionally be substituted by one to four independent substituents selected from the following: halogens, C 1- C6 alkyl, OR 13 and C(O)R 13 In which hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 6 Selected from C 3- C7 cycloalkyl, C 3-C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C4 alkylene C 3- C7 cycloalkyl, C 1- C4 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C4 alkylene C 6- C 10 Aryl, C 1- C4 alkylene C 5- C 10 heteroaryl, C 1- C4 fluoroalkyl C 3- C7 cycloalkyl, C 1- C4 fluoroalkyl C 3- C 10 Heterocyclic alkyl, C 1- C4 fluoroalkyl C 6- C 10 Aryl, C 1- C4 fluoroalkyl C 5- C 10 heteroaryl, C 1- C4 deuteride C 3- C7 cycloalkyl, C 1- C4 deuteride C 3- C 10 Heterocyclic alkyl, C 1- C4 deuteride C 6- C 10 Aryl, C 1- C4 deuteride C 5- C 10 heteroaryl, C 1- C4 deuterated fluorine-alkyl C 3- C7 cycloalkyl, C 1- C4 deuterated fluorine-alkyl C 3- C 10 Heterocyclic alkyl, C 1- C4 deuterated fluorine-alkyl C 6- C 10 Aryl and C 1- C4 deuterated fluorine-alkyl C 5- C 10 Heteroaryl groups, wherein each of the cyclic groups is optionally substituted by one to four independent substituents selected from: F, Cl, Br, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1-C4 deuterated fluoroalkyl, OR 13 and C(O)R 13 In which hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 6 Selected from C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C2 alkylene C 3- C7 cycloalkyl, C 1- C2 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C2 alkylene C 6- C 10 Aryl, C 1- C2 alkylene C 5- C 10 heteroaryl, C 1- C2 fluoroalkyl C 3- C7 cycloalkyl, C 1- C2 fluoroalkyl C 3- C 10 Heterocyclic alkyl, C 1- C2 fluoroalkyl C 6- C 10 Aryl, C 1- C2 fluoroalkyl C 5- C 10 heteroaryl, C 1- C2 deuteride C 3- C7 cycloalkyl, C 1- C2 deuteride C 3- C 10 Heterocyclic alkyl, C 1- C2 deuteride C 6- C 10 Aryl, C 1- C2 deuteride C 5- C 10 heteroaryl, C 1- C2-deuterated fluorine-alkyl C 3- C7 cycloalkyl, C 1- C2-deuterated fluorine-alkyl C 3- C 10 Heterocyclic alkyl, C 1- C2-deuterated fluorine-alkyl C 6- C 10 Aryl and C 1- C2-deuterated fluorine-alkyl C 5- C10 Heteroaryl groups, wherein each of the cyclic groups is optionally substituted by one to four independent substituents selected from: F, Cl, Br, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 13 and C(O)R 13 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0140] In some embodiments, R 6 C in 3- The C7 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which is optionally substituted by one to four independent substituents selected from the following: F, Cl, Br, C. 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 13 and C(O)R 13 In which hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 6 C in 3- The C7 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is optionally divided by one to three independently selected from F, Cl, Br, C. 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 13 and C(O)R 13 The substituents are substituted, wherein hydrogen atoms may optionally be replaced by fluorine and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 6 C in 3- The C7 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is optionally substituted by one or two independent substituents selected from the following: F, Cl, Br, C. 1- C4 alkyl, C 1- C4 fluoroalkyl, C1 - C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 13 and C(O)R 13In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0141] In some embodiments, R 6 C in 3- C 10 Heterocyclic alkyl groups are monocyclic C 3- C7 heterocyclic alkyl or bicyclic C 7- C 10 Heterocyclic alkyl groups, each of which may optionally be substituted by one to four independent substituents selected from the following: F, Cl, Br, C. 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 13 and C(O)R 13 .

[0142] In some embodiments, R 6 The single-ring C 3- C7 heterocyclic alkyl groups are selected from aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, 1,3-dioxacyclohexyl, aziridinyl, oxiranyl, thiiranyl, diaziridinyl, dioxacyclobutyl, dithiobutyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2H-1λ3-thiophenyl, pyrrolyl, imidazoalkyl, pyrazolyl, isoxothiolidinyl, thiazoalkyl, isothiolidinyl, imidazoalkyl, imidazolinyl, dioxolanyl, and dithiophenanyl. thiolanyl), triazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxetetazolyl, tetrahydropyranyl, dihydropyranyl, isothiazolinyl, morpholinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylalkyl, piperidinyl, piperazinyl, tetrahydropyridinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl dioxide, dioxanyl, thiazolinyl, thiohexanealkyl, thiohexanealkyl, thiohexanealkyl oxide, thiohexanealkyl dioxide, dithiohexanealkyl, azepanyl, pyrazolyl, oxehanealkyl, thiohexanealkyl, diazepanyl and 2,5-pyrrolidinedione (e.g., succinimide), each of which is optionally substituted by one to four substituents independently selected from: F, Cl, Br, C 1- C4 alkyl, C 1-C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 13 and C(O)R 13 In which hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 6 The single-ring C 3- C7 heterocyclic alkyl groups are selected from oxetane, tetrahydrofuranyl, tetrahydrothiophenyl, 2H-1λ3-thiophenyl, pyrrolyl, imidazoalkyl, tetrahydropyranyl, dihydropyranyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperazinyl, piperidinyl, piperazinyl, thioheterocyclic butyl, thioheterocyclic butyl oxide, thioheterocyclic butyl dioxide, dithioheterocyclic butyl and 2,5-pyrrolidinedione, each of which is optionally substituted by one to three or one or two independent substituents selected from: F, Cl, Br, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 13 and C(O)R 13 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0143] In some embodiments, R 6 The double-ring C 7- C 10 The heterocyclic alkyl group is selected from benzoisoxazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzopyranyl, benzothiopyranyl, chromanyl, isochromyl, dihydroindenyl, isoyindolinyl, 1-oxoisoindolinyl, 3-oxoisoindolinyl, 1,3-dioxoisoindolinyl (e.g., phthalimide), octahydroisoindolinyl, octahydro-isoindolin-1-one (e.g., tetrahydroisoquinoline), and hexahydroisoindolin-1,3-diketoyl (e.g., cis-hexahydrophthalimide), each of which is optionally substituted by one to four independent substituents selected from: F, Cl, B, C. 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 13 and C(O)R 13 In which hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 6 The double-ring C 7- C10 The heterocyclic alkyl group is selected from isoindolinyl, 1-oxoisoindololinyl, 3-oxoisoindololinyl, 1,3-dioxoisoindololinyl, octahydro-1H-isoindololinyl, octahydro-1H-isoindololin-1-one, and hexahydro-1H-isoindololin-1,3-dione, each of which is optionally substituted by one to three or one or two independent substituents selected from the following: F, Cl, Br, C. 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 13 and C(O)R 13 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0144] In some embodiments, C in R6 6- C 10 The aryl group is a phenyl group, optionally substituted by one to four, one to three, or one or two substituents independently selected from the following: F, Cl, Br, C. 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 13 and C(O)R 13 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0145] In some embodiments, R 6 C in 5- C 10 The heteroaryl group is selected from aziridine heptatrienyl, benzofuranyl, benzofurazolyl, benzothiazolyl, benzothiophene, benzooxazolyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, isoquinolinyl, isothiazolyl, naphridinyl, oxadiazolyl, 2-oxoaziridine heptatrienyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyrrolylyl, pyrrolidinyl, quinazolinyl, quinolinyl, quinoxolinyl, thiazolyl, thiophenefuranyl, triazolyl, and thienyl (e.g., thiophenyl), each of which is optionally substituted by one to four, one to three, or one or two substituents independently selected from: F, Cl, Br, C. 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR13 and C(O)R 13 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0146] In some embodiments, R 6 The substituents on the [substituent name] are independently selected from one to four of the following: F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CD2H, CDH2, CD3, CF3, CHF2, CH2F, CH2CH2F, CF2CF3, CH2CH2D, CH2CD2H, CD2CD3, OR 14 and C(O)R 14 In some embodiments, R 6 The substituents on the plate are independently selected from one to three of the following: F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)2, CD2H, CDH2, CD3, CF3, CHF2, CH2F, OR 14 and C(O)R 14 In some embodiments, R 6 One, more, or all of the substituents are independently selected from one or more of the following: F, Cl, CH3, CH(CH3)2, CH(CH3)2, CF3, CHF2, CH2F, OR 14 and C(O)R 14 .

[0147] In some embodiments, Z is selected from NR 16 C(O), NR 16 C(O)O、C(O)NR 16 OC(O)NR 16 and NR 16 In some embodiments, Z is selected from O, C(O), NR 16 C(O) and NR 16 C(O)O. In some embodiments, Z is O. In some embodiments, Z is C(O). In some embodiments, Z is NR. 16 C(O). In some embodiments, Z is NR. 16 C(O)O.

[0148] In some embodiments, R 7 and R 8 Independently selected from H, halogens and C 1- C4 alkyl, wherein the available hydrogen atoms are optionally replaced by halogen atoms, and / or the available atoms are optionally replaced by their substituted isotopes. In some embodiments, R 7and R 8 Independently selected from H, halogens and C 1- C4 alkyl, wherein hydrogen atoms may optionally be replaced by iodine, fluorine, and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In embodiments where X is S, S(O), or SO2, and in embodiments where X is O or absent, R 7 and R 8 Independently selected from H, D, F, Cl, Br, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl and C 1- C4 deuterated fluoroalkyl group. In some embodiments, R 7 and R 8 Independently selected from H, halogens and C 1- C4 alkyl, wherein hydrogen atoms may optionally be replaced by fluorine and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 7 and R 8 Independently selected from H, D, F, Cl, Br, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl and C 1- C4 deuterated fluoroalkyl group.

[0149] In some embodiments, R 7 and R 8 Independently selected from H, F, Br, Cl, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 7 and R 8 Independently selected from H, D, F, Br, Cl, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 7 and R 8 Independently selected from H, D, F, Br, CH3, CF2H, CFH2, CF3, CD2H, CDH2, and CD3. In some embodiments, R 7 and R 8 Independently selected from H, D, F, CH3, CF3, and CD3. In some embodiments, R 7 and R 8 Independently selected from H, D, CH3, and CD3. In some embodiments, R 7 and R8 Independently selected from H, F, and D. In some embodiments, R 7 and R 8 Independently selected from H and D. In some embodiments, R 7 and R 8 All are H. In some embodiments, R 7 and R 8 All are D. In some embodiments, R 7 It is H. In some embodiments, R 7 It is D. In some embodiments, R 8 It is H. In some embodiments, R 8 It is D.

[0150] In some embodiments, each R 9 Independently selected from D, halogen, C 1- C4 alkyl, OH, OC 1- C4 alkyl, C 1- C4 alkylene OH and C 1- C4 Alkylene OC 1- C6 alkyl, wherein available hydrogen atoms are optionally replaced by halogen atoms, and / or available atoms are optionally replaced by their substituted isotopes. In some embodiments, each R 9 Independently selected from D, halogen, C 1- C4 alkyl, OH, OC 1- C4 alkyl, C 1- C4 alkylene OH and C 1- C4 Alkylene OC 1- C6 alkyl, wherein hydrogen atoms may optionally be replaced by iodine, fluorine, and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, each R 9 Independently selected from D, halogen, C 1- C4 alkyl, OH, OC 1- C4 alkyl, C 1- C4 alkylene OH and C 1- C4 Alkylene OC 1- C6 alkyl, wherein hydrogen atoms may be optionally replaced by fluorine and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0151] In some embodiments, at least one R 9 Selected from halogenated and C 1- C4 alkyl, wherein hydrogen atoms may optionally be replaced by fluorine and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, at least one R 9 Selected from F, Cl, Br, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C1- C4 deuterated alkyl and C 1- C4 deuterated fluoroalkyl group. In some embodiments, at least one R 9 Selected from F, Cl, Br, OH, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3, CD2CD3, CH2CH2CH3, CH2C H2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3, CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2, CH(CHD2)2, CH(CDH2)2 C(CH3)3, C(CF3)3, C(CHF2)3, C(CFH2)3, C(CD3)3, C(CHD2)3, C(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3, and CH2CH2C(CD3)3. In some embodiments, at least one R 9 Selected from F, Cl, CH3, CF2H, CFH2, CF3 and CD3.

[0152] In some embodiments, at least one R 9 Selected from OH, OC 1- C4 alkyl, C 1- C4 alkylene OH and C 1- C4 Alkylene OC 1- C6 alkyl, wherein hydrogen atoms may optionally be replaced by fluorine and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, at least one R 9 Selected from OH, OC 1- C4 alkyl, OC 1- C4 deuterated alkyl, OC 1- C4 fluoroalkyl, OC 1- C4 deuterated fluoroalkyl, C 1- C4 alkylene OH, C 1- C4 fluoroalkylene OH, C 1- C4 deuteride alkylene OH, C 1-C4 deuterated fluorine alkyl OH, C 1- C4 Alkylene OC 1- C4 alkyl, C 1- C4 Alkylene OC 1- C4 fluoroalkyl, C 1- C4 Alkylene OC 1- C4 deuterated alkyl, C 1- C4 Alkylene OC 1- C4 deuterated fluoroalkyl, C 1- C4 fluoroalkyl OC 1- C4 alkyl, C 1- C4 deuteride OC 1- C4 alkyl, C 1- C4 deuterated fluorine alkyl OC 1- C4 alkyl, C 1- C4 fluoroalkyl OC 1- C4 fluoroalkyl, C 1- C4 fluoroalkyl OC 1- C4 deuterated alkyl, C 1- C4 deuteride OC 1- C4 fluoroalkyl, C 1- C4 deuteride OC 1- C4 deuterated alkyl, C 1- C4 deuterated fluorine alkyl OC 1- C4 fluoroalkyl, C 1- C4 fluoroalkyl OC 1- C4 deuterated fluoroalkyl and C 1- C4 deuterated fluorine alkyl OC 1- C4 deuterated fluoroalkyl group. In some embodiments, at least one R 9 Selected from OH, OC 1- C4 alkyl, OC 1- C4 deuterated alkyl, OC 1- C4 fluoroalkyl, OC 1- C4 deuterated fluoroalkyl, C 1- C4 alkylene OH, C 1- C4 fluoroalkylene OH, C 1- C4 Alkylene OC 1- C4 alkyl, C 1- C4 Alkylene OC 1- C4 fluoroalkyl, C 1- C4 Alkylene OC 1- C4 deuterated alkyl and C 1- C4 Alkylene OC 1- C4 deuterated fluoroalkyl group. In some embodiments, at least one R 9 Selected from OH, OC 1- C4 alkyl, OC 1- C4 deuterated alkyl, OC1- C4 fluoroalkyl, OC 1- C4 deuterated fluoroalkyl, C 1- C4 alkylene OH, C 1- C4 fluoroalkylene OH, C 1- C4 deuteride alkylene OH, C 1- C4 deuterated fluorine alkyl OH, C 1- C4 Alkylene OC 1- C3 alkyl and C 1- C4 Alkylene OC 1- C3 fluoroalkyl.

[0153] In some embodiments, at least one R 9Selected from OH, OCH3, OCD2H, OCDH2, OCD3, OCF2H, OCFH2, OCF3, OCH2CH3, OCH2CH2F, OCH2CF2H, OCH2CF3, OCF2CF3, OCH2CH2D , OCH2CD2H, OCH2CD3, OCD2CD3, OCH2CH2CH3, OCH2CH2CHF2, OCH2CH2CFH2, OCH2CH2CF3, OCH2CH2CHD2, OCH2CH2CDH 2. OCH2CH2CD3, OCH(CH3)2, OCH(CF3)2, OCH(CHF2)2, OCH(CFH2)2, OCH(CD3)2, OCH(CHD2)2, OCH(CDH2)2, OC(CH3) 3. OC(CF3)3, OC(CHF2)3, OC(CFH2)3, OC(CD3)3, OC(CHD2)3, OC(CDH2)3, OCH2CH2CH2CH3, OCH2CH2CH2CF3, OCH2CH 2CH2CD3, OCH2CH(CH3)2, OCH2CH(CD3)2, OCH2CH(CF3)2, OCH(CH3)CH2CH3, OCH(CH3)CH2CF3, OCH(CH3)CH2CD3, OC H2C(CH3)3, OCH2C(CF3)3, OCH2C(CD3)3, OCH2CH2C(CH3)3, OCH2CH2C(CF3)3, OCH2CH2C(CD3)3, CH2OH, CF2OH, CD2 OH, CH2CH2OH, CF2CF2OH, CH2CF2OH, CH2CD2OH, CD2CD2OH, CH2OCH3, CH2OCD2H, CH2OCDH2, CH2OCD3, CH2OCF3, CH2OCHF2, CH2OCH2F, CH2CH2OCH3, CH2CH2OCD2H, CH2CH2OCDH2, CH2CH2OCD3, CH2CH2OCF3, CH2CH2OCHF2, and CH2CH2OCH2F. In some embodiments, at least one R 9 Selected from OH, OCH3, OCF2H, OCFH2, OCF3 and OCD3.

[0154] In some embodiments, n is an integer selected from 0, 1, and 2. In some embodiments, n is 2. In some embodiments, n is an integer selected from 0 and 1. In some embodiments, n is 1. In some embodiments, n is 0.

[0155] In some embodiments, R 10 Selected from H, C 1- C6 alkyl, C 2-C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene Z'R 14 C 2- C6 imene-Z'R 14 C 2- C6-Imyynyl Z'R 14 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C4 alkylene C 3- C7 cycloalkyl, C 1- C4 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C4 alkylene C 6- C 10 Aryl and C 1- C4 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogenated, C-shaped. 1- C6 alkyl, OR 15 and C(O)R 15 In which hydrogen atoms may optionally be replaced by halogen atoms, and / or atoms may optionally be replaced by their substituted isotopes. In some embodiments, R 10 Selected from H, C 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene Z'R 14 C 2- C6 imene-Z'R 14 C 2- C6-Imyynyl Z'R 14 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C4 alkylene C 3- C7 cycloalkyl, C 1- C4 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C4 alkylene C 6- C10 Aryl and C 1- C4 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 15 and C(O)R 15 In which hydrogen atoms may optionally be replaced by iodine atoms, fluorine atoms, and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 10 Selected from H, C 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene Z'R 14 C 2- C6 imene-Z'R 14 C 2- C6-Imyynyl Z'R 14 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C4 alkylene C 3- C7 cycloalkyl, C 1- C4 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C4 alkylene C 6- C 10 Aryl and C 1- C4 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 15 and C(O)R 15 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0156] In some embodiments, R 6 and R 10 One of them is not H or C 1- C6 alkyl, C 1- C6 fluoroalkyl, C 1- C6 deuterated alkyl or C 1- C6 deuterated fluoroalkyl group. In some embodiments, R 6 and R10 One of them is not H or C 1- C6 fluoroalkyl, C 1- C6 deuterated alkyl or C 1- C6 deuterated fluoroalkyl group. In some embodiments, R 6 Selected from C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene ZR 12 C 2- C6 imenoyl ZR 12 C 2- C6-Isoynyl ZR 12 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C4 alkylene C 3- C7 cycloalkyl, C 1- C4 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C4 alkylene C 6- C 10 Aryl and C 1- C4 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 13 and C(O)R 13 R 10 Selected from H and C 1- C6 alkyl, wherein the available hydrogen atoms are optionally replaced by halogen atoms, and / or the available atoms are optionally replaced by their substituted isotopes.

[0157] In some embodiments, R 6 Selected from H and C 1- C6 alkyl, R 10 Selected from C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene Z'R 14 C 2- C6 imene-Z'R 14 C 2- C6-Imyynyl Z'R 14 C 3- C7 cycloalkyl, C 3- C 10Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C4 alkylene C 3- C7 cycloalkyl, C 1- C4 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C4 alkylene C 6- C 10 Aryl and C 1- C4 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 15 and C(O)R 15 In which hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes.

[0158] In some embodiments, R 10 Selected from H and C 1- C6 alkyl, wherein hydrogen atoms may optionally be replaced by fluorine and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 10 Selected from H, D, C 1- C6 alkyl, C 1- C6 deuterated alkyl, C 1- C6 fluoroalkyl and C 1- C6 deuterated alkyl. In some embodiments, R 10Selected from H, D, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3, CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2, CH(CHD2)2, CH(CDH2)2, C(CH3)3, C(CF3)3, C(CHF2)3, C(CFH2)3, C(CD3)3, C(CHD2)3, C(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2CH(CH3)CH3, CH2CH(CH3)CF3, CH2CH(CH3)CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3 and CH2CH2C(CD3)3. In some embodiments, R 10 Selected from H, CH3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH(CH3)2, CH(CF3)2, C(CH3)3, C(CF3)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CHF2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH2C(CH3)3, CH2C(CF3)3, CH2CH2C(CH3)3 and CH2CH2C(CF3)3. In some embodiments, R 10 Selected from H, CH3, CH2CH3, CH2CF3, CH2CH2CH3, CH(CH3)2, CH2C(CH3)3, CH2CH2C(CH3)3, CD3, CF3, CHF2, CH2F, CH2CF2H, CH2CH2F, CH2CH2CHF2 and CH2CH2CF3.

[0159] In some embodiments, R 10 Selected from C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene Z'R 14 C 2- C6 imene-Z'R 14 C 2- C6-Imyynyl Z'R 14 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C4 alkylene C 3- C7 cycloalkyl, C 1- C4 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C4 alkylene C 6- C 10 Aryl and C 1- C4 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 15 and C(O)R 15 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0160] In some embodiments, R 10 Selected from C 4- C6 alkenyl and C 2- C6 alkynyl group, wherein the hydrogen atom may optionally be replaced by a fluorine atom and / or a chlorine atom, and / or the hydrogen atom may optionally be replaced by a deuterium atom. In some embodiments, R 10 Selected from C 2- C6 alkenyl, C 2- C6 fluoroolefin, C 2- C6 deuterated alkenyl, C 2- C6 deuterated fluoroolefin, C 2- C6 ynyl group, C 2- C6 fluoroynyl group, C 2- C6 deuterated ynyl group and C 2- C6 deuterated fluoroalkynyl. In some embodiments, R 10 Selected from C 2- C4 alkenyl, C 2- C4 fluoroolefin, C 2-C6 deuterated alkenyl, C 2- C6 deuterated fluoroolefin, C 2- C4 ynyl group, C 2- C4 fluoroynyl group, C 2- C4 deuterated ynyl group and C 2- C4 deuterated fluoroalkynyl. In some embodiments, R 10 Selected from CH=CH2, CH2CH=CH2, CF2CH=CH2, CD2CH=CH2, CH=CH2CH3, CH=CH2CF3, CH=CH2CHF2, CH=CH2 CH2F, CH=CH2CD3, CH=CH2CHD2, CH=CH2CH2D, C≡CH, C≡CCH3, C≡CCF3, C≡CCHF2, C≡CCFH2, C≡CCD 3、 C≡CCHD2, C≡CCDH2, CH2C≡CH, CF2C≡CH, CD2C≡CH, CH2C≡CCH3, CF2C≡CCH3, CD2C≡CCH3, CH2C≡CCD3, CF2C≡CCD3, CD2C≡CCD3, CH2C≡CCF3, CF2C≡CCF3, CD2C≡CCF 3、 CH2C≡CCHD2, CF2C≡CHD2, CD2C≡CHD2, CH2C≡CHF2, CF2C≡CHF2, and CD2C≡CHF2. In some embodiments, R 10 Selected from CH=CH2, CH2CH=CH2, C≡CH, C≡CCH3, CH2C≡CH and CH2C≡CCH3.

[0161] In some embodiments, R 10 Selected from C 1- C6 alkylene Z'R 14 C 2- C6 imene-Z'R 14 and C 2- C6-Imyynyl Z'R 14 In which hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 10 Selected from C 1- C6 alkylene Z'R 14 C 2- C6 imene-Z'R 14 and C 2- C6-Imyynyl Z'R 14 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0162] In some embodiments, R 10 Selected from C1- C6 alkylene Z'R 14 C 1- C6 fluoroalkyl Z'R 14 C 1- C6 deuteride Z'R 14 C 1- C6 deuterated fluorine-alkylene Z'R 14 C 2- C6 imene-Z'R 14 C 2- C6 fluoroimide Z'R 14 C 2- C6 deuterated alkenyl Z'R 14 C 2- C6 deuterated fluorine-imide Z'R 14 C 2- C6-Imyynyl Z'R 14 C 2- C6-Fluoro-ynyl Z'R 14 C 2- C6-deuterated ynylene Z'R 14 and C 2- C6-deuterated fluoroalkynyl Z'R 14 In some embodiments, R 10 Selected from C 1- C6 alkylene Z'R 14 C 1- C6 fluoroalkyl Z'R 14 C 1- C6 deuteride Z'R 14 C 1- C6 deuterated fluorine-alkylene Z'R 14 C 2- C6 imene-Z'R 14 and C 2- C6-Imyynyl Z'R 14 In some embodiments, R 10 Selected from C 1- C4 alkylene Z'R 14 C 1- C4 fluoroalkyl ZR 14 C 1- C4 deuteride Z'R 14 C 1- C4 deuterated fluorine-alkyl group Z'R 14 C 2- C4 imenoyl Z'R 14 C 2- C4 fluoroimide Z'R 14 C 2- C4 deuterated alkenyl Z'R 14 C 2-C4 deuterated fluorine-imide Z'R 14 C 2- C4-Imyynyl Z'R 14 C 2- C4 fluoroynyl Z'R 14 C 2- C4-deuterated ynylene Z'R 14 and C 2- C4-deuterated fluoroalkynyl Z'R 14 In some embodiments, R 10 Selected from C 1- C4 alkylene Z'R 14 C 1- C4 fluoroalkyl Z'R 14 C 1- C4 deuteride Z'R 14 C 1- C4 deuterated fluorine-alkyl group Z'R 14 C 2- C4 imenoyl Z'R 14 and C 2- C4-Imyynyl Z'R 14 .

[0163] In some embodiments, R 10 Selected from CH2Z'R 14 CH2CH2Z'R 14 CH2CH2CH2Z'R 14 CH2CH2CH2CH2Z'R 14 CH(CH3)CH2Z'R 14 CH(CH3)CH2CH2Z'R 14 CH2CH(CH3)Z'R 14 、 CF2Z'R 14 CFHZ'R 14 CH2CHFZ'R 14 CH2CF2Z'R 14 ,CF2CF2Z'R 14 CH2CH2CF2Z'R 14 CH2CH2CFHZ'R 14 CH2CH2CF2Z'R 14 CH(CH3)CF2Z'R 14 CH(CH3)CHFZ'R 14 CH2CH2CH2CF2Z'R 14 CH2CH2CH2CHFZ'R 14 CH(CH3)CH2CF2Z'R 14CH(CH3)CH2CHFZ'R 14 CD2Z'R 14 CDHZ'R 14 CH2CHDZ'R 14 CH2CD2Z'R 14 CD2CD2Z'R 14 CH2CH2CD2Z'R 14 CH2CH2CDHZ'R 14 CH2CH2CD2Z'R 14 CH(CH3)CD2Z'R 14 CH(CH3)CHDZ'R 14 CH2CH2CH2CD2Z'R 14 CH2CH2CH2CHDZ'R 14 CH(CH3)CH2CD2Z'R 14 CH(CH3)CH2CHDZ'R 14 CH=CHZ'R 14 CH2CH=CHZ'R 14 、C≡CZ'R 14 、C≡CCH2Z'R 14 CH2C≡CZ'R 14 and CH2C≡CH2Z'R 14 In some embodiments, R 10 Selected from CH2Z'R 14 CH2CH2Z'R 14 CH2CH2CH2Z'R 14 CH2CH2CH2CH2Z'R 14 CH(CH3)CH2Z'R 14 CH(CH3)CH2CH2Z'R 14 CH2CH(CH3)Z'R 14 CH=CHZ'R 14 CH2CH=CHZ'R 14 CH=CH2CHZ'R 14 、C≡CCH2Z'R 14 CH2C≡CZ'R 14 and CH2C≡CH2Z'R 14 .

[0164] In some embodiments, R 10 Selected from C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C10 Aryl, C 5- C 10 heteroaryl, C 1- C4 alkylene C 3- C7 cycloalkyl, C 1- C4 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C4 alkylene C 6- C 10 Aryl and C 1- C4 alkylene C 5- C 10 Heteroaryl groups, each of which may optionally be substituted by one to four independent substituents selected from the following: halogens, C 1- C6 alkyl, OR 15 and C(O)R 15 In which hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 10 Selected from C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C4 alkylene C 3- C7 cycloalkyl, C 1- C4 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C4 alkylene C 6- C 10 Aryl, C 1- C4 alkylene C 5- C 10 heteroaryl, C 1- C4 fluoroalkyl C 3- C7 cycloalkyl, C 1- C4 fluoroalkyl C 3- C 10 Heterocyclic alkyl, C 1- C4 fluoroalkyl C 6- C 10 Aryl, C 1- C4 fluoroalkyl C 5- C 10 heteroaryl, C 1- C4 deuteride C 3- C7 cycloalkyl, C 1- C4 deuteride C 3- C 10 Heterocyclic alkyl, C 1-C4 deuteride C 6- C 10 Aryl, C 1- C4 deuteride C 5- C 10 heteroaryl, C 1- C4 deuterated fluorine-alkyl C 3- C7 cycloalkyl, C 1- C4 deuterated fluorine-alkyl C 3- C 10 Heterocyclic alkyl, C 1- C4 deuterated fluorine-alkyl C 6- C 10 Aryl and C 1- C4 deuterated fluorine-alkyl C 5- C 10 Heteroaryl groups, wherein each of the cyclic groups is optionally substituted by one to four independent substituents selected from: F, Cl, Br, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 15 and C(O)R 15 In which hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 10 Selected from C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C2 alkylene C 3- C7 cycloalkyl, C 1- C2 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C2 alkylene C 6- C 10 Aryl, C 1- C2 alkylene C 5- C 10 heteroaryl, C 1- C2 fluoroalkyl C 3- C7 cycloalkyl, C 1- C2 fluoroalkyl C 3- C 10 Heterocyclic alkyl, C 1- C2 fluoroalkyl C 6- C 10 Aryl, C 1- C2 fluoroalkyl C5- C 10 heteroaryl, C 1- C2 deuteride C 3- C7 cycloalkyl, C 1- C2 deuteride C 3- C 10 Heterocyclic alkyl, C 1- C2 deuteride C 6- C 10 Aryl, C 1- C2 deuteride C 5- C 10 heteroaryl, C 1- C2-deuterated fluorine-alkyl C 3- C7 cycloalkyl, C 1- C2-deuterated fluorine-alkyl C 3- C 10 Heterocyclic alkyl, C 1- C2-deuterated fluorine-alkyl C 6- C 10 Aryl and C 1- C2-deuterated fluorine-alkyl C 5- C 10 Heteroaryl groups, wherein each of the cyclic groups is optionally substituted by one to four independent substituents selected from: F, Cl, Br, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 15 and C(O)R 15 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0165] In some embodiments, R 10 C in 3- The C7 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which is optionally substituted by one to four independent substituents selected from the following: F, Cl, Br, C. 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 15 and C(O)R 15 In which hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 10 C in 3-The C7 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is optionally substituted by one to three independent substituents selected from the following: F, Cl, Br, C. 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 15 and C(O)R 15 In which hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 10 C in 3- The C7 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is optionally substituted by one or two independent substituents selected from the following: F, Cl, Br, C. 1- C4 alkyl, C1 - C4 fluoroalkyl, C1 - C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 15 and C(O)R 15 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0166] In some embodiments, R 10 C in 3- C 10 Heterocyclic alkyl groups are monocyclic C 3- C7 heterocyclic alkyl or bicyclic C 7- C 10 Heterocyclic alkyl groups, each of which may optionally be substituted by one to four, one to three, or one or two independent substituents selected from the following: F, Cl, Br, C. 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 15 and C(O)R 15 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0167] In some embodiments, R 10 The single-ring C 3-C7 heterocyclic alkyl groups are selected from aziridinyl, oxetrazyl, thiohexacyclopropane, aziridinyl, dioxetrazyl, 1,3-dioxetrazyl, aziridinyl, oxetrazyl, thiohexacyclopropane, diaziridinyl, dioxetrazyl, dithiohexacyclopropane, tetrahydrofuranyl, tetrahydrothiopheneyl, 2H-1λ3-thiopheneyl, pyrrolyl, imidazoalkyl, pyrazolyl, isoxothioalkyl, thiazoalkyl, isothiazolyl, imidazoalkyl, imidazolinyl, dioxetrazyl, dithiohexacyclopentane, triazolyl, dioxazolyl, dithiazoyl, tetrazolyl, oxetrazolyl, tetrahydropyranyl, dihydropyranyl. The following groups are selected: isothiazolinyl, morpholinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopyrrolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl dioxide, dioxacyclohexyl, thiazolinyl, thiohexylbutyl, thiohexylbutyl oxide, thiohexylbutyl dioxide, dithiohexylbutyl, azirheptanyl, pyrazolyl, oxacycloheptanyl, thioheptanyl, diazirheptanyl, and 2,5-pyrrolidinedione (e.g., succinimide), each of which is optionally substituted by one to four substituents independently selected from: F, Cl, Br, C. 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 15 and C(O)R 15 In which hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 10 The single-ring C 3- C7 heterocyclic alkyl groups are selected from oxetane, tetrahydrofuranyl, tetrahydrothiophenyl, 2H-1λ3-thiophenyl, pyrrolyl, imidazoalkyl, tetrahydropyranyl, dihydropyranyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperazinyl, piperidinyl, piperazinyl, thioheterocyclic butyl, thioheterocyclic butyl oxide, thioheterocyclic butyl dioxide, dithioheterocyclic butyl and 2,5-pyrrolidinedione, each of which is optionally substituted by one to three or one or two independent substituents selected from: F, Cl, Br, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 15 and C(O)R 15 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0168] In some embodiments, R 10 The double-ring C 7- C 10 The heterocyclic alkyl group is selected from benzoisoxazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzopyranyl, benzothiopyranyl, chromanyl, isochromyl, dihydroindenyl, isoyindolinyl, 1-oxoisoindolinyl, 3-oxoisoindolinyl, 1,3-dioxoisoindolinyl (e.g., phthalimide), octahydroisoindolinyl, octahydro-isoindolin-1-one (e.g., tetrahydroisoquinoline), and hexahydroisoindolin-1,3-diketoyl (e.g., cis-hexahydrophthalimide), each of which is optionally substituted by one to four independent substituents selected from: F, Cl, B, C. 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 15 and C(O)R 15 In which hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 10 The double-ring C 7- C 10 The heterocyclic alkyl group is selected from isoindolinyl, 1-oxoisoindololinyl, 3-oxoisoindololinyl, 1,3-dioxoisoindololinyl, octahydro-1H-isoindololinyl, octahydro-1H-isoindololin-1-one, and hexahydro-1H-isoindololin-1,3-diketoyl, each of which is optionally substituted by one to three or one to two independent substituents selected from the following: F, Cl, Br, C. 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 15 and C(O)R 15 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0169] In some embodiments, R 10 C in 6- C 10 The aryl group is a phenyl group, optionally substituted by one to four, one to three, or one or two substituents independently selected from the following: F, Cl, Br, C. 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 15 and C(O)R15 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0170] In some embodiments, R 10 C in 5- C 10 The heteroaryl group is selected from aziridine heptatrienyl, benzofuranyl, benzofurazolyl, benzothiazolyl, benzothiophene, benzooxazolyl, cyclolinyl, furanyl, imidazolyl, indololinyl, indolyl, isoquinolinyl, isothiazolyl, naphridinyl, oxadiazolyl, 2-oxoaziridine heptatrienyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolylyl, pyrrolidinyl, quinazolinyl, quinolinyl, quinoxolinyl, thiazolyl, thiophenefuranyl, triazolyl, and thienyl (e.g., thiophenyl), each of which is optionally substituted by one to four, one to three, or one or two substituents independently selected from: F, Cl, Br, C. 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl, C 1- C4 deuterated fluoroalkyl, OR 15 and C(O)R 15 In which hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0171] In some embodiments, R 10 The substituents on the [substituent name] are independently selected from one to four of the following: F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CD2H, CDH2, CD3, CF3, CHF2, CH2F, CH2CH2F, CF2CF3, CH2CH2D, CH2CD2H, CD2CD3, OR 15 and C(O)R 15 In some embodiments, R 10 The substituents on the plate are independently selected from one to three of the following: F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)2, CD2H, CDH2, CD3, CF3, CHF2, CH2F, OR 15 and C(O)R 15 In some embodiments, R 10 The substituents on the [substituent name] are independently selected from one or both of the following: F, Cl, CH3, CH(CH3)2, CH(CH3)2, CF3, CHF2, CH2F, OR 15and C(O)R 15 .

[0172] In some embodiments, particularly when X is absent or O, and when X is S, S(O) or SO2, R 6 Selected from C 1- C4 fluoroalkyl, C 1- C4 alkylene ZR 12 and C 1- C4 fluoroalkyl ZR 12 , or R 10 Selected from C 1- C4 fluoroalkyl, C 1- C4 alkylene Z'R 14 and C 1- C4 fluoroalkyl Z'R 14 In some embodiments, particularly when X is absent or 0, and in other embodiments, R 6 Selected from C 1- C4 alkylene ZR 12 and C 1- C4 fluoroalkyl ZR 12 , or R 10 Selected from C 1- C4 alkylene Z'R 14 and C 1- C4 fluoroalkyl Z'R 14 .

[0173] In some embodiments, particularly when X is absent or O, or when X is S, S(O), or SO2, Z' is selected from NR. 17 C(O), NR 17 C(O)O、C(O)NR 17 OC(O)NR 17 and NR 17 In some embodiments, Z is selected from O, C(O), NR 17 C(O) and NR 17 C(O)O. In some embodiments, Z' is O. In some embodiments, Z' is C(O). In some embodiments, Z' is NR. 17 C(O). In some embodiments, Z' is NR. 17 C(O)O.

[0174] In some embodiments, R 12 and R 14 Independently selected from H and C 1- C4 alkyl, C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl and C 5- C10 The heteroaryl group, wherein the last four groups are optionally substituted by one to four independent substituents selected from the following: F, Cl, Br, C. 1- C4 alkyl, OC 1- C4 alkyl and C(O)C 1- C4 alkyl, wherein the available hydrogen atoms are optionally replaced by halogen atoms, and / or the available atoms are optionally replaced by their substituted isotopes. In some embodiments, R 12 and R 14 Independently selected from H and C 1- C4 alkyl, C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl and C 5- C 10 The heteroaryl group, wherein the last four groups are optionally substituted by one to three independent substituents selected from the following: F, Cl, C 1- C4 alkyl and OC 1- C4 alkyl, wherein hydrogen atoms may optionally be replaced by iodine, fluorine, and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 12 and R 14 Independently selected from H and C 1- C4 alkyl, C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl and C 5- C 10 The heteroaryl group, wherein the last four groups are optionally substituted by one to three independent substituents selected from the following: F, Cl, C 1- C4 alkyl and OC 1- C4 alkyl, wherein hydrogen atoms may be optionally replaced by fluorine and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0175] In some embodiments, R 12 and R 14 Independently selected from H and C 1- C6 alkyl, wherein hydrogen atoms may optionally be replaced by fluorine and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 12 and R 14 Independently selected from H, D, C 1- C6 alkyl, C 1- C6 fluoroalkyl, C 1- C6 deuterated alkyl and C 1- C6 deuterated fluoroalkyl group.

[0176] In some embodiments, R 12 and R 14 Independently selected from H, D, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, CF2H, CFH2, CF3, CH2CH2 F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, C(CF3)3, C(CHF2)3, C(CFH 2)3. CH2CH2CH2CF3, CH2CH(CF3)2, CH(CH3)CH2CF3, CD2H, CDH2, CD3, CH2CH2D, CH2CD2H, CH2CD3, CD2CD3, CH2CH2CHD2, CH2CH2CD H2, CH2CH2CD3, CH(CD3)2, CH(CHD2)2, CH(CDH2)2, C(CD3)3, C(CHD2)3, C(CDH2)3, CH2CH2CH2CD3, CH2CH(CD3)2 and CH(CH3)CH2CD3. In some embodiments, R 12 and R 14 Independently selected from H, D, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF2H, CFH2, CF3, CH2CH2F, CH2CF2H, CH2CF3, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, C(CF3)3, C(CHF2)3, C(CFH2)3, CD2H, CDH2, CD3, CH2CH2D, CH2CD2H, CH2CD3, CH(CD3)2, CH(CHD2)2, CH(CDH2)2, C(CD3)3, C(CHD2)3, and C(CDH2)3. In some embodiments, R 12 and R 14 It is independently selected from H, D, CH3, CH(CH3)2, C(CH3)3, CF2H, CDF2, CF3, CD2H, CDH2 and CD3.

[0177] In some embodiments, R 12 and R 14 Selected independently from C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl and C 5- C 10Each of the heteroaryl groups is optionally substituted with one to four substituents independently selected from the following: halogen, C1-C4 alkyl, OC1-C4 alkyl and C(O)C1-C4 alkyl, wherein hydrogen atoms may optionally be substituted with fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be substituted with deuterium.

[0178] In some embodiments, R 12 and / or R 14 C in 3- The C7 cycloalkyl group is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which is optionally substituted by one to four substituents independently selected from the following: halogen, C 1- C4 alkyl, OC1-C4 alkyl and C(O)C1-C4 alkyl, wherein hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0179] In some embodiments, R 12 and / or R 14 C in 3- C 10 Heterocyclic alkyl groups are independently monocyclic C 3- C7 heterocyclic alkyl or bicyclic C 7- C 10 Heterocyclic alkyl groups, each of which is optionally substituted by one to four substituents independently selected from the following: halogen, C1-C4 alkyl, OC1-C4 alkyl and C(O)C1-C4 alkyl, wherein hydrogen atoms may optionally be substituted by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be substituted by deuterium.

[0180] In some embodiments, R 12 and / or R 14 The single-ring C 3-The C7 heterocyclic alkyl group is independently selected from aziridinyl, oxacyclopropane, thiocyclopropane, oxaaziridinyl, dioxacyclopropane, 1,3-dioxacyclohexane, aziridine, oxacyclobutane, thiocyclobutane, diazacyclobutane, dioxacyclobutane, dithiocyclobutane, tetrahydrofuranyl, tetrahydrothiopheneyl, 2H-1λ3-thiopheneyl, pyrrolyl, imidazoalkyl, pyrazolyl, isoxothioalkyl, thiazoalkyl, isothiazolyl, imidazoalkyl, imidazolinyl, dioxacyclopentane, dithiocyclopentane, triazolyl, dioxazolyl, dithiazoyl, tetrazolyl, oxetetazolyl, tetrahydropyranyl, dihydropyranyl, isothiazolinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxo... Pyrrolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl dioxide, dioxacyclohexyl, thiazolinyl, thiohexylbutyl, thiohexylbutyl oxide, thiohexylbutyl dioxide, dithiohexylbutyl, azirheptanyl, pyrazolyl, oxacycloheptanyl, thioheptanyl, diazirheptanyl, and 2,5-pyrrolidinedione (e.g., succinimide), each of which is optionally substituted by one to four substituents independently selected from: halogen, C1-C4 alkyl, OC1-C4 alkyl, and C(O)C1-C4 alkyl, wherein hydrogen atoms may optionally be substituted by fluorine and / or chlorine atoms, and / or hydrogen atoms may optionally be substituted by deuterium. In some embodiments, R 12 and / or R 14 The single-ring C 3- The C7 heterocyclic alkyl group is independently selected from oxobutyryl, tetrahydrofuranyl, tetrahydrothiophenyl, 2H-1λ3-thiophenyl, pyrrolyl, imidazoalkyl, tetrahydropyranyl, dihydropyranyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidyl, piperidinyl, piperazine, thiobutyryl, thiobutyryl oxide, thiobutyryl dioxide, dithiobutyryl and 2,5-pyrrolidinedione, each of which is optionally substituted by one to four substituents independently selected from: halogen, C1-C4 alkyl, OC1-C4 alkyl and C(O)C1-C4 alkyl, wherein the hydrogen atom may optionally be substituted by a fluorine atom and / or a chlorine atom, and / or the hydrogen atom may optionally be substituted by a deuterium atom.

[0181] In some embodiments, R 12 and / or R 14 The double-ring C 7- C 10The heterocyclic alkyl group is independently selected from benzoisoxazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzopyranyl, benzothiopyranyl, chromanyl, isochromyl, dihydroindenyl, isoyindolinyl, 1-oxoisoindolinyl, 3-oxoisoindolinyl, 1,3-dioxoisoindolinyl (e.g., phthalimide), octahydroisoindolinyl, octahydro-isoindolin-1-one (e.g., tetrahydroisoindolinyl). Quinoline) and hexahydroisoindoline-1,3-diketone (e.g., cis-hexahydrophthalimide), each of which is optionally substituted with one to four substituents independently selected from: halogen, C1-C4 alkyl, OC1-C4 alkyl, and C(O)C1-C4 alkyl, wherein hydrogen atoms may optionally be substituted with fluorine and / or chlorine atoms, and / or hydrogen atoms may optionally be substituted with deuterium. In some embodiments, R 12 and / or R 14 The double-ring C 7- C 10 The heterocyclic alkyl group is independently selected from isoindolinyl, 1-oxoisoindololinyl, 3-oxoisoindololinyl, 1,3-dioxoisoindololinyl, octahydro-1H-isoindololinyl, octahydro-1H-isoindololin-1-one, and hexahydro-1H-isoindololin-1,3-diketone, each of which is optionally substituted by one to four substituents independently selected from: halogen, C 1- C4 alkyl, OC1-C4 alkyl and C(O)C1-C4 alkyl, wherein hydrogen atoms may be optionally replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0182] In some embodiments, R 12 and / or R 14 C in 6- C 10 The aryl group is independently propyl, optionally substituted by one to four substituents independently selected from the following: halogenated, C-substituted, etc. 1- C4 alkyl, OC1-C4 alkyl and C(O)C1-C4 alkyl, wherein hydrogen atoms may optionally be replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium.

[0183] In some embodiments, R 12 and / or R 14 C in 5- C 10The heteroaryl group is independently selected from the following: heptatrienyl, benzofuranyl, benzofurazolyl, benzothiazolyl, benzothiophene, benzooxazolyl, cenyl, furanyl, imidazolyl, indololinyl, indolyl, isoquinolinyl, isothiazolyl, naphridinyl, oxadiazolyl, 2-oxoazapyridine heptatrienyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, quinazolinyl, quinolinyl, quinoxalyl The group may be linyl, thiazolyl, thiophenfuranyl, triazolyl, or thienyl (e.g., thiophenyl), each of which may be optionally substituted with one to four substituents independently selected from the group consisting of halogen, C1-C4 alkyl, OC1-C4 alkyl, and C(O)C1-C4 alkyl, wherein a hydrogen atom may be optionally substituted with a fluorine atom and / or a chlorine atom, and / or a hydrogen atom may be optionally substituted with a deuterium atom.

[0184] In some embodiments, R 12 and / or R 14 The substituents on the [substituent name] are independently selected from one to four, one to three, and one to two of the following: F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CD2H, CDH2, CD3, CF3, CHF2, CH2F, CH2CH2F, CF2CF3, CH2CH2D, CH2CD2H, CD2CD3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OC(CH3)3, OCD2H, OCDH2, OCD3, OCF3, OCHF2. OCH2F, OCH2CH2F, OCF2CF3, OCH2CH2D, OCH2CD2H, OCD2CD3, C(O)CH3, C(O)CH2CH3, C(O)CH2CH2CH3, C(O)CH(CH3)2, C(O)C(CH3)3, C (O)CD2H, C(O)CDH2, C(O)CD3, C(O)CF3, C(O)CHF2, C(O)CH2F, C(O)CH2CH2F, C(O)CF2CF3, C(O)CH2CH2D, C(O)CH2CD2H and C(O)CD2CD3.

[0185] In some embodiments, R 11 R 13 R 15 R 16 and R 17 Independently selected from H and C 1- C4 alkyl, wherein the available hydrogen atoms are optionally replaced by halogen atoms, and / or the available atoms are optionally replaced by their substituted isotopes. In some embodiments, R 11 R13 R 15 R 16 and R 17 Independently selected from H and C 1- C4 alkyl, wherein hydrogen atoms may optionally be replaced by iodine, fluorine, and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium. In some embodiments, R 11 R 13 R 15 R 16 and R 17 Independently selected from H and C 1- C4 alkyl, wherein hydrogen atoms may be optionally replaced by fluorine and / or chlorine atoms, and / or hydrogen atoms may be optionally replaced by deuterium.

[0186] In some embodiments, R 11 R 13 R 15 R 16 and R 17 Independently selected from H, D, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl and C 1- C4 deuterated fluoroalkyl group. In some embodiments, R 11 R 13 R 15 R 16 and R 17 Independently selected from H, D, F, Br, Cl, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2F, CH2CH3, CH2CH2F, CF2CF3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 11 R 13 R 15 R 16 and R 17 Independently selected from H, CH3, CF3, CHF2, CD2H, CDH2, and CD3. In some embodiments, R 11 R 13 R 15 R 16 and R 17 Independently selected from H, D, CH3, CF3, CHF2, CH2F, CD2H, CDH2, and CD3. In some embodiments, R 11 R 13 R 15 R 16 and R 17 It is independently selected from H, D, CH3, CF3 and CD3.

[0187] In some embodiments, particularly when X is selected from S, S(O), and SO2, and for the case where X is O or does not exist, R 6 Selected from

[0188]

[0189] , and .

[0190] In some embodiments, R 10 Selected from (especially when X is S, S(O) or SO2, and other embodiments where X is O or not present) or R 6 and R 10 Independently selected (particularly when X is absent or oxygen is present, and for other embodiments of X):

[0191]

[0192] C1-C4 alkylene OCH3, C1-C4 alkylene OCHF2, C1-C4 alkylene OCH2F

[0193] C1-C4 alkylene C(O)CHF2, C1-C4 alkylene C(O)CF3

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212] 。

[0213] In the above embodiments and other embodiments using the terminology herein, C1-C4 alkylene groups include, for example, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, and -CH(CH3)CH(CH3)-. Available hydrogen atoms on C1-C4 alkylene groups are optionally replaced by deuterium and / or one or more halogen atoms, such as, but not limited to, -CF2-, -CBr2-, -CCl2-, -CHD-, -CD2-, -CDF-, -CF2CF2-, -CH2CD2-, -CD2CH2-, -CH2CHD-, -CHDCH2-, -CH2CHY-, -CHYCH2-, -CH2CY2-, -CY2CH2-, -CHYCHY-, -CHDCHY-, -CHYCHD-, -CD2CHY-, CHYCD2-, -CHDCY2-, -CY2CHD-, -CY2CD2-, -CD2CY2-, -CD2 CHD-, -CHDCD2-, -CD2CD2-, -CD2CD2CD2-, -CH2CD2CD2-, -CD2CH2CH2-, -CH2CH2CD2-, -CD2CD2CH2-, -CH2CD2CH2-, -CH2CH2CHD-, -CHDCHDCH2-, -CH2CHDCHD-, -CD2CD(CH3)-, -CD2CHDCH2-, -CH2CD(CH3)-, -CH2CHDCH2-, -CD2CH(CH3)-, -CHDCH2CH2-, -CHDCH(CH3)-, etc. (where each Y is independently selected from F, Cl, Br and I).

[0214] In some embodiments, particularly when X is absent or oxygen, and for other embodiments where X is S, S(O), or SO2, in addition to the above list, R 10 H is further independent.

[0215] In some embodiments, the compound of formula (I) is a compound of formula (IA): Formula (IA) Or its pharmaceutically acceptable salts, solvates and / or prodrugs, in: X, n, R 1 R 2 R 3 R 4 R5 R 6 R 7 R 8 R 9 and R 10 As defined in formula (I) including its embodiments, where X is selected from S, S(O) and SO2; Hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes. The condition is when R 9 Selected from halogens and C 1- C6 alkyl, R 10 Selected from H and C 1- C6 alkyl, n is 0, 1, 2, 3 or 4, and R 6 Selected from H, or substituted or unsubstituted C 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl and C 5- C 10 When the compound is heteroaryl, then the compound of formula (I) does not contain deuterium.

[0216] In some embodiments, the compound of formula (I) is the compound of formula (IB): Formula (IB) Or its pharmaceutically acceptable salts, solvates and / or prodrugs, in: X, n, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 and R 10 As defined in formula (I) including its embodiments, where X is selected from S, S(O) and SO2; Hydrogen atoms can be optionally replaced by halogen atoms.

[0217] In some embodiments, the compound of formula (I) is a compound of formula (IC): Formula (IC) Or its pharmaceutically acceptable salts, solvates and / or prodrugs, in: Each R9 Independently selected from OH and OC 1- C6 alkyl, C 1- C6 alkylene OH and C 1- C6 alkylene OC 1- C6 alkyl; X, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 and R 10 And n is as defined in formula (I) including its embodiments, wherein X is selected from S, S(O) and SO2; Hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes.

[0218] In some embodiments, the compound of formula (I) is the compound of formula (ID): Formula (ID) Or its pharmaceutically acceptable salts, solvates and / or prodrugs, in: R 10 Selected from C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene Z'R 14 C 2- C6 imene-Z'R 14 C 2- C6-Imyynyl Z'R 14 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C6 alkylene C 3- C7 cycloalkyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 6- C 10 Aryl, C 1- C6 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1-C6 alkyl, OR 15 and C(O)R 15 ; X, Z', R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 14 R 15 X and n are as defined in formula (I) including its embodiments, wherein X is selected from S, S(O) and SO2; Hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes.

[0219] In some embodiments, the compound of formula (I) is the compound of formula (IE): Formula (IE) Or its pharmaceutically acceptable salts, solvates and / or prodrugs, in: R 6 Selected from C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene ZR 12 C 2- C6 imenoyl ZR 12 C 2- C6-Isoynyl ZR 12 C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C6 alkylene C 3- C7 cycloalkyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 6- C 10 Aryl and C 1- C6 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 13 and C(O)R 13 ; X, Z, R 1 R 2 R 3 R 4 R 5 R 7 R 8 R 9 R 10 、 R 12 and R 13 And n is as defined in formula (I) including its embodiments, wherein X is selected from S, S(O) and SO2; Hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes.

[0220] In some embodiments, X is S, R 2 R 3 R 4 and R 5 Both are H, and compounds of formula (I) are compounds of formula (IF). Therefore, in some embodiments, this disclosure includes a compound of formula (IF): Formula (IF) Or its pharmaceutically acceptable salts, solvates and / or prodrugs, in: R 6 R 7 R 8 R 9 R 10 and n are as defined in formula (I), including its embodiments. The available hydrogen atoms may be optionally replaced by halogen atoms, and / or the available atoms may be optionally replaced by their substituted isotopes.

[0221] In some embodiments, in compounds of formula (IF), R 10 Selected from C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene Z'R 14 C 2- C6 imene-Z'R 14 C 2- C6-Imyynyl Z'R 14 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1-C6 alkylene C 3- C7 cycloalkyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 6- C 10 Aryl, C 1- C6 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 15 and C(O)R 15 Among them, Z' and R 14 and R 15 As defined in formula (I), which includes embodiments thereof.

[0222] In some embodiments, the compound of formula (I) is selected from one or more of the compounds listed in Table 1 below: Table 1

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237] Or its pharmaceutically acceptable salts, solvates and / or prodrugs.

[0238] In some embodiments, the compound of formula (I) is selected from one or more of the compounds listed in Table 2 below: Table 2

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247] Or its pharmaceutically acceptable salts, solvates and / or prodrugs.

[0248] In some embodiments, the compound of formula (I) is a compound of formula (IG): Formula (IG) Or its pharmaceutically acceptable salts, solvates and / or prodrugs, in: X, n, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 and R 10 As defined in formula (I), which includes embodiments thereof, where X is absent or oxygen; Hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes; The condition is that when X is 0, R 9 Selected from halogens and C 1- C6 alkyl, R 10 Selected from H and C 1- C6 alkyl, n is 0, 1, 2, 3 or 4, and R 6 Selected from H, or substituted or unsubstituted C1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl and C 5- C 10 When the compound is heteroaryl, then the compound does not contain deuterium; The condition is that when X is O, R 1 R 2 R 3 R 4 R 5 R 7 and R 8 It is H or D, n is 0, and R 6 When it is H, CH3 or CD3, then R 10 Not H, CH3, or CD3; The condition is that when X is O, R 1 R 2 R 3 R 4 R 5 R 7 and R 8 It is H or D, n is 0, and R 6 When it is CH3 or CHF2, then R 10 Not H, CH3, or CD3; The condition is that X does not exist and R 6 When it is H, then n is not 0, or R. 10 Not H or C 1- C6 alkyl.

[0249] In some embodiments, the compound of formula (I) is a compound of formula (IH): Formula (IH) Or its pharmaceutically acceptable salts, solvates and / or prodrugs, in: X, n, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 and R 10 As defined in formula (I), which includes embodiments thereof, where X is absent or oxygen; Hydrogen atoms can be optionally replaced by halogens. The condition is that when X is O, R 9 It is halogen, C 1- C6 alkyl or C1-C6 haloalkyl, n is 0, 1, 2, 3 or 4, and R 10 It is H, C 1- When it is a C6 alkyl or a C1-C6 haloalkyl, then R 6 Not H, C 1- C6 alkyl or C1-C6 haloalkyl; The condition is that when X is O, R 1 R 2 R 3 R 4 R 5 R 7 and R 8 It is H or D, n is 0, and R 6 When it is H, CH3 or CD3, then R 10 Not H, CH3, or CD3; The condition is that when X is O, R 1 R 2 R 3 R 4 R 5 R 7 and R 8 It is H or D, n is 0, and R 6 When it is CH3 or CHF2, then R 10 Not H, CH3, or CD3; The condition is that X does not exist and R 6 When it is H, then n is not 0, or R. 10 Not H or C 1- C6 alkyl.

[0250] In some embodiments, the compound of formula (I) is a compound of formula (II): Equation (II) Or its pharmaceutically acceptable salts, solvates and / or prodrugs, in: n is an integer selected from 1, 2, 3, and 4; Each R 9 Independently selected from OH and OC 1- C6 alkyl, C 1- C6 alkylene OH and C 1- C6 alkylene OC 1- C6 alkyl; X, R 1 R 2 R 3 R 4 R5 R 6 R 7 R 8 and R 10 As defined in formula (I), which includes embodiments thereof, where X is absent or oxygen; Hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes.

[0251] In some embodiments, the compound of formula (I) is a compound of formula (IJ): Formula (IJ) Or its pharmaceutically acceptable salts, solvates and / or prodrugs, in: R 10 Selected from C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene Z'R 14 C 2- C6 imene-Z'R 14 C 2- C6-Imyynyl Z'R 14 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C6 alkylene C 3- C7 cycloalkyl, C 1- C6 alkylene C 3- C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 6- C 10 Aryl and C 1- C6 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 15 and C(O)R 15 ; X, Z', R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8R 9 R 14 R 15 and n are as defined in formula (I) including its embodiments, wherein X is absent or oxygen; Hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes.

[0252] In some embodiments, the compound of formula (I) is a compound of formula (IK): Formula (IK) Or its pharmaceutically acceptable salts, solvates and / or prodrugs, in: R 6 Selected from C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene ZR 12 C 2- C6 imenoyl ZR 12 C 2- C6-Isoynyl ZR 12 C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C6 alkylene C 3- C7 cycloalkyl, C 1- C6 alkylene C 3- C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 6- C 10 Aryl and C 1- C6 alkylene C 5- C 10 Heteroaryl, the last eight groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 13 and C(O)R 13 ; X, Z, R 1 R 2 R 3 R 4 R 5 R 7 R 8 R 9 R 10 R 12 R13 and n are as defined in formula (I) including its embodiments, wherein X is absent or oxygen; Hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes.

[0253] In some embodiments, R 2 R 3 R 4 and R 5 Both are H, and the compound of formula (I) is a compound of formula (IL). Therefore, in some embodiments, this disclosure includes a compound of formula (IL): Formula (IL) Or its pharmaceutically acceptable salts, solvates and / or prodrugs, in: X, n, R 6 R 7 R 8 R 9 and R 10 As defined in formula (I), which includes embodiments thereof, where X is absent or oxygen; Hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes. The condition is that when X is O, R 7 and R 8 It is H or D, n is 0, and R 6 When it is H, CH3 or CD3, then R 10 Not H, CH3, or CD3; The condition is that when X is O, R 7 and R 8 It is H or D, n is 0, and R 6 When it is CH3 or CHF2, then R 10 Not H, CH3, or CD3; The condition is that X does not exist and R 6 When it is H, then n is not 0, or R. 10 Not H or C 1- C6 alkyl.

[0254] In some embodiments, X is absent, and the compound of formula (I) is a compound of formula (IM). Therefore, in some embodiments, this disclosure includes a compound of formula (IM): Formula (IM) Or its pharmaceutically acceptable salts, solvates and / or prodrugs, in: X does not exist; n, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 and R 10 As defined in formula (I), including its embodiments; Hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes. The condition is when R 6 When it is H, then n is not 0, or R. 10 Not H or C 1- C6 alkyl.

[0255] In some embodiments, the compound of formula (I) is selected from one or more of the compounds listed in Table 3 below: Table 3

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278] Or its pharmaceutically acceptable salts, solvates and / or prodrugs.

[0279] In some embodiments, the compound of formula (I) is selected from one or more compounds listed in Tables 4 and 5 below: Table 4

[0280]

[0281] Or its pharmaceutically acceptable salts, solvates and / or prodrugs.

[0282] Table 5

[0283]

[0284]

[0285]

[0286]

[0287]

[0288] Or its pharmaceutically acceptable salts, solvates and / or prodrugs.

[0289] In some embodiments, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. Those skilled in the art can select a suitable salt. Suitable salts include acid addition salts, which can be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. In addition, acids generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are discussed in, for example, the following literature: P. Stahl et al., Camille G. (eds.) and Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley VCH; S. Berge et al., Journal of Pharmaceutical Sciences 1977 66(1) 1-19; P. Gould, International Journal of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (FDA website, Washington, D.C.).

[0290] Acid addition salts suitable for or compatible with the treatment of a subject are any non-toxic organic or inorganic acid addition salts of any basic compound. Basic compounds forming acid addition salts include, for example, compounds containing an amino group. Exemplary inorganic acids forming suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acidic metal salts such as sodium monohydrogen phosphate and potassium hydrogen sulfate. Exemplary organic acids forming suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids. Exemplary such organic acids are, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In some embodiments, typical acid addition salts also include acetates, ascorbic acid salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphor salts, camphor sulfonates, fumarates, hydrochlorides, hydrobromates, hydroiodides, lactates, maleates, methanesulfonates (“methanesulfonates”), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also known as tosylates), etc. In some embodiments, monoacid salts or diacid salts are formed, and such salts are present in hydrated, solvated, or substantially anhydrous forms. Generally, acid addition salts are more soluble in water and a variety of hydrophilic organic solvents and typically exhibit higher melting points compared to their free basic forms. The selection criteria for suitable salts are known to those skilled in the art. Other non-pharmaceuticalally acceptable salts, such as, but not limited to, oxalates, may be used, for example, to isolate the compounds disclosed herein for laboratory use or for subsequent conversion into pharmaceutically acceptable acid addition salts.

[0291] A base addition salt suitable for or compatible with the treatment of a subject is any non-toxic organic or inorganic base addition salt of any acidic compound. Acidic compounds that form basic addition salts include, for example, compounds containing a carboxylic acid group. Exemplary inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide, as well as ammonia. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, methylpyridine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Typical organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. Choosing a suitable salt can be useful, for example, to prevent the hydrolysis of ester functional groups (if present) elsewhere in the compound. Criteria for choosing a suitable salt are known to those skilled in the art. In some embodiments, typical basic salts also include ammonium salts, alkali metal salts (such as sodium, lithium, and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts), salts containing organic bases (e.g., organic amines) (such as dicyclohexylamine, butylamine, and choline), and salts containing amino acids (such as arginine, lysine, etc.). Basic nitrogen-containing groups can be quaternized using reagents such as lower alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, and butyl), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, and dibutyl sulfate), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, lauryl, and stearyl), and aralkyl halides (e.g., benzyl bromide and phenethyl bromide). Compounds carrying acidic moieties can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands, such as quaternary ammonium salts. Furthermore, in the presence of an acid (-COOH) or alcohol group, pharmaceutically acceptable esters can be used to modify the solubility or hydrolytic properties of the compound.

[0292] Within the scope of this disclosure, all such acid salts and base salts are intended to be pharmaceutically acceptable salts, and for the purposes of this disclosure, all acid salts and base salts are considered equivalent to the free form of the corresponding compound. Additionally, when the compounds of this disclosure contain both a basic moiety, such as, but not limited to, aliphatic primary amines, secondary amines, tertiary amines or cyclic amines, aromatic amines or heteroaryl amines, pyridine or imidazole, and an acidic moiety, such as, but not limited to, tetrazolium or carboxylic acids, zwitterions (“internal salts”) may be formed and included in the term “salt” as used herein. It should be understood that certain compounds of this disclosure may exist in zwitterionic form, possessing both anionic and cation centers within the same compound and carrying a net neutral charge. Such zwitterions are included in this disclosure.

[0293] Solvents of the compounds disclosed herein include those prepared, for example, with pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvate is referred to as a hydrate) and ethanol. Suitable solvents are physiologically tolerable at the administered dose.

[0294] The prodrugs of the compounds disclosed herein include, for example, conventional esters formed from hydroxyl, thiol, amino, or carboxyl groups. Some common esters used as prodrugs are phenyl esters, aliphatic (C1-C4) esters, and others. 24 Esters, acyloxymethyl esters, carbamates and amino acid esters.

[0295] It should be understood and recognized that, in some embodiments, the compounds of this disclosure may have at least one chiral center and therefore may exist as enantiomers and / or diastereomers. It should be understood that all such isomers and mixtures thereof in any proportion are covered within the scope of this disclosure. It should be further understood that, while the stereochemistry of a compound may be as shown by any given compound listed herein, such a compound may also contain an amount (e.g., less than 20%, suitably less than 10%, more suitably less than 5%) of a compound of this disclosure having an alternative stereochemistry. Any optical isomer, whether isolated, pure, or partially purified, or a racemic mixture thereof, is intended to be included within the scope of this disclosure.

[0296] In some embodiments, the compounds of this disclosure may also include tautomeric forms, such as keto-enol tautomeric forms. Through appropriate substitution, the tautomeric forms may be in equilibrium or spatially locked into one form. Any tautomeric forms formed by the compounds and mixtures thereof are intended to be included within the scope of this disclosure.

[0297] The compounds disclosed herein may further exist in different amorphous and polymorphic forms, and it is conceivable that any amorphous form, polymorph, or mixture thereof is included within the scope of this disclosure.

[0298] 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 to specific isotopes having the same atomic number but a different atomic mass or mass number than those predominantly found in nature. This disclosure is intended to include all suitable isotopic variants of the compounds of this disclosure and their pharmaceutically acceptable salts, solvates, and / or prodrugs. For example, different isotopic forms of hydrogen (H) include protium (¹H), deuterium (²H), and tritium (³H). Protium is the predominant hydrogen isotope found in nature.

[0299] The compounds disclosed herein can be further radiolabeled, and therefore all radiolabeled versions of the compounds disclosed herein are included within the scope of this disclosure. Therefore, the compounds disclosed herein also include those compounds incorporating one or more radioactive atoms in their structure.

[0300] III. Composition The compounds of this disclosure are suitably formulated into compositions using one or more carriers in a conventional manner. Therefore, this disclosure also includes compositions comprising one or more compounds of this disclosure and a carrier. The compounds of this disclosure are suitably formulated into pharmaceutical compositions for administration to a subject in a biocompatible form suitable for in vivo administration. Therefore, this disclosure further includes pharmaceutical compositions comprising one or more compounds of this disclosure and a pharmaceutically acceptable carrier. In embodiments of this disclosure, the pharmaceutical compositions are used to treat any disease, condition, or symptom described herein.

[0301] The compounds of this disclosure may be administered to a subject in various forms depending on the chosen route of administration, as will be understood by those skilled in the art. For example, the compounds of this disclosure may be administered orally, by inhalation, parenteral administration, buccal, sublingual, insufflation, epidural, nasal, rectal, vaginal, patch, pump, micropump, topical, or transdermal administration, and the pharmaceutical composition may be formulated accordingly. In some embodiments, administration may be performed by a pump for periodic or continuous delivery. Conventional procedures and ingredients for selecting and preparing suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000–20th edition) and The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999.

[0302] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, including, for example, intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (e.g., by using an aerosol), intrathecal, rectal, and local (including by using a patch or other transdermal delivery device) administration modes. Parenteral administration can be performed by continuous infusion over a selected time period.

[0303] In some embodiments, the compounds of this disclosure are administered orally, for example, with an inert diluent or with an assimilated edible carrier, or encapsulated in hard or soft-shell gelatin capsules, or compressed into tablets, or directly incorporated into a diet. In some embodiments, the compounds are incorporated with excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, pouches, pills, microparticles, tablets, chewing gum, powders, syrups, elixirs, flakes, aqueous solutions, suspensions, etc. In the case of tablets, the carriers used include lactose, corn starch, sodium citrate, and phosphates. Pharmaceutically acceptable excipients include binders (e.g., pregelatinized 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); wetting agents (e.g., sodium lauryl sulfate); and / or solvents (e.g., medium-chain triglycerides, ethanol, or water). In the examples, the tablets are coated using methods known in the art. In the case of tablets, capsules, pouches, pills, or microparticles intended for oral administration, pH-sensitive enteric coatings, such as Eudragits designed to control the release of the active ingredient, are optionally used. TM Oral dosage forms also include modified release formulations, such as immediate-release and timed-release formulations. Examples of modified release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), timed-release or timed-release, controlled-release (CR), or sustained-release (CR or Contin), for example, in the form of coated tablets, permeable delivery devices, coated capsules, microencapsulated microspheres, agglomerated particles (e.g., molecular sieve particles), or fine hollow permeable fiber bundles or chopped hollow permeable fibers, agglomerated or retained in a fiber package. Timed-release compositions are formulated, for example, into liposomes or liposomes in which the active compound is protected by different degradable coatings (e.g., by microencapsulation, multiple coatings, etc.). Liposome delivery systems include, for example, small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. In some embodiments, liposomes are formed from various phospholipids such as cholesterol, stearamine, or phosphatidylcholine. For oral administration in capsule form, useful carriers, solvents, or diluents include lactose, medium-chain triglycerides, ethanol, and dried corn starch.

[0304] In some embodiments, the liquid formulation for oral administration is in the form of, for example, a solution, syrup, or suspension, or the liquid formulation may suitably be presented as a dried product for reconstitution with water or other suitable mediator prior to use. When the aqueous suspension and / or emulsion is administered orally, the compounds of this disclosure are suitably suspended or dissolved in an oil phase combined with an emulsifier and / or suspending agent. If desired, certain sweeteners and / or flavoring agents and / or coloring agents may be added. Such liquid formulations for oral administration are prepared by conventional methods using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous mediators (e.g., medium-chain triglycerides, almond oil, oily esters, or ethanol); and / or preservatives (e.g., methylparaben or propylparaben or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycol.

[0305] The compounds disclosed herein can also be freeze-dried and the resulting lyophilized products used, for example, in the preparation of injectable products.

[0306] In some embodiments, the compounds of this disclosure are administered parenterally. For example, solutions of the compounds of this disclosure may be prepared in water suitably mixed with a surfactant, such as hydroxypropyl cellulose. In some embodiments, dispersions may be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, as well as in oils. Under normal storage and use conditions, these formulations contain preservatives to prevent microbial growth. Those skilled in the art know how to prepare suitable formulations. For parenteral administration, a sterile solution of the compounds of this disclosure is typically prepared, and the pH of the solution is appropriately adjusted and buffered. For intravenous injection, the total concentration of the solute should be controlled to make the formulation isotonic. For ocular administration, ointments or droppers may be delivered, for example, by ocular delivery systems known in the art, such as applicators or droppers. In some embodiments, such compositions include mucus mimics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose, or polyvinyl alcohol; preservatives such as sorbic acid, EDTA, or benzyl chromium chloride; and a commonly used amount of diluent or carrier. For lung application, a diluent or carrier will be selected to suit the formation of an aerosol.

[0307] In some embodiments, the compounds of this disclosure are formulated for parenteral administration by injection, including using conventional catheter insertion techniques or infusion. The injectable formulation is, for example, in a unit dosage form, such as in an ampoule or multi-dose container, and contains preservatives. In some embodiments, the composition takes the form of a sterile suspension, solution, or emulsion in an oily or aqueous medium and contains formulation agents such as suspending agents, stabilizers, and / or dispersants. In all cases, the dosage form must be sterile and must be an easily injectable fluid. Alternatively, the compounds of this disclosure are suitably in the form of a sterile powder for reconstitution with a suitable medium, such as sterile pyrogen-free water, prior to use.

[0308] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels, and powders. For intranasal or inhalation administration, the compounds of this disclosure are conveniently delivered as solutions, dry powder formulations, or suspensions from a pump-operated spray container squeezed or pumped by a patient, or as an aerosol spray from a pressurized container or nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are typically present in a sterile, single- or multi-dose form in a sealed container, such as a cartridge or refill for use with a nebulizer. Alternatively, the sealed container is an integral dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser with a metering valve, intended to be discarded after use. When the dosage form includes an aerosol dispenser, it will contain a propellant, such as a compressed gas like compressed air or an organic propellant like chlorofluorocarbons. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkane, carbon dioxide, or another suitable gas. In the case of pressurized aerosols, the dosage unit is appropriately determined by a valve that provides the amount of delivery. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound. Capsules and cartridges for inhalers or blow-throughs (e.g., made of gelatin) are formulated, for example, into a powder mixture containing the compounds of this disclosure and a suitable powder matrix such as lactose or starch. Aerosol dosage forms may also be in the form of pump nebulizers.

[0309] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and soft lozenges, wherein the compounds of this disclosure are formulated with a carrier such as sugar, guar gum, gum, gelatin, and glycerin. Compositions for rectal administration are conveniently in suppository form containing a conventional suppository matrix such as cocoa butter.

[0310] The suppository forms of the compounds disclosed herein are for vaginal, urethral, ​​and rectal administration. Such suppositories typically consist of a mixture of substances that are solid at room temperature but melt at body temperature. Substances commonly used to generate such media include, but are not limited to, cocoa butter (also known as cocoa brittle), glycerin gelatin, other glycerides, hydrogenated vegetable oils, and mixtures of polyethylene glycol and polyethylene glycol fatty acid esters of various molecular weights. See, for example, further discussion on suppository dosage forms, *Remington's Pharmaceutical Sciences*, 16th edition, Mack Publishing, Easton, PA, 1980, pp. 1530-1533.

[0311] In some embodiments, the compounds of this disclosure are coupled with a soluble polymer as a targeted drug carrier. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparagine-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, the compounds of this disclosure are coupled with a class of biodegradable polymers that can be used to achieve controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0312] The compounds disclosed herein, including their pharmaceutically acceptable salts, solvates, and / or prodrugs, are suitable for use alone, but are generally administered in the form of pharmaceutical compositions, wherein one or more of the disclosed compounds (active ingredients) are bound to a pharmaceutically acceptable carrier. Depending on the administration regimen, the pharmaceutical composition will comprise about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt% of the active ingredient and about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of a pharmaceutically acceptable carrier, all weight percentages being based on the total composition.

[0313] In some embodiments, the compounds of this disclosure, including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, are administered in the form of a composition comprising an additional therapeutic agent. Therefore, this disclosure also includes a pharmaceutical composition comprising one or more compounds of this disclosure or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, and an additional therapeutic agent, and optionally one or more pharmaceutically acceptable excipients. In some embodiments, the additional therapeutic agent is another known drug that can be used to treat a disease, condition, or symptom by activating serotonin receptors, such as those listed in the Methods and Uses section below. In some embodiments, the additional therapeutic agent is a psychoactive drug.

[0314] In the above text, the term "compound" also includes examples in which one or more compounds are referenced.

[0315] IV. Methods and Uses of this Disclosure The compounds disclosed herein are serotonergic binders that act as agonists or partial agonists at the serotonin receptor.

[0316] Therefore, this disclosure includes a method for activating serotonin receptors in cells of a biological sample or a patient, the method comprising administering an effective amount of one or more of the compounds of this disclosure to the cells. This disclosure also includes one or more of the compounds of this disclosure for activating serotonin receptors in cells, and the use of one or more of the compounds of this disclosure in the preparation of a medicament for activating serotonin receptors in cells. This disclosure further includes one or more of the compounds of this disclosure for activating serotonin receptors in cells. In some embodiments, the method for activating serotonin receptors is performed in or on cells.

[0317] Because the compounds of this disclosure can activate serotonin receptors, they can be used to treat diseases, conditions, or symptoms by activating serotonin receptors. Therefore, the compounds of this disclosure can be used as pharmaceuticals. This disclosure also includes the compounds of this disclosure for use as pharmaceuticals.

[0318] This disclosure also includes a method for treating a disease, condition, or symptom by activating a serotonin receptor, the method comprising administering a therapeutically effective amount of one or more compounds of this disclosure to a subject in need.

[0319] This disclosure also includes the use of one or more of the disclosed compounds for treating diseases, conditions, or symptoms by activating serotonin receptors, and the use of one or more of the disclosed compounds for preparing a medicament for treating diseases, conditions, or symptoms by activating serotonin receptors. This disclosure further includes one or more of the disclosed compounds for treating diseases, conditions, or symptoms by activating serotonin receptors.

[0320] In some embodiments, the serotonin receptor is 5-HT 2A Therefore, this disclosure includes a method for activating 5-HT in cells of a biological sample or patient. 2A The method comprises administering an effective amount of one or more of the compounds disclosed herein to cells. This disclosure also includes one or more of the compounds disclosed herein for activating 5-HT in cells. 2A The uses of, and one or more of the compounds disclosed herein, for the preparation of 5-HT for activating cells. 2A The use of the drug. This disclosure further includes one or more of the drugs disclosed herein for activating 5-HT in cells. 2AThe compound. In some embodiments, it is used to activate 5-HT. 2A The method is performed in or on cells.

[0321] This disclosure also includes a method for activating 5-HT 2A A method for treating a disease, condition, or symptom, the method comprising administering a therapeutically effective amount of one or more of the compounds disclosed herein to a subject in need. This disclosure also includes one or more of the compounds disclosed for use by activating 5-HT. 2A Use for treating diseases, conditions, or symptoms, and one or more of the compounds disclosed herein for preparation of [a specific treatment] via activating 5-HT. 2A Use of a medicament for treating diseases, conditions, or symptoms. This disclosure further includes one or more of the methods disclosed herein for activating 5-HT. 2A Compounds used to treat diseases, symptoms, or conditions.

[0322] In some embodiments, the compounds of this disclosure can be used to prevent, treat, and / or reduce the severity of mental illness symptoms and / or conditions in a subject. Therefore, in some embodiments, the disease, condition, or symptom treated by activating serotonin receptors is a mental illness. Therefore, this disclosure also includes a method of treating a mental illness, the method comprising administering a therapeutically effective amount of one or more of the compounds of this disclosure to a subject in need. This disclosure also includes the use of one or more of the compounds of this disclosure for treating mental illness and the use of one or more of the compounds of this disclosure for preparing a medicament for treating mental illness. This disclosure further includes one or more of the compounds of this disclosure for treating mental illness.

[0323] In some embodiments, mental illnesses are selected from 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 ideation; mood disorders such as depression, bipolar disorder, cancer-related depression, major depressive disorder (MDD), treatment-resistant depression (TRD), postpartum depression (PPD), anxiety, and cyclothymic mood disorders; psychotic disorders such as hallucinations, delusions, and schizophrenia; impulse control and addiction disorders such as pyrokinesis, kleptomania, and compulsive gambling; alcohol addiction (e.g., reducing alcohol consumption); drug addiction such as opioid addiction; and personality disorders such as antisocial personality disorder. Personality disorders, obsessive-compulsive personality disorder, and paranoid personality disorder; obsessive-compulsive disorder (OCD), such as thoughts or fears that compel a subject to perform certain rituals or routines; post-traumatic stress disorder (PTSD); stress response syndrome (formerly known as adjustment disorder); dissociative disorders (formerly known as multiple personality disorder or “splitting personality” and depersonalization disorder); affective disorders; sexual and gender disorders, such as sexual dysfunction, gender identity disorder, and sexual perversion; somatic symptom disorders (formerly known as psychosomatic disorders or somatic symptom disorders); physical deformity disorders; disorders affecting goal-oriented behavior; mood state disorders (e.g., reducing negative emotions and promoting positive emotions); enhancing creativity and its combinations.

[0324] In some embodiments, diseases, conditions, or symptoms treated by activating serotonin receptors include cognitive impairment (e.g., enhancing cognitive abilities, enhancing and / or improving cognitive flexibility); ischemia, including stroke; neurodegeneration; refractory substance use disorders; sleep disorders; pain, such as social pain, acute pain, cancer pain, chronic pain, breakthrough pain, bone pain, soft tissue pain, neuralgia, referred pain, phantom limb pain, neuropathic pain, cluster headache, and migraine; obesity and eating disorders; epilepsy and paroxysmal symptoms; neuronal cell death; excitotoxic cell death; inflammation (e.g., autoimmune neuroinflammation); or combinations thereof.

[0325] In some embodiments, mental illness is selected from hallucinations and delusions and combinations thereof.

[0326] In some embodiments, hallucinations are selected from visual hallucinations, visual disorders (e.g., perophthalmos (PMO), processing of emotional faces that affect facial recognition and improve treatment-resistant depression (TRD), auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, balance hallucinations, nociceptive hallucinations, thermal hallucinations, and time hallucinations, and combinations thereof.

[0327] In some embodiments, the disease, condition, or symptom treated by activating serotonin receptors is psychosis or psychotic symptoms. Therefore, this disclosure also includes a method of treating psychosis or psychotic symptoms, the method comprising administering a therapeutically effective amount of one or more compounds of this disclosure to a subject in need.

[0328] This disclosure also includes the use of one or more of the disclosed compounds for treating psychosis or psychotic symptoms, and the use of one or more of the disclosed compounds for preparing a medicament for treating psychosis or psychotic symptoms. This disclosure further includes one or more of the disclosed compounds for treating psychosis or psychotic symptoms.

[0329] In some embodiments, administration of a therapeutically effective amount of the disclosed compound to the subject in need does not worsen psychosis or psychotic symptoms (such as, but not limited to, hallucinations and delusions). In some embodiments, administration of a therapeutically effective amount of the disclosed compound to the subject in need improves psychosis or psychotic symptoms (such as, but not limited to, hallucinations and delusions). In some embodiments, administration of a therapeutically effective amount of the disclosed compound to the subject in need improves psychosis or psychotic symptoms.

[0330] In some embodiments, the disease, condition, or symptom treated by activating serotonin receptors is a central nervous system (CNS) disease, condition, or symptom and / or a neurological disease, condition, or symptom. Therefore, this disclosure also includes a method of treating a CNS disease, condition, or symptom and / or a neurological disease, condition, or symptom by activating serotonin receptors, the method comprising administering to a subject in need a therapeutically effective amount of one or more of the compounds of this disclosure, the subject being a subject suffering from a central nervous system (CNS) disease, condition, or symptom and / or a neurological disease, condition, or symptom. This disclosure also includes the use of one or more of the compounds of this disclosure for treating a CNS disease, condition, or symptom and / or a neurological disease, condition, or symptom by activating serotonin receptors, and the use of one or more of the compounds of this disclosure for preparing a medicament for treating a CNS disease, condition, or symptom and / or a neurological disease, condition, or symptom treated by activating serotonin receptors. This disclosure further includes one or more compounds disclosed herein for treating CNS diseases, conditions or symptoms and / or neurological diseases, conditions or symptoms by activating serotonin receptors.

[0331] In some embodiments, CNS diseases, conditions, or symptoms and / or neurological diseases, conditions, or symptoms are selected from neurological diseases, including neurodevelopmental and neurodegenerative diseases such as Alzheimer's disease (e.g., restoration of mGluR2 expression); early-onset dementia; senile dementia; vascular dementia; Lewy body dementia; cognitive impairment; Parkinson's disease and Parkinson's disease-related conditions such as Parkinson's dementia, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease. Diseases; mitochondrial disorders; Fragile X syndrome; Angelman syndrome; hereditary ataxia; neurogenic ear and eye movement disorders; neurodegenerative diseases of retinal myofascitis and lateral sclerosis; tardive dyskinesia; ADHD; Attention deficit hyperactivity disorder and attention deficit disorder; Restless legs syndrome; Tourette's syndrome; schizophrenia; autism spectrum disorders; tuberous sclerosis; Rett syndrome; cerebral palsy; reward system disorders, including eating disorders such as anorexia nervosa (“AN”) and bulimia nervosa (“BN”); and bulimia nervosa (“BED”); pica; rumination disorders; avoidance / restriction of food intake disorders; trichotillomania, scratching, nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology; reduced convergent thinking; increased spontaneous divergent thinking and goal-oriented divergent thinking; and combinations thereof.

[0332] This disclosure also includes a method for treating nonpsychiatric symptoms such as fibromyalgia, irritable bowel syndrome (IBS), fragility X, short-term unilateral neuropathic headache attacks with cranial autonomic symptoms (SUHNA), chronic cluster, persistent post-concussion syndrome (PPCS), Alzheimer's disease, Lyme disease, neuropathic pain, migraine, Parkinson's disease, cluster headache, stroke, traumatic brain injury (TBI), pain, obesity, and smoking cessation.

[0333] In some embodiments, the subject is a mammal. In another embodiment, the subject is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a canine. In some embodiments, the subject is a feline. Therefore, the compounds, methods, and uses of this disclosure are targeted at diseases, conditions, or symptoms in humans and veterinarians.

[0334] In some embodiments, a “subject in need” is a subject suffering from a disease, condition, or symptom that requires treatment.

[0335] In some embodiments, the compounds disclosed herein can be used to treat behavioral problems in subjects who are felines or canines.

[0336] Therefore, in some embodiments, the disease, condition, or symptom treated by activating serotonin receptors is a behavioral problem in a subject who is a feline or canine. Therefore, this disclosure also includes a method of treating a behavioral problem, the method comprising administering a therapeutically effective amount of one or more of the compounds of this disclosure to a non-human subject in need. This disclosure also includes the use of one or more of the compounds of this disclosure for treating behavioral problems in non-human subjects, and the use of one or more of the compounds of this disclosure for preparing a medicament for treating behavioral problems in non-human subjects. This disclosure further includes one or more of the compounds of this disclosure for treating behavioral problems in non-human subjects.

[0337] In some embodiments, behavioral problems are selected from, but are not limited to, anxiety, fear, stress, sleep disorders, cognitive impairment, aggression, excessive noise, scratching, biting, and combinations thereof.

[0338] In some embodiments, the non-human subject is a canine. In some embodiments, the non-human subject is a feline.

[0339] This disclosure also includes a method of treating a disease, condition, or symptom by activating a serotonin receptor, the method comprising administering to a subject in need a therapeutically effective amount of one or more of the disclosed compounds in combination with another known pharmaceutical agent that can be used to treat a disease, condition, or symptom by activating a serotonin receptor. This disclosure also includes the use of a combination of one or more of the disclosed compounds in combination with another known pharmaceutical agent that can be used to treat a disease, condition, or symptom by activating a serotonin receptor for the purpose of treating a disease, condition, or symptom by activating a serotonin receptor, and the use of a combination of one or more of the disclosed compounds in combination with another known pharmaceutical agent that can be used to treat a disease, condition, or symptom by activating a serotonin receptor for the purpose of preparing a medicament for treating a disease, condition, or symptom by activating a serotonin receptor. This disclosure further includes a combination of one or more of the disclosed compounds in combination with another known pharmaceutical agent that can be used to treat a disease, condition, or symptom by activating a serotonin receptor for the purpose of treating a disease, condition, or symptom by activating a serotonin receptor.

[0340] In some embodiments, the disease, condition, or symptom treated by activating serotonin receptors is a mental illness. In some embodiments, a mental illness is selected from hallucinations and delusions and combinations thereof. In some embodiments, the disease, condition, or symptom treated by activating serotonin receptors is a central nervous system (CNS) condition. In some embodiments, the disease, condition, or symptom treated by activating serotonin receptors is psychosis or psychotic symptoms. In some embodiments, the disease, condition, or symptom treated by activating serotonin receptors is a behavioral problem in a non-human subject.

[0341] In some embodiments, the disease, condition, or symptom treated by activating serotonin receptors is a mental illness, and the one or more compounds disclosed herein are administered in combination with one or more additional treatments for the mental illness. In some embodiments, the additional treatments for the mental illness 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.

[0342] In some embodiments, the disease, condition, or symptom treated by activating serotonin receptors is selected from attention deficit hyperactivity disorder (ADHD) and attention deficit disorder, and combinations thereof. In some embodiments, the disease, condition, or symptom treated by activating serotonin receptors is ADHD and / or attention deficit disorder and combinations thereof, wherein one or more of the compounds disclosed herein are administered in combination with one or more additional treatments for ADHD and / or attention deficit disorder and combinations thereof. In some embodiments, the additional treatments for ADHD and / or attention deficit disorder are selected from methylphenidate, atoxetine, and amphetamines, and combinations thereof.

[0343] In some embodiments, the disease, condition, or symptom treated by activating serotonin receptors is dementia or Alzheimer's disease, and the one or more compounds disclosed herein are administered in combination with one or more additional treatments for dementia or Alzheimer's disease. In some embodiments, the additional treatments for dementia and Alzheimer's disease are selected from acetylcholinesterase inhibitors, NMDA antagonists, muscarinic agonists and antagonists, and nicotinic agonists.

[0344] In some embodiments, the acetylcholinesterase inhibitor is selected from donepezil, galantamine, rivastigmine, phenserine, and combinations thereof.

[0345] In some embodiments, the NMDA antagonist is selected from MK-801, ketamine, phencyclidine, memantine, and combinations thereof.

[0346] In some embodiments, the nicotine agonist is nicotine, nicotinic acid, nicotine α7 agonist, α2β4 agonist, or a combination thereof.

[0347] In some embodiments, the muscarinic agonist is a muscarinic M1 agonist, a muscarinic M4 agonist, or a combination thereof.

[0348] In some embodiments, the muscarinic antagonist is a muscarinic M2 antagonist.

[0349] In some embodiments, the disease, condition, or symptom treated by activating serotonin receptors is psychosis or psychotic symptoms, wherein the one or more compounds disclosed herein 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 and atypical antipsychotics.

[0350] In some embodiments, typical antipsychotic drugs are selected from acepromazine, acetophenazine, benperidol, bromperidol, butaperazine, carfenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, and cyamemazine. ), dixyrazine, droperidol, fluanisone, flupentixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, lenperone, loxapine, mesoridazine, metitepine, molindone, mopiperone (moperone), oxypertine, oxyprotepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, piperacetazine, pipotiazine, prochlorperazine, promazine, p-thiophene Rothipendyl), spirperone, sulforidazine, thiopropazate, thioproperazine, thioridazine, thiothixene, timiperone, trifluoperazine, trifluperidol, triflupromazine, and zuclopenthixol, and combinations thereof.

[0351] In some embodiments, the atypical antipsychotic drug is selected from amoxapine, amisulpride, aripiprazole, asenapine, blonanserin, brexpiprazole, cariprazine, carpipramine, clocapramine, clonotepine, clotiapine, clozapine, iloperidone, levosulpiride, and lurasidone. Melperone, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpiride, sultopride, tiapride, veralipride, ziprasidone, and zotepine, and combinations thereof.

[0352] In some embodiments, the disease, condition, or symptom treated by activating serotonin receptors is a mental illness, and the one or more compounds disclosed herein are administered in combination with one or more additional treatments for mental illness. In some embodiments, the additional treatments for mental illness are selected from typical and atypical antipsychotics.

[0353] In some embodiments, the effective amount varies based on factors such as the subject's or species' disease state, age, sex, and / or weight. In some embodiments, the amount of one or more given compounds corresponding to the effective amount will vary based on factors such as the given drug or compound, the drug formulation, the route of administration, the symptoms, the type of disease or condition, the identity of the subject being treated, etc., but can be conventionally determined by those skilled in the art.

[0354] In some embodiments, the compounds of this disclosure are administered once, twice, three times, or four times a year. In some embodiments, the compounds of this disclosure are administered at least once a week. However, in another embodiment, the compounds are administered to the subject approximately once a week, every two weeks, every three weeks, or once a month. In another embodiment, the compounds are administered from approximately once a week to approximately once a day. In another embodiment, the compounds are administered once, twice, three times, four times, five times, or six times a day. The duration of treatment depends on a variety of factors, such as the severity of the disease, condition, or symptom, the age of the subject, the concentration and / or activity of the compounds of this disclosure, and / or combinations thereof. It should also be understood that the effective dose of the compound used for treatment may be increased or decreased during a particular treatment regimen. Dosage variations may occur and become apparent using standard diagnostic assays known in the art. In some cases, long-term administration is required. For example, the compound is administered to the subject in an amount and for a duration sufficient to treat the subject.

[0355] In some embodiments, the compounds of this disclosure are administered to the subject at doses that are hallucinogenic or psychotropic and in combination with psychotherapy or treatment, and may be administered once, twice, three times, or four times per year. However, in some embodiments, the compounds are administered to the subject at non-hallucinogenic or psychotropic doses once daily, every two days, every three days, once weekly, every two weeks, once monthly, every two months, or every three months.

[0356] The compounds of this disclosure may be used alone or in combination with other known pharmaceutical agents (such as those disclosed) that can be used to treat diseases, conditions, or symptoms by activating serotonin receptors. One embodiment of this method of use, when combined with other known pharmaceutical agents that can be used to treat diseases, conditions, or symptoms by activating serotonin receptors, is the simultaneous administration of the compounds of this disclosure with these agents. As used herein, “simultaneous administration” of two substances to a subject means providing each of the two substances such that they are simultaneously active in the individual. The exact details of administration will depend on the pharmacokinetics of the two substances in the presence of each other and may include administration of the two substances at intervals of several hours, or even administration of one substance within 24 hours of administration of the other substance, if pharmacokineticly appropriate. The design of suitable dosing regimens is conventional to those skilled in the art. In certain embodiments, the two substances will be administered substantially simultaneously, i.e., at intervals of several minutes, or in a single composition containing both substances. Another embodiment of this disclosure is the administration of the combination of pharmaceutical agents to a subject in a non-simultaneous manner. In some embodiments, the compounds of this disclosure are administered simultaneously or sequentially with another therapeutic agent in a single unit dosage form, or together in a single unit dosage form. Therefore, this disclosure provides a single-unit dosage form comprising one or more compounds of this disclosure, additional therapeutic agents, and / or pharmaceutically acceptable carriers.

[0357] The dosage of the compounds disclosed herein can vary depending on many factors, such as the pharmacokinetic properties of the compounds; the administration modality; the recipient's age, health, and weight; the nature and severity of symptoms; the frequency of treatment and the type of concurrent treatment (if any); and the clearance of the compounds in the subject being treated. Those skilled in the art can determine an appropriate dosage based on the above factors. In some embodiments, one or more of the compounds disclosed herein are initially administered at an appropriate dosage, which is adjusted as needed based on clinical response. Typically, a dosage is selected to maintain serum levels of the one or more compounds disclosed herein at about 0.01 µg / cc to about 1000 µg / cc or about 0.1 µg / cc to about 100 µg / cc. As a representative example, for an adult, an oral dose of one or more of the compounds disclosed herein would be between about 10 µg per day and about 1000 mg per day, suitably between about 10 µg per day and about 500 mg per day, and more suitably between about 10 µg per day and about 200 mg per day. For parenteral administration, representative doses are about 0.0001 mg / kg to about 10 mg / kg, about 0.0001 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, or about 0.0001 mg / kg to about 0.01 mg / kg. For oral administration, representative doses are about 0.001 µg / kg to about 10 mg / kg, about 0.1 µg / kg to about 10 mg / kg, about 0.01 µg / kg to about 1 mg / kg, or about 0.1 µg / kg to about 1 mg / kg. For suppository administration, representative doses are about 0.1 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. In some embodiments of this disclosure, the compositions are formulated for oral administration, wherein the one or more compounds are suitably in tablet form, each tablet containing 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 5.0 mg, 10.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 40.0 mg, 50.0 mg, 60.0 mg, 70.0 mg, 75.0 mg, 80.0 mg, 90.0 mg, 100.0 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg of the active ingredient (one or more compounds of this disclosure).In some embodiments of this disclosure, the one or more compounds of this disclosure are administered in a single daily, weekly or monthly dose, or the total daily dose is divided into two, three or four daily doses.

[0358] In some embodiments, the compounds of this disclosure are used or administered in an effective amount, which includes administering a dose or dosing regimen that does not have clinically significant hallucinogenic / psychopathic effects. In some embodiments, the compounds of this disclosure are used or administered in an effective amount, which includes administering a solution that provides and exhibits human plasma photocytokinin C. max 4 ng / mL or less and / or human 5-HT 2A A dose or dosing regimen in which the human CNS receptor occupancy is 40% or less, or which exhibits human plasma photopic apigenin C max 1 ng / mL or less and / or human 5-HT 2A A dose or dosing regimen with a human CNS receptor occupancy of 30% or less has a clinical effect similar to that of human CNS receptor occupancy. In some embodiments, the compounds of this disclosure are used or administered in an effective amount, which comprises administering a dose or dosing regimen that exhibits the same clinical effect as human plasma pachyphorin T. max Doses or dosing regimens that have a clinical effect similar to those that last for more than 60 minutes, 120 minutes, or 180 minutes.

[0359] For clarity, in the foregoing, the term "compound" also includes examples that refer to one or more compounds. Similarly, the term "compounds of this disclosure" also includes examples that refer to only one compound.

[0360] V. Preparation of Compounds The compounds of this disclosure can be prepared by a variety of synthetic methods. The choice of specific structural features and / or substituents may influence the choice of one method relative to another. The specific method for preparing a given compound of this disclosure is within the knowledge of those skilled in the art. Some starting materials used to prepare the compounds of this disclosure are available from commercial chemical sources or can be extracted from cells, plants, animals, or fungi. Other starting materials can be readily prepared from available precursors using direct transformations well known in the art, such as those described below. In some embodiments of methods for preparing the compounds of this disclosure shown below, all variables are as defined in formula (I) unless otherwise stated.

[0361] In some embodiments, the compound of formula (I) is prepared as shown in Scheme I.

[0362]

[0363] Option I Therefore, in the presence of a catalyst (such as a Pd catalyst), the o-iodoaniline compound of formula (A) can be coupled with a suitable unsaturated precursor (such as a disubstituted alkyne compound of formula (B)) to provide the compound of formula (I) by known methods, such as the Pd catalytic procedure found in Chem. Eur. J. 2019, 25, 897-903.

[0364] In some embodiments, the compound of formula (I) is synthesized according to scheme II.

[0365]

[0366] Option II Therefore, in the presence of a suitable coupling agent (such as oxalyl chloride), the substituted indole compound of formula (C) is coupled with a suitable pyrrolidine carboxylic acid compound of formula (E) to provide 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 provide the compound of general formula (I).

[0367] In some embodiments, the compound of formula (I) is synthesized according to scheme III.

[0368]

[0369] Option III In some embodiments, as shown in Scheme III, the compound of formula (I) is prepared using known methods, such as the synthetic procedures found in Gerasimov et al., J. Med. Chem. 1999, 42, 4257-4263 and / or Macor et al., J. Med. Chem. 1992, 35, 4503-4505. Thus, the substituted indole compound of formula (C) is brominated with a suitable brominating agent (such as N-bromosuccinimide (NBS)) to provide the brominated indole compound of formula (F). The compound of formula (F) is coupled with a suitable pyrrolidine carboxylic acid compound of formula (E) in the presence of a suitable coupling agent (such as oxalyl chloride) to provide 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 provide the compound of general formula (I).

[0370] In some embodiments, the compound of formula (C) in which X is S is prepared as shown in Scheme IV.

[0371]

[0372] Option IV Therefore, in some embodiments, as shown in Scheme IV, the indole of a compound (G) wherein Hal is a halide (I or Br) is reacted with formula R under suitable coupling conditions, such as in the presence of a suitable catalyst (e.g., bis(dibenzylacetone)palladium(O) (Pd(dba)2)), a ligand (e.g., 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (Xantphos)), and a base (e.g., diisopropylethylamine), in a suitable inert solvent (e.g., dioxane), with the indole of formula R. 6 The thiol compounds of SH are coupled to synthesize compounds of formula (C) of S, where X is S.

[0373] In some embodiments, compounds of formula (C) where X is S are synthesized as shown in Scheme IV using methods known in the art, such as those described in Shmatova, OI, Eur. J. Org. Chem. 2015, 6479–6488.

[0374] In some embodiments, a compound of formula (C) where X is S is prepared as shown in scheme V.

[0375]

[0376] Option V Therefore, in some embodiments, as shown in scheme V, compounds of formula (C) in which X is S are synthesized by desulfinating a compound of formula (H) in which Y is a suitable alkyl or aryl group, in the presence of trifluoroacetic acid and thiols as scavenging agents (such as methyl thiosalicylate).

[0377] In some embodiments, compounds of formula (C) where X is S are prepared as shown in Scheme V using methods known in the art, such as those described in Hamel, P., J. Org. Chem. 1994, 59, 6372-6377.

[0378] In some embodiments, a compound of formula (C) where X is S is prepared as shown in scheme VI.

[0379]

[0380] Solution VI Therefore, in some embodiments, as shown in Scheme VI, the compound of formula (C), where X is S, is synthesized using the Fischer indole synthesis method. For example, in some embodiments, under suitable conditions, such as in the presence of zinc chloride and phosphorus pentachloride, the hydrazine compound of compound J is reacted with pyruvate to provide the compound of formula (C).

[0381] In some embodiments, compounds of formula (C) where X is S are prepared as shown in Scheme VI using methods known in the art, such as those described in Bratulescu, G., Letters 49 (2008) 984–986.

[0382] In some embodiments, the compound of formula (I) where X is S(O) (compound of formula I(b)) and the compound of formula (I) where X is SO2 (compound of formula I(c)) are prepared according to scheme VII from the compound of formula (I) where X is S (compound of formula I(a)).

[0383]

[0384] Option VII In some embodiments, as shown in Scheme VII, a compound of formula (I) wherein X is S (compound I(a)) is oxidized to a compound of formula (I) wherein X is S(O) (compound I(b)) under suitable oxidizing conditions (such as about one equivalent of m-chloroperoxybenzoic acid (m-CPBA)). Then, under suitable oxidizing conditions (such as m-chloroperoxybenzoic acid (m-CPBA)), the compound of formula (I) wherein X is S(O) (compound I(b)) is oxidized to a compound of formula (I) wherein X is SO2 (compound I(c)).

[0385] In some embodiments, the compounds of formula (I) where X is S(O) (compound I(b)) and the compounds of formula (I) where X is SO2 (compound I(c)) are prepared as shown in scheme VII using methods known in the art, such as those described in U.S. Patent Application 2004 / 0043965, from the compounds of formula (I) where X is S (compound I(a)).

[0386] In some embodiments, X is S and R 6 The CD3 compound of formula (C) (compound of formula C') is prepared as shown in scheme VIII.

[0387]

[0388] Scheme VIII Therefore, in some embodiments, as shown in Scheme VII, in the presence of a suitable reducing agent (such as zinc powder) and a base (such as 2,2-bipyridine), a suitable catalyst (such as a nickel-based catalyst (e.g., nickel acetate)) and a suitable electrophilic SCD3 reagent (such as S-(methyl-D3)4-methylbenzenethiosulfonate) In the presence of ), X is synthesized by indole coupling of compound (G) (compound G') in which Hal is I, and R is S. 6It is a compound of formula (C) (compound of formula (C')) of CD3, to provide that X is S and R 6 It is a compound of formula (C) of CD3 (compound of formula C').

[0389] In some embodiments, as shown in scheme VII, where X is S and R 6 Compounds of formula (C) of CD3 (compounds of formula C') are synthesized using methods known in the art, for example, Zhang, Y., Org. Lett. 2022, 24, 6794. The method described in 6799.

[0390] For example, on a suitable starting substrate, the R-deuterium exchange reaction can be used to obtain R. 1 -R 5 One or more of them are deuterium compounds of formula (I), wherein this exchange reaction is catalyzed by Pd / C in D2O, as described by Esaki, H. et al., Tetrahedron, 2006, 62:10954-10961 and variants thereof known to those skilled in the art.

[0391] In particular, for embodiments where X is absent or oxygen is present, and for other embodiments where XR 6 The compound of formula (I) of OCD3 is available, for example, using the methods described in Xu, YZ and Chen, CJ Label Compd. Radiopharm. (2006)49:897-902 and their modifications, as well as modifications known to those skilled in the art.

[0392] Those skilled in the art will understand that the intermediates and final compounds in the above schemes can be further controlled with known chemistry to provide alternative compounds of this disclosure.

[0393] For example, particularly for embodiments where X is S, S(O), or SO2, and for other embodiments of X, those skilled in the art will understand that R 1 In compound (I), H is present, then R is present. 1 Compounds of formula (I) with H can be further reacted to prepare other compounds of formula (I). For example, where R 1 Compounds of formula (I) with H can be alkylated with alkyl halides in the presence of a suitable base (such as NaH, NaOtBu or LiHMDS).

[0394] For example, particularly in embodiments where X is absent or oxygen is present, and in other embodiments for X, those skilled in the art will understand that R 1In compounds C and D above, H is present (see, for example, schemes II and III), thus producing R where... 1 If it is a compound of formula (I) with H, then R in it is... 1 Compounds of formula (I) with H can be further reacted to prepare other compounds of formula (I). For example, where R 1 Compounds of formula (I) with H can be alkylated with alkyl halides in the presence of a suitable base (such as NaH, NaOtBu or LiHMDS).

[0395] Salts of the compounds disclosed herein can be formed by methods known to those skilled in the art, such as by reacting the compounds disclosed herein with a certain amount of an acid or base (e.g., an equal amount of acid or base) in a medium (e.g., a salt precipitation medium or an aqueous medium) and then freeze-drying it.

[0396] The formation of solvates varies depending on the compound and the solvate. Typically, solvates are formed by dissolving the compound in a suitable solvent and separating the solvate by cooling or using an antisolvent. Solvates are typically dried or azeotropic under ambient conditions. Those skilled in the art can select suitable conditions for the formation of a particular solvate. Examples of suitable solvents are ethanol, water, etc. When water is used as the solvent, the molecule is called a "hydrate". The formation of solvates of the compounds disclosed herein varies depending on the compound and the solvate. Typically, solvates are formed by dissolving the compound in a suitable solvent and separating the solvate by cooling or using an antisolvent. Solvates are typically dried or azeotropic under ambient conditions. Those skilled in the art can select suitable conditions for the formation of a particular solvate.

[0397] The isotope-rich compounds of this disclosure and their pharmaceutically acceptable salts, solvates and / or prodrugs can be prepared without excessive experimentation using conventional techniques well known to those skilled in the art or by methods similar to those described in the schemes and examples herein, using appropriate isotope-enriched reagents and / or intermediates.

[0398] Throughout the process described herein, it should be understood that, where appropriate, suitable protecting groups will be added to and subsequently removed from various reactants and intermediates in a manner readily understood by those skilled in the art. Conventional procedures 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 the conversion of one group or substituent into another through chemical manipulation can be performed on any intermediate or final product along the synthetic pathway toward the final product, wherein the possible types of conversion are limited only by the inherent incompatibility of the other functional groups carried by the molecule at that stage with the conditions or reagents used in the conversion. Such inherent incompatibility and the methods for overcoming them by performing appropriate conversions and synthetic steps in a suitable order are 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 general groups or substituents as examples of conversion. Other suitable transformations are referenced and described in “Comprehensive Organic Transformations – A Guide to Functional Group Preparations”, RC Larock, VHC Publishing Ltd. (1989). References and descriptions of other suitable reactions are found in organic chemistry textbooks such as “Advanced Organic Chemistry”, March, 4th edition, McGraw Hill (1992) or “Organic Synthesis”, Smith, McGraw Hill, (1994). Techniques for purifying intermediates and final products include, for example, normal and reversed-phase chromatography on columns or rotating plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, which are readily understood by those skilled in the art.

[0399] It should also be understood that the conversion of one group or substituent into another group or substituent by chemical manipulation can be carried out on any intermediate or final product along the synthetic pathway toward the final product, wherein the possible types of conversion are limited only by the inherent incompatibility of the other functional groups carried by the molecule at that stage with the conditions or reagents used in the conversion. Such inherent incompatibility and the methods for overcoming them by performing appropriate conversion and synthetic steps in a suitable order are 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 general groups or substituents that are examples of conversions. References and descriptions of other suitable conversions are given in “Comprehensive Organic Conversions - A Guide to the Preparation of Functional Groups”, RC Larock, VHC Publishers Ltd. (1989). References and descriptions of other suitable reactions are found in organic chemistry textbooks such as “Advanced Organic Chemistry”, March, 4th edition, McGraw Hill (1992) or “Organic Synthesis”, Smith, McGraw Hill, (1994).

[0400] Techniques for purifying intermediates and final products include, for example, normal and reversed-phase chromatography on columns or rotating plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, which are readily understood by those skilled in the art.

[0401] The products of the methods disclosed herein can be separated according to known methods, for example, compounds can be separated by solvent evaporation, filtration, centrifugation, chromatography or other suitable methods.

[0402] The prodrugs of the compounds disclosed herein can be, for example, conventional esters formed using hydroxyl, thiol, amino, or carboxyl groups. For example, hydroxyl or amino groups can be activated with an acid in the presence of a base and optionally acylated in an inert solvent (e.g., an acyl chloride in pyridine).

[0403] Those skilled in the art will recognize that, when the reaction steps of this disclosure are carried out in a variety of solvents or solvent systems, the reaction steps can also be carried out in a mixture of suitable solvents or solvent systems.

[0404] Example The following non-limiting examples illustrate this disclosure.

[0405] General methods All starting materials used in this paper were commercially available or described in the literature. The use of materials targeted at… 1 H NMR measurements were performed using Bruker 300, Bruker DPX400, or Varian +400 spectrometers operating at 300, 400, and 400 MHz, respectively. 1 H and 13C10 NMR spectra. Unless otherwise indicated, the TMS or residual solvent signal is used as an internal reference; deuterated chloroform is used as the solvent. All reported chemical shifts are in ppm on the δ scale, and fine splitting of the signal appearing in the recording is generally represented as, for example, s: singlet, br; s: broad singlet, d: doublet, t: triplet, q: tetrad, m: multipeak. Unless otherwise specified, they are indicated in the table below. 1 HNMR data were obtained at 400 MHz using CDCl3 as the solvent.

[0406] The product was purified using a Chem Elut extraction column (Varian, catalog number 1219-8002), a Mega BE-SI (Bond ElutSilica) SPE column (Varian, catalog numbers 12256018; 12256026; 12256034) or by rapid chromatography using a silica-filled glass column.

[0407] Use CHEMDRAW Professional 22.2.0 64-bit to generate IUPAC names.

[0408] The following compounds were prepared using one or more synthetic methods outlined in Schemes I and II.

[0409] Part I A. Synthesis of exemplary compounds of this disclosure Example 1: (R)-3-((1-methylpyrrolidone-2-yl)methyl)-5-(methylthio)-1H-indole ((R) I-1)

[0410] Synthesis of (R)-2-(2-(5-(methylthio)-1H-indol-3-carbonyl)pyrrolidine-1-yl)-1-phenylethane-1-one (2): A solution of 1-(2-oxo-2-phenylethyl)-D-proline (3.0 g, 12.03 mmol) in anhydrous THF (50 mL) was treated with thionyl chloride (1.75 mL, 24.07 mmol) at 0 °C. The reaction mixture was then heated to room temperature and refluxed for 2 hours. The solvent was evaporated and the crude product was dried under vacuum to obtain the corresponding acyl chloride.

[0411] Within 15 minutes, a solution of 5-(methylthio)-1H-indole (1.96 g, 12.03 mmol) in anhydrous CH2Cl2 (50 mL) at 5–10 °C was simultaneously treated with the above-mentioned crude acyl chloride and ethyl magnesium bromide (8.0 mL, 24.07 mmol, 3 M, in THF) in anhydrous CH2Cl2 (30 mL), and stirred for another 15 minutes at the same temperature. The reaction solution was quenched with concentrated HCl (5 mL), followed by quenching with water (50 mL), and the product was extracted into CH2Cl2 (2 x 50 mL). The CH2Cl2 layers were washed with saturated NaHCO3 solution (50 mL), brine (25 mL), and dried over Na2SO4. The solvent was evaporated, and the crude compound was purified on silica gel by rapid column chromatography (CH2Cl2 to EtOAc:CH2Cl2, 1:4) to obtain title compound 2 (6.67 g, 75.3%), which was a light brown foam. 1 H NMR (DMSO- d 6): δ 12.07, 12.05 (2s, 1H),8.47, 8.44 (2d, 1H, J = 6.0 Hz), 8.16, 8.12 (2s, 1H), 7.47-7.33 (m, 3H),7.23-7.01 (m, 3H), 5.25-4.90 (m, 3H), 3.55-3.50 (m, 2H), 3.34 (s, 3H), 2.45-2.29 (m, 1H), 1.91-1.84 (m, 3H); ESI-MS (m / z, %): 453 (100), 417 (M+Na).

[0412] Synthesis of (R)-3-((1-methylpyrrolidone-2-yl)methyl)-5-(methylthio)-1H-indole ((R)I-1): At 0 °C, a solution of (R)-2-(2-(5-(methylthio)-1H-indol-3-carbonyl)pyrrolidine-1-yl)-1-phenylethane-1-one (2.5 g, 6.33 mmol) in anhydrous THF (50 mL) was treated with LiAlH4 (1.2 g, 31.68 mmol) over 10 minutes. The reaction mixture was heated to room temperature and then refluxed overnight (16 h). The reaction mixture was cooled to 0 °C and quenched with water (1.2 mL), 4 N NaOH solution (1.2 mL), and water (1.2 mL). The reaction mixture was heated to room temperature and stirred for another 30 minutes. The reaction mixture was filtered through a sodium sulfate pad and washed with THF (3 x 25 mL). The combined THF layer was evaporated and the crude extract was purified on silica gel by column chromatography (2 M NH3 in MeOH:CH2Cl2 (5:95)) to obtain the title compound (R) I-1 (1.53 g, 88.4%) as a pale yellow solid. 1 H NMR (DMSO- d 6): δ 10.84 (s, 1H), 7.47 (s,1H), 7.30 (d, 1H, J = 6.0 Hz), 7.15 (s, 1H), 7.07 (dd, 1H, J = 3.0, 6.0 Hz), 3.04-2.95 (m, 2H), 2.50-2.31 (m, 8H), 2.14-2.07 (m, 1H), 1.74-1.40 (m, 4H); ESI-MS (m / z, %): 261 (MH + , 100).

[0413] B. Biological testing Example 2: Human 5-HT 2A Functional fluorescence imaging plate reader (FLIPR) measurement Target: Evaluation of targeting human serotonin receptor 2A (5-HT2A) in agonist mode 2A The potential excitatory effects of compounds.

[0414] 1. Materials and Instruments 1.1 Cell lines (Table 6)

[0415] 1.2 Materials (Table 7)

[0416] 1.3 Use of instruments and consumables (Table 8)

[0417] 2 Experimental Methods 2.1 Cell Culture HTR 2A &Gα15-HEK293 cells were cultured in DMEM medium containing 10% dialyzed FBS, 1× penicillin-streptomycin, 100 µg / mL hygromycin B, and 300 µg / mL G418. Cells were passaged approximately three times per week, maintaining a confluence of approximately 30% to approximately 90%.

[0418] 2.2 Cell Plating 1. Prepare the cell culture medium (DMEM medium containing 10% dialyzed FBS and 1× penicillin-streptomycin, 100 µg / mL hygromycin B and 300 µg / mL G418) and TrypLE in advance. TM Warm Express and DPBS to room temperature.

[0419] 2. For induction, add 1 µg / mL tetracycline (final concentration) to the cell culture medium and incubate for 48 hours before seeding cells into plates at 37°C and 5% (v / v) CO2. Remove the cell culture medium from the flask. Wash the cells with DPBS.

[0420] 3. Add 2 mL of TrypLE TM Add Express to the flask, mix thoroughly by gentle shaking, and incubate the cells at 37°C for a few minutes.

[0421] 4. Examine the morphological changes of the cells under a microscope. When most cells become rounded, stop the digestion by adding 4 mL of cell culture medium to the flask.

[0422] 5. Transfer the cell suspension to a 15 mL centrifuge tube and centrifuge at 1,200 rpm for 5 minutes.

[0423] 6. Remove the supernatant. Resuspend the cell clumps in 2 mL of cell culture medium.

[0424] 7. Calculate cell density using a cell counter. Only use cells with a viability >85% for the assay.

[0425] 8. Dilute the cells to 6.67 × 10⁻⁶ using cell culture medium. 5 / mL.

[0426] 9. Add 30 µL / well of cell suspension to a 384-well cell plate (cell density of 20,000 cells / well).

[0427] 10. Incubate the cell plate overnight at 37°C and 5% (v / v) CO2.

[0428] 2.3 Cell Treatment On the day of the experiment, the culture medium was removed from the cell plate.

[0429] Add 10 µL of assay buffer (20 mM HEPES in 1× HBSS, pH 7.4) to each well of the cell plate.

[0430] Prepare a double dye solution according to the FLIPR® Calcium 6 Assay Kit user manual: i. Dilute the dye with the assay buffer.

[0431] ii. Add probenecid to a final concentration of 5 mM.

[0432] iii. Vigorous vortexing for 1-2 minutes.

[0433] 4. Add 10 µL of 2x dye solution to each well of the cell plate.

[0434] 5. Place the cell plate on a plate shaker and shake at 600 rpm for 2 minutes.

[0435] 6. Incubate the plate at 37°C for 2 hours, then incubate it at 25°C for another 15 minutes.

[0436] 2.4 Preparation of 3 times the compound.

[0437] 1. Prepare serotonin HCl to a concentration of 10 mM using DMSO.

[0438] 2. Prepare the test compound to a concentration of 10 mM using DMSO.

[0439] 3. Add the compound to the 384-well compound source plate.

[0440] 4. Perform a 3-fold serial dilution with DMSO.

[0441] 5. Transfer serially diluted compounds of 90 nL / well from the source plate to the 384-well compound plate using Echo.

[0442] 6. Add 30 µL / well of assay buffer (20 mM HEPES in 1× HBSS, pH 7.4) to the compound plate.

[0443] 7. Mix the plates on a plate shaker for 2 minutes.

[0444] 2.5 FLIPR determination 1. After incubating the cells with the dye solution, place the cell plate, the compound plate containing 3 times the amount of the compound, and the FLIPR tip into the FLIPR.

[0445] 2. Transfer 10 µL of the compound (3 times the amount) from the compound plate to the cell plate using FLIPR.

[0446] 3. Read the plate every 1 second for 160 seconds to obtain data on the agonist mode.

[0447] 3. Data Analysis 1. Normalized fluorescence readings (RFU) are calculated as follows, where F max and F min This represents the maximum and minimum values ​​of the calcium signal during the defined time window: RFU = F max - F min .

[0448] 2. Using XLfit, EC was calculated by fitting the logarithm of RFU to the compound concentration using Hill's equation. 50 .

[0449] Results and discussion Table 9 summarizes the targets of human serotonin receptor 2A (5-HT). 2A The results of the potential competitive binding properties of the exemplary compounds of this disclosure are shown in Table 9, EC. 50 As shown.

[0450] Table 9: Effects of exemplary formula (I) compounds on human 5-HT as determined using FLIPR function 2A The role of receptors

[0451] The efficacy of compound of exemplary formula (I) on human 5-HT was evaluated using FLIPR assay. 2A The function of receptors. EC 50 The (nM) concentrations are shown in Table 9. This determination confirms that the compounds disclosed herein are the target human 5-HT. 2A An effective agonist of the receptor.

[0452] Example 2A: Human 5-HT 2A -β-inhibitory protein assay plan: In a β-repressor reporter gene assay based on G protein-coupled receptor (GPCR) cells, the β-repressor protein was measured against human 5-HT in stably transfected U2OS cells. 2A Receptor compound potency (EC) 50 ) and efficacy (Max response).

[0453] Cells were seeded in 20 µL total volume into white-walled 384-well microplates and incubated overnight at 37°C prior to analysis. For agonist determination, cells were incubated with the sample to induce the reaction. Intermediate dilutions of the sample stock solution were performed to generate 5X samples in the assay buffer. 5 µL of the 5X sample was added to the cells and incubated at 37°C for 120 min. The final assay media concentration was 1%. In Table 10, the results are expressed as the percentage of maximum response efficacy relative to the control ligand (serotonin).

[0454] Table 10: Exemplary Formula (I) compounds as determined using β-repressor reporter gene assays for human 5-HT 2A The role of receptors

[0455] Example 2B: Human 5HT 1A -cAMP assay plan: In a GPCR-based cAMP assay, human 5-HT3 receptor antagonists were measured in stably transfected CHO-K1 cells. 1A Receptor compound potency (EC) 50 ) and efficacy (Max response).

[0456] Cells were seeded at a total volume of 20 µL into white-walled 384-well microplates and incubated overnight at 37°C prior to analysis. The cell-coating medium was exchanged with 10 µL of assay buffer (HBSS + 10 mM HEPES) before testing. In short, intermediate dilutions of the sample stock solution were performed to generate 4X samples in the assay buffer. 5 µL of 4X sample + 5 µL of 4X forscolin was added to the cells and incubated at 37°C for 30 min. The final assay media concentration was 1%. In Table 11, the results are expressed as the percentage of maximum response power relative to the control ligand (serotonin).

[0457] Table 11: Effects of exemplary formula (I) compounds on human 5-HT levels as determined using cAMP function 1A The role of receptors

[0458] Example 2C: Human 5HT 2B FLIPR assay plan: In a calcium mobilization-based assay, human 5-HT was measured in stably transfected HEK293 cells. 2B Receptor compound potency (EC) 50 ) and efficacy (Max response).

[0459] Cells were seeded at a total volume of 20 µL into 384-well microplates with white walls and incubated overnight at 37°C. Prior to testing, the cell-coating medium was exchanged with 20 µL of dye loading buffer (HBSS + 20 mM HEPES, containing 1X dye, 1X additive A, and 2.5 mM probenecid). The plates were incubated at 37°C for 45 minutes, followed by incubation at room temperature for 15 minutes.

[0460] 10 µL of assay buffer (HBSS + 20 mM HEPES) was added to the cells. The sample stock solution was diluted intermediately to generate a 4X sample in the assay buffer. The assay plate and compound plate were loaded into the FLIPR instrument. 10 µL of sample was added using the FLIPR onboard robot 5 seconds after the start of the calcium measurement. The final assay media concentration was 1%. In Table 12, the results are expressed as the percentage of maximum response power relative to the control ligand (serotonin).

[0461] Table 12: Effects of exemplary formula (I) compounds on human 5-HT as determined using FLIPR function 2B The role of receptors

[0462] Example 2D: Human 5HT 2C FLIPR assay plan: In a calcium mobilization-based assay, human 5-HT was measured in stably transfected U2OS cells. 2C Receptor compound potency (EC) 50 ) and efficacy (Max response).

[0463] Cells were seeded at a total volume of 20 µL into 384-well microplates with white walls and incubated overnight at 37°C. Prior to testing, the cell-coating medium was exchanged with 20 µL of dye loading buffer (HBSS + 20 mM HEPES, containing 1X dye, 1X additive A, and 2.5 mM probenecid). The plates were incubated at 37°C for 45 minutes, followed by incubation at room temperature for 15 minutes.

[0464] 10 µL of assay buffer (HBSS + 20 mM HEPES) was added to the cells. The sample stock solution was diluted intermediately to generate a 4X sample in the assay buffer. The assay plate and compound plate were loaded into the FLIPR instrument. 10 µL of sample was added using the FLIPR onboard robot 5 seconds after the start of the calcium measurement. The final assay media concentration was 1%. In Table 13, the results are expressed as the percentage of maximum response power relative to the control ligand (serotonin).

[0465] Table 13: Effects of exemplary formula (I) compounds on human 5-HT as determined using FLIPR function 2C The role of receptors

[0466] Example 2E: Human 5HT 2B Determination of allosteric modifiers (PAM) plan: In a GPCR-based assay, human 5-HT3 was measured in stably transfected HEK293 cells. 2B Receptor compound potency (EC) 50 ) and efficacy (Max response).

[0467] For the determination of the positive allosteric modulator, cells were pre-incubated with the sample, followed by the addition of EC20. An intermediate dilution of the sample stock solution was performed to generate a 5X sample in the assay buffer. 5 µL of the 5X sample was added to the cells and incubated at 37°C for 10 min. 5 µL of the agonist at a concentration of 6X EC20 was added, and the cells were incubated at 37°C for 120 min. The final assay mediator concentration was 1%. In Table 14, the results are expressed as the percentage of maximum response efficacy relative to the control ligand (serotonin).

[0468] Table 14: Effects of exemplary formula (I) compounds on human 5-HT as determined using PAM function 2B The role of receptors

[0469] Example 3: Human 5-HT 2A Radioligand binding assay: Target The goal of this study is to evaluate the effect of the exemplary compound (I) on 5-hydroxytryptamine receptor 2A (5-HT) 2A The binding properties of ).

[0470] 1. Materials and Instruments 1.1 Reagents (Table 15)

[0471] 1.2 Instruments and Consumables (Table 16)

[0472] 2. Experimental Methods 1. Prepare the assay buffer according to Table 17 below.

[0473]

[0474] 2. As needed, prepare eight doses of reference and test compounds by serial dilution of 100% (v / v) DMSO, starting with a 10 mM stock solution.

[0475] 3. Preprocess the UniFilter-96 GF / B board: i. Add 50 µL / well of 0.5% (v / v) PEI to the UniFilter-96 GF / C plate. Seal the plate and incubate at 4°C for 3 hours (h).

[0476] ii. After incubation, wash the plate three times with ice-cold washing buffer (50 mM Tris, pH 7.4).

[0477] 4. Preparation of the test plate: i. Dilute the cell membrane with assay buffer and add it to a 96-well circular deep-well plate at a rate of 330 µL / well to achieve a concentration of 20 µg / well.

[0478] ii. Prepare eight concentrations of reference or test compounds and add them to a 96-well circular deep-well plate at a rate of 110 µL / well.

[0479] iii. Dilute [3H]-ketoserin to 5 nM (5X final concentration) with assay buffer and add 110 µL / well to a 96-well circular deep plate.

[0480] 5. Centrifuge the plate at 1000 rpm for 30 seconds, then stir at 600 rpm at room temperature for 5 minutes.

[0481] 6. Seal the plate and then incubate it at 27ºC for 90 minutes.

[0482] 7. Stop the incubation by vacuum filtration through a GF / B filter plate, then wash four times with ice-cold washing buffer (50 mM Tris, pH 7.4).

[0483] 8. Dry the plate at 37°C for 45 minutes.

[0484] 8. Seal the filter plate and add 40 µL / well of scintillation cocktail.

[0485] 10. By using Microbeta 2 Microboard counter reading board.

[0486] 3. Data Analysis 1. For reference and test compounds, the results are expressed as % inhibition using the normalized equation: N = 100 - 100 × (U - C2) / (C1 - C2), where U is an unknown value, C1 is the average of the high control and C2 is the average of the low control.

[0487] 2. Using XLfit, the IC was determined by fitting the percentage of inhibition as a function of compound concentration using Hill's equation. 50 .

[0488] Results and discussion Targeting human serotonin receptor 2A (5-HT) 2A The results of potential competitive binding properties of the exemplary compounds of this disclosure are summarized in Table 18. The results for the exemplary compounds of this disclosure are as provided in Table 18 (IC). 50 As shown.

[0489] Table 18: Exemplary compounds of formula (I) for human 5-HT using radioligand binding assays 2A The role of receptors

[0490] II. Results and Discussion Evaluation of the effect of compound of exemplary formula (I) on human 5-HT using radioligand binding assay 2A The function of receptors. IC 50 The (nM) concentrations are shown in Table 18. This determination confirms that the compounds disclosed herein are the target human 5-HT. 2A Effective ligands for receptors.

[0491] Example 4: Human 5-HT 1A Functional FLIPR Measurement 1. Objective Evaluation of targeting serotonin receptor 1A (5-HT) in agonist mode 1A The potential excitatory effects of compounds.

[0492] 2. Materials and Instruments 2.1 Cell lines (Table 19)

[0493] 2.2 Materials (Table 20)

[0494] 2.3 Instruments and Consumables (Table 21)

[0495] 3 Experimental Methods 3.1 Cell Culture HTR1A&Gα15-CHO cells were cultured in DMEM / F12 medium containing 10% dialyzed FBS, 1× penicillin-streptomycin, and 600 µg / mL hygromycin B. Cells were passaged approximately three times per week, maintaining a confluence of approximately 30% to approximately 90%.

[0496] 3.2 Cell Plating 1. Prepare the cell culture medium (DMEM / F12 medium containing 10% dialyzed FBS, 1× penicillin-streptomycin and 600 µg / mL hygromycin B) and TrypLE in advance. TM Warm Express and DPBS to room temperature.

[0497] 2. Remove the cell culture medium from the flask. Wash the cells with DPBS.

[0498] 3. Add 1 mL TrypLE TM Add Express to the flask, mix thoroughly by gentle shaking, and incubate the cells at 37°C for a few minutes.

[0499] 4. Examine the morphological changes of the cells under a microscope. When most cells become rounded, stop the digestion by adding 2 mL of cell culture medium to the flask.

[0500] 5. Transfer the cell suspension to a 15 mL centrifuge tube and centrifuge at 1,200 rpm for 5 minutes.

[0501] 6. Remove the supernatant. Resuspend the cell clumps in 2 mL of cell culture medium.

[0502] 7. Calculate cell density using a cell counter. Only use cells with a viability >85% for the assay.

[0503] 8. Dilute the cells to 4 × 10⁻⁶ using cell culture medium. 5 / mL.

[0504] 9. Add 30 µL / well of cell suspension to a 384-well cell plate (cell density of 12,000 cells / well).

[0505] 10. Incubate the cell plate overnight at 37°C and 5% (v / v) CO2.

[0506] 3.3 Cell Treatment 1. On the day of the experiment, remove the culture medium from the cell plate.

[0507] 2. Add 10 µL of assay buffer (20 mM HEPES in 1× HBSS, pH 7.4) to each well of the cell plate.

[0508] 3. Prepare a 2x dye solution according to the manufacturer's instructions for the FLIPR® Calcium 6 Assay Kit: i. Dilute the dye with the assay buffer.

[0509] ii. Add probenecid to a final concentration of 5 mM.

[0510] iii. Vortex vigorously for 1-2 minutes to adjust the pH to 7.4.

[0511] 4. Add 10 µL of 2x dye solution to each well of the cell plate.

[0512] 5. Place the cell plate on a plate shaker and shake at 600 rpm for 2 minutes.

[0513] 6. Incubate the plate at 37°C for 2 hours, then incubate it at 25°C for another 15 minutes.

[0514] 3.4 Preparation of 3-fold compound.

[0515] 1. Prepare serotonin to a concentration of 10 mM using DMSO, and then perform a 3-fold serial dilution using DMSO.

[0516] 2. Prepare the test compound to a concentration of 10 mM using DMSO, and then perform serial 3-fold dilutions using DMSO.

[0517] 3. Add the compound to the 384-well compound source plate.

[0518] 4. Transfer serially diluted compounds of 90 nL / well from the source plate to the 384-well compound plate using Echo.

[0519] 5. Add 30 µL / well of assay buffer to the compound plate.

[0520] 6. Mix the plates on a plate shaker for 2 minutes.

[0521] 3.5 FLIPR Measurement 1. After incubating the cells with the dye solution, place the cell plate, the compound plate containing 3 times the amount of the compound, and the FLIPR tip into the FLIPR.

[0522] 2. Transfer 10 µL of the compound (3 times the amount) from the compound plate to the cell plate using FLIPR.

[0523] 3. Read the board for 160 seconds at 1-second intervals to obtain data on the agonist mode.

[0524] 4. Data Analysis 1. Normalized fluorescence readings (RFU) are calculated as follows, where F max and Fmin This represents the maximum and minimum values ​​of the calcium signal during the defined time window: RFU = F max - F min。

[0525] 2. Using XLfit, EC was calculated by fitting the logarithm of RFU to the compound concentration using the Hill equation. 50 .

[0526] Results and discussion Targeting human serotonin receptor 1A (5-HT) 1A The results of the potential competitive binding properties of the exemplary compounds of this disclosure are summarized in Table 22. The results for the exemplary compounds of this disclosure are as provided in Table 22. 50 As shown.

[0527] Table 22: Effects of exemplary formula (I) compounds on human 5-HT as determined using FLIPR function 1A The role of receptors

[0528] The functional FLIPR assay was used to evaluate the effect of the compound of exemplary formula (I) on human 5-HT. 1A The function of receptors. EC 50 (nM) concentrations are shown in Table 22. This determination confirms the activity of the disclosed compounds in the target human 5-HT 1A It has functional activity at the receptor site.

[0529] Example 5: Human 5-HT 1A Radioligand binding assay: 1. Objective The goal of this study is to evaluate the effect of the tested compounds on 5-hydroxytryptamine receptor 1A (5-HT). 1A The binding properties of ).

[0530] 2 Materials and Instruments 2.1 Reagents (Table 23)

[0531] 2.2 Instruments and Consumables (Table 24)

[0532] 3 Experimental Methods 1. Prepare the assay buffer according to Table 25 below.

[0533] Table 25

[0534] 2. As needed, prepare eight doses of reference and test compounds by serial dilution of 100% (v / v) DMSO, starting with a 10 mM stock solution.

[0535] 3. Preprocess the UniFilter-96 GF / B board: i. Add 50 µL / well of 0.5% (v / v) PEI to the UniFilter-96 GF / B plate. Seal the plate and incubate at 4°C for 3 hours.

[0536] ii. After incubation, wash the plate three times with ice-cold washing buffer (50 mM Tris, pH 7.4).

[0537] 4. Preparation of the test plate: i. Dilute the cell membrane with assay buffer and add it to a 96-well plate at a rate of 100 µL / well to achieve a concentration of 20 µg / well.

[0538] ii. Prepare eight concentrations of reference or test compounds and add them to a 96-well circular deep-well plate at a rate of 50 µL / well.

[0539] iii. Dilute [3H]-8-hydroxy-DPAT to 2 nM (4X final concentration) with assay buffer and add 50 µL / well to a 96-well plate.

[0540] 5. Centrifuge the plate at 1000 rpm for 30 seconds, then stir at 600 rpm at room temperature for 5 minutes.

[0541] 6. Seal the plate and then incubate it at 27°C for 90 minutes.

[0542] 7. Stop the incubation by vacuum filtration through a GF / B filter plate, then wash four times with ice-cold washing buffer (50 mM Tris, pH 7.4).

[0543] 8. Dry the plate at 37°C for 45 minutes.

[0544] 9. Seal the filter plate and add 40 µL / pore of scintillation mixture.

[0545] 10. By using Microbeta 2 Microboard counter reading board.

[0546] 4. Data Analysis 1. For reference and test compounds, the results are expressed as % inhibition using the normalized equation: N = 100 - 100 × (U - C2) / (C1 - C2), where U is an unknown value, C1 is the average of the high control and C2 is the average of the low control.

[0547] 2. Using XLfit, the IC was determined by fitting the percentage of inhibition as compound concentration binding using Hill's equation. 50 .

[0548] Results and discussion Targeting human serotonin receptor (5-HT) 1A The potential competitive binding properties of exemplary compounds of this disclosure are represented as IC. 50 The results are summarized in Table 26.

[0549] Table 26: Exemplary compounds of formula (I) for human 5-HT using radioligand binding assays 1A The role of receptors

[0550] Results and discussion The efficacy of the exemplary compound (I) against human 5-HT was evaluated using a radioligand binding assay. 1A The function of receptors. IC 50 (nM) concentrations are shown in Table 26. This determination confirms that the compound of formula (I) of this disclosure is the target human 5-HT. 1A Effective ligands for receptors.

[0551] Example 5A: Human 5-HT 2B Radioligand binding assay: The goal of this study is to evaluate the effect of the tested compounds on 5-HT. 2B The binding properties.

[0552] Materials and Instruments (Table 27)

[0553] Instruments and consumables (Table 28)

[0554] Experimental methods 1) Prepare the assay buffer according to Table 29 below.

[0555] Table 29

[0556] Adjust the pH to 7.4, then perform 0.2 µM sterile filtration. 2) As required, starting with a 10 mM stock solution, eight doses of reference and test compounds were obtained by serial dilution with 100% (v / v) DMSO at a rate of 5-fold.

[0557] 3) Preprocess the UniFilter-96 GF / B board: a. Add 50 µL / well of 0.5% (v / v) PEI to the UniFilter-96 GF / B plate. Seal the plate and incubate at 4°C for 3 hours.

[0558] b. After incubation, wash the plate three times with ice-cold washing buffer (50 mM Tris, pH 7.4).

[0559] 4) Preparation of the measuring plate: a. Dilute the cell membrane with assay buffer and add it to a 96-well circular deep-well plate at a concentration of 330 µL / well to achieve a concentration of 1 unit / well.

[0560] b. Prepare eight concentrations of reference or test compounds and add them to a 96-well circular deep-well plate at a rate of 110 µL / well.

[0561] c. Dilute [3H]-LSD to 5 nM (5X final concentration) with assay buffer and add it to 96-well circular deep-well plates at a rate of 110 µL / well.

[0562] 5) Centrifuge the plate at 1000 rpm for 30 seconds, then stir at 600 rpm at room temperature for 5 minutes.

[0563] 6) Seal the plate and incubate it at 37°C for 90 minutes.

[0564] 7) Stop the incubation by vacuum filtration on a GF / B filter plate, followed by washing four times with ice-cold washing buffer (50 mM Tris, pH 7.4).

[0565] 8) Dry the plate at 37°C for 45 minutes.

[0566] 9) Seal the filter plate and add 40 µL / pore of scintillation mixture.

[0567] 10) Use the Microbeta2 microboard counter to read the board.

[0568] Data Analysis For reference and test compounds, the results were expressed as % inhibition using a normalized equation: N = 100 - 100 × (U - C2) / (C1 - C2), where U is an unknown value, C1 is the high control mean, and C2 is the low control mean. IC50 was determined by fitting the percentage of inhibition as a function of compound concentration using Hill's equation.50 .

[0569] Table 30: Exemplary compounds of formula (I) for human-5-HT using radioligand binding assays 2B The role of receptors

[0570] Example 6: Hallucinogenic effects of exemplary compound (I) The effects of different doses of the exemplary formula (I) compound on head twitching response (HTR) were evaluated as a behavior-based hallucinogenic activity model.

[0571] Head Twitch Response (HTR) Measurement Protocol: Prior to testing, adult C57BL / 6J mice (weighing 20–30 g) were individually placed in open-topped test cages made of transparent plastic for 20–30 minutes for habituation. Habituation and testing were conducted under low-light conditions (approximately 100 lux). Mice received subcutaneous (SC) injections of a mordant, positive control (e.g., 2,5-dimethoxy-4-iodophenylpropanol (DOI)), or test compound at an appropriate dose and volume (10 mL / kg). Immediately after treatment, each mouse was returned to its corresponding test cage. The cages were placed approximately 50 cm apart on a white, height-adjustable table / flat surface, allowing the experimenter to easily monitor the fine motor behavior of both mice in the test environment. Opaque separators were placed between the cages to prevent the animals from observing each other. Immediately after returning the mice to their test cages, the experimenter sat directly in front of both cages and recorded the number of head twitching responses (HTR, defined as rapid left-right rotational shaking of the head) performed by each mouse in real time for 20 minutes, subdivided at 5-minute intervals using a silent timer. To ensure scoring accuracy and consistency, an experienced experimenter recorded the HTR (Heat-to-Treatment Rating) of all mice included in the study. While mice were being tested for HTR, another pair of mice were acclimatized in a separate set of test cages, so that at the end of the HTR scoring period, the new animals were ready for substance administration and testing. Between individual HTR tests, the cages were cleaned with water, disinfected with a 70% ethanol solution, and dried using paper towels.

[0572] Results and discussion Figure 1 This is a graph illustrating the effects of various doses of the exemplary compound (I), namely (R)I-1, on head twitching response (HTR) in male C57BL6 mice. Mice were treated with the exemplary compound (R)I-1 via the SC route, and the total number of head twitches was recorded over 20 minutes. Data are presented as mean ± SEM. It is believed that the 5-HT... 2AThe induction of head twitching induced by receptor agonists represents a behavioral proxy for their hallucinogenic effects.

[0573] Example 7: Pharmacokinetic Study in Rats plan Research details: Animals: Male Sprague-Dawley rats (approximately 225-350 g) from Charles River Labs were acclimatized for at least 5 days prior to the start of the study program. Weight was recorded on the day of administration.

[0574] Food restrictions: None.

[0575] Clinical observation results: Observe the animals at the time of administration and at each sample collection. Record any abnormalities, including the presence / absence of wet dog shaking / back muscle contraction (WDS / BMC).

[0576] Administration: Intravenous administration via the tail vein using a 25G needle attached to a 1 cc syringe. iv .) Apply the preparation.

[0577] preparation: The exemplary compound (I) was freshly prepared in a brine solution containing 5% Tween-80 at an appropriate concentration.

[0578] Sample collection: Blood collection time (hours): 0.25, 1, and 4; Volume / time point: Approximately 0.25 mL (saphenous vein).

[0579] Bioanalytical method development and sample analysis: Analyte: Compound of formula (I) Matrix: Rat plasma.

[0580] Instrument: AB Sciex QTRAP 4000 or 6500 MS / MS system, equipped with an LC system featuring a binary pump, solvent degasser, temperature-controlled column compartment, and multi-plate autosampler.

[0581] The development of bioanalytical methods includes: 1. Select the ion transformations of the test compound and potential internal standard (i.e., identify the parent ion and product ion).

[0582] 2. Optimize mass spectrometry operating parameters.

[0583] 3. Establish chromatographic conditions for the analytes.

[0584] 4. Select an appropriate internal standard (IS).

[0585] 5. Develop a method for purifying S-samples using protein precipitation.

[0586] Quantitative methods: 1. Determine the dynamic range of quantitation using non-zero calibration standards (STDs) in a single peak. An STD consists of a blank matrix sample (without IS), a zero sample (with IS), and at least six non-zero STDs covering the expected range and including the lower level of quantitation (LLOQ).

[0587] 2. Perform three injections on the system suitability sample (a pure solution containing the analyte and IS) from the batch.

[0588] Method acceptance criteria: 1. At least 75% of the non-zero STDs are included in the calibration curve, where all reverse-calculated concentrations deviate from the nominal concentrations within ±20% (for lower quantitation levels LLOQ, the deviation is ±25%).

[0589] 2. Use quadratic regression analysis (1 / x) 2 (Weighted), the correlation coefficient (r) of the calibration curve is greater than or equal to 0.99.

[0590] 3. The area ratio change of the system suitability sample before and after the injection is within ±25%.

[0591] Sample analysis batch: 1. Perform three injections on the system suitability sample containing the batch.

[0592] 2. Arrange STDs in ascending order.

[0593] 3. Dilute the study sample and the drug solution into the blank matrix (plasma) three times independently.

[0594] 4. For more than 40 research samples in a batch, use two sets of STDs containing the samples.

[0595] Dilute the sample to a concentration 25% higher than the highest calibration standard and re-measure it together with the corresponding diluted quality control standard. If the diluted standard is within 25% accuracy of the target concentration, it is acceptable.

[0596] PK Analysis Analysis software: Phoenix® WinNonlin® 8.3 (Pharsight, Certara, Mountainview, CA).

[0597] Analysis method: non-compartmental analysis, linear upward / log downward trapezoidal rule.

[0598] PK parameter: Estimated t 1 / 2 and AUC 0-tlast .

[0599] result Table 31 shows the plasma concentrations of the exemplary compound (R) I-1 after a dose of 1.19 iv administered.

[0600] Table 31: Plasma concentrations of (R) I-1 after administration of 1.10 mg / kg IV (Group 2).

[0601]

[0602] Table 32 shows the plasma apparent values ​​of exemplary compound I-1 after intravenous administration of 1.10 mg / kg. 1 / 2 and AUC 0-tlast Summary (Group 2).

[0603] Table 32: Plasma apparent t-values ​​of I-1 after administration of 1.19 mg / kg IV. 1 / 2 and AUC 0-tlast Summary (Group 2).

[0604]

[0605] Example 8: Stability of liver microsomes in humans, rats, and mice Target The objective of this study was to evaluate the in vitro metabolic stability of compounds of exemplary formula (I) or their pharmaceutically acceptable salts, solvates, and / or prodrugs in mixed human, male rat, and male mouse liver microsomes. The concentrations of the compounds in the reaction systems were evaluated by LC-MS / MS to assess their stability in mixed human, male rat, and male mouse liver microsomes. The intrinsic in vitro clearance of the test compounds was also determined.

[0606] plan According to Table 33, prepare the master solution containing phosphate buffer, ultrapure H2O, MgCl2 solution, and liver microsomes for the "incubation plate". Preheat the mixture in a 37°C water bath for 5 minutes.

[0607] Table 33: Preparation of the main solution

[0608] Add 40 µL of 10 mM nicotinamide adenine dinucleotide phosphate (NADPH) solution to each well. The final NADPH concentration is 1 mM. Prepare a negative control sample by replacing NADPH with 40 µL of ultrapure H2O. Samples are prepared in duplicate. The negative control is prepared in single-sample form.

[0609] At the start of the reaction, 4 µL of the 200 µM exemplary test or control compound disclosed herein was added to each master solution to obtain a final concentration of 2 µM. This study was performed in duplicate.

[0610] At 0, 15, 30, 45, and 60 minutes, 50 µL aliquots were taken from the reaction solution. The reaction was terminated by adding 4 volumes of cold methanol with IS (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol, and 2 µM ketoprofen). The samples were centrifuged at 3,220 g for 40 minutes. Aliquots of 90 µL of the supernatant were mixed with 90 µL of ultrapure H₂O and then used for LC-MS / MS analysis.

[0611] All samples in this study were analyzed by LC / MS using a Shimadzu liquid chromatography separation system equipped with a DGU-20A5R degasser, an LC-30AD solvent delivery device, a SIL-30AC system controller, a CTO-30A column oven, and an HTC PAL CTC analysis system. Mass spectrometry was performed using a Triple Quad™ 5500 instrument.

[0612] 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 chromatogram.

[0613] 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 natural logarithm of the remaining percentage of the parent drug versus incubation time.

[0614] The in vitro half-life (in vitro t) is determined based on the slope value. 1 / 2 ): In vitro t 1 / 2 = - (0.693 / k) The following equation (average of repeated measurements) is used to calculate the in vitro t 1 / 2 (minutes) converted to in vitro intrinsic clearance (in vitro CL) int (in µL / min / mg protein) .

[0615] For exemplary or control compounds of this disclosure that exhibit an initial rapid disappearance followed by a slow disappearance, the calculations include only time points within the initial rate.

[0616] Results and discussion Human, rat, and mouse liver microsomes contain a variety of drug-metabolizing enzymes and are commonly used to support in vitro ADME (absorption, distribution, metabolism, and excretion) studies. These microsomes are used to examine potential first-pass metabolic byproducts of orally administered drugs. The stability of representative compounds of this disclosure in human, rat, and mouse liver microsomes was evaluated.

[0617] In the liver microsomes of three species, namely humans, rats and mice, most of the exemplary compounds of this disclosure were recovered within a 60-minute time period, indicating that the compounds were not rapidly eliminated (see exemplary compounds of formula (I) in Tables 34 and 35).

[0618] Table 34: Metabolic stability of the tested compounds in liver microsomes of different species (a)

[0619] Table 35: Metabolic stability of the tested compounds in liver microsomes of different species (b)

[0620] discuss The stability of the exemplary compounds of this disclosure, represented by (R) I-1, in human, rat, and mouse liver microsomes was evaluated. Tables 34 and 35 show the results of the stability studies. These results indicate that the compounds of this disclosure exhibit stability profiles across different species, including humans, rats, and mice.

[0621] Example 9: Protein binding measurements in plasma from different species (human, rat, mouse, and dog) using balanced dialysis. plan: 1. Thaw the frozen plasma (stored at -80°C) immediately in a 37°C water bath.

[0622] 2. Preparation of working solution Working solutions of the test and control compounds were prepared in DMSO at a concentration of 200 µM, and then incorporated into plasma. The final concentration of the compounds was 1 µM. The final concentration of DMSO was 0.5%. Ketoconazole was used as a positive control for the assay.

[0623] 3. Preparation of dialysis membranes The dialysis membrane was immersed in ultrapure water for 60 minutes to separate the bands, then in 20% ethanol for 20 minutes, and finally in dialysis buffer for 20 minutes.

[0624] 4. Balanced dialysis procedure Assemble the dialysis apparatus according to the manufacturer's instructions. Dialyze each cell with 150 µL of plasma sample relative to an equal volume of dialysis buffer (PBS). Perform assays in duplicate. Seal the dialysis plate and incubate at 37°C and 5% CO2 at 100 rpm for 6 hours. At the end of the incubation, transfer 50 µL of sample from both the buffer chamber and the plasma chamber into the wells of a 96-well plate.

[0625] 5. Sample Analysis Procedure Add 50 µL of plasma to each buffer sample and replenish the collected plasma sample with an equal volume of PBS. Add 400 µL of precipitation buffer acetonitrile containing internal standards (IS, 200 nM labetalol, 100 nM tolbutamide, and 100 nM ketoprofen) to precipitate proteins and release compounds. Vortex the sample for 2 min and centrifuge at 3,220 g for 30 min. Dilute 50 µL of the supernatant aliquots with 150 µL of acetonitrile containing internal standards:ultrapure H2O = 1:1 and use the mixture for LC-MS / MS analysis.

[0626] 6. Data Analysis All calculations were performed using Microsoft Excel. The concentrations of the test compounds in the buffer and plasma chambers were determined based on the peak area ratio. The percentages of the compounds were calculated as follows: Free % = (Peak area ratio buffer chamber / Peak area ratio plasma chamber) * 100% Binding % = 100% - Free % Recovery % = (Peak area ratio buffer chamber + Peak area ratio plasma chamber) / Peak area ratio of total sample * 100% Material: Plasma information (Table 36)

[0627] Bioanalytical methods (Table 37)

[0628] Injection volume (Table 38)

[0629] Column temperature: 40℃.

[0630] MS parameters: Ion source: turbine spray; Ionization model: ESI; Scan type: MRM; Collision gas: 6 L / min; Curtain air: 30 L / min; Atomizing gas: 50 L / min; Assist gas: 50 L / min; Temperature: 500 degrees Celsius; Ion spray voltage: +5500 V (positive MRM).

[0631] Results and discussion: Table 39 shows the results of protein binding measurements in different species using exemplary compounds of this disclosure.

[0632] Table 39

[0633] Part II The following compounds were prepared using one or more synthetic methods outlined in Schemes I and II.

[0634] A. Synthesis of exemplary compounds of this disclosure Example 10 :(R)-5-methoxy-3-((1-(2-methoxyethyl)pyrrolidine-2-yl)methyl)-1H-indole ((R) I-98)

[0635] Synthesis of (R)-5-methoxy-3-(pyrrolidone-2-ylmethyl)-1H-indole (1): prepared according to literature procedure (WO2022183288A1). 1 H NMR (DMSO-d6): δ 10.68 (s, 1H), 7.23 (d, 1H, J = 6.0 Hz), 7.14 (s, 1H), 7.02 (d, 1H, J = 3.0 Hz), 6.72 (dd, 1H, J = 3.0, 6.0 Hz), 3.38(s, 3H), 3.36-3.31 (m, 1H), 3.01-2.95 (m, 1H), 2.87-2.72 (m, 3H), 1.82-1.62(m, 3H), 1.44-1.37 (m, 1H); ESI-MS (m / z, %): 231 (MH + , 100).

[0636] Synthesis of (R)-5-methoxy-3-((1-(2-methoxyethyl)pyrrolidine-2-yl)methyl)-1H-indole (2): At room temperature, a solution of (R)-5-methoxy-3-(pyrrolidine-2-ylmethyl)-1H-indole (1.1 g, 4.77 mmol) in anhydrous DMF (20 mL) was treated with 2-methoxyethyl 4-methylbenzenesulfonic acid (1.32 g, 5.73 mmol) and triethylamine (1.65 mL, 11.94 mmol) and stirred overnight (16 h). The reaction solution was quenched with water (50 mL) and the product was extracted into ethyl acetate (2 × 50 mL). The combined ethyl acetate layers were washed with water (25 mL) and brine (25 mL) and dried (Na2SO4). The solvent was evaporated and the crude compound was purified on silica gel by column chromatography (2 M NH3 in MeOH:CH2Cl2 (5:95)) to obtain the title compound (R) I-98 (1.0 g, 73%) as a light brown gel. 1 H NMR (DMSO- d 6): δ 10.60 (s, 1H), 7.21 (d, 1H, J = 6.0 Hz), 7.09 (s, 1H), 6.98 (s, 1H), 6.70 (dd, 1H, J = 3.0, 6.0 Hz), 3.76 (s, 3H), 3.47 (t, 2H, J = 6.0 Hz), 3.13(s, 3H), 3.09-3.06 (m, 2H), 2.97-2.93 (m, 1H), 2.65-2.60 (m, 1H), 2.48-2.37(m, 2H), 2.22-2.15 (m, 1H), 1.71-1.57 (m, 3H), 1.48-1.42 (m, 1H); ESI-MS (m / z, %): 289 (MH + , 100).

[0637] Example 11: (R)-2-(4-((3-((1-(methyl-d 3 )pyrrolidine-2-yl)methyl-d 2 )-1H-indole-5-yl) (Oxy)Butyl)isoindoline-1,3-dione ((R)I-244)

[0638] Synthesis of (R)-2-(2-(5-(benzyloxy)-1H-indole-3-carbonyl)pyrrolidine-1-yl)-1-phenylethane-1-one (4): A solution of 1-(2-oxo-2-phenylethyl)-D-proline (4.0 g, 16.04 mmol) in anhydrous THF (50 mL) was treated with thionyl chloride (2.34 mL, 32.09 mmol) at 0 °C. The reaction mixture was then heated to room temperature and refluxed for 2 hours. The solvent was evaporated, and the crude product was dried under vacuum to obtain the corresponding acyl chloride.

[0639] Within 15 minutes, a solution of 5-(benzyloxy)-1H-indole (3.58 g, 16.04 mmol) in anhydrous CH2Cl2 (50 mL) at 5–10 °C was simultaneously treated with the above-mentioned crude acyl chloride and ethyl magnesium bromide (10.7 mL, 32.09 mmol, 3 M, in THF) in anhydrous CH2Cl2 (30 mL), and stirred for another 15 minutes at the same temperature. The reaction solution was quenched with concentrated HCl (10 mL), followed by quenching with water (100 mL), and the product was extracted into CH2Cl2 (2 x 100 mL). The combined CH2Cl2 layers were washed with water (50 mL) and brine (50 mL) and dried (Na2SO4). The solvent was evaporated, and the crude extract was purified by column chromatography (EtOAc:CH2Cl2, 1:4) on silica gel to obtain title compound 4 (5.6 g, 76.7%) as a pale brown solid. 1 H NMR (DMSO- d 6): δ 11.94, 11.92 (2s, 1H), 8.40, 8.38 (2d, 1H, J = 3.0Hz), 7.85, 7.81 (2d, 1H, J = 3.0 Hz), 7.51-7.34 (m, 9H), 7.15-6.94 (m, 3H),5.24-4.92 (m, 5H), 3.55-3.50 (m, 2H), 2.44-2.29 (m, 1H), 2.29-1.83 (m, 3H);ESI-MS (m / z, %): 514 (100), 477 (M+Na), 455 (MH + ).

[0640] (R)-5-(benzyloxy)-3-((1-(methyl- d 3)pyrrolidine-2-yl)methyl- d 2) Synthesis of 1H-indole (5): A solution of (R)-2-(2-(5-(benzyloxy)-1H-indole-3-carbonyl)pyrrolidine-1-yl)-1-phenylethane-1-one (5.5 g, 12.10 mmol) in anhydrous THF (100 mL) was treated with LiAlD4 (2.54 g, 60.50 mmol) over 15 minutes. The reaction mixture was heated to room temperature and then refluxed overnight (16 h). The reaction mixture was cooled to 0 °C and quenched with water (2.54 mL), 4 N NaOH solution (2.54 mL), and water (2.54 mL). The reaction mixture was heated to room temperature and stirred for another 30 minutes. The reaction mixture was filtered through a sodium sulfate pad and washed with THF (3 x 50 mL). The combined THF layer was evaporated and the crude extract was purified on silica gel by column chromatography (2 M NH3 in MeOH:CH2Cl2 (5:95)) to obtain title compound 5 (3.6 g, 91.4%) as a pale yellow gel. 1 H NMR (DMSO- d 6): δ 10.62 (s, 1H), 7.49-7.30 (m, 5H), 7.23 (d, 1H, J = 6.0 Hz), 7.09-7.05 (m, 1H), 6.80 (dd, 1H, J =3.0, 6.0 Hz), 5.11 (s, 2H), 2.99-2.95 (m, 1H), 2.32-2.28 (m, 1H), 2.11-2.07(m, 1H), 1.66-1.41 (m, 4H); ESI-MS (m / z, %): 326 (MH + , 100).

[0641] (R)-3-((1-(methyl- d 3)pyrrolidine-2-yl)methyl- d 2) Synthesis of 1H-indole-5-ol (6): (R)-5-(benzyloxy)-3-((1-(methyl-) d 3)pyrrolidine-2-yl)methyl- d2) A solution of 1H-indole (3.55 g, 10.90 mmol) was treated with carbon-supported palladium (0.35 g, 10% dry basis) and stirred for 16 hours (overnight) under hydrogen atm (balloon pressure). The reaction mixture was filtered through a diatomaceous earth mat and washed with methanol (3 x 15 mL). The combined methanol layers were evaporated and the crude extract was purified on silica gel by rapid column chromatography (2 M NH3 in MeOH:CH2Cl2 (5:95)) to obtain title compound 6 (2.35 g, 91.4%) as a grayish-white foam. 1 H NMR (DMSO- d 6): δ10.44 (s, 1H), 8.55 (s, 1H), 7.11 (d, 1H, J = 6.0 Hz), 7.02 (d, 1H, J = 3.0Hz), 6.81 (d, 1H, J = 3.0 Hz), 6.58 (dd, 1H, J = 3.0, 6.0 Hz), 3.00-2.96 (m,1H), 2.34-2.30 (m, 1H), 2.15-2.10 (m, 1H), 1.69-1.42 (m, 4H); ESI-MS (m / z,%): 236 (MH + , 100).

[0642] (R)-2-(4-((3-((1-(methyl- d 3)pyrrolidine-2-yl)methyl- d Synthesis of 2)-1H-indol-5-yl)oxy)butyl)isoindolline-1,3-dione ((R)I-244) At room temperature, (R)-3-((1-(methyl-) d 3)pyrrolidine-2-yl)methyl- d 2) A solution of 1H-indole-5-ol (1.0 g, 4.24 mmol) was treated with Cs₂CO₃ (2.07 g, 6.37 mmol), followed by treatment with 2-(4-bromobutyl)isoindoline-1,3-dione (1.32 g, 5.73 mmol) and stirred for 48 hours. The reaction mixture was quenched with water (100 mL), and the product was extracted into ethyl acetate (2 × 50 mL). The combined ethyl acetate layers were washed with water (50 mL) and brine (50 mL) and dried (Na₂SO₄). The solvent was evaporated, and the crude extract was purified by column chromatography (2 M NH₃ in MeOH:CH₂Cl₂ (5:95)) on silica gel to obtain the title compound (R) I-244 (0.81 g, 44%) as a pale yellow gel.1 H NMR (DMSO- d 6): δ 10.59 (s, 1H), 7.89-7.83 (m, 4H), 7.18 (d,1H, J = 6.0 Hz), 7.07 (s, 1H), 6.95 (s, 1H), 6.69 (d, 1H, J = 6.0 Hz), 3.98(t, 2H, J = 3.0, 6.0 Hz), 3.66 (t, 2H, J = 3.0, 6.0 Hz), 2.97 (t, 1H, J = 6.0Hz), 2.35-2.30 (m, 1H), 2.15-2.10 (m, 1H), 1.79-1.42 (m, 8H), ESI-MS (m / z,%): 437 (MH + , 100).

[0643] Example 12: (R)-2-(5-((3-((1-(methyl-d 3 )pyrrolidine-2-yl)methyl-d 2 )-1H-indole-5-yl) (Oxyl)pentyl)isoindoline-1,3-dione ((R) I-245)

[0644] (R)-2-(5-((3-((1-(methyl- d 3)pyrrolidine-2-yl)methyl- d Synthesis of 2)-1H-indol-5-yl)oxy)pentyl)isoindolline-1,3-dione ((R) I-245) At room temperature, (R)-3-((1-(methyl-) d 3)pyrrolidine-2-yl)methyl- d 2) A solution of 1H-indo-5-ol (1.0 g, 4.24 mmol) was treated with Cs₂CO₃ (2.07 g, 6.37 mmol), followed by treatment with 2-(5-bromopentyl)isoindoline-1,3-dione (2.51 g, 8.49 mmol) and stirred for 48 hours. The reaction solution was treated and purified as described for compound (R) I-244 to obtain the title compound (R) I-245 (0.8 g, 42%), which was a pale yellow gel. 1 H NMR (DMSO- d6): δ 10.58 (s, 1H), 7.89-7.83 (m, 4H), 7.18 (d,1H, J = 6.0 Hz), 7.07 (s, 1H), 6.95 (s, 1H), 6.67 (dd, 1H, J = 1.5, 6.0 Hz), 3.94 (t, 2H, J = 3.0, 6.0 Hz), 3.62 (t, 2H, J = 3.0, 6.0 Hz), 2.96 (t, 1H, J= 3.0, 6.0 Hz), 2.32 (t, 1H, J = 6.0 Hz), 2.10-2.06 (m, 1H), 1.78-1.43 (m,10H); ESI-MS (m / z, %): 451 (MH + , 100).

[0645] Example 13: 2-(5-((3-(((R)-1-(methyl-d 3 )pyrrolidine-2-yl)methyl-d 2 )-1H-indole-5-yl) (Oxyl)pentyl)hexahydro-1H-isoindole-1,3(2H)-dione ((R) I-248) (a mixture of cis diastereomers)

[0646] 2-(5-((3-(((R)-1-(methyl-d) 3 )pyrrolidine-2-yl)methyl-d 2 )-1H-indol-5-yl)oxy)pentyl) Synthesis of hexahydro-1H-isoindole-1,3(2H)-dione (9) (a mixture of cis diastereomers): At room temperature, (R)-3-((1-(methyl-) d 3)pyrrolidine-2-yl)methyl- d 2) A solution of 1H-indole-5-ol (0.78 g, 3.31 mmol) was treated with Cs₂CO₃ (1.62 g, 4.97 mmol), followed by treatment with cis-2-(4-bromobutyl)hexahydro-1H-isoindole-1,3(2H)-dione (2.0 g, 6.62 mmol) and stirred for 48 hours. The reaction solution was treated and purified as described for compound (R) I-248 to obtain the title compound (R) I-248 (0.88 g, 58%) as a light brown gel. 1 H NMR (DMSO- d6): δ 10.59 (s, 1H), 7.20 (d, 1H,J = 6.0 Hz), 7.08 (d, 1H, J = 1.5 Hz), 6.95 (d, 1H, J = 1.5 Hz), 6.69 (dd,1H, J = 3.0, 6.0 Hz), 3.93 (t, 2H, J = 6.0 Hz), 3.40 (t, 2H, J = 6.0 Hz), 3.00-2.89 (m, 3H), 2.35 (t, 1H, J = 3.0, 6.0 Hz), 2.15-2.09 (m, 1H), 1.74-1.25 (m, 18H); ESI-MS (m / z, %): 457 (MH + , 100).

[0647] Example 13A: (R)-4-fluoro-5-methoxy-3-((1-methylpyrrolidone-2-yl)methyl)-1H-indole(R) I- Synthesis of 250

[0648] Synthesis of (R)-2-(2-(4-fluoro-5-methoxy-1H-indole-3-carbonyl)pyrrolidine-1-yl)-1-phenylethane-1-one 2A: A solution of 1-(2-oxo-2-phenylethyl)-D-proline (2.2 g, 8.83 mmol) in anhydrous THF (40 mL) was treated with thionyl chloride (1.28 mL, 17.65 mmol) at 0 °C. The reaction mixture was then heated to room temperature and refluxed for 2 hours. The solvent was evaporated, and the crude acyl chloride was dried under vacuum to obtain the corresponding acyl chloride.

[0649] Within 5 minutes, a solution of 4-fluoro-5-methoxy-1H-indole (1.45 g, 8.83 mmol) in anhydrous CH2Cl2 (50 mL) at 5–10 °C was simultaneously treated with the above-mentioned crude acyl chloride and ethyl magnesium bromide (6.2 mL, 18.53 mmol, 3 M, in diethyl ether) in anhydrous CH2Cl2 (20 mL), and stirred for another 15 minutes at the same temperature. The reaction mixture was quenched with concentrated HCl (10 mL), followed by quenching with water (50 mL), and the product was extracted into CH2Cl2 (2 x 100 mL). The CH2Cl2 layer was washed with saturated NaHCO3 solution (50 mL), brine (25 mL), and dried (Na2SO4). The solvent was evaporated, and the crude product was purified from a 1:5 mixture of CH2Cl2 and hexane by crystallization to obtain the title compound 2A (2.25 g, 64.3%) as a beige solid. 1 H NMR (DMSO- d6): δ 12.15, 12.13 (2s, 1H), 8.44 (d, 1H, J = 12.0 Hz), 7.39-7.05 (m, 7H), 5.30-5.22 (m, 1H), 5.11-4.91 (m, 2H), 3.86 (s, 3H), 3.54-3.48 (m, 2H), 2.42-2.30 (m, 1H), 1.90-1.75 (m, 3H); ESI-MS (m / z, %): 397 (MH + ), 419 (M+Na).

[0650] Synthesis of (R)-4-fluoro-5-methoxy-3-((1-methylpyrrolidone-2-yl)methyl)-1H-indole(R) I-250: At 0 °C, a solution of (R)-2-(2-(4-fluoro-5-methoxy-1H-indole-3-carbonyl)pyrrolidine-1-yl)-1-phenylethane-1-one (2.0 g, 5.04 mmol) in anhydrous THF (30 mL) was treated with lithium aluminum hydride (26 mL, 25.22 mmol, 1 M solution in THF). The reaction mixture was heated to room temperature and then refluxed for 16 hours. The reaction mixture was then heated to room temperature and cooled to 0 °C, and quenched by adding water (1.0 mL), 4 N NaOH solution (1.0 mL), and water (1.0 mL) sequentially. The reaction mixture was then heated to room temperature and stirred for 30 minutes. The reaction mixture was filtered and washed with THF (2 x 50 mL). The combined THF layer was evaporated, and the crude product was purified on silica gel by column chromatography (2 M NH3 in MeOH:CH2Cl2 (5:95)) to obtain the title compound (R) I-250 (1.0 g, 75.7%) as a pale yellow gel. 1 HNMR (DMSO- d 6): δ 10.87 (s, 1H), 7.12 (s, 1H), 7.06 (d, 1H, J = 6.0 Hz), 6.93(t, 1H, J = 6.0 Hz), 3.81 (s, 3H), 3.15-3.10 (m, 1H), 2.99-2.95 (m, 1H),2.48-2.45 (m, 1H), 2.36-2.30 (m, 4H), 2.14-2.00 (m, 1H), 1.66-1.46 (m, 4H);ESI-MS (m / z, %): 263 (MH + , 100).

[0651] Example 13B: (R)-4-fluoro-5-methoxy-3-((1-(methyl-d) 3 )pyrrolidine-2-yl)methyl)-1H-indole Synthesis of (R) I-251

[0652] Synthesis of (R)-2-(2-((4-fluoro-5-methoxy-1H-indol-3-yl)methyl)pyrrolidine-1-yl)-1-phenylethane-1-one 4A: At room temperature, a solution of (R)-2-(2-(4-fluoro-5-methoxy-1H-indole-3-carbonyl)pyrrolidine-1-yl)-1-phenylethane-1-one (2.5 g, 6.31 mmol) in anhydrous THF (30 mL) was treated with lithium borohydride solution (12.61 mL, 25.23 mmol, 2 M solution in THF), and the reaction mixture was refluxed for 4 hours. The reaction mixture was cooled to 0 °C over 15 minutes and quenched carefully with methanol (25 mL). The reaction mixture was then warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated NaHCO3 solution (30 mL), and the product was extracted into ethyl acetate (3 × 50 mL). The combined ethyl acetate layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude product was purified by rapid column chromatography (MeOH:CH2Cl2, 2:98) on silica gel to obtain the title compound 4A (1.2 g, 49.8%) as a pale yellow semi-solid. The compound was ready for subsequent steps without any characterization.

[0653] (R)-4-Fluoro-5-methoxy-3-((1-(methyl- d 3) Synthesis of pyrrolidine-2-yl)methyl)-1H-indole (R) I-251: At 0 °C, a suspension of (R)-2-(2-(((4-fluoro-5-methoxy-1H-indol-3-yl)methyl)pyrrolidine-1-yl)-1-phenylethane-1-one (1.2 g, 3.14 mmol) in anhydrous THF (25 mL) was treated with lithium aluminum deuteride (0.32 g, 7.57 mmol). The reaction mixture was heated to room temperature and then refluxed for 16 hours. The reaction mixture was then heated to room temperature and cooled to 0 °C, and quenched sequentially with water (1.0 mL), 4 N NaOH solution (1.0 mL), and water (1.0 mL). The reaction mixture was then heated to room temperature and stirred for 30 minutes. The reaction mixture was filtered and washed with THF (2 x 50 mL). The combined THF layer was evaporated, and the crude product was purified on silica gel by column chromatography (2 M NH3 in MeOH:CH2Cl2 (5:95)) to obtain the title compound (R) I-251 (0.73 g, 87.7%) as a grayish-white solid. 1 H NMR (DMSO- d 6): δ 10.86 (s, 1H), 7.12 (s, 1H), 7.06 (d, 1H, J = 6.0 Hz), 6.93 (t, 1H, J = 6.0 Hz), 3.81 (s, 3H), 3.14-3.10 (m, 1H), 2.99-2.95 (m, 1H), 2.51-2.45 (m, 1H), 2.38-2.32(m, 1H), 2.14-2.06 (m, 1H), 1.64-1.45 (m, 4H); ESI-MS (m / z, %): 266 (MH + ,100).

[0654] Example 13C: (R)-5-methoxy-6-methyl-3-((1-methylpyrrolidone-2-yl)methyl)-1H-indole(R) Synthesis of I-254

[0655] Synthesis of (R)-2-(2-(5-methoxy-6-methyl-1H-indole-3-carbonyl)pyrrolidine-1-yl)-1-phenylethane-1-one 7A: A solution of 1-(2-oxo-2-phenylethyl)-D-proline (3.0 g, 12.03 mmol) in anhydrous THF (30 mL) was treated with thionyl chloride (1.75 mL, 24.07 mmol) at 0 °C. The reaction mixture was then heated to room temperature and refluxed for 2 hours. The solvent was evaporated, and the crude product was dried under vacuum to obtain the corresponding acyl chloride.

[0656] Within 5 minutes, a solution of 5-methoxy-6-methyl-1H-indole (1.94 g, 12.03 mmol) in anhydrous CH2Cl2 (50 mL) at 5–10 °C was simultaneously treated with the above-mentioned crude acyl chloride and ethyl magnesium bromide (8.4 mL, 25.27 mmol, 3 M, in diethyl ether) in anhydrous CH2Cl2 (20 mL), and stirred for another 15 minutes at the same temperature. The reaction mixture was quenched with concentrated HCl (10 mL), followed by quenching with water (50 mL), and the product was extracted into CH2Cl2 (2 x 100 mL). The CH2Cl2 layer was washed with saturated NaHCO3 solution (50 mL), brine (25 mL), and dried (Na2SO4). The solvent was evaporated, and the crude product was purified from a 1:5 mixture of CH2Cl2 and hexane by crystallization to obtain the title compound 7A (3.3 g, 70.2%) as a pale brown solid. 1 H NMR (DMSO- d 6): δ 11.81 (s, 1H), 8.31 (dd, 1H, J = 3.0 Hz), 7.68 (d,1H, J = 12.0 Hz), 7.40-7.32 (m, 2H), 7.15 (d, 1H, J = 3.0 Hz), 7.11-7.03 (m,3H), 5.24-4.91 (m, 3H), 3.83 (s, 3H), 3.56-3.49 (m, 2H), 2.43-2.25 (m, 4H),1.90-1.80 (m, 3H); ESI-MS (m / z, %): 393 (MH + ), 415 (M+Na).

[0657] Synthesis of (R)-5-methoxy-6-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole(R) I-254: A solution of (R)-2-(2-(5-methoxy-6-methyl-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenylethane-1-one (1.2 g, 3.05 mmol) in anhydrous THF (20 mL) was treated with lithium aluminum hydride (15.3 mL, 15.29 mmol, 1 M solution in THF) over 10 minutes at 0 °C. The reaction mixture was heated to room temperature and then refluxed for 16 hours. The reaction mixture was then heated to room temperature, cooled to 0 °C, and quenched sequentially with water (1.0 mL), 4 N NaOH solution (1.0 mL), and water (1.0 mL). The reaction mixture was then heated to room temperature and stirred for another 30 minutes. The reaction solution was filtered and washed with THF (2 x 50 mL). The combined THF layers were evaporated and the crude product was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2 (5:95)) on silica gel to obtain the title compound (R) I-254 (0.75 g, 94.5%) as a grayish-white solid. 1 HNMR (DMSO- d 6): δ 10.45 (s, 1H), 7.08 (s, 1H), 6.98 (s, 1H), 6.93 (s, 1H), 3.79 (s, 3H), 3.01-2.95 (m, 2H), 2.49-2.43 (m, 1H), 2.38-2.32 (m, 4H), 2.22(s, 3H), 2.10-2.06 (m, 1H), 1.76-1.41 (m, 4H); ESI-MS (m / z, %): 259 (MH + ,100).

[0658] Example 13D: (R)-5-methoxy-6-methyl-3-((1-(methyl-d) 3 )pyrrolidine-2-yl)methyl)-1H-in Synthesis of Dole(R) I-255

[0659] Synthesis of (R)-2-(2-((5-methoxy-6-methyl-1H-indol-3-yl)methyl)pyrrolidine-1-yl)-1-phenylethane-1-one 9A: At room temperature, a solution of (R)-2-(2-(5-methoxy-6-methyl-1H-indole-3-carbonyl)pyrrolidine-1-yl)-1-phenylethane-1-one (2.0 g, 5.10 mmol) in anhydrous THF (30 mL) was treated with lithium borohydride solution (10.2 mL, 20.38 mmol, 2 M solution in THF), and the reaction mixture was refluxed for 4 hours. The reaction mixture was cooled to 0 °C over 15 minutes and quenched carefully with methanol (25 mL). The reaction mixture was then warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated NaHCO3 solution (30 mL), and the product was extracted into ethyl acetate (3 × 50 mL). The combined ethyl acetate layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude product was purified on silica gel by rapid column chromatography (MeOH:CH2Cl2, 2:98) to obtain the title compound 9A (1.32 g, 68.7%), which appeared as a pale yellow foam. The compound was ready for subsequent steps without any characterization.

[0660] (R)-5-methoxy-6-methyl-3-((1-(methyl- d 3) Synthesis of pyrrolidine-2-yl)methyl)-1H-indole (R) I-255: At 0 °C, a solution of (R)-2-(2-((5-methoxy-6-methyl-1H-indol-3-yl)methyl)pyrrolidine-1-yl)-1-phenylethane-1-one (1.3 g, 3.43 mmol) in anhydrous THF (20 mL) was treated with lithium aluminum deuteride (0.36 g, 8.58 mmol) over 10 minutes. The reaction mixture was heated to room temperature and then refluxed for 16 hours. The reaction mixture was then heated to room temperature and cooled to 0 °C, and quenched by adding water (1.0 mL), 4 N NaOH solution (1.0 mL), and water (1.0 mL) sequentially. The reaction mixture was then heated to room temperature and stirred for 30 minutes. The reaction mixture was filtered and washed with THF (2 x 50 mL). The combined THF layer was evaporated, and the crude product was purified on silica gel by column chromatography (2 M NH3 in MeOH:CH2Cl2 (5:95)) to obtain the title compound (R) I-255 (0.75 g, 84.6%) as a grayish-white solid. 1 H NMR (DMSO- d6): δ10.46 (s, 1H), 7.08 (s, 1H), 6.98 (s, 1H), 6.93 (s, 1H), 3.79 (s, 3H), 3.01-2.95 (m, 2H), 2.49-2.43 (m, 4H), 2.37-2.32 (m, 1H), 2.22 (s, 3H), 2.11-2.07(m, 1H), 1.76-1.41 (m, 4H); ESI-MS (m / z, %): 262 (MH + , 100).

[0661] Example 13E: (R)-6-fluoro-5-methoxy-3-((1-methylpyrrolidone-2-yl)methyl)-1H-indole(R) I- Synthesis of 256

[0662] Synthesis of (R)-2-(2-(6-fluoro-5-methoxy-1H-indole-3-carbonyl)pyrrolidine-1-yl)-1-phenylethane-1-one 12A: A solution of 1-(2-oxo-2-phenylethyl)-D-proline (4.6 g, 18.45 mmol) in anhydrous THF (50 mL) was treated with thionyl chloride (2.7 mL, 36.90 mmol) at 0 °C. The reaction mixture was then heated to room temperature and refluxed for 2 hours. The solvent was evaporated, and the crude product was dried under vacuum to obtain the corresponding acyl chloride.

[0663] Within 5 minutes, a solution of 6-fluoro-5-methoxy-1H-indole (3.0 g, 18.45 mmol) in anhydrous CH2Cl2 (50 mL) at 5–10 °C was simultaneously treated with the above-mentioned crude acyl chloride and ethyl magnesium bromide (12.9 mL, 38.74 mmol, 3 M, in diethyl ether) in anhydrous CH2Cl2 (20 mL), and stirred for another 15 minutes at the same temperature. The reaction mixture was quenched with concentrated HCl (10 mL), followed by quenching with water (50 mL), and the product was extracted into CH2Cl2 (2 x 100 mL). The CH2Cl2 layer was washed with saturated NaHCO3 solution (50 mL), brine (25 mL), and dried (Na2SO4). The solvent was evaporated, and the crude product was purified from a 1:5 mixture of CH2Cl2 and hexane by crystallization to obtain title compound 12A (5.7 g, 78.8%) as a beige solid. 1 H NMR (DMSO- d6): δ 11.96, 11.95 (2s, 1H), 8.40 (dd, 1H, J = 3.0, 6.0Hz), 7.85, 7.84 (2d, 1H, J = 6.0 Hz), 7.39-7.34 (m, 3H), 7.15-7.02 (m, 3H),5.24-4.91 (m, 3H), 3.87 (s, 3H), 3.56-3.49 (m, 2H), 2.40-2.28 (m, 1H), 1.92-1.84 (m, 3H); ESI-MS (m / z, %): 397 (MH + ), 419 (M+Na).

[0664] Synthesis of (R)-6-fluoro-5-methoxy-3-((1-methylpyrrolidone-2-yl)methyl)-1H-indole(R) I-256: At 0 °C, a solution of (R)-2-(2-(6-fluoro-5-methoxy-1H-indole-3-carbonyl)pyrrolidine-1-yl)-1-phenylethane-1-one (2.0 g, 5.04 mmol) in anhydrous THF (30 mL) was treated with lithium aluminum hydride (25.2 mL, 25.22 mmol, 1 M solution in THF). The reaction mixture was heated to room temperature and then refluxed for 16 hours. The reaction mixture was then heated to room temperature and cooled to 0 °C, and quenched by adding water (1.0 mL), 4 N NaOH solution (1.0 mL), and water (1.0 mL) sequentially. The reaction mixture was then heated to room temperature and stirred for 30 minutes. The reaction mixture was filtered and washed with THF (2 x 50 mL). The combined THF layer was evaporated, and the crude product was purified on silica gel by column chromatography (2 M NH3 in MeOH:CH2Cl2 (5:95)) to obtain the title compound (R) I-256 (0.93 g, 70.4%) as a grayish-white foam. 1 HNMR (DMSO- d 6): δ 10.69 (s, 1H), 7.16-7.08 (m, 3H), 3.84 (s, 3H), 3.02-2.95 (m, 2H), 2.47-2.42 (m, 1H), 2.38-2.30 (m, 4H), 2.14-2.08 (m, 1H), 1.75-1.41(m, 4H); ESI-MS (m / z, %): 263 (MH + , 100).

[0665] Example 13F: (R)-6-fluoro-5-methoxy-3-((1-(methyl-d) 3)pyrrolidine-2-yl)methyl)-1H-indole Synthesis of (R) I-257

[0666] Synthesis of (R)-2-(2-((6-fluoro-5-methoxy-1H-indol-3-yl)methyl)pyrrolidine-1-yl)-1-phenylethane-1-one 14A: At room temperature, a solution of (R)-2-(2-(6-fluoro-5-methoxy-1H-indole-3-carbonyl)pyrrolidine-1-yl)-1-phenylethane-1-one (2.5 g, 6.31 mmol) in anhydrous THF (30 mL) was treated with lithium borohydride solution (12.6 mL, 25.22 mmol, 2 M solution in THF) and the reaction mixture was refluxed for 4 hours. The reaction mixture was cooled to 0 °C over 15 minutes and quenched carefully with methanol (25 mL). The reaction mixture was then warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated NaHCO3 solution (30 mL), and the product was extracted into ethyl acetate (3 × 50 mL). The combined ethyl acetate layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude product was purified on silica gel by rapid column chromatography (MeOH:CH2Cl2, 2:98) to obtain the title compound 14A (1.65 g, 68.5%) as a pale yellow gel. The compound was ready for subsequent steps without any characterization.

[0667] Synthesis of (R)-6-fluoro-5-methoxy-3-((1-(methyl-d3)pyrrolidine-2-yl)methyl)-1H-indole(R) I-257: At 0 °C, a solution of (R)-2-(2-((6-fluoro-5-methoxy-1H-indol-3-yl)methyl)pyrrolidine-1-yl)-1-phenylethane-1-one (1.65 g, 4.31 mmol) in anhydrous THF (25 mL) was treated with lithium aluminum deuteride (0.45 g, 10.78 mmol) over 10 minutes. The reaction mixture was heated to room temperature and then refluxed for 16 hours. The reaction mixture was then heated to room temperature and cooled to 0 °C, and quenched by adding water (1.0 mL), 4 N NaOH solution (1.0 mL), and water (1.0 mL) sequentially. The reaction mixture was then heated to room temperature and stirred for 30 minutes. The reaction mixture was filtered and washed with THF (2 x 50 mL). The combined THF layer was evaporated, and the crude product was purified on silica gel by column chromatography (2 M NH3 in MeOH:CH2Cl2 (5:95)) to obtain the title compound (R) I-257 (0.97 g, 85.1%) as a grayish-white solid. 1H NMR (DMSO- d 6): δ10.69 (s, 1H), 7.16-7.08 (m, 3H), 3.84 (s, 3H), 3.01-2.95 (m, 2H), 2.49-2.45(m, 1H), 2.38-2.29 (m, 1H), 2.14-2.07 (m, 1H), 1.77-1.40 (m, 4H); ESI-MS (m / z, %): 266 (MH + , 100).

[0668] B. Biological testing Example 14: Human 5-HT 2A Functional FLIPR Measurement Target: Evaluation of targeting human serotonin receptor 2A (5-HT2A) in agonist mode 2A The potential excitatory effects of compounds.

[0669] 1. Materials and Instruments 1.1 Cell lines (Table 40)

[0670] 1.2 Materials (Table 41)

[0671] 1.3 Instruments and Consumables (Table 42)

[0672] 2. Experimental Methods 2.1 Cell Culture HTR2A&Gα15-HEK293 cells were cultured in DMEM medium containing 10% dialyzed FBS, 1× penicillin-streptomycin, 100 µg / mL hygromycin B, and 300 µg / mL G418. Cells were passaged approximately three times per week, maintaining a confluence of approximately 30% to approx...

Claims

1. A compound of formula (I) Formula (I) Or its pharmaceutically acceptable salts, solvates and / or prodrugs, in: X does not exist or is selected from O, S, S(O) and SO2; R 1 Selected from H, C 1- C6 alkyl, C 1- C6 alkylene P(O)(OR) 11 2. C 1- C6 alkylene OP(O)(OR) 11 2. C(O)R 11 CO2R 11 C(O)N(R) 11 )2、S(O)R 11 and SO2R 11 ; R 2 selected from H, halogen and C 1- C6alkyl; R 3 R 4 and R 5 Independently selected from H, CN, halogens, C 1- C6 alkyl, C 2- C6 alkenyl and C 2- C6 ynyl group; R 6 Selected from H, C 1- C 10 Alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene ZR 12 C 2- C6 imenoyl ZR 12 C 2- C6-Isoynyl ZR 12 C 3- C7 cycloalkyl, C 3- C7 heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C6 alkylene C 3- C7 cycloalkyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 6- C 10 Aryl and C 1- C6 alkylene C 5- C 10 The heteroaryl group, the last eight groups being optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 13 and C(O)R 13 ; R 7 and R 8 are independently selected from H, halogen and C 1- C6alkyl; Each R 9 Independently selected from halogens, C 1- C6 alkyl, OH, OC 1- C6 alkyl, C 1- C6 alkylene OH and C 1- C6 alkylene OC 1- C6 alkyl; R 10 Selected from H, C 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene Z'R 14 C 2- C6 imenoyl Z'R 14 C 2- C6-Imyynyl Z'R 14 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C6 alkylene C 3- C7 cycloalkyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 6- C 10 Aryl and C 1- C6 alkylene C 5- C 10 The heteroaryl group, the last eight groups being optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 15 and C(O)R 15 ; Z is selected from O, C(O), NR 16 C(O), NR 16 C(O)O、C(O)NR 16 OC(O)NR 16 and NR 16 ; Z' is selected from O, C(O), NR 17 C(O), NR 17 C(O)O、C(O)NR 17 OC(O)NR 17 and NR 17 ; n is an integer selected from 0, 1, 2, 3, and 4; R 11 , R 13 , R 15 , R 16 and R 17 are independently selected from H and C 1- C6alkyl; R 12 and R 14 Independently selected from H and C 1- C6 alkyl, C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl and C 5- C 10 Heteroaryl, the last four groups are optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C4 alkyl, OC 1- C4 alkyl and C(O)C 1- C4 alkyl, Hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes. The condition is that when X is O, R 1 R 2 R 3 R 4 R 5 R 7 and R 8 It is H or D, n is 0, and R 6 When it is H, CH3 or CD3, then R 10 Not H, CH3, or CD3; When X is O, R 1 R 2 R 3 R 4 R 5 R 7 and R 8 It is H or D, n is 0, and R 6 When it is CH3 or CHF2, then R 10 Not H, CH3, or CD3; and when X is absent and R 6 is H, then n is not 0, or R 10 is not H or C 1- C6alkyl.

2. The compound according to claim 1, wherein (1) when X is absent, then R 6 It is not H, D, or a halogen, and (2) when X is O, S, S(O), or SO2, then each R9 is not independently selected from H, D, a halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, and C1-C6 deuterated haloalkyl, and / or R 10 Not selected from H, D, halogens, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl and C1-C6 deuterated haloalkyl.

3. The compound according to claim 1 or claim 2, wherein hydrogen atoms may optionally be independently replaced by iodine atoms, fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium.

4. The compound according to claim 1 or claim 2, wherein X is S(O).

5. The compound according to claim 1 or claim 2, wherein X is SO2.

6. The compound according to claim 1 or claim 2, wherein X is S.

7. The compound according to claim 1 or claim 2, wherein X is absent.

8. The compound according to claim 1 or claim 2, wherein X is O.

9. The compound according to claim 1 or claim 2, wherein R 6 Selected from H, C 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene ZR 12 C 2- C6 imenoyl ZR 12 C 2- C6-Isoynyl ZR 12 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C4 alkylene C 3- C7 cycloalkyl, C 1- C4 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C4 alkylene C 6- C 10 Aryl and C 1- C4 alkylene C 5- C 10 The heteroaryl group, the last eight groups being optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 13 and C(O)R 13 In which hydrogen atoms may be optionally replaced by halogen atoms, and / or atoms may be optionally replaced by their substituted isotopes.

10. The compound according to claim 1 or claim 2, wherein R 6 It is a member selected from the following: C 3- C 10 Heterocyclic alkyl, C 3- C 10 Heterocyclic alkenyl, C 3- C 10 Heterocyclic alkynyl, C 5- C 10 heteroaryl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkenyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkynyl and C 1- C6 alkylene C 5- C 10 Heteroaryl groups, wherein the member comprises one or more heteromers selected from the group consisting of O, S, S(O), SO2, and N, wherein the member optionally contains one or two C=O groups, and wherein the member is optionally substituted by one to four independent substituents selected from the group consisting of halogens, C 1- C6 alkyl, OR 13 and C(O)R 13 The member is optionally a substituted or unsubstituted polycyclic group or a substituted or unsubstituted benzofused group, wherein hydrogen atoms may optionally and independently be substituted with halogen atoms, and / or hydrogen atoms may optionally be substituted with their substituted isotopes.

11. The compound according to claim 1 or claim 2, wherein R 7 and R 8 Independently selected from H, D, F, Cl, Br, C 1- C4 alkyl, C 1- C4 fluoroalkyl, C 1- C4 deuterated alkyl and C 1- C4 deuterated fluoroalkyl group.

12. The compound of claim 1 or claim 2, wherein R 7 and R 8 are independently selected from H, F, and D.

13. The compound according to claim 1 or claim 2, wherein at least one R 9 Selected from D, halogen, C 1- C4 alkyl, C 1- C4 deuterated alkyl, C 1- C4 haloalkyl and C 1- C4 deuterated haloalkyl.

14. The compound according to claim 1 or claim 2, wherein at least one R 9 Selected from OH, OC 1- C4 alkyl, OC 1- C4 deuterated alkyl, OC 1- C4 fluoroalkyl, OC 1- C4 deuterated fluoroalkyl, C 1- C4 alkylene OH, C 1- C4 fluoroalkylene OH, C 1- C4 deuteride alkylene OH, C 1- C4 deuterated fluorine alkyl OH, C 1- C4 Alkylene OC 1- C4 alkyl, C 1- C4 Alkylene OC 1- C4 fluoroalkyl, C 1- C4 Alkylene OC 1- C4 deuterated alkyl, C 1- C4 Alkylene OC 1- C4 deuterated fluoroalkyl, C 1- C4 fluoroalkyl OC 1- C4 alkyl, C 1- C4 deuterated alkylene OC 1- C4 alkyl, C 1- C4 deuterated fluorine alkyl OC 1- C4 alkyl, C 1- C4 fluoroalkyl OC 1- C4 fluoroalkyl, C 1- C4 fluoroalkyl OC 1- C4 deuterated alkyl, C 1- C4 deuterated alkylene OC 1- C4 fluoroalkyl, C 1- C4 deuterated alkylene OC 1- C4 deuterated alkyl, C 1- C4 deuterated fluorine alkyl OC 1- C4 fluoroalkyl, C 1- C4 fluoroalkyl OC 1- C4 deuterated fluoroalkyl and C 1- C4 deuterated fluorine alkyl OC 1- C4 deuterated fluoroalkyl group.

15. The compound according to claim 1 or claim 2, wherein R 10 Selected from H, C 1- C6 alkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 1- C6 alkylene Z'R 14 C 2- C6 imene-Z'R 14 C 2- C6-Imyynyl Z'R 14 C 3- C7 cycloalkyl, C 3- C 10 Heterocyclic alkyl, C 6- C 10 Aryl, C 5- C 10 heteroaryl, C 1- C4 alkylene C 3- C7 cycloalkyl, C 1- C4 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C4 alkylene C 6- C 10 Aryl and C 1- C4 alkylene C 5- C 10 The heteroaryl group, the last eight groups being optionally substituted by one to four independent substituents selected from the following: halogen, C 1- C6 alkyl, OR 15 and C(O)R 15 In which hydrogen atoms may optionally be independently replaced by fluorine atoms and / or chlorine atoms, and / or hydrogen atoms may optionally be replaced by deuterium.

16. The compound according to claim 1 or claim 2, wherein R 10 It is a member selected from the following: C 3- C 10 Heterocyclic alkyl, C 3- C 10 Heterocyclic alkenyl, C 3- C 10 Heterocyclic alkynyl, C 5- C 10 heteroaryl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkenyl, C 1- C6 alkylene C 3- C 10 Heterocyclic alkynyl, C 1- C6 alkylene C 5- C 10 heteroaryl and C 1- C6 alkylene Z'R 14 C 2- C6 imene-Z'R 14 and C 2- C6-Imyynyl Z'R 14 , where R 14 It is C 3- C 10 Heterocyclic alkyl or C 5- C 10 Heteroaryl groups, wherein the member comprises one or more heteromers selected from the group consisting of O, S, S(O), SO2, and N, wherein the member optionally comprises one or two C=O groups, and wherein the member is optionally substituted by one to four independent substituents selected from the group consisting of halogens, C, and N. 1- C6 alkyl, OR 15 and C(O)R 15 The member is optionally a substituted or unsubstituted polycyclic group or a substituted or unsubstituted benzofused group, wherein hydrogen atoms may optionally and independently be substituted with halogen atoms, and / or hydrogen atoms may optionally be substituted with their substituted isotopes.

17. The compound of claim 1 or claim 2, wherein R 6 is selected from: , and .

18. The compound of claim 1 or claim 2, wherein R 6 and R 10 are independently selected from C1-C4 alkylene OCH3, C1-C4 alkylene OCHF2, C1-C4 alkylene OCH2F C1-C4 alkylene C(O)CHF2, C1-C4 alkylene C(O)CF3 。 19. The compound according to claim 1 or claim 2, wherein the compound of formula (I) is selected from the following table: Or its pharmaceutically acceptable salts, solvates and / or prodrugs.

20. The compound according to claim 1 or claim 2, wherein the compound of formula (I) is selected from the following table: Or its pharmaceutically acceptable salts, solvates and / or prodrugs.

21. The compound according to claim 1 or claim 2, wherein the compound of formula (I) is selected from the following table: Or its pharmaceutically acceptable salts, solvates and / or prodrugs.

22. The compound according to claim 1 or claim 2, wherein the compound of formula (I) is selected from the following table: Or its pharmaceutically acceptable salts, solvates and / or prodrugs.

23. A composition comprising one or more compounds according to claim 1 or claim 2 and a carrier.

24. A pharmaceutical composition comprising one or more compounds according to claim 1 or claim 2 and a pharmaceutically acceptable carrier.

25. A method for treating a mental illness, the method comprising administering to a subject in need a therapeutically effective amount of one or more compounds according to claim 1 or claim 2; wherein the mental illness is selected from anxiety disorders, generalized anxiety disorder, panic disorder, social anxiety disorder, specific phobias, depression, hopelessness, loss of pleasure, fatigue, suicidal ideation, mood disorders, depression, bipolar disorder, cancer-related depression, major depressive disorder (MDD), treatment-resistant depression (TRD), postpartum depression (PPD), anxiety, cyclothymic mood disorder, schizophrenia, impulse control, addiction disorder, pyrokinesis, kleptomania, compulsive gambling, etc. Alcohol addiction, drug addiction, opioid addiction, personality disorders, antisocial personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, obsessive-compulsive disorder (OCD), thoughts or fears that cause the subject to perform certain rituals or routines, post-traumatic stress disorder (PTSD), stress response syndrome, adjustment disorder, dissociative disorder, multiple personality disorder, "split personality", depersonalization disorder, affective disorder, sexual and gender disorders, sexual dysfunction, gender identity disorder, sexual abnormalities, somatic symptom disorder, psychosomatic disorder, somatic symptom disorder, physical deformity disorder; affecting goal-oriented behavior, mood state disorders, reducing negative emotions to promote positive emotions, enhancing creativity and its combinations.

26. A method for treating a central nervous system (CNS) disease, condition, or symptom and / or a neurological disease, condition, or symptom, said method comprising administering to a subject in need one or more therapeutically effective doses. The compound according to claim 1 or claim 2; wherein the central nervous system (CNS) disease, condition or symptom and / or neurological disease, condition or symptom is selected from neurological diseases, neurodevelopmental diseases, neurodegenerative diseases, Alzheimer's disease, early-onset dementia, senile dementia, vascular dementia, Lewy body dementia, cognitive impairment, Parkinson's disease, Parkinson's disease-related conditions, Parkinson's dementia, corticobasal degeneration, supranuclear palsy, epilepsy, CNS trauma, CNS infection, CNS inflammation, stroke, multiple sclerosis, Huntington's disease, mitochondrial diseases, Fragile X syndrome, Angelman syndrome, hereditary ataxia, neurogenic oculomotor disorders, retinal diseases. Neurodegenerative diseases of membranous lateral sclerosis, tardive dyskinesia, ADHD, attention deficit hyperactivity disorder and attention deficit disorder, restless legs syndrome, Tourette syndrome, schizophrenia, autism spectrum disorders, tuberous sclerosis, Tourette syndrome, cerebral palsy, reward system disorders including eating disorders, anorexia nervosa ("AN"), bulimia nervosa ("BN"), bulimia nervosa ("BED"), pica, rumination disorders, avoidance / restriction of food intake disorders, trichotillomania, scratching disorder, nail biting disorder, migraine, fibromyalgia, peripheral neuropathy of any etiology, decreased convergent thinking, increased spontaneous divergent thinking and goal-oriented divergent thinking and their combinations.

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