Indoline derivatives as serotonergic agents useful in the treatment of serotonin-related disorders

Abstract

The present application relates to a method for activating intracellular serotonin receptors using an indoline derivative of general formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, and a method for treating a disease, disorder, or condition by activating intracellular serotonin receptors. The disease, disorder, or condition includes, for example, psychosis, psychiatric disorders, and CNS disorders. The present application also relates to novel indoline derivatives, and compositions and uses thereof. wherein Q is selected from (Q1), (Q2), (Q3), (Q4), (Q5), and (Q6).

Description

[Technical Field]

[0001] (Related Applications) This application claims priority to co-pending U.S. Provisional Patent Application No. 63 / 401,847, filed August 29, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present application relates to a method for activating intracellular serotonin receptors using an indoline derivative of formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, and to treating various conditions, such as psychiatric and neurological disorders, that are treated by activating serotonin receptors in the fields of psychiatry, neurobiology, and pharmacotherapy. The present application also relates to an indoline derivative of formula IA and compositions thereof, and uses thereof. [Background technology]

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

[0004] The field of hallucinations neuroscience has recently re-emerged after decades of limited research due to legal restrictions. Hallucinogens (serotonergic hallucinogens) are potent psychoactive substances that alter perception and mood and affect numerous cognitive processes. Today, it is generally understood that hallucinogens are agonists or partial agonists of the brain's serotonin (5-hydroxytryptamine) 2A (5-HT2A) receptors.

[0005] Psychedelics have both immediate effects and long-lasting effects, including changes in mood and brain function. Long-lasting effects may be due to their unique receptor affinities (which affect neurotransmission through neuromodulator systems, which regulate brain activity, i.e., neuroplasticity and promote cell survival), providing neuroprotection and modulating the brain's neuroimmune system. The mechanisms underlying these long-term neuromodulator changes are related to epigenetic modifications, changes in gene expression, and modulation of pre- and postsynaptic receptor density. These previously understudied psychedelics may offer the next generation of neurotherapeutics, potentially enabling treatments with a low pharmacological risk profile for treatment-resistant psychiatric and neurological disorders, such as depression, post-traumatic stress disorder, dementia, and addiction.

[0006] Although hallucinogens are generally perceived as dangerous, from a physiological safety perspective, they are one of the safest known classes of central nervous system (CNS) drugs. Preliminary data indicate that administration of hallucinogens to humans results in a unique profile of potential adverse responses that must be appropriately addressed to maximize efficacy and safety. Primary safety concerns are primarily psychological rather than physiological in nature. Physical effects vary, but are relatively minor, even at potent psychoactive doses. When administered in a controlled environment, psilocybin has often been reported to produce a transient, delayed headache with dose-related increases in incidence, duration, and severity [Johnson et al., Drug Alcohol Depend (2012) 123(1-3):132-140]. Repeated administration of hallucinogens has been found to result in the very rapid development of tolerance known as tachyphylaxis, a phenomenon thought to be partially mediated by 5-HT2A receptors. Indeed, several studies have shown that rapid tolerance to hallucinogens correlates with downregulation of 5-HT2A receptors. For example, daily administration of LSD selectively reduced 5-HT2 receptor density 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] Classical and dissociative hallucinogens are known to have rapid-onset antidepressant and anti-addictive effects unlike any currently available treatment. Randomized, controlled clinical trials have confirmed the antidepressant and anxiolytic effects of classical hallucinogens in humans.

[0008] Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) has the chemical formula C 12 H 17It has NOP, a tryptamine, which is one of the major psychoactive components of the Shibiratake mushroom. It was first isolated from the Shibiratake mushroom by Hofmann in 1957 and later synthesized by him in 1958 [Passie et al. Addict Biol., 2002, 7(4):357-364] and was used in psychiatric and psychological research and psychotherapy from the early to mid-1960s until its scheduling as a controlled drug in the United States in the 1970s and in Germany in the 1980s [Passie 2005; Passie et al. Addict Biol., 2002, 7(4):357-364]. Research into the effects of psilocybin resumed in the mid-1990s, and it is now the preferred compound for use in studying the effects of serotonergic hallucinogens [Carter et al. J. Cogn. Neurosci., 2005 17(10):1497-1508; Gouzoulis-Mayfrank et al. Neuropsychopharmacology 1999, 20(6):565-581; Hasler et al. Psychopharmacology (Berl) 2004, 172(2):145-156], likely due to its shorter duration of action and less notorious nature compared to LSD. Like other members of this class, psilocybin induces sometimes profound changes in perception, cognition, and affect, including emotional lability.

[0009] In humans and other mammals, psilocybin is converted to its active metabolite, psilocin, or 4-hydroxy-N,N-dimethyltryptamine. Psilocybin likely partially or completely produces most of psilocybin's subjective and physiological effects in humans and nonhuman animals. Recent studies of psilocybin in humans have confirmed the 5-HT2A activity of psilocybin and psilocybin, providing some support for indirect effects on dopamine through 5-HT2A activity and activity at other serotonin receptors. Indeed, the most consistent finding regarding the involvement of other receptors in the action of hallucinogens is the 5-HT1A receptor. This is particularly true for tryptamines and LSD, which generally have significant affinity and functional capacity for this receptor. 5-HT1A receptors colocalize with 5-HT2A receptors on cortical pyramidal cells [Martin-Ruiz et al. J Neurosci. 2001, 21(24):9856-986], and the two receptor types are known to have opposing functional effects [Araneda et al. Neuroscience 1991, 40(2):399-412].

[0010] Although the precise role of the 5-HT2A receptor and other 5-HT2 receptor family members in the amygdala is not fully understood, it is clear that the 5-HT2A receptor plays a key role in emotional responses and is an important target to consider in the actions of 5-HT2A agonist hallucinogens. Indeed, the majority of known 5-HT2A agonists produce hallucinogenic effects in humans, and rodents generalize from one 5-HT2A agonist to another, such as from psilocybin to LSD [Aghajanian et al., Eur J Pharmacol., 1999, 367(2-3):197-206; Nichols et al., J Neurochem., 2004, 90(3):576-584]. Psilocybin has a stronger affinity for human 5-HT2A receptors than for rat receptors, and psilocybin has a lower K(i) than LSD for both 5-HT2A and 5-HT2C receptors. Furthermore, results from a series of drug discrimination tests in rats found that 5-HT2A antagonists, but not 5-HT1A antagonists, prevented rats from recognizing psilocybin [Winter et al., Pharmacol Biochem Behav., 2007, 87(4):472-480]. Daily doses of LSD and psilocybin decrease 5-HT2 receptor density in the rat brain.

[0011] Today, psilocybin is one of the most widely used hallucinogens in human research due to its relative safety, moderately long duration of activity, and good absorption in subjects. It has shown varying degrees of success in treating neurotic disorders, alcoholism, depression in terminal cancer patients, obsessive-compulsive disorder, addiction, anxiety, post-traumatic stress disorder, and even cluster headaches, suggesting strong research and therapeutic potential for psilocybin. It may also be useful as a psychosis model for developing novel treatments for psychotic disorders. [Dubovyk and Monahan-Vaughn, ACS Chem. Neurosci. (2018), 9(9):2241-2251]

[0012] Recent advances in the field have occurred in clinical trials, including several double-blind, placebo-controlled, phase 2 trials of psilocybin-assisted psychotherapy in patients with treatment-resistant, major depressive disorder, and cancer-related psychosocial distress, which have demonstrated unprecedented positive relief of anxiety and depression. Two recent small pilot trials of psilocybin-assisted psychotherapy have also demonstrated positive benefits in the treatment of both alcoholism and nicotine dependence. Recently, blood oxygen level-dependent functional magnetic resonance imaging and magnetoencephalography have been used for in vivo brain imaging in humans after hallucinogen administration, and results indicate that intravenously administered psilocybin and LSD produced a decrease in oscillatory power in regions of the brain's default mode network [Nichols DE. Pharmacol Rev., 2016, 68(2):264-355].

[0013] Preliminary studies using positron emission tomography (PET) have shown that in healthy participants, psilocybin ingestion (15 or 20 mg orally) increased absolute glucose metabolic rates in the frontal cortex and, to a lesser extent, in other cortical regions and in the striatum and limbic subcortical structures, suggesting that some of psilocybin's key behavioral effects involve the frontal cortex [Gouzoulis-Mayfrank et al., Neuropsychopharmacology, 1999, 20(6):565-581; Vollenweider et al., Brain Res. Bull. 2001, 56(5):495-507]. Although 5-HT2A agonism is widely recognized as the primary action of classical hallucinogens, psilocybin has lower affinity for a wide range of other pre- and postsynaptic serotonin and dopamine receptors, as well as the serotonin reuptake transporter [Tyls et al., Eur. Neuropsychopharmacol., 2014, 24(3):342-356]. Psilocybin activates 5-HT1A receptors, which may contribute to its antidepressant / anxiety effects.

[0014] Depression and anxiety are two of the most common mental disorders worldwide. Depression is a multifaceted condition characterized by mood disturbances and other symptoms, such as episodes of anhedonia, psychomotor symptoms, guilt, attention deficits, and suicidal ideation, all of which can vary in severity. Similarly, anxiety disorders are a collection of etiologically complex disorders characterized by intense psychosocial distress and other symptoms depending on the subtype. Anxiety associated with life-threatening illnesses is the only anxiety subtype that has been studied from the perspective of hallucinogen-assisted therapy. Pharmacological and psychosocial interventions are commonly used to manage this type of anxiety, but their efficacy is mixed and limited, such that they often fail to provide sufficient emotional relief. Recent interest in the use of hallucinogen-assisted therapy may represent a promising alternative for patients with depression and anxiety ineffectively managed by conventional methods.

[0015] Generally, the hallucinogen treatment model involves administering an orally active drug to induce a mystical experience lasting 4–9 hours, depending on the hallucinogen [Halberstadt, Behav Brain Res., 2015, 277:99–120; Nichols, Pharmacol Rev., 2016, 68(2):264–355]. This allows participants to confront and integrate difficult emotions and situations, leading to lasting antidepressant and anxiolytic effects. Classic hallucinogens such as psilocybin and LSD are being investigated as potential candidates. One study using classic hallucinogens for the treatment of depression and anxiety associated with life-threatening illness found that, in a supportive environment, psilocybin and LSD consistently produced significant and sustained antidepressant and anxiolytic effects.

[0016] Psychedelic treatments are generally well tolerated with no persistent side effects. Their primary therapeutic effects are mediated biochemically through serotonin receptor agonism and psychologically by eliciting meaningful psychospiritual experiences that contribute to mental flexibility. Given the limited success of current treatments for anxiety and mood disorders and the high morbidity associated with these conditions, psychedelics have the potential to alleviate symptoms in patients who are inadequately managed by conventional methods.

[0017] Furthermore, emerging clinical research and evidence suggests that psychedelic-assisted therapy may also show promise as an alternative treatment for refractory substance use disorders and mental health conditions, and therefore may be an important tool in crisis situations where existing approaches have had limited success [dos Santos et al., Ther Adv Psychopharmacol., 2016, 6(3):193-213]. Similarly encouraging, findings from a recent pilot study of psilocybin-assisted therapy for tobacco use disorder demonstrated an 80% abstinence rate at 6-month follow-up and a 67% abstinence rate at 12-month follow-up [Johnson et al., https: / / www.ncbi.nlm.nih.gov / pubmed / 27441452J Drug Alcohol Abuse, 2017, 43(1):55-60; Johnson et al., Psychopharmacol. 2014, 28(11):983-992]; these rates are significantly higher than those documented in any smoking cessation literature. Notably, the mystical-type experiences produced by psilocybin sessions were significantly correlated with positive treatment outcomes. These results are consistent with a growing body of evidence from recent clinical trials supporting the efficacy of psilocybin-assisted therapy for treatment-resistant depression and end-of-life anxiety [Carhart-Harris et al. Neuropsychopharmacology, 2017, 42(11):2105-2113]. Research on the potential benefits of psychedelic-assisted therapy for opioid use disorder (OUD) is beginning to emerge, and evidence is accumulating to support the need to advance this line of research. Available evidence from a previous randomized clinical trial suggests a promising role for treating OUD: higher rates of drug withdrawal were observed at long-term follow-up in participants receiving high-dose LSD- and ketamine-assisted therapy for heroin dependence compared with controls.Recently, a large-scale US population study of 44,000 individuals found that hallucinogen use, as defined by DSM-IV criteria, was associated with a 40% lower risk of next-year opioid abuse and a 27% lower risk of next-year opioid dependence [Pisano et al., J Psychopharmacol., 2017, 31(5):606-613]. Similarly, a protective moderating effect of hallucinogen use was found in the relationship between prescription opioid use and suicide risk among marginalized women [Argento et al., J Psychopharmacol., 2018, 32(12):1385-1391]. Despite these promising preliminary findings about classic hallucinogens, further research is warranted to determine what may contribute to the opioid crisis response, given their potential toxicity. Meanwhile, growing evidence of the safety and efficacy of psilocybin for psychiatric and substance use disorders should help motivate further clinical research into its use as a novel intervention for OUD.

[0018] Sleep disorders are common among depressed patients, with over 80% complaining of poor sleep quality. Regular doses of hallucinogens can also improve sleep problems. These sleep symptoms often do not resolve with first-line treatment, carrying a greater risk of relapse and recurrence. Interestingly, sleep problems often appear before other depressive symptoms, and subjective sleep quality deteriorates before the onset of an episode of depressive relapse. Two other studies evaluating electroencephalographic (EEG) brain activity during sleep have shown that hallucinogens, such as LSD, positively affect sleep patterns. Furthermore, partial or overnight sleep deprivation has been shown to alleviate depressive symptoms, suggesting that this is due to resetting the circadian rhythm through modification of clock gene expression. It has further been suggested that a single dose of hallucinogens can cause a reset of the body's internal clock, which underlies the sleep / wake cycle, and in doing so enhance cognitive-emotional processes in depressed people, as well as increase feelings of well-being and improve mood in healthy individuals [Kuypers, Medical Hypotheses, 2019, 125:21-24].

[0019] A systematic meta-analysis of clinical trials from 1960 to 2018 that used psychedelics to treat patients with serious or terminal illnesses and associated psychiatric disorders found that psychedelic therapy (mostly LSD-based) may improve cancer-related depression, anxiety, and fear of death. Four randomized controlled clinical trials published between 2011 and 2016, mostly psilocybin-based, demonstrated that psychedelic-assisted therapy can produce rapid, robust, and sustained improvements in cancer-related psychological and existential distress [Ross S, Int Rev Psychiatry, 2018, 30(4):317-330]. Therefore, the use of psychedelics in oncology and palliative care is of interest for several reasons. First, many patients facing cancer or other life-threatening illnesses experience significant existential distress related to a loss of meaning or purpose in life, which can be associated with hopelessness, demoralization, feelings of helplessness, perceived burdensomeness, and a desire for an early death. These characteristics are often central to clinically significant anxiety and depression, which can substantially reduce the quality of life in this patient population. Alleviating these forms of distress should be a central goal of palliative care. Accordingly, several manualized psychotherapies for cancer-related existential distress, focusing on dignity and meaning, have been developed in recent years. However, there are currently no pharmacological interventions for existential distress itself, and available pharmacological treatments for depressive symptoms in cancer patients have not demonstrated superiority over placebo. There remains a need for additional effective treatments for these conditions [Rosenbaum et al., Curr. Oncol., 2019, 26(4):225-226].

[0020] Recently, there has been growing interest in a new administration paradigm for hallucinogens such as psilocybin and LSD, colloquially referred to as microdosing.In this paradigm, a sub-perceptual dose of serotonergic hallucinogens, approximately 10% or less of the total dose, is taken on a more consistent basis, such as once a day, once every two days, or once every three days.This administration paradigm is not only consistent with the current standard of pharmacological care, but may also be particularly beneficial for some pathologies, such as Alzheimer's disease and other neurodegenerative diseases, attention deficit disorder, attention deficit hyperactivity disorder, and for some patient groups, such as elderly patients, young patients, and patients who are afraid of or opposed to hallucinogen-assisted therapy.Furthermore, this approach may be particularly suitable for managing cognitive impairment and preventing neurodegeneration. For example, subpopulations of attentive and disengaged rats showed improved performance on a five-choice reaction time task and a progressive ratio task after subthreshold psilocybin doses that elicited the classic wet dog shake behavioral response associated with hallucinogenic doses (Blumstock et al., WO2020 / 157569 A1; Higgins et al., Front. Pharmacol., 2001, DOI:10.3389). Similarly, treating patients with hallucinogenic doses of a 5HT2A agonist increased BDNF and activated the mTOR pathway, which is thought to promote neuroplasticity and may serve as a molecular target for treating dementia and other neurodegenerative disorders (Ly et al., Cell Rep., 2018, 23(11):3170-3182).Additionally, several groups have demonstrated that low, non-hallucinogenic, and non-psychotropic doses of 5HT2A agonists also exhibit similar neuroprotective, neuroplasticity-enhancing (neuroplastogenic) and neuroinflammation-reducing effects, which may be beneficial for both neurodegenerative and neurodevelopmental disorders, as well as chronic disorders (Manfredi et al., WO2020 / 181194; Flanagan et al., Int. Rev. Psychiatry, 2018, 13:1-13; Nichols et al., 2016, Psychedelics as medicines; an emerging new paradigm). Such repeated low-dose paradigms may prove useful for extending the utility of these compounds to additional indications and health applications.

[0021] Psychosis is often referred to as an abnormal mental state characterized by hallucinatory experiences, delusional thoughts, and disordered thoughts. This state is further accompanied by social-cognitive dysfunction, inappropriate emotional expression, and bizarre behavior. In most cases, psychosis manifests as a subset of psychiatric disorders, particularly schizophrenia. It corresponds to the most aggressive phase of the illness. The first symptom of psychosis in a patient is called first-episode psychosis. It reflects a critical transition toward chronic disease establishment, i.e., it is presumed to be mediated by progressive abnormalities in structure and function observed in diagnosed patients. [ACS Chem. Neurosci., 2018, 9, 2241-2251]. There is scant evidence to support the suggestion that regularly administered small, non-hallucinogenic doses (microdosing) of hallucinogens can reduce the symptoms of schizophrenia and psychosis. Summary of the Invention

[0022] Applicants have discovered that indoline derivatives modulate the activity of serotonin receptor subtypes, particularly 5-HT2A, by directly binding to these receptors.

[0023] Accordingly, the present application includes a method for treating a disease, disorder, or condition through activation of a serotonin receptor, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] [In formula: R 1 and R 1 ' is independently H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxyl, NH(C 1~6 alkyl) and N(C 1~6 alkyl)2; R 2 and R 2 ' is independently H, halo, NH2, C 1~6 Alkyl, C 1~6 Alkoxyl, NH(C 1~6 alkyl) and N(C 1~6 alkyl)2; Q is Q1, Q2, Q3, Q4, Q5 and Q6: [ka] Selected from the structure: [ka] is a single or double bond, provided that the structure in Q1: [ka] is a double bond, R 9 and R 15 does not exist, and the structure in Q2: [ka] is a double bond, R 17 and R 25 does not exist, and the structure in Q5: [ka] is a double bond, R 48 and R 57 does not exist; R 4 and R 5 One or both of may independently be H, halo, or C 1~6 Alkyl and C 1~6 alkoxy; R 4 and R 5 together to form O-(CH2) 1~2 Form O, or R 4 and R 5 One of the two is selected from XLA and R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy; X is a direct bond, O, C(O), or NR a , N.R. a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a Selected from; L is a direct bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 1~6 Alkylene O, C 2~6 Alkenylene O,C 1~6 Alkylene C(O), C 2~6 Alkenylene C(O), C 1~6 Alkylene NR b C(O), C 2~6 Alkenylene NR b C(O), C 1~6 AlkyleneC(O)NR b , C 2~6 AlkenyleneC(O)NR b , C 1~6 Alkylene OC(O), C 2~6 Alkenylene OC(O), C1~6 Alkylene C(O)O, C 2~6 Alkenylene C(O)O, C 1~6 Alkylene OC(O)NR b , C 2~6 Alkenylene OC(O)NR b , C 1~6 Alkylene NR b C(O)OC 2~6 Alkenylene NR b C(O)O, C 1~6 Alkylene O-C(O)O, C 2~6 Alkenylene O-C(O)O, C 1~6 Alkylene NR b C(O)NR b and C 2~6 Alkenylene NR b C(O)NR b Selected from; R a is H and C 1~6 alkyl; R b is H, C 1~6 alkyl and A; A is H, C 1~30 Alkyl, C 2~30 Alkenyl, phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 64 and 3-6 membered heterocycloalkyl containing 1-4 hetero moieties independently selected from O, S, S(O), SO, N, and NR 64 wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with halo, C 1~4 Alkyl and OC 1~4 optionally substituted with one or more substituents independently selected from alkyl; R 3 and R 6 H, halo, OH, C 1~6 Alkyl and C 1~6 independently selected from alkoxy; R8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently H, halo, and C 1~6 alkyl; R 12 , R 20 , R 29 , R 39 and R 51 are independently H, C 1~6 Alkyl, C(O)C 1~6 selected from alkyl and C(O)-A'; R 60 and R 61 are independently H and C 1~6alkyl; or R 60 and R 61 One of them is C(O)-A' and the other is H and C 1~6 alkyl; where A' is Y, OY and OC 1~4 alkylene-OC(O)-Y; Y is C 7~30 Alkyl and C 7~30 alkenyl; or R 60 and R 61 together with the nitrogen atom to which they are attached, form O, S, S(O), SO2, N, and NR 65 and optionally includes one or two additional hetero moieties selected from halo, OH, C 1~4 Alkyl and OC 1~4 forming a 3- to 6-membered heterocyclic ring optionally substituted with one or more substituents independently selected from alkyl; R 64 and R 65 are independently H and C 1~6 alkyl; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; provided that when Q is Q6, the compound of formula I includes D].

[0024] The present application also includes a method of treating psychosis or psychotic symptoms, the method comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need of treatment.

[0025] The present application also includes methods of treating psychiatric disorders, the methods comprising administering to a subject in need of treatment a therapeutically effective amount of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof.

[0026] The present application also includes methods of treating CNS diseases, disorders or conditions, and / or neurological disorders, comprising administering to a subject in need of treatment a therapeutically effective amount of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof.

[0027] The present application includes one or more compounds of formula IA, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof [ka] [In formula: R 1 and R 1 ' is independently H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxyl, NH(C 1~6 alkyl) and N(C 1~6 alkyl)2; R 2 and R 2 ' is independently H, halo, NH2, C 1~6 Alkyl, C 1~6 Alkoxyl, NH(C 1~6 alkyl) and N(C 1~6 alkyl)2; Q is Q1, Q2, Q3, Q4, Q5 and Q6: [ka] Selected from the structure: [ka] is a single or double bond, provided that the structure in Q1: [ka] is a double bond, R 9 and R 15 does not exist, Structure in Q2: [ka] is a double bond, R 17 and R 25 does not exist, and the structure in Q5: [ka] is a double bond, R 48 and R 57 does not exist; R 4 and R 5 One or both of may independently be H, halo, or C 1~6 Alkyl and C 1~6 alkoxy; R 4 and R 5 together to form O-(CH2) 1~2 Form O, or R 4 and R 5 One of them is selected from XLA and R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy; X is a direct bond, O, C(O), or NR a , N.R. a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a Selected from; L is a direct bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 1~6 Alkylene O, C 2~6 Alkenylene O,C 1~6 Alkylene C(O), C 2~6 Alkenylene C(O), C 1~6 Alkylene NR b C(O), C 2~6 Alkenylene NR b C(O), C 1~6 AlkyleneC(O)NRb , C 2~6 AlkenyleneC(O)NR b , C 1~6 Alkylene OC(O), C 2~6 Alkenylene OC(O), C 1~6 Alkylene C(O)O, C 2~6 Alkenylene C(O)O, C 1~6 Alkylene OC(O)NR b , C 2~6 Alkenylene OC(O)NR b , C 1~6 Alkylene NR b C(O)O, C 2~6 Alkenylene NR b C(O)O, C 1~6 Alkylene O-C(O)O, C 2~6 Alkenylene O-C(O)O, C 1~6 Alkylene NR b C(O)NR b and C 2~6 Alkenylene NR b C(O)NR b Selected from; R a is H and C 1~6 alkyl; R b is H, C 1~6 alkyl and A; A is H, C 1~30 Alkyl, C 2~30 Alkenyl, phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 64 and 3-6 membered heterocycloalkyl containing 1-4 hetero moieties independently selected from O, S, S(O), SO, N, and NR 64 and wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with halo, C 1~4 Alkyl and OC 1~4 optionally substituted with one or more substituents independently selected from alkyl; R 3and R 6 are independently H, halo, OH, C 1~6 Alkyl and C 1~6 selected from alkoxy; R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently H, halo, and C 1~6 alkyl; R 12 , R 20 , R 29 , R 39 and R 51 are independently H, C 1~6 Alkyl, C(O)C 1~6selected from alkyl and C(O)-A'; R 60 and R 61 are independently H and C 1~6 alkyl; or R 60 and R 61 One of them is C(O)-A' and the other is H and C 1~6 alkyl; A' is Y, OY and OC 1~4 alkylene-OC(O)-Y; Y is C 7~30 Alkyl and C 7~30 alkenyl; or R 60 and R 61 together with the nitrogen atom to which they are attached, form O, S, S(O), SO2, N, and NR 65 and optionally includes one or two additional hetero moieties independently selected from halo, OH, C 1~4 Alkyl and OC 1~4 forming a 3- to 6-membered heterocyclic ring, optionally substituted with one or more substituents independently selected from alkyl; R 64 and R 65 are independently H and C 1~6 alkyl; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; with the proviso that when Q is Q6, the compound of formula I includes D, If Q is Q3 or Q4, then R 5 is H or OCH3, and R 29 or R 39 If is CH3, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 6 , R 26 , R 27, R 28 , R 30 ~R 35 , R 36 , R 37 , R 38 and R 40 ~R 47 is not all H, Q is Q4 and R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 6 , R 38 and R 40 ~R 47 are all H, and R 39 If is CD3, R 36 and R 37 are not both D].

[0028] The present application additionally provides processes for preparing the compounds of the present application, the general and specific processes being discussed in detail below and presented in the examples below.

[0029] Other features and advantages of the present application will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while showing embodiments of the present application, are given by way of example only, and the scope of the claims is not limited by these embodiments, but should be accorded the broadest interpretation consistent with the entire description. DETAILED DESCRIPTION OF THE INVENTION

[0030] (Detailed explanation) I. Definition Unless otherwise stated, the definitions and embodiments set forth in this and other sections are intended to be applicable to all embodiments and aspects of this application and are appropriately described herein as understood by one of ordinary skill in the art.

[0031] The terms "compound(s) of the present application" or "compound(s) of the present application," and the like, as used herein, refer to compounds of Formula I and IA, including pharmaceutically acceptable salts, solvates and / or prodrugs thereof, and all stereoisomers and positional isomers thereof.

[0032] The terms "composition(s) of the present application" or "composition(s) of the present application" and the like, as used herein, refer to a composition, e.g., a pharmaceutical composition, comprising one or more compounds of the present application.

[0033] The term "and / or," as used herein, refers to the presence or use of the listed items, either individually or in combination. In effect, the term means that "at least one" or "one or more" of the listed items are used or present. With respect to pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, the term "and / or" means that the compounds of the present application are present as individual salts, solvates, and / or prodrugs, as well as in combinations, e.g., solvate salts of the compounds of the present application.

[0034] As used in this application, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, an embodiment including "a compound" should be understood to represent one compound, or several embodiments with two or more additional compounds.

[0035] As used in this application and in the claims, the words "comprising" (and any form of comprising, e.g., "comprise" and "comprises"), "having" (and any form of having, e.g., "have" and "has"), "including" (and any form of including, e.g., "include" and "includes" or "containing" (and any form of containing, e.g., "contain" and "contains") are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0036] The term "consisting of" and its derivatives, as used herein, is intended to be a qualifying term specifying the presence of stated features, elements, components, groups, integers and / or steps, and excluding the presence of other unstated features, elements, components, groups, integers and / or steps.

[0037] The term "consisting essentially of," as used herein, is intended to identify the presence of the stated features, elements, components, groups, integers, and / or steps, and that which does not materially affect the basic property(ies) and novel property(ies) of those features, elements, components, groups, integers, and / or steps.

[0038] In embodiments that include an "additional" or "second" component, e.g., an additional or second compound, the second component, as used herein, is chemically distinct from the other or first component. A "third" component is different from the other, first, or second component, and further listed or "additional" components are similarly distinct.

[0039] The term "suitable," as used herein, means that the selection of a particular compound or conditions will depend on the specific synthetic operation being performed, the properties of the molecule(s) being altered, and / or the specific use of the compound, but such selection would be well within the skill of one of ordinary skill in the art. All process / method steps described herein are carried out under conditions sufficient to provide the indicated product. One of ordinary skill in the art will understand that all reaction conditions, such as reaction solvent, reaction time, reaction temperature, reaction pressure, ratio of reactants, and whether the reaction should be carried out under anhydrous conditions or an inert atmosphere, can be varied to optimize production of the desired product, and this is within the skill of one of ordinary skill in the art.

[0040] The terms "about," "substantially," and "approximately," as used herein, refer to a reasonable amount of deviation from the modified word that does not significantly change the end result. These terms of degree should be interpreted as including a deviation of at least ±5% of the modified word, unless the deviation would negate the meaning of the modified word or the context would suggest otherwise to one of ordinary skill in the art.

[0041] This description makes reference to numerous chemical terms and abbreviations used by those of ordinary skill in the art. Nonetheless, definitions of selected words are provided for clarity and consistency.

[0042] The term "solvate" as used herein means a compound or a salt and / or prodrug of a compound, wherein suitable solvent molecules are incorporated into the crystal lattice.

[0043] The term "prodrug," as used herein, means a compound or a salt of a compound that is converted into an active drug after administration.

[0044] The term "alkyl," as used herein, whether used alone or as part of another group, refers to a straight or branched chain saturated alkyl group. The possible number of carbon atoms in the referenced alkyl group is indicated by the prefix "C n1-n2 ". Thus, for example, the term "C 1~6 "Alkyl" (or "C1-C6 alkyl") means an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0045] The term "alkenyl," as used herein, whether used alone or as part of another group, refers to a saturated alkenyl group that is straight or branched and contains at least one double bond. The possible number of carbon atoms in the referenced alkenyl group is indicated by the prefix "C n1-n2 ". Thus, for example, the term "C 2~6 "Alkyl" (or "C2-C6 alkyl") means an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms.

[0046] The term "alkenylene," as used herein, whether used alone or as part of another group, refers to a straight or branched chain unsaturated alkylene group, i.e., an unsaturated carbon chain containing substituents at both ends thereof and containing at least one double bond. The possible number of carbon atoms in the referenced alkenylene group is indicated by the prefix "C n1~n2 For example, the term C 2~6 Alkenylene means an alkenylene group having 2, 3, 4, 5 or 6 carbon atoms.

[0047] The term "alkoxy" as used herein, alone or in combination, includes an alkyl group bound to an atom which is bound to an oxygen.

[0048] The term "cycloalkyl," as used herein, whether used alone or as part of another group, refers to a saturated carbocyclic group containing from 3 to 6 carbon atoms and one or more rings. The possible number of carbon atoms in a referenced cycloalkyl group is determined by the numerical prefix "C n1~n2 For example, the term C 3~6 Cycloalkyl means a cycloalkyl group having 3, 4, 5 or 6 carbon atoms.

[0049] The term "heterocycloalkyl," as used herein, whether used alone or as part of another group, refers to a heterocycloalkyl group containing 3 to 6 atoms, one or more of which may be O, S, S(O), SO, NH, NC, or a combination thereof. 1~6 Heterocycloalkyl groups refer to cyclic groups containing at least one non-aromatic ring containing a hetero group (hetero group selected from alkyl and N, with the remaining atoms being C). Heterocycloalkyl groups are either saturated or unsaturated (i.e., contain one or more double bonds). Heterocycloalkyl groups are defined by the prefix C. n1~n2 or "n1-n2", this prefix refers to the number of carbon atoms in the corresponding carbocyclic group, where one or more, preferably 1 to 4, of the ring atoms are O, S, S(O), SO2, NH, NC 1~6 substituted with hetero moieties selected from alkyl and N, the remaining atoms being C;

[0050] The term "aryl," as used herein, whether used alone or as part of another group, refers to a carbocyclic group containing at least one aromatic ring and containing from 6 to 10 carbon atoms.

[0051] The term "heteroaryl," as used herein, whether used alone or as part of another group, refers to a cyclic group containing at least one heteroaromatic ring containing 5 to 6 atoms, of which one or more atoms are heteroatoms selected from O, S, and N, and the remaining atoms are C. A heteroaryl group is denoted by the prefix C. n1~n2When included, the prefix refers to the number of carbon atoms in the corresponding carbocyclic group, where one or more, preferably one to four, of the ring atoms is replaced by a heteroatom as defined above.

[0052] The term "halogen" (or "halo"), whether used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo, and iodo.

[0053] The term "haloalkyl," as used herein, refers to an alkyl group, as defined above, in which one or more available hydrogen atoms has been replaced with a halogen. Thus, for example, "C 1~6 "Haloalkyl" refers to a C1 to C6 straight or branched chain alkyl group as defined above having one or more halogen substituents.

[0054] The term "deuteroalkyl," as used herein, refers to an alkyl group, as defined above, in which one or more available hydrogen atoms have been replaced with deuterium. Thus, for example, "C 1~6 "Deuteroalkyl" refers to a C1-C6 straight or branched chain alkyl group as defined above having one or more deuterium substituents.

[0055] The term "available" as in "available hydrogen atom" or "available atom" refers to an atom known by those skilled in the art to be replaceable with a substituent.

[0056] As used herein, the term "one or more" includes a single item selected from the list and a mixture of two or more items selected from the list.

[0057] The term "alternative isotopes thereof," as used herein, refers to isotopes of an element other than the isotope that is most prevalent in nature. In the compounds of general formula I and IA, and their pharmaceutically acceptable salts, solvates, and / or prodrugs, atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number that predominates in nature. The present application is intended to include all appropriate isotopic variations of the compounds of general formula I and IA, and their pharmaceutically acceptable salts, solvates, and / or prodrugs. For example, protium ( 1 H), deuterium ( 2 H) and tritium ( 3 Protium is the predominant hydrogen isotope found in nature.

[0058] The term "compound" refers to the compound, and in some embodiments, to any hydrates or solvates thereof, to the extent they are stable. A hydrate is a compound complexed with water, and a solvate is a compound complexed with a solvent, which may be an organic or inorganic solvent. A "stable" compound is one that can be prepared and isolated, and whose structure and properties remain essentially unchanged or essentially unchanged for a period of time sufficient to use the compound for the purposes described herein (e.g., administering a therapeutic agent to a subject). The compounds of the present application are limited to stable compounds encompassed by the general formula (IA), or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0059] The term "pharmaceutically acceptable" refers to compatible with the treatment of a subject.

[0060] The term "pharmaceutically acceptable carrier" refers to a non-toxic solvent, dispersant, excipient, adjuvant or other material that is mixed with an active ingredient to enable the formulation of a pharmaceutical composition, i.e., a dosage form that can be administered to a subject.

[0061] The term "pharmaceutically acceptable salt" means either an acid addition salt or a base addition salt which is appropriate or compatible with the treatment of a subject.

[0062] Acid addition salts suitable or compatible for the treatment of a subject are any non-toxic organic or inorganic acid addition salts of any basic compounds.

[0063] A base addition salt that is suitable or compatible for the treatment of a subject is any non-toxic organic or inorganic base addition salt of any acidic compound.

[0064] The term "protecting group" or "PG" as used herein refers to a chemical moiety that protects or masks a reactive site of a molecule, preventing side reactions at that reactive site while a different site of the molecule is manipulated or reacted. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remainder of the molecule. The selection of an appropriate protecting group can be made by one skilled in the art. Many conventional protecting groups are known in the art and are described, for example, in "Protective Groups in Organic Chemistry" McOmie, JFW Ed., Plenum Press, 1973, in Greene, TW and Wuts, PGM, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3rd Edition, 1999, and Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0065] The term "subject," as used herein, includes all members of the animal kingdom, including mammals, and suitably refers to humans. Thus, the methods of the present application are applicable to both human therapy and veterinary uses.

[0066] The terms "treating" or "treatment," as used herein and as well understood in the art, refer to an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in disease extent, stabilized (i.e., not worsening) disease, preventing disease spread, delay or slowing of disease progression, palliative care, reduction in disease recurrence, and remission (partial or complete remission), which may or may not be detectable. "Treating" and "treatment" can also mean prolonging survival compared to expected survival in the absence of treatment. "Treating" and "treatment," as used herein, also include prophylactic treatment. For example, a subject with an early stage neurological disease can be treated to prevent progression, or a subject in remission can be treated with a compound or composition of the present application to prevent recurrence. The method of treatment involves administering to the subject a therapeutically effective amount of one or more compounds of the present application, which may consist of a single dose or may include a series of multiple doses, as appropriate.

[0067] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of one or more compounds of the present application that is effective at dosages and for periods of time necessary to achieve a desired result. For example, in the context of treating a disease, disorder, or condition mediated or treated by agonism or activation of serotonergic receptors and downstream second messengers, an effective amount is, for example, an amount that improves activation compared to the activation when one or more compounds are not administered.

[0068] "Palliating" a disease, disorder, or condition means reducing the severity and / or undesirable clinical symptoms of the disease, disorder, or condition and / or slowing or prolonging the course of progression compared to not treating the disorder.

[0069] The term "administered," as used herein, means administering a therapeutically effective amount of one or more compounds or compositions of the present application to a cell, tissue, organ, or subject.

[0070] The terms "prevention" or "prophylaxis," or synonyms thereof, as used herein, refer to reducing the risk or likelihood that a patient will acquire a disease, disorder, or condition, or develop symptoms associated with a disease, disorder, or condition.

[0071] "Disease, disorder or condition," as used herein, refers to any condition that results from activation of serotonin receptors (e.g., 5-HT 2A The term "disease, disorder, or condition" refers to a disease, disorder, or condition that is treated or treatable by a serotonin receptor agonist, particularly using one or more of the compounds of the present application described herein. The disease, disorder, or condition may also be a disease, disorder, or condition that is caused by another mechanism, such as activation of a serotonin receptor (5-HT 2A and / or 5-HT 1A The present invention may be treated or treatable by modulation, inactivation, antagonism or inverse agonism of a neurotransmitter, including

[0072] The term "treating a disease, disorder, or condition by activating serotonin receptors," as used herein, means that the disease, disorder, or condition to be treated is directly or indirectly affected, modulated, and / or has some biological basis that includes (particularly increases) serotonergic activity. These diseases preferably respond when the serotonergic activity associated with the disease, disorder, or condition is modulated (e.g., agonized) by one or more compounds or compositions of the present application.

[0073] The term "activation" as used herein includes agonism, partial agonism, and positive allosteric modulation of serotonin receptors.

[0074] The term "5-HT 1A " and "5-HT2A " as used herein refers to the activity of the 5-HT serotonin receptor, 1A and 5-HT 2A It refers to the receptor subtype.

[0075] The term "therapeutic agent," as used herein, refers to any drug or active agent that has a pharmacological effect when administered to a subject.

[0076] II. Methods and Uses of the Present Application The applicant has found that indoline derivatives are useful for treating diseases, disorders, or conditions by modulating (e.g., activating) serotonin receptors. Accordingly, indoline derivatives are useful as pharmaceuticals. Accordingly, the present application also includes indoline derivatives for use as pharmaceuticals.

[0077] Accordingly, the present application includes methods for treating a disease, disorder, or condition by activating a serotonin receptor, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] [In formula: R 1 and R 1 ' is independently H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxyl, NH(C 1~6 alkyl) and N(C 1~6 alkyl)2; R 2 and R 2 ' is independently H, halo, NH2, C 1~6 Alkyl, C 1~6 Alkoxyl, NH(C 1~6 alkyl) and N(C 1~6 alkyl)2; Q is Q1, Q2, Q3, Q4, Q5 and Q6: [ka] Selected from; structure: [ka] is a single or double bond, provided that the structure in Q1: [ka] is a double bond, R 9 and 15 does not exist, and the structure in Q2: [ka] is a double bond, R 17 and R 25 does not exist, and the structure in Q5: [ka] is a double bond, R 48 and R 57 does not exist; R 4 and R 5 One or both of may independently be H, halo, or C 1~6 Alkyl and C 1~6 alkoxy; R 4 and R 5 together to form O-(CH2) 1~2 Form O, or R 4 and R 5 One of them is selected from XLA and R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy; X is a direct bond, O, C(O), or NR a , N.R. a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NRa C(O)O, OC(O)NR a and N.R. a C(O)NR a Selected from; L is a direct bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 1~6 Alkylene O, C 2~6 Alkenylene O,C 1~6 Alkylene C(O), C 2~6 Alkenylene C(O), C 1~6 Alkylene NR b C(O), C 2~6 Alkenylene NR b C(O), C 1~6 AlkyleneC(O)NR b , C 2~6 AlkenyleneC(O)NR b , C 1~6 Alkylene OC(O), C 2~6 Alkenylene OC(O), C 1~6 Alkylene C(O)O, C 2~6 Alkenylene C(O)O, C 1~6 Alkylene OC(O)NR b , C 2~6 Alkenylene OC(O)NR b , C 1~6 Alkylene NR b C(O)O, C 2~6 Alkenylene NR b C(O)O, C 1~6 Alkylene O-C(O)O, C 2~6 Alkenylene O-C(O)O, C 1~6 Alkylene NR b C(O)NR b and C 2~6 Alkenylene NR b C(O)NR b Selected from; R a is H and C 1~6 alkyl; R b is H, C 1~6 alkyl and A; A is H, C 1~30 Alkyl, C 2~30Alkenyl, phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 64 and 3-6 membered heterocycloalkyl containing 1-4 hetero moieties independently selected from O, S, S(O), SO, N, and NR 64 wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with halo, C 1~4 Alkyl and OC 1~4 optionally substituted with one or more substituents independently selected from alkyl; R 3 and R 6 H, halo, OH, C 1~6 Alkyl and C 1~6 independently selected from alkoxy; R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently H, halo, and C 1~6 alkyl; R 12 , R 20 , R 29 , R 39 and R 51 are independently H, C 1~6 Alkyl, C(O)C 1~6 selected from alkyl and C(O)-A'; R 60 and R 61 are independently H and C 1~6 alkyl; or R 60 and R 61 One of them is C(O)-A' and the other is H and C 1~6 alkyl; where A' is Y, OY and OC 1~4 alkylene-OC(O)-Y; Y is C 7~30 Alkyl and C 7~30 alkenyl; or R 60 and R 61 together with the nitrogen atom to which they are attached, form O, S, S(O), SO2, N, and NR 65 and optionally includes one or two additional hetero moieties selected from halo, OH, C 1~4 Alkyl and OC 1~4 forming a 3- to 6-membered heterocyclic ring optionally substituted with one or more substituents independently selected from alkyl; R 64 and R 65 are independently H and C 1~6 alkyl; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; provided that when Q is Q6, the compound of formula I includes D].

[0078] The present application includes the use of one or more compounds of Formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof for treating a disease, disorder or condition through activation of a serotonin receptor, as well as the use of one or more compounds of Formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof for preparing a medicament for treating a disease, disorder or condition through activation of a serotonin receptor. The present application further includes one or more compounds of Formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof for use in treating a disease, disorder or condition through activation of a serotonin receptor.

[0079] In some embodiments, the serotonin receptor is 5-HT 2A Thus, the present application provides a method for detecting 5-HT in cells, either in a biological sample or in a patient. 2A The present application also provides a method for activating intracellular 5-HT2 receptor agonists, comprising administering to said cells an effective amount of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof. 2A and using one or more compounds of formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof to activate intracellular 5-HT 2A The present application also includes the use of the compound of the present invention for preparing a medicament for activating intracellular 5-HT. 2A The present invention also includes one or more compounds of Formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof for use in activating

[0080] In some embodiments, the serotonin receptor is 5-HT 1A Thus, the present application provides a method for detecting 5-HT in cells, either in a biological sample or in a patient. 1A The present application includes a method for activating a 5-HT receptor in a cell, the method comprising administering to the cell an effective amount of one or more compounds of Formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof. 1A and using one or more compounds of formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof to activate intracellular 5-HT receptors. 1A The present application also includes the use of the compound of the present invention for preparing a medicament for activating the 5-HT receptor in cells. 1A The present invention includes one or more compounds of Formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof for use in activating a receptor.

[0081] This application relates to 5-HT 2A The present application also includes a method for treating a disease, disorder, or condition by activation of 5-HT, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. 2A and the use of one or more compounds of formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof in the treatment of diseases, disorders or conditions resulting from activation of 5-HT 2A The present application also includes the use of the compounds of the present invention for the preparation of a medicament for the treatment of a disease, disorder, or condition resulting from activation of 5-HT. 2A The present invention also includes one or more compounds of Formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof for use in the treatment of a disease, disorder or condition through activation of

[0082] This application relates to 5-HT 1A The present application also includes a method for treating a disease, disorder, or condition by activating 5-HT, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula I or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. 1A and the use of one or more compounds of formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof in the treatment of diseases, disorders or conditions resulting from activation of 5-HT 1A The present application also includes the use of the compounds of the present invention for the preparation of a medicament for the treatment of a disease, disorder, or condition caused by activation of 5-HT. 1A The present invention also includes one or more compounds of Formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof for use in the treatment of a disease, disorder or condition through activation of

[0083] The disease, disorder or condition may be due to another mechanism, e.g., 5-HT 2A and / or 5-HT 1A The present invention may be treated or treatable through modulation, inactivation, antagonism or inverse agonism of serotonin receptors, including

[0084] In some embodiments, compounds of Formula I or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof are useful for preventing, treating, and / or reducing the severity of psychiatric disorders and / or conditions in a subject. Accordingly, in some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is a psychiatric disorder. Accordingly, the present application also includes a method of treating a psychiatric disorder, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula I or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. The present application also includes the use of one or more compounds of Formula I or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof for the treatment of a psychiatric disorder, as well as the use of one or more compounds of Formula I or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof for preparing a medicament for treating a psychiatric disorder. The present application further includes one or more compounds of Formula I or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof for use in treating a psychiatric disorder.

[0085] In some embodiments, the psychiatric disorder is selected from: anxiety disorders, such as generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia; depression, such as hopelessness, anhedonia, fatigue, and suicidal ideation; mood disorders, such as depression, bipolar disorder, cancer-related depression, anxiety, and cyclothymia; psychotic disorders, such as hallucinations, delusions, schizophrenia; impulse control and addictive disorders, such as pyromania (fire-setting), kleptomania (stealing), and compulsive gambling; alcoholism; drug dependence, such as opioid dependence; personality disorders, such as antisocial personality disorder. personality disorder, obsessive-compulsive personality disorder and paranoid personality disorder; obsessive-compulsive disorder (OCD), e.g., thoughts or fears that cause the subject to perform some ritualistic or daily activity; post-traumatic stress disorder (PTSD); stress response syndromes (formerly called adjustment disorders); dissociative disorders (formerly called multiple personality disorder, or "split personality," and depersonalization disorder); functional disorders; sexual and gender disorders, e.g., sexual dysfunction, gender identity disorder and paraphilia; somatoform disorders (formerly known as psychosomatic or somatic symptom disorders); and combinations of these.

[0086] In some embodiments, diseases, disorders, or conditions treated by activation of serotonin receptors include: cognitive dysfunction; ischemic stroke; neurodegeneration; refractory substance use disorders; sleep disorders; pain, e.g., social pain, acute pain, cancer pain, chronic pain, breakthrough pain, bone pain, soft tissue pain, neuralgia, referred pain, phantom limb pain, neuropathic pain, cluster headaches, and migraines; obesity and eating disorders; epilepsy and seizure disorders; neuronal cell death; excitotoxic cell death; or combinations thereof.

[0087] In some embodiments, the psychiatric disorder is selected from hallucinations and delusions, and combinations thereof.

[0088] In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, and chronoceptive hallucinations, and combinations thereof.

[0089] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is psychosis or a psychotic condition. Accordingly, the present application also includes a method of treating psychosis or a psychotic condition, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0090] The present application also includes the use of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, for treating psychosis or psychotic symptoms, as well as the use of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, for preparing a medicament for treating psychosis or psychotic symptoms. The present application further includes one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, for use in treating psychosis or psychotic symptoms.

[0091] In some embodiments, administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, to the subject in need of treatment does not worsen psychosis or psychotic symptoms (such as, but not limited to, hallucinations and delusions). In some embodiments, administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, to the subject in need of treatment ameliorates psychosis or psychotic symptoms (such as, but not limited to, hallucinations and delusions). In some embodiments, administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, to the subject in need of treatment ameliorates psychosis or psychotic symptoms.

[0092] In some embodiments, the compounds of formula I, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, are useful for treating central nervous system (CNS) disorders in a subject in need of therapy, which therapy comprises administering to said subject a therapeutically effective amount of a compound of general formula I, or a pharmaceutically acceptable salt thereof.

[0093] Thus, in some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a central nervous system (CNS) disease, disorder, or condition, and / or a neurological disease, disorder, or condition. Thus, the present application also includes a method for treating a CNS disease, disorder, or condition, and / or a neurological disease, disorder, or condition, comprising administering a therapeutically effective amount of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, to a subject in need thereof. The present application also includes the use of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, for the treatment of a CNS disease, disorder, or condition, and / or a neurological disease, disorder, or condition, as well as the use of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, for the preparation of a medicament for treating a CNS disease, disorder, or condition, and / or a neurological disease, disorder, or condition. The application further includes one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, for use in treating a CNS disease, disorder or condition, and / or a neurological disease, disorder or condition.In some embodiments, the CNS disease, disorder or condition, and / or neurological disease, disorder or condition is selected from neurological diseases, including neurodevelopmental and neurodegenerative diseases, such as Alzheimer's disease; presenile dementia; senile dementia; vascular dementia; dementia with Lewy bodies; cognitive impairment, Parkinson's disease and Parkinson's disease-related disorders, such as Parkinsonism, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disorders; Fragile X syndrome; Angelman syndrome; hereditary movement disorders. These conditions include ataxia; neuro-otological and oculomotor disorders; retinal neurodegenerative diseases; amyotrophic lateral sclerosis; tardive dyskinesia; hyperactivity disorder; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette's syndrome; schizophrenia; autism spectrum disorders; tuberous sclerosis; Rett's syndrome; cerebral palsy; eating disorders, such as reward system disorders including anorexia nervosa ("AN") and bulimia nervosa ("BN"); and binge eating disorder ("BED"), trichotillomania, excoriation disorder, nail biting; migraine; fibromyalgia; and peripheral neuropathies of any etiology, and combinations thereof.

[0094] In some embodiments, the subject is a mammal. In other embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. Thus, the compounds, methods, and uses of the present application are directed to diseases, disorders, and conditions in both human and veterinary medicine.

[0095] In some embodiments, compounds of Formula I, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, are useful for treating problem behaviors in feline or canine subjects.

[0096] Thus, in some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is problem behavior in a cat or dog subject. Thus, the present application also includes a method for treating problem behavior, comprising administering a therapeutically effective amount of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, to a non-human subject in need thereof. The present application also includes the use of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, for treating problem behavior in a non-human subject, as well as the use of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, for preparing a medicament for treating problem behavior in a non-human subject. The present application further includes one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, for use in treating problem behavior in a non-human subject.

[0097] In some embodiments, the problem behavior is selected from, but not limited to, anxiety, fear, stress, sleep disorders, cognitive impairment, aggression, excessive fussing, scratching, biting, and combinations thereof.

[0098] In some embodiments, the non-human subject is a dog. In some embodiments, the non-human subject is a cat.

[0099] The present application also includes a method for treating a disease, disorder, or condition by activating a serotonin receptor, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, in combination with other known agents useful for treating the disease, disorder, or condition by activating a serotonin receptor. The present application also includes the use of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, in combination with other known agents useful for treating the disease, disorder, or condition by activating a serotonin receptor, to treat a disease, disorder, or condition by activating a serotonin receptor, as well as the use of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, in combination with other known agents useful for treating the disease, disorder, or condition by activating a serotonin receptor, to prepare a medicament for treating a disease, disorder, or condition by activating a serotonin receptor. The present application further includes one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, for use in the treatment of diseases, disorders or conditions through activation of serotonin receptors, in combination with other known agents useful in treating diseases, disorders or conditions through activation of serotonin receptors.

[0100] In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a psychiatric disorder. In some embodiments, the psychiatric disorder is selected from hallucinations and delusions, and combinations thereof. In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a disorder of the central nervous system (CNS). In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is psychosis or a psychotic symptom. In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is problematic behavior in non-human subjects.

[0101] In some embodiments, the disease, disorder or condition that is treated by activating serotonin receptors is a psychiatric disorder, and one or more compounds of Formula I, or its pharmaceutically acceptable salts, solvates and / or prodrugs, are administered in combination with one or more additional treatments for the psychiatric disorder.In some embodiments, the additional treatment for the psychiatric disorder is selected from antipsychotic drugs, including typical antipsychotic drugs and atypical antipsychotic drugs; antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and monoamine oxidase inhibitors (MAOIs) (e.g., bupropion); antianxiety drugs, including benzodiazepines such as alprazolam; mood stabilizers, such as lithium, and anticonvulsants, such as carbamazepine, dipalproex (valproic acid), lamotrigine, gabapentin, and topiramate.

[0102] In some embodiments, the disease, disorder or condition that is treated by activating serotonin receptor is selected from attention deficit hyperactivity disorder and attention deficit disorder, and combinations thereof.In some embodiments, the disease, disorder or condition that is treated by activating serotonin receptor is selected from attention deficit hyperactivity disorder and / or attention deficit disorder, and combinations thereof, and one or more compounds of Formula I or its pharmaceutically acceptable salt, solvate and / or prodrug are administered in combination with one or more additional treatments for attention deficit hyperactivity disorder and / or attention deficit disorder, and combinations thereof.In some embodiments, the one or more additional treatments for attention deficit hyperactivity disorder and / or attention deficit disorder, and combinations thereof are selected from methylphenidate, atomoxetine and amphetamine, and combinations thereof.

[0103] In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is dementia or Alzheimer's disease, and one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, 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 an acetylcholinesterase inhibitor, an NMDA antagonist, a muscarinic agonist, a muscarinic antagonist, and a nicotinic agonist.

[0104] In some embodiments, the acetylcholinesterase inhibitor is selected from donepezil, galantamine, rivastigmine, and phenserine, and combinations thereof.

[0105] In some embodiments, the NMDA antagonist is selected from MK-801, ketamine, phencyclidine, and memantine, and combinations thereof.

[0106] In some embodiments, the nicotinic agonist is nicotine, nicotinic acid, a nicotinic alpha 7 agonist, or an alpha 2 beta 4 agonist, or a combination thereof.

[0107] In some embodiments, the muscarinic agonist is a muscarinic M1 agonist or a muscarinic M4 agonist, or a combination thereof.

[0108] In some embodiments, the muscarinic antagonist is a muscarinic M2 antagonist.

[0109] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is psychosis or a psychotic symptom, and one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, are administered in combination with one or more additional treatments for the psychosis or psychotic symptom. In some embodiments, the additional treatment for the psychosis or psychotic symptom is selected from a typical antipsychotic and an atypical antipsychotic.

[0110] In some embodiments, the typical antipsychotic is acepromazine, acetophenazine, benperidol, bromperidol, butaperazine, carphenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, dixyrazine, droperidol, fluanisone, flupenthixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, lenperone, loxapine, mesoridazine, methytepin, molindone, mope The active ingredient is selected from the group consisting of thiazol-3, thiazol-4, thiazol-5, thiazol-6, thiazol-7, thiazol-8, thiazol-9, thiazol-10, thiazol-11, thiazol-12, thiazol-13, thiazol-14, thiazol-15, thiazol-16, thiazol-17, thiazol-18, thiazol-19, thiazol-20, thiazol-21, thiazol-22, thiazol-23, thiazol-24, thiazol-25, thiazol-26, thiazol-27, thiazol-28, thiazol-29, thiazol-30, thiazol-31, thiazol-32, thiazol-33, thiazol-34, thiazol-35, thiazol-36, thiazol-37, thiazol-38, thiazol-40, thiazol-41, thiazol-42, thiazol-43, thiazol-44, thiazol-45, thiazol-46, thiazol-47, thiazol-48, thiazol-49, thiazol-50, thiazol-51, thiazol-52, thiazol-53, thiazol-54, thiazol-55, thiazol-56, thiazol-57, thiazol-58, thiazol-59, thiaz

[0111] In some embodiments, the atypical antipsychotic is selected from amoxapine, amisulpride, aripiprazole, asenapine, blonanserin, brexpiprazole, cariprazine, carpipramine, clocapramine, chlorothepine, clotiapine, clozapine, iloperidone, levosulpiride, lurasidone, melperone, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpiride, sultopride, tiapride, veralipride, ziprasidone, and zotepine, and combinations thereof.

[0112] In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a psychiatric disorder, and one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, are administered in combination with one or more additional treatments for the psychiatric disorder. In some embodiments, the additional treatment for the psychiatric disorder is selected from a typical antipsychotic and an atypical antipsychotic.

[0113] In some embodiments, an effective amount varies depending on factors such as the disease state, age, sex, and / or weight of the subject or species. In some embodiments, the amount of a given compound, or the amount of a compound that corresponds to an effective amount, will vary depending on factors such as the given agent(s) or compound(s), pharmaceutical formulation, route of administration, condition, type of disease or disorder, identity of the subject being treated, etc., but can nevertheless be routinely determined by one of ordinary skill in the art.

[0114] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, is administered once, twice, three times, or four times per year. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, is administered at least once per week. However, in other embodiments, the compound is administered to a subject from about once per two weeks, three weeks, or month. In other embodiments, the compound is administered from about once per week to about once per day. In other embodiments, the compound is administered 1, 2, 3, 4, 5, or 6 times per day. The length of the treatment period depends on various factors, such as the severity of the disease, disorder, or condition, the age of the subject, the concentration and / or activity of the compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, and / or a combination thereof. It will also be understood that the effective dosage of the compound used for treatment may increase or decrease during a particular treatment regimen. Dosage changes can be made and determined by 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 period sufficient to treat the subject.

[0115] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, is administered at a hallucinogenic or psychotomimetic dose, is taken in conjunction with psychotherapy or therapy, and may be administered once, twice, three times, or four times per year. However, in some embodiments, the compound is administered to a subject at a dose that is not hallucinogenic or psychotomimetic, once per day, once every two days, once per three days, once per week, once every two weeks, once per month, once every two months, or once per three months.

[0116] The compound of Formula I, or its pharmaceutically acceptable salts, solvates, and / or prodrugs, may be used alone or in combination with other known drugs (e.g., compounds of the present application) that are useful for treating diseases, disorders, or conditions by activating serotonin receptors. When used in combination with other known drugs that are useful for treating diseases, disorders, or conditions by activating serotonin receptors, it is an embodiment for the compound of Formula I, or its pharmaceutically acceptable salts, solvates, and / or prodrugs, to be administered simultaneously with those drugs. As used herein, "co-administration" of two substances to a subject means providing each of the two substances so that they are both active in the individual at the same time. The exact details of administration depend on the pharmacokinetics of the two substances in the presence of each other, but may include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of the other, if the pharmacokinetics are suitable. Designing an appropriate dosing regimen is a routine task for those skilled in the art. In certain embodiments, the two substances are administered substantially simultaneously, i.e., within a few minutes of each other, or in a single composition containing both substances. It is a further embodiment of the present application that the combination of drugs is administered to a subject non-simultaneously. In some embodiments, the compounds of the present application are administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or together in a single unit dosage form. Thus, the present application provides a single unit dosage form comprising one or more compounds of the present application, an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0117] The dosage of a compound of Formula I, or its pharmaceutically acceptable salts, solvates, and / or prodrugs, varies depending on many factors, including the pharmacokinetic properties of the compound, the mode of administration, the age, health, and weight of the recipient, the nature and severity of the symptoms, the frequency of treatment and type of concurrent treatment (if any), and the clearance rate of the compound in the treated subject. One of ordinary skill in the art can determine the appropriate dosage based on the above factors. In some embodiments, one or more compounds of Formula I, or their pharmaceutically acceptable salts, solvates, and / or prodrugs, are initially administered at an appropriate dosage, and the dosage is adjusted as necessary depending on the clinical response. The dosage is generally selected to maintain serum levels of one or more compounds of Formula I, or their pharmaceutically acceptable salts, solvates, and / or prodrugs, between about 0.01 μg / cc and about 1000 μg / cc, or between about 0.1 μg / cc and about 100 μg / cc. Typically, oral dosages of one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, range from about 10 μg / day to about 1000 mg / day for adults, preferably from about 10 μg / day to about 500 mg / day, and more preferably from about 10 μg / day to about 200 mg / day. For parenteral administration, typical amounts would be about 0.0001 mg / kg to about 10 mg / kg, about 0.0001 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, or about 0.0001 mg / kg to about 0.01 mg / kg. For oral administration, typical amounts are about 0.001 μg / kg to about 10 mg / kg, about 0.1 μg / kg to about 10 mg / kg, about 0.01 μg / kg to about 1 mg / kg, or about 0.1 μg / kg to about 1 mg / kg. For administration in suppository form, typical amounts are 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 the present application, the compositions are formulated for oral administration, and the one or more compounds are preferably in tablet form, with each tablet containing 0.1, 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the active ingredient (one or more compounds of the present application). In some embodiments of the present application, one or more compounds of Formula I, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, are administered in a once-daily, once-weekly, or once-monthly dose, or the total daily dose is divided into two-daily, three-daily, or four-daily doses.

[0118] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, is used or administered in an effective amount, including administering a dose or dosage regimen lacking clinically significant hallucinogenic / psychotometic effects. ... 2A Clinical effects manifested by human CNS receptor occupancy, or human plasma psilocin Cmax of 1 ng / mL or less and / or human 5-HT of 30% or less 2A It is used or administered in an effective amount, including administering a dose or dosage regimen that provides a clinical effect similar to that manifested by human CNS receptor occupancy. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, is used or administered in an effective amount, including administering a dose or dosage regimen that provides a clinical effect similar to that manifested by human plasma psilocin Tmax of greater than 60 minutes, greater than 120 minutes, or greater than 180 minutes.

[0119] For clarity, in the above, the term "a compound" includes embodiments in which more than one compound is referenced. Similarly, the term "compounds of the present application" includes embodiments in which only one compound is referenced.

[0120] In some embodiments, all available hydrogen atoms in a group may be optionally replaced with deuterium, provided that all available atoms may be optionally replaced with their alternative isotopes.

[0121] In some embodiments, Q is Q1: [ka] and the structure: [ka] is a single bond, and compounds of formula I have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 is as defined for formula I, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0122] In some embodiments, Q is Q1: [ka] and the structure: [ka] is a double bond, and compounds of formula I have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 8 , R 10 , R 11 , R 12 , R 13 and R 14 is as defined for formula I, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0123] In some embodiments, Q is Q2: [ka] and the structure: [ka] is a single bond, and compounds of formula I have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1, R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 and R 25 is as defined for formula I, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0124] In some embodiments, Q is Q2: [ka] and the structure: [ka] is a double bond, and compounds of formula I have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 16 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 is as defined for formula I, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0125] In some embodiments, Q is Q3: [ka] and the compound of formula I has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 and R 35 is as defined for formula I, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0126] In some embodiments, Q is Q4: [ka] and the compound of formula I has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 and R 47 is as defined for formula I, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0127] In some embodiments, Q is Q5: [ka] and the structure: [ka] is a single bond, and compounds of formula I have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 48 , R 49 , R50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 and R 57 is as defined for formula I, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0128] In some embodiments, Q is Q5: [ka] and the structure: [ka] is a double bond, and compounds of formula I have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 48 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 and R 56 is as defined for formula I, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0129] In some embodiments, Q is Q6: [ka] and the compound of formula I has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 58 , R 59 , R 60 , R 61 , R 62 and R 63 is as defined for formula I, any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by an alternative isotope thereof; provided that compounds of formula I include D].

[0130] In some embodiments, R 1 , R 2 , R 2 ', R 2 '', R 3 , R 5 and R 6 are all H, and the compound of formula I has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 4 and Q is as defined for formula I; All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0131] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 and R 6 are all H, and the compound of formula I has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 5 and Q is as defined for formula I; All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0132] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 and R 6 are all H, and the compound of formula I has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 4 , R 5 and Q is as defined for formula I; All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0133] In some embodiments, R 1 , R 1 ', R 2 and R 2 ' are all H and R 3 , R 4 , R 5 and R 6 are all D, and the compound of formula I has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: Q is as defined for formula I; All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0134] In some embodiments, R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46, R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently H, D, F, Cl, C 1~6 Alkyl, C 1~6 Fluoroalkyl and C 1~6 In some embodiments, R is selected from deuteroalkyl. 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58, R 59 , R 62 and R 63 is independently selected from H, F, D, CH, CDH, CDH, CD, CF, CHF, CHCH, CHCHD, CHCDH, and CDCD. 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 is independently selected from H and D.

[0135] In some embodiments, R 8 , R 9 , R 10 , R 11, R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 and R 57 is independently selected from H and D.

[0136] In some embodiments, R 58 , R 59 , R 62 and R 63 is independently selected from H and D. In some embodiments, R 58 , R 59 , R 62 and R 63 is H. In some embodiments, R 58 , R 59 , R 62 and R 63 is D. In some embodiments, R 58 and R 59 is H and R 62 and R63 is D. In some embodiments, R 58 and R 59 is D and R 62 and R 63 is H.

[0137] In some embodiments, Q has the structure: [ka] If R 28 or R 38 The stereochemistry at the carbon to which is attached is either R or S. Thus, in some embodiments, Q3 has the structure: [ka] and Q4 has the structure: [ka] is.

[0138] In some embodiments, R 28 or R 38 The stereochemistry at the carbon to which is attached is R. In some embodiments, R 28 or R 38 The stereochemistry at the carbon to which is attached is S.

[0139] In some embodiments, Q has the structure: [ka] and the structure: [ka] is a single bond, R 15 , R 25 or R 48 The stereochemistry at the carbon to which is attached is either R or S. Thus, in some embodiments, Q1 has the structure: [ka] and Q2 has the structure: [ka] and Q5 has the structure: [ka] is.

[0140] In some embodiments, R 15 , R 25 or R 48 The stereochemistry of the carbon atom to which is attached is R. In some embodiments, R 15 , R 25 or R 48 The stereochemistry of the carbon atom to which is attached is S.

[0141] In some embodiments, Q is selected from one of the following groups: [ka] [ka] [In the formula, R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 are independently H, D, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 In some embodiments, R 12 , R 20 , R 29 and R 39 are independently H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 In some embodiments, R is selected from deuteroalkyl and C(O)-A'. 12 , R 20 , R 29, R 39 , R 51 , R 60 and R 61 is independently selected from H, CH, CD, CDH, CFH, and CF. In some embodiments, R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 is independently selected from H, CH3, and CD3. In some embodiments, R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 is independently selected from CH3 and CD3.

[0142] In some embodiments, Q is selected from one of the following groups: [ka] [In the formula, R 29 H, D, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 In some embodiments, R 29 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 In some embodiments, R is selected from deuteroalkyl and C(O)-A'. 29 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, R is selected from deuteroalkyl. 29 is selected from H, CH, CD, CDH, CFH, and CF. In some embodiments, R 29 is selected from H, CH3 and CD3. In some embodiments, R 29 is selected from CH3 and CD3.

[0143] In some embodiments, R 60 and R 61 together with the nitrogen atom to which they are attached, form O, N, and NR 65 and optionally includes one or two additional hetero moieties independently selected from halo, OH, C 1~4 Alkyl and OC 1~4 It forms a 3- to 6-membered heterocyclic ring which may be optionally substituted with one or more substituents independently selected from alkyl.

[0144] In some embodiments, R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 are independently selected from C(O)-A'.

[0145] In some embodiments, R 60 and R 61 One of them is C(O)-A', and the other is H and C 1~6 In some embodiments, R 60 and R 61 One of them is C(O)-A', and the other is H and C 1~4 alkyl.

[0146] In some embodiments, A' is selected from the group consisting of Y, OY, and OC. 1~2 alkylene-OC(O)-Y, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms. In some embodiments, A' is selected from Y, OY, and O-C alkylene-OC(O)-Y, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms.

[0147] In some embodiments, Y is C 10~25In some embodiments, Y is C alkyl, and all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms. 13~21 It is alkyl, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0148] In some embodiments, Y is C 10~25 In some embodiments, Y is C 13~21 In some embodiments, Y is C 10~25 is alkenyl and contains 1, 2, 3, 4, 5 or 6 double bonds;

[0149] In some embodiments, the alkyl or alkene group of Y is an alkyl or alkenyl group present in a fatty acid, optionally with all available hydrogen atoms replaced with deuterium atoms. In some embodiments, Y is an alkenyl group present in a fatty acid, optionally with all available hydrogen atoms replaced with deuterium atoms. In some embodiments, the fatty acid is an ω-6 fatty acid (i.e., an unsaturated or polyunsaturated fatty acid in which the double bond closest to the terminal methyl is at carbon number 6 from the terminal methyl group) or an ω-3 fatty acid (i.e., an unsaturated or polyunsaturated fatty acid in which the double bond closest to the terminal methyl is at carbon number 3 from the terminal methyl group), optionally with all available hydrogen atoms replaced with deuterium atoms. In some embodiments, Y is an alkyl group present in a fatty acid, optionally with all available hydrogen atoms replaced with deuterium atoms. In some embodiments, the alkyl or alkene group of Y is an alkyl or alkene group present in a fatty acid, selected from the list of fatty acids set forth in Table 1: [Table 1] [Table 2] [Table 3] wherein all available hydrogen atoms may be optionally replaced with deuterium atoms.

[0150] In some embodiments, the alkene group of Y is an alkyl or alkenyl group present in linoleic acid, eicosadienoic acid, or decosahexanoic acid.

[0151] In some embodiments, Y is an alkyl or alkenyl group of a fatty acid in which 1 to 10, 2 to 8, 2 to 6, or 2 to 4 hydrogen atoms are replaced with deuterium.

[0152] In some embodiments, Y is (CH2)7CH=CH(CH2)7CH3. In some embodiments, Y is (CH2)7CH=CHCH2CH=CH(CH2)4CH3. In some embodiments, Y is (CH2)8CH=CHCH2CH=CH(CH2)4CH3. In some embodiments, Y is (CH2)7CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3. In some embodiments, Y is (CH2)3CH=CHCH2CH=CH(CH2)1CH=CHCH2CH=CH(CH2)3CH3. In some embodiments, Y is (CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3. In some embodiments, Y is (CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3. Thus, in some embodiments, Y is (CH2)7CH=CH(CH2)7CH3, (CH2)7CH=CHCH2CH=CH(CH2)4CH3, (CH2)8CH=CHCH2CH=CH(CH2)4CH3, (CH2)7CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3, (CH2)3CH=CHCH2CH=CH(CH2)1CH=CHCH2CH=CH(CH2)3CH3, or (CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3.

[0153] In some embodiments, A' is Y.

[0154] In some embodiments, A' is -OY.

[0155] In some embodiments, A' is -O-C3 alkylene-OC(O)-Y.

[0156] In some embodiments, R 1 and R 1 ' is independently H, OH, halo, NH2, C 1~4 Alkyl, C 1~4 Alkoxy, NH(C 1~4 alkyl) and N(C 1~4 In some embodiments, R 1 and R 1 ' are independently H, D, Cl, F, OH, NH2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkyl, C 1~4 Deuteroalkyl, NH(C 1~4 alkyl), NH(C 1~4 Deuteroalkyl), NH(C 1~4 fluoroalkyl), N(C 1~4 alkyl)2, N(C 1~4 Fluoroalkyl)2, N(C 1~4 Deuteroalkyl)2, N(C 1~4 Fluoroalkyl)(C 1~4 alkyl), N(C 1~4 Fluoroalkyl)(C 1~4 Deuteroalkyl) and N(C 1~4 Deuteroalkyl)(C 1~4 In some embodiments, R 1 and R 1 ' are independently H, D, Cl, F, OH, NH2, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Fluoroalkyl and C 1~2 Deuteroalkyl, NH(C 1~2alkyl), NH(C 1~2 Deuteroalkyl), NH(C 1~2 fluoroalkyl), N(C 1~2 alkyl)2, N(C 1~2 Fluoroalkyl)2, N(C 1~2 Deuteroalkyl)2, N(C 1~2 Fluoroalkyl)(C 1~2 alkyl), N(C 1~2 Fluoroalkyl)(C 1~2 Deuteroalkyl) and N(C 1~2 Deuteroalkyl)(C 1~2 In some embodiments, R 1 is selected from H, D, F, NH, CH, CF, H, CD, CH, O, CF, CD, NH(CH), NH(CD), NH(CF), N(CH), N(CF), and N(CD). In some embodiments, R 1 and R 1 R' is independently selected from H, D, F, NH2, CH3, CF2H, CD2H, CH3O, CF3, and CD3. In some embodiments, R 1 and R 1 R' is independently selected from H, D, F, OH, CH, CFH, CDH, CHO, CF, and CD. In some embodiments, R 1 and R 1 ' is independently H, D, or F. In some embodiments, R 1 and R 1 In some embodiments, R 1 and R 1 ' are both H.

[0157] In some embodiments, R 2 and R 2 ' is independently H, halo, NH2, C 1~4 Alkyl, C 1~4 Alkoxy, NH(C 1~4 alkyl) and N(C 1~4 In some embodiments, R 2and R 2 ' are independently H, D, Cl, F, NH2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkyl, C 1~4 Deuteroalkyl, NH(C 1~4 alkyl), NH(C 1~4 Deuteroalkyl), NH(C 1~4 fluoroalkyl), N(C 1~4 alkyl)2, N(C 1~4 Fluoroalkyl)2, N(C 1~4 Deuteroalkyl)2, N(C 1~4 Fluoroalkyl)(C 1~4 alkyl), N(C 1~4 Fluoroalkyl)(C 1~4 Deuteroalkyl) and N(C 1~4 Deuteroalkyl)(C 1~4 In some embodiments, R 2 and R 2 ' is independently H, D, Cl, F, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Fluoroalkyl, C 1~2 Deuteroalkyl, NH(C 1~2 alkyl), NH(C 1~2 Deuteroalkyl), NH(C 1~2 fluoroalkyl), N(C 1~2 alkyl)2, N(C 1~2 Fluoroalkyl)2, N(C 1~2 Deuteroalkyl)2, N(C 1~2 Fluoroalkyl)(C 1~2 alkyl), N(C 1~2 Fluoroalkyl)(C 1~2 Deuteroalkyl) and N(C 1~2 Deuteroalkyl)(C 1~2 In some embodiments, R 2 and R 2R' is independently selected from H, D, F, NH, CH, CFH, CDH, CHO, CF, CD, NH(CH), NH(CD), NH(CF), N(CH), N(CF), and N(CD). In some embodiments, R 1 is selected from H, D, F, NH, CH, CF, CD, CH, O, CF, and CD. 2 and R 2 R' is independently selected from H, D, F, CH, CFH, CDH, CHO, CF, and CD. In some embodiments, R 2 and R 2 ' is independently H, D, or F. In some embodiments, R 2 and R 2 In some embodiments, R 2 and R 2 ' are all H's.

[0158] In some embodiments, R 1 , R 1 ', R 2 and R 2 ' is independently H, D, or F. In some embodiments, R 1 , R 1 ', R 2 and R 2 In some embodiments, R 1 , R 1 ', R 2 and R 2 ' are all H's.

[0159] In some embodiments, R 3 and R 6 are independently H, D, Cl, F, OH, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy, C 1~4 Deuteroalkoxy, C 1~4 Fluoroalkyl and C 1~4In some embodiments, R is selected from deuteroalkyl. 3 and R 6 are independently H, D, Cl, F, OH, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, R is selected from deuteroalkyl. 3 and R 6 are independently H, D, Cl, F, OH, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Fluoroalkoxy, C 1~2 Deuteroalkoxy, C 1~2 Fluoroalkyl and C 1~2 In some embodiments, R is selected from deuteroalkyl. 3 and R 6 are independently H, D, Cl, F, OH, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Fluoroalkyl and C 1~2 In some embodiments, R is selected from deuteroalkyl. 3 and R 6 is independently selected from H, D, F, OH, CH, CHO, CFHO, CDHO, CFO, CDO, CFH, CDH, CF and CD. In some embodiments, R 3 and R 6 is independently selected from H, D, F, OH, CH, CHO, CFH, CDH, CF, and CD. In some embodiments, R 3 and R 6 is independently selected from H, D, F, OH, CH, CHO, CFHO, CFO, and CDO. In some embodiments, R 3 and R 6 is independently selected from H and D. In some embodiments, R 3 and R 6 At least one of R is D. In some embodiments, R 3 and R 6are each D. In some embodiments, R 3 and R 6 are H, respectively.

[0160] In some embodiments, R 4 and R 5 One or both of these may independently be H, D, F, Cl, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 Deuteroalkyl, C 1~6 Alkoxy, C 1~6 Fluoroalkoxy and C 1~6 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 4 and R 5 Both independently H, D, F, Cl, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Deuteroalkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy and C 1~4 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 4 and R 5 are independently selected from H, D, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, CD3, CH(CH3)2O, CH3CH2CH2O, CH3CHO, CH3O, CF3O, CHF2O, CF2HCH2O, CF3CHO, (CF3)2CHO, and CD3O. 4 and R 5 are independently selected from H, D, F, Cl, CH3, CH(CH3)2, CF3, CF2H, CD3, CH3O, CH(CH3)2O, CF3O, CHF2O, and CD3O.

[0161] In some embodiments, R 4 and R 5 Both independently H, D, F, Cl, C 1~6 Alkyl, C1~6 Fluoroalkyl, C 1~6 Deuteroalkyl, C 1~6 Alkoxy, C 1~6 Fluoroalkoxy and C 1~6 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 4 and R 5 Both D, F, Cl, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 Deuteroalkyl, C 1~6 Alkoxy, C 1~6 Fluoroalkoxy and C 1~6 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 4 and R 5 Both independently H, D, F, Cl, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Deuteroalkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy and C 1~4 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 4 and R 5 are both independently selected from H, D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CFO, CHFO, and CDO. 4 and R 5 are both independently selected from D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CFO, CHFO, and CDO. 4 and R 5 are both independently selected from CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 4 and R 5 Both are CD3O or R 4 and R 5 Both are CHO.

[0162] In some embodiments, R 4 is H or D, and R 5 are H, D, F, Cl, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 Deuteroalkyl, C 1~6 Alkoxy, C 1~6 Fluoroalkoxy and C 1~6 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 4 is H or D, and R 5 are H, D, F, Cl, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Deuteroalkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy and C 1~4 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 4 is H or D, and R 5 is selected from H, D, F, Cl, CH(CH3)2, CH3, CF3, CF2H, CD3, CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 4 is H or D, and R 5 is selected from D, F, Cl, CH(CH), CH, CF, CFH, CD, CH(CH)O, CHO, CFO, CHFO, and CDO. 4 is H or D, and R 5 is selected from CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 4 is H and R 5 is selected from CH3O and CD3O.

[0163] In some embodiments, R 5 is H or D, and R 4 are H, D, F, Cl, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6Deuteroalkyl, C 1~6 Alkoxy, C 1~6 Fluoroalkoxy and C 1~6 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 5 is H or D, and R 4 are H, D, F, Cl, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Deuteroalkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy and C 1~4 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 5 is H or D, and R 4 is selected from D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CFO, CHFO, and CDO. 5 is H or D, and R 4 is selected from CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 5 is H and R 4 is selected from CH3O and CD3O.

[0164] In some embodiments, R 4 and R 5 together to form O-CHO.

[0165] In some embodiments, R 3 , R 4 , R 5 and R 6 is selected from D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CFO, CHFO, and CDO. 3 , R 4 , R 5 and R 6 are all H, or in some embodiments, R 3 , R 4 , R5 and R 6 are all D. In some embodiments, R 3 , R 4 , R 5 and R 6 is selected from CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 3 , R 4 , R 5 and R 6 Two of them are H or D, and R 3 , R 4 , R 5 and R 6 and the remainder of R is selected from CH(CH)O, CHO, CFO, CHFO, and CDO. 3 , R 4 , R 5 and R 6 Two of the groups are selected from H or D, and R 3 , R 4 , R 5 and R 6 and the remainder of R is selected from CHO and CDO. 3 , R 4 , R 5 and R 6 is selected from H or D, and R 3 , R 4 , R 5 and R 6 and the remainder of R is selected from CH(CH)O, CHO, CFO, CHFO, and CDO. 3 , R 4 , R 5 and R 6 is selected from H or D, and R 3 , R 4 , R 5 and R 6 the remainder being selected from CH3O and CD3O.

[0166] In some embodiments, R 4 and R 5 One of them is selected from XLA and R4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 Alkoxy is selected from:

[0167] In some embodiments, X is a direct bond and R 4 and R 5 One of the two is selected from LA, and the other is R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 In some embodiments, X is selected from O, C(O), NR a , N.R. a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, X is selected from O, C(O), OC(O), C(O)O and OC(O)O. In some embodiments, X is selected from O, OC(O) and C(O)O. In some embodiments, X is O. In some embodiments, X is selected from OC(O) and C(O)O. In some embodiments, X is O, NR a , N.R. a C(O), C(O)NR a , N.R. a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, X is selected from NR a C(O), C(O)NR a , N.R. a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, X is selected from NR a C(O) and C(O)NR a In some embodiments, X is selected from NRa C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, X is selected from O, OC(O), C(O)O, NR a C(O) and C(O)NR a is selected from.

[0168] In some embodiments, L is a direct bond, C 1~4 Alkylene, C 2~4 Alkenylene, C 1~4 Alkylene O, C 2~4 Alkenylene O,C 1~4 Alkylene C(O), C 2~4 Alkenylene C(O), C 1~4 Alkylene NR b C(O), C 2~4 Alkenylene NR b C(O), C 1~4 AlkyleneC(O)NR b , C 2~4 AlkenyleneC(O)NR b , C 1~4 Alkylene OC(O), C 2~4 Alkenylene OC(O), C 1~4 Alkylene C(O)O, C 2~4 Alkenylene C(O), C 1~4 Alkylene OC(O)NR b , C 2~4 Alkenylene OC(O)NR b , C 1~4 Alkylene NR b C(O)O, C 2~4 Alkenylene NR b C(O)O, C 1~4 Alkylene O-C(O)O, C 2~4 Alkenylene O-C(O)O, C 1~4 Alkylene NR b C(O)NR b and C 2~4 Alkenylene NR b C(O)NR b In some embodiments, L is selected from a direct bond, C 1~2 Alkylene, C 2~4Alkenylene, C 1~2 Alkylene O, C 2~4 Alkenylene O,C 1~2 Alkylene C(O), C 2~4 Alkenylene C(O), C 1~2 Alkylene NR b C(O), C 2~4 Alkenylene NR b C(O), C 1~2 AlkyleneC(O)NR b , C 2~4 AlkenyleneC(O)NR b , C 1~2 Alkylene OC(O), C 2~4 Alkenylene OC(O), C 1~2 Alkylene C(O)O, C 2~4 Alkenylene C(O), C 1~2 Alkylene OC(O)NR b , C 2~4 Alkenylene OC(O)NR b , C 1~2 Alkylene NR b C(O)O, C 2~4 Alkenylene NR b C(O)O, C 1~2 Alkylene O-C(O)O, C 2~4 Alkenylene O-C(O)O, C 1~2 Alkylene NR b C(O)NR b and C 2~4 Alkenylene NR b C(O)NR b In some embodiments, L is selected from a direct bond, C 1~2 Alkylene, C 1~2 Alkylene O, C 1~2 Alkylene C(O), C 1~2 Alkylene NR b C(O), C 1~2 AlkyleneC(O)NR b , C 1~2 Alkylene OC(O), C 1~2 Alkylene C(O)O, C 1~2 Alkylene OC(O)NR b , C 1~2 Alkylene NR b C(O)O, C 1~2Alkylenes OC(O)O, and C 1~2 Alkylene NR b C(O)NR b In some embodiments, L is selected from a direct bond, CH, CF, CD, CH—O, CF—O, CD—O, CH—C(O), CF—C(O), CD—C(O), CH—NR b C(O), CD2-NR b C(O), CF2-NR b C(O), CH2-C(O)NR b , CF2-C(O)NR b , CD2-C(O)NR b , CH2-OC(O), CD2-OC(O), CF2-OC(O), CH2-C(O)O, CF2-C(O)O, CD2-C(O)O, CH2-OC(O)NR b , CD2-OC(O)NR b , CF2-OC(O)NR b , CH2-NR b C(O)O, CF2-NR b C(O)O, CD2-NR b C(O)O, CH2-OC(O)O, CF2-OC(O)O, CD2-OC(O)O, CH2-NR b C(O)NR b , CF2-NR b C(O)NR b and CD2-NR b C(O)NR b is selected from.

[0169] In some embodiments, X is a direct bond, L is a direct bond, and R 4 and R 5 one of which is selected from A and R 4 and R 5 The other is H, halo, C 1~4 Alkyl and C 1~4 Alkoxy is selected from:

[0170] In some embodiments, X is O, OC(O), C(O)O, NR a C(O) and C(O)NR a Selected from R 4and R 5 On the other hand, OC 1~2 Alkylene-A, OC 1~2 Alkylene OA, OC 1~2 Alkylene C(O)-A, OC 1~2 Alkylene NR b C(O)-A, OC 1~2 AlkyleneC(O)NR b -A, O.C. 1~2 Alkylene OC(O)-A, OC 1~2 Alkylene C(O)OA, OC 1~2 Alkylene OC(O)NR b -A, O.C. 1~2 Alkylene NR b C(O)OA, OC 1~2 Alkylene OC(O)OA, OC 1~2 Alkylene NR b C(O)NR b -A, OC(O)-C 1~2 Alkylene-A, OC(O)-C 1~2 Alkylene OA, OC(O)-C 1~2 Alkylene C(O)-A, O-C(O)-C 1~2 Alkylene NR b C(O)-A, OC(O)-C 1~2 AlkyleneC(O)NR b -A, OC(O)-C 1~2 Alkylene OC(O)-A, OC(O)-C 1~2 Alkylene C(O)OA, OC(O)-C 1~2 Alkylene OC(O)NR b -A, OC(O)-C 1~2 Alkylene NR b C(O)OA, OC(O)-C 1~2 Alkylene OC(O)OA, OC(O)-C 1~2 Alkylene NR b C(O)NR b -A, C(O)OC 1~2 Alkylene-A, C(O)OC 1~2 Alkylene OA, C(O)OC 1~2 Alkylene C(O)-A, C(O)OC 1~2 Alkylene NR bC(O)-A, C(O)OC 1~2 AlkyleneC(O)NR b -A, C(O)OC 1~2 Alkylene OC(O)-A, C(O)OC 1~2 Alkylene C(O)OA, C(O)OC 1~2 Alkylene OC(O)NR b -A, C(O)OC 1~2 Alkylene NR b C(O)OA, C(O)OC 1~2 Alkylene OC(O)OA, C(O)OC 1~2 Alkylene NR b C(O)NR b -A, NR a C(O)-C 1~2 Alkylene-A, NR a C(O)-C 1~2 Alkylene OA, NR a C(O)-C 1~2 Alkylene C(O)-A, NR a C(O)-C 1~2 Alkylene NR b C(O)-A, NR a C(O)-C 1~2 AlkyleneC(O)NR b -A, NR a C(O)-C 1~2 Alkylene OC(O)-A, NR a C(O)-C 1~2 Alkylene C(O)OA, NR a C(O)-C 1~2 Alkylene OC(O)NR b -A, NR a C(O)-C 1~2 Alkylene NR b C(O)OA, NR a C(O)-C 1~2 Alkylene OC(O)OA, NR a C(O)-C 1~2 Alkylene NR b C(O)NR b -A, C(O)NR a -C 1~2 Alkylene-A, C(O)NR a -C 1~2 Alkylene OA, C(O)NRa -C 1~2 Alkylene C(O)-A, C(O)NR a -C 1~2 Alkylene NR b C(O)-A, C(O)NR a -C 1~2 AlkyleneC(O)NR b -A, C(O)NR a -C 1~2 Alkylene OC(O)-A, C(O)NR a -C 1~2 Alkylene C(O)OA, C(O)NR a -C 1~2 Alkylene OC(O)NR b -A, C(O)NR a -C 1~2 Alkylene NR b C(O)OA, C(O)NR a -C 1~2 Alkylenes OC(O)OA, and C(O)NR a -C 1~2 Alkylene NR b C(O)NR b - selected from A and R 4 and R 5 The other is H, halo, C 1~4 Alkyl and C 1~4 In some embodiments, X is selected from O, OC(O), C(O)O, NR a C(O) and C(O)NR a Selected from R 4 and R 5 On the other hand, OC 1~2 Alkylene-A, OC 1~2 Alkylene OA, OC 1~2 Alkylene C(O)-A, OC 1~2 Alkylene NR b C(O)-A, OC 1~2 AlkyleneC(O)NR b -A, O.C. 1~2 Alkylene OC(O)-A, OC 1~2 Alkylene C(O)OA, OC 1~2Alkylene OC(O)NR b -A, O.C. 1~2 Alkylene NR b C(O)OA, OC 1~2 Alkylene OC(O)OA, OC 1~2 Alkylene NR b C(O)NR b -A, OC(O)-C 1~2 Alkylene-A, OC(O)-C 1~2 Alkylene OA, OC(O)-C 1~2 Alkylene C(O)-A, O-C(O)-C 1~2 Alkylene NR b C(O)-A, OC(O)-C 1~2 AlkyleneC(O)NR b -A, OC(O)-C 1~2 Alkylene OC(O)-A, OC(O)-C 1~2 Alkylene C(O)OA, OC(O)-C 1~2 Alkylene OC(O)NR b -A, OC(O)-C 1~2 Alkylene NR b C(O)OA, OC(O)-C 1~2 Alkylene OC(O)OA, OC(O)-C 1~2 Alkylene NR b C(O)NR b -A, C(O)OC 1~2 Alkylene, C(O)OC 1~2 Alkylene OA, C(O)OC 1~2 Alkylene C(O)-A, C(O)OC 1~2 Alkylene NR b C(O)-A, C(O)OC 1~2 AlkyleneC(O)NR b -A, C(O)OC 1~2 Alkylene OC(O)-A, C(O)OC 1~2 Alkylene C(O)OA, C(O)OC 1~2 Alkylene OC(O)NR b -A, C(O)OC 1~2 Alkylene NR b C(O)OA, C(O)OC 1~2 Alkylene OC(O)OA, C(O)OC 1~2Alkylene NR b C(O)NR b -A, NR a C(O)-C 1~2 Alkylene-A, NR a C(O)-C 1~2 Alkylene OA, NR a C(O)-C 1~2 Alkylene C(O)-A, NR a C(O)-C 1~2 Alkylene NR b C(O)-A, NR a C(O)-C 1~2 AlkyleneC(O)NR b -A, NR a C(O)-C 1~2 Alkylene OC(O)-A, NR a C(O)-C 1~2 Alkylene C(O)OA, NR a C(O)-C 1~2 Alkylene OC(O)NR b -A, NR a C(O)-C 1~2 Alkylene NR b C(O)OA, NR a C(O)-C 1~2 Alkylene OC(O)OA, NR a C(O)-C 1~2 Alkylene NR b C(O)NR b -A, C(O)NR a -C 1~2 Alkylene-A, C(O)NR a -C 1~2 Alkylene OA, C(O)NR a -C 1~2 Alkylene C(O)-A, C(O)NR a -C 1~2 Alkylene NR b C(O)-A, C(O)NR a -C 1~2 AlkyleneC(O)NR b -A, C(O)NR a -C 1~2 Alkylene OC(O)-A, C(O)NR a -C 1~2 Alkylene C(O)OA, C(O)NR a-C 1~2 Alkylene OC(O)NR b -A, C(O)NR a -C 1~2 Alkylene NR b C(O)OA, C(O)NR a -C 1~2 Alkylenes OC(O)OA, and C(O)NR a -C 1~2 Alkylene NR b C(O)NR b - selected from A and R 4 and R 5 The other is H, halo, C 1~4 Alkyl and C 1~4 alkoxy, wherein all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0171] In some embodiments, R 4 and R 5 The other is H, F, Cl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Deuteroalkyl and C 1~4 alkoxy, where any available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 4 and R 5 is selected from D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CF, CHF, and CD, where any available hydrogen atom may be independently replaced with a fluorine atom or a deuterium atom, as appropriate; 4 and R 5 The other is H or D.

[0172] In some embodiments, R 4 is XLA and R 5 H, halo, C 1~6 Alkyl and C 1~6 In some embodiments, R is selected from alkoxy. 5is XLA and R 4 H, halo, C 1~6 Alkyl and C 1~6 Alkoxy is selected from:

[0173] In some embodiments, R a is H and C 1~4 alkyl.

[0174] In some embodiments, R b is H, C 1~4 A is selected from alkyl and A.

[0175] In some embodiments, A is H and R 4 and R 5 One of them is OH, C(O)H, NHR a , NHR a C(O), C(O)NHR a , OC(O)H, C(O)OH, OC(O)OH, NR a C(O)OH, OC(O)NHR a , NHR a C(O)NR a , XC 1~4 Alkylene, XC 2~4 Alkenylene, XC 1~4 Alkylene OH, XC 2~4 Alkenylene OH, XC 1~4 Alkylene C(O)H, XC 2~4 Alkenylene C(O)H, XC 1~4 Alkylene NR b C(O)H, XC 2~4 Alkenylene NR b C(O)H, XC 1~4 AlkyleneC(O)NHR b , XC 2~4 AlkenyleneC(O)NHR b , XC 1~4 Alkylene OC(O)H, XC 2~4 Alkenylene OC(O)H, XC 1~4 Alkylene C(O)OH, C 2~4 Alkenylene C(O)H, XC 1~4 Alkylene OC(O)NHRb , XC 2~4 AlkenyleneOC(O)NHR b , XC 1~4 Alkylene NR b C(O)OH, XC 2~4 Alkenylene NR b C(O)OH, XC 1~4 Alkylene OC(O)OH, XC 2~4 Alkenylene OC(O)OH, XC 1~4 Alkylene NR b C(O)NHR b and XC 2~4 Alkenylene NR b C(O)NHR b Selected from R 4 and R 5 The other is H, halo, C 1~4 Alkyl and C 1~4 In some embodiments, A is H and R is selected from the group consisting of alkoxy, wherein all available hydrogen atoms are independently replaced with fluorine or deuterium atoms, as appropriate. 4 and R 5 One of them is OH, C(O)H, NHR a , NHR a C(O), C(O)NHR a , OC(O)H, C(O)OH, OC(O)OH, NR a C(O)OH, OC(O)NHR a , NHR a C(O)NR a , XC 1~2 Alkylene, XC 2~4 Alkenylene, XC 1~2 Alkylene OH, XC 2~4 Alkenylene OH, XC 1~2 Alkylene C(O)H, XC 2~4 Alkenylene C(O)H, XC 1~2 Alkylene NR b C(O)H, XC 2~4 Alkenylene NR b C(O)H, XC 1~2 AlkyleneC(O)NHR b , XC 2~4 AlkenyleneC(O)NHR b, XC 1~2 Alkylene OC(O)H, XC 2~4 Alkenylene OC(O)H, XC 1~2 Alkylene C(O)OH, C 2~4 Alkenylene C(O)H, XC 1~2 Alkylene OC(O)NHR b , XC 2~4 AlkenyleneOC(O)NHR b , XC 1~2 Alkylene NR b C(O)OH, XC 2~4 Alkenylene NR b C(O)OH, XC 1~2 Alkylene OC(O)OH, XC 2~4 Alkenylene OC(O)OH, XC 1~2 Alkylene NR b C(O)NHR b and XC 2~4 Alkenylene NR b C(O)NHR b Selected from R 4 and R 5 The other is H, halo, C 1~4 Alkyl and C 1~4 alkoxy, wherein all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0176] In some embodiments, A is H and X is a direct bond. Thus, in some embodiments, R 4 and R 5 One of them is C 1~4 Alkyl, C 2~4 Alkenyl, C 1~4 Alkylene OH, C 2~6 Alkenylene OH, C 1~4 Alkylene C(O)H, C 2~4 Alkenylene C(O)H, C 1~4 Alkylene NR b C(O)H, C 2~4 Alkenylene NR b C(O)H, C 1~4 AlkyleneC(O)NHR b , C 2~4AlkenyleneC(O)NHR b , C 1~4 Alkylene OC(O)H, C 2~4 Alkenylene O-C(O)H, C 1~4 Alkylene C(O)OH, C 2~4 Alkenylene C(O)H, C 1~4 Alkylene OC(O)NHR b , C 2~6 AlkenyleneOC(O)NHR b , C 1~4 Alkylene NR b C(O)OH, C 2~4 Alkenylene NR b C(O)OH, C 1~4 Alkylene OC(O)OH, C 2~4 Alkenylene OC(O)OH, C 1~4 Alkylene NR b C(O)NHR b and C 2~4 Alkenylene NR b C(O)NHR b Selected from R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 Alkoxy is selected from:

[0177] In some embodiments, A is H and X is O, C(O), NR a , N.R. a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, A is H and X is selected from O, C(O), OC(O), C(O)O and OC(O)O. In some embodiments, A is H and X is selected from O, OC(O) and C(O)O. In some embodiments, A is H and X is O. In some embodiments, A is H and X is selected from OC(O) and C(O)O. In some embodiments, A is H and X is NR a , N.R.a C(O), C(O)NR a , N.R. a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, A is H and X is selected from NR a C(O), C(O)NR a , N.R. a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, A is H and X is selected from NR a C(O) and C(O)NR a In some embodiments, A is H and X is selected from NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a is selected from.

[0178] In some embodiments, A is H, L is a direct bond, and R 3 and R 4 One of R is selected from XH. Thus, in some embodiments, R 3 and R 4 One of them is OH, C(O)H, NHR a , NHR a C(O), C(O)NHR a , OC(O)H, C(O)OH, OC(O)OH, NR a C(O)OH, OC(O)NHR a and NHR a C(O)NR a wherein all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0179] In some embodiments, when A is H, R b is H and C 1~4 alkyl, where any available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0180] In some embodiments, R 4 and R 5 One side is A, OA, C(O)-A, C(O)-A, C(O)OA, C 1~4 Alkylene-A, C 1~4 Alkylene-C(O)-A,C 1~4 Alkylene-C(O)OA, OC 1~4 Alkylene-A, OC 1~4 Alkylene-C(O)-A, and O-C 1~4 alkylene-C(O)OA; R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy, wherein all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0181] In some embodiments, R 4 and R 5 is selected from A, OA, C(O)-A, C(O)-A, and C(O)OA; R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy, where any available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 4 and R 5 One of R is A. In some embodiments, R 4 and R 5 One of R is OA. 4 and R 5 One of R is C(O)-A. In some embodiments, R 4 and R 5 One of them is C(O)OA.

[0182] In some embodiments, R 4 and R 5 One of them is C 1~4Alkylene-A, C 1~4 Alkylene-C(O)-A,C 1~4 Alkylene-C(O)OA, OC 1~4 Alkylene-A, OC 1~4 Alkylene-C(O)-A, and O-C 1~4 alkylene-C(O)OA; R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy, where any available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 4 and R 5 One of them is C 1~4 In some embodiments, R 4 and R 5 One of them is C 1~4 In some embodiments, R 4 and R 5 One of them is C 1~4 alkylene-C(O)OA. In some embodiments, R 4 and R 5 On the other hand, OC 1~4 In some embodiments, R 4 and R 5 On the other hand, OC 1~4 In some embodiments, R 4 and R 5 On the other hand, OC 1~4 It is alkylene-C(O)OA.

[0183] In some embodiments, R 4 and R 5 One side is A, OA, C(O)-A, C(O)OA, C 1~4 Alkylene-A, C 1~4 Alkylene-C(O)-A,C 1~4 Alkylene-C(O)OA, OC 1~4 Alkylene-A, OC 1~4 Alkylene-C(O)-A, and O-C1~4 alkylene-C(O)OA; R 4 and R 5 The other is H, F, Cl, C 1~4 Alkyl and C 1~4 alkoxy, where any available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 4 and R 5 One side is A, OA, C(O)-A, C(O)OA, C 1~4 Alkylene-A, C 1~4 Alkylene-C(O)-A,C 1~4 Alkylene-C(O)OA, OC 1~4 Alkylene-A, OC 1~4 Alkylene-C(O)-A, and O-C 1~4 alkylene-C(O)OA; R 4 and R 5 The other is H, F, Cl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Deuteroalkyl and C 1~4 alkoxy, where any available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 4 and R 5 One side is A, OA, C(O)-A, C(O)OA, C 1~2 Alkylene-A, C 1~2 Alkylene-C(O)-A,C 1~2 Alkylene-C(O)OA, OC 1~2 Alkylene-A, OC 1~2 Alkylene-C(O)-A, and O-C 1~2 alkylene-C(O)OA; R 4 and R 5 and the other is selected from D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CF, CHF, and CD, where any available hydrogen atoms may be independently replaced with fluorine or deuterium atoms, as appropriate. 4and R 5 One side is A, OA, C(O)-A, C(O)OA, C 1~2 Alkylene-A, C 1~2 Alkylene-C(O)-A,C 1~2 Alkylene-C(O)OA, OC 1~2 Alkylene-A, OC 1~2 Alkylene-C(O)-A, and O-C 1~2 alkylene-C(O)OA; R 4 and R 5 and the other is H or D, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 4 and R 5 One side is A, OA, C(O)-A, C(O)OA, CH2-A, CD2-A, CF2-A, CH2-C(O)-A, CF2-C(O)-A, CD2-C(O)-A, CH2-C(O)OA, CD2-C(O)OA, CF2-C(O)O A, O-CH2A, O-CF2A, O-CD2A, -CH2-C(O)-A, O-CD2-C(O)-A, O-CF2-C(O)-A, O-CH2-C(O)OA, O-CF2-C(O)OA, O-CD2-C(O)OA, R 4 and R 5 The other is H or D.

[0184] In some embodiments, R 4 is A, OA, C(O)-A, C(O)OA, C 1~2 Alkylene-A, C 1~2 Alkylene-C(O)-A,C 1~2 Alkylene-C(O)OA, OC 1~2 Alkylene-A, OC 1~2 Alkylene-C(O)-A, and O-C 1~2 alkylene-C(O)OA; R 5 is H or D, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 4are A, OA, C(O)-A, C(O)OA, CH2-A, CD2-A, CF2-A, CH2-C(O)-A, CF2-C(O)-A, CD2-C(O)-A, CH2-C(O)OA, CD2-C(O)OA, CF2-C(O)OA, O- CH2A, O-CF2A, O-CD2A, O-CH2-C(O)-A, O-CD2-C(O)-A, O-CF2-C(O)-A, O-CH2-C(O)OA, O-CF2-C(O)OA, and O-CD2-C(O)OA, R 5 is H or D. In some embodiments, R 5 is A, OA, C(O)-A, C(O)OA, C 1~2 Alkylene-A, C 1~2 Alkylene-C(O)-A,C 1~2 Alkylene-C(O)OA, OC 1~2 Alkylene-A, OC 1~2 Alkylene-C(O)-A, and O-C 1~2 alkylene-C(O)OA; R 4 is H or D, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 5 are A, OA, C(O)-A, C(O)OA, CH2-A, CD2-A, CF2-A, CH2-C(O)-A, CF2-C(O)-A, CD2-C(O)-A, CH2-C(O)OA, CD2-C(O)OA, CF2-C(O)OA, O- CH2A, O-CF2A, O-CD2A, O-CH2-C(O)-A, O-CD2-C(O)-A, O-CF2-C(O)-A, O-CH2-C(O)OA, O-CF2-C(O)OA, and O-CD2-C(O)OA, R 4 is H or D.

[0185] In some embodiments, A is C 1~30 Alkyl, C 2~30 Alkenyl, phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 64and 3-6 membered heterocycloalkyl containing 1-3 hetero moieties independently selected from O, S, S(O), SO, N, and NR 64 and wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with F, Cl, OH, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 In some embodiments, A is optionally substituted with one or two substituents independently selected from fluoroalkyl, and all available hydrogen atoms are optionally substituted independently with fluorine or deuterium atoms. 1~30 Alkyl, C 2~30 Alkenyl, phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 64 and 3-6 membered heterocycloalkyl containing 1-3 hetero moieties independently selected from O, S, S(O), SO, N, and NR 64 and wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with F, Cl, OH, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 It may be optionally substituted with one or two substituents independently selected from fluoroalkyl.

[0186] In some embodiments, A is phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 64and 3-6 membered heterocycloalkyl containing 1-3 hetero moieties independently selected from O, S, S(O), SO, N, and NR 64 and wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with F, Cl, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 In some embodiments, A is optionally substituted with one or two substituents independently selected from phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 48 and 5-6 membered heterocycloalkyl containing 1-2 hetero moieties independently selected from O, S, S(O), SO, N, and NR 64 and wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with F, Cl, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 It may be optionally substituted with one or two substituents independently selected from fluoroalkyl.

[0187] In some embodiments, C in A 3~6 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. 3~6 Cycloalkyl is F, Cl, C 1~4 Alkyl, C 1~4Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 and cyclopropyl optionally substituted with one or two substituents independently selected from fluoroalkyl.

[0188] In some embodiments, O, S, S(O), SO, N, and NR in A 64 and 3-6 membered heterocycloalkyl containing 1 to 3 hetero moieties independently selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, titanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxathiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithietanyl, selected from oranyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl oxide, tetrahydrothiopyranyl dioxide, dihydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, and dithianyl, which are selected from F, C, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 In some embodiments, A is optionally substituted with one or two substituents independently selected from O, S, S(O), SO, N, and NR 64and 3-6 membered heterocycloalkyl containing 1-3 heteromoieties independently selected from tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, piperidinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl oxide, tetrahydrothiopyranyl dioxide, dihydropyranyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl, each of which is selected from F, C, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 It may be optionally substituted with one or two substituents independently selected from fluoroalkyl.

[0189] In some embodiments, the 5- to 6-membered heteroaryl in A is selected from furyl, imidazolyl, isothiazolyl, thiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyrrolyl, thienofuryl, triazolyl, and thienyl, each of which is selected from F, C, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 In some embodiments, the 5- to 6-membered heteroaryl in A is selected from furyl, isothiazolyl, thiazolyl, pyridyl, and pyrrolyl, each of which is selected from F, C, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 It may be optionally substituted with one or two substituents independently selected from fluoroalkyl.

[0190] In some embodiments, in A, phenyl, C 3~10 The cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl may be optionally substituted with one or two substituents independently selected from F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, CD3, CH(CH3)2O, CH3CH2CHO, CH3CHO, CHO, CF3O, CHF2O, CF2HCHO, CF3CHO, (CF3)2CHO, and CD3O.

[0191] In some embodiments, A is C 1~30 Alkyl and C 2~30 alkenyl, wherein all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0192] In some embodiments, A is C 10~25 In some embodiments, A is alkyl, and all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms. 13~21 It is alkyl, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0193] In some embodiments, A is C 10~25 In some embodiments, A is an alkenyl group, and all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms. 13~21 In some embodiments, A is an alkenyl group, and all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms. 10~25 is alkenyl and contains 1, 2, 3, 4, 5 or 6 double bonds;

[0194] In some embodiments, the alkyl or alkene group in A is an alkyl or alkenyl group present in a fatty acid, and all hydrogen atoms may be optionally replaced with deuterium atoms. In some embodiments, A is an alkenyl group present in a fatty acid, and all hydrogen atoms may be optionally replaced with deuterium atoms. In some embodiments, the fatty acid is an ω-6 fatty acid (i.e., an unsaturated or polyunsaturated fatty acid in which the double bond closest to the terminal methyl is at the 6th carbon from the terminal methyl group) or an ω-3 fatty acid (i.e., an unsaturated or polyunsaturated fatty acid in which the double bond closest to the terminal methyl is at the 3rd carbon from the terminal methyl group), and all available hydrogen atoms may be optionally replaced with deuterium atoms. In some embodiments, A is an alkyl group present in a fatty acid, and all available hydrogen atoms may be optionally replaced with deuterium atoms. In some embodiments, the alkyl or alkene group in A is an alkyl or alkene group present in a fatty acid selected from the list of fatty acids set forth in Table 1, and all available hydrogen atoms may be optionally replaced with deuterium atoms.

[0195] In some embodiments, the alkene group in A is an alkyl or alkenyl group present in linoleic acid, eicosadienoic acid, or decosahexanoic acid.

[0196] In some embodiments, when A is an alkyl or alkenyl group present in the fatty acid, 1 to 10, 2 to 8, 2 to 6, or 2 to 4 hydrogen atoms are replaced with deuterium.

[0197] In some embodiments, A is (CH2)7CH=CH(CH2)7CH3. In some embodiments, A is (CH2)7CH=CHCH2CH=CH(CH2)4CH3. In some embodiments, A is (CH2)8CH=CHCH2CH=CH(CH2)4CH3. In some embodiments, A is (CH2)7CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3. In some embodiments, A is (CH2)3CH=CHCH2CH=CH(CH2)1CH=CHCH2CH=CH(CH2)3CH3. In some embodiments, A is (CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3. In some embodiments, A is (CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3.

[0198] In some embodiments, R 64 and R 65 are independently H, D, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, R is selected from deuteroalkyl. 64 and R 65 is independently selected from H, D, CH, CF, and CD. In some embodiments, R 64 and R 65 is independently selected from CH3 and CD3.

[0199] In some embodiments, the compound of formula I is defined as follows: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof [In formula: Q is Q1, Q2, Q3, Q4, Q5 and Q6: [ka] Selected from the structure: [ka] is a single or double bond, provided that the structure in Q1: [ka] is a double bond, R 9 and R 15 does not exist, and the structure in Q2: [ka] is a double bond, R 17 and R 25 does not exist, and the structure in Q5: [ka] is a double bond, R 48 and R 57 does not exist; R 1 , R 1 ', R 2 , R 2 ', R 3 and R 6 is independently selected from H, D, and F; R 4 and R 5 One or both of these are H, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy and C 1~4 deuteroalkoxy; or R 4 and R 5 together to form O-(CH2) 1~2 Forming O; R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25, R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 is independently selected from H and D; R 12 , R 20 , R 29 , R 39 and R 51 are independently H, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 is selected from deuteroalkyl; R 60 and R 61 are independently H and C 1~6 alkyl, provided that when Q is Q6, the compound of formula I includes D].

[0200] In some embodiments, the compound of formula I is defined as follows: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof [In formula: R 1 and R 1 ' is independently H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxyl, NH(C 1~6 alkyl) and N(C 1~6 alkyl)2; R 2 and R 2 ' is independently H, halo, NH2, C 1~6 Alkyl, C 1~6 Alkoxyl, NH(C 1~6 alkyl) and N(C 1~6 alkyl)2; Q is Q1, Q2, Q3, Q4, Q5 and Q6: [ka] Selected from: [ka] is a single or double bond, provided that the structure in Q1: [ka] is a double bond, R 9 and R 15 does not exist, and the structure in Q2: [ka] is a double bond, R 17 and R 25 does not exist, and the structure in Q5: [ka] is a double bond, R 48 and R 57 does not exist; R 4 and R 5 One or both of may independently be H, halo, or C 1~6 Alkyl and C 1~6alkoxy; R 4 and R 5 together to form O-(CH2) 1~2 Form O, or R 4 and R 5 One of them is selected from XLA and R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy; X is a direct bond, O, C(O), or NR a , N.R. a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a Selected from; L is a direct bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 1~6 Alkylene O, C 2~6 Alkenylene O,C 1~6 Alkylene C(O), C 2~6 Alkenylene C(O)C 1~6 Alkylene NR b C(O), C 2~6 Alkenylene NR b C(O), C 1~6 AlkyleneC(O)NR b , C 2~6 AlkenyleneC(O)NR b , C 1~6 Alkylene OC(O), C 2~6 Alkenylene OC(O), C 1~6 Alkylene C(O)O, C 2~6 Alkenylene C(O), C 1~6 Alkylene OC(O)NR b , C 2~6 Alkenylene OC(O)NR b , C 1~6 Alkylene NR b C(O)O, C 2~6 Alkenylene NRb C(O)O, C 1~6 Alkylene O-C(O)O, C 2~6 Alkenylene O-C(O)O, C 1~6 Alkylene NR b C(O)NR b and C 2~6 Alkenylene NR b C(O)NR b Selected from; R a is H and C 1~6 alkyl; R b is H, C 1~6 alkyl and A; A is H, C 1~30 Alkyl, C 2~30 Alkenyl, phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 64 and 3-6 membered heterocycloalkyl containing 1-4 hetero moieties independently selected from O, S, S(O), SO, N, and NR 64 and wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with halo, C 1~4 Alkyl and OC 1~4 optionally substituted with one or more substituents independently selected from alkyl; R 3 and R 6 are independently H, halo, OH, C 1~6 Alkyl and C 1~6 selected from alkoxy; R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently H, halo, and C 1~6 alkyl; R 12 , R 20 , R 29 , R 39 and R 51 are independently H, C 1~6 Alkyl, C(O)C 1~6 selected from alkyl and C(O)-A'; R 60 and R 61 are independently H and C 1~6 alkyl; or R 60 and R 61 One of them is C(O)-A' and the other is H and C 1~6 alkyl; where A' is Y, OY and OC 1~4 alkylene-OC(O)-Y; Y is C7~30 Alkyl and C 7~30 alkenyl; or R 60 and R 61 together with the nitrogen atom to which they are attached, form O, S, S(O), SO2, N, and NR 65 and optionally includes one or two additional hetero moieties independently selected from halo, OH, C 1~4 Alkyl and OC 1~4 forming a 3- to 6-membered heterocyclic ring, optionally substituted with one or more substituents independently selected from alkyl; R 64 and R 65 are independently H and C 1~6 alkyl; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; However, R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 one of which is C(O)-A; or R 4 and R 5 One of them is selected from XLA and R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy, provided that when both X and L are direct bonds, A is selected from H, C 1~6 Alkyl or C 1~6 not alkenyl].

[0201] Those skilled in the art will recognize that R 2 and R 2 If ' is different, R 2 and R 2 It will be understood that the carbon to which ' is attached is chiral. Thus, the present application includes all stereoisomers at this carbon center and mixtures thereof.

[0202] Those skilled in the art will recognize that R 1 and R 1 If ' is different, R 1 and R 1 It will be understood that the carbon to which ' is attached is also chiral. Thus, the present application includes all stereoisomers at this carbon center and mixtures thereof.

[0203] In some embodiments, the compound of Formula I is selected from the compounds listed below, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16]

[0204] III. Novel Compounds of the Present Application Some compounds of formula I are novel, and therefore the present application includes these compounds and compositions containing these compounds, as well as uses thereof. Thus, in some embodiments, the compound of formula I is a compound of formula IA. Thus, the present application includes compounds of formula IA: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 5 and Q is as defined above for formula I; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; with the proviso that when Q is Q6, the compound of formula IA contains D, If Q is Q3 or Q4, then R 5 is H or OCH3, and R 29 or R 39 If is CH3, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 6 , R 26 , R 27 , R 28 , R 30 ~R 35 , R 36 , R 37 , R 38 and R 40 ~R47 is not all H, Q is Q4 and R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 6 , R 38 and R 40 ~R 47 are all H, and R 39 If is CD3, R 36 and R 37 are not both D].

[0205] In some embodiments, all available hydrogen atoms may be independently and optionally replaced with fluorine atoms, and all available atoms may be optionally replaced with their alternative isotopes.

[0206] In some embodiments, Q is Q1: [ka] and the structure: [ka] is a single bond, and compounds of formula IA have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15is as defined for formula IA, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0207] In some embodiments, Q is Q1: [ka] and the structure: [ka] is a double bond, and compounds of formula IA have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 8 , R 10 , R 11 , R 12 , R 13 and R 14 is as defined for formula IA, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0208] In some embodiments, when all available hydrogen atoms in a group are optionally substituted with halogen atoms, the halogen atom is F, Cl, or Br. In some embodiments, when all available hydrogen atoms in a group are optionally substituted with halogen atoms, the halogen atom is F or Br. In some embodiments, when all available hydrogen atoms are optionally substituted with halogen atoms, the halogen atom is F or Cl. In some embodiments, when all available hydrogen atoms in a group are optionally substituted with halogen atoms, the halogen atom is F.

[0209] In some embodiments, all available hydrogen atoms may be optionally replaced with deuterium atoms, where all available atoms may be optionally replaced with their alternative isotopes.

[0210] In some embodiments, Q is Q2: [ka] and the structure: [ka] is a single bond, and compounds of formula IA have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R24 and R 25 is as defined for formula IA, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0211] In some embodiments, Q is Q2: [ka] and the structure: [ka] is a double bond, and compounds of formula IA have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 16 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 is as defined for formula IA, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0212] In some embodiments, Q is Q3: [ka] and the compound of formula IA has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 and R 35 is as defined for formula IA, any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; However, R 5 is H or OCH3, and R 29 If is CH3, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 6 , R 26 , R 27 , R 28 , R 30 ~R 35 , R 36 , R 37 , R 38 and R 40 ~R 47 is not all H].

[0213] In some embodiments, Q is Q4: [ka] and the compound of formula IA has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 and R 47 is as defined for formula IA, Any available hydrogen atom may be independently replaced with a fluorine or chlorine atom, and any available atom may be optionally replaced with its alternative isotope, provided that R 5 is H or OCH3, and R 39 If is CH3, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 6 , R 36 , R 37 , R 38 and R 40 ~R 47 is not all H, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 6 , R 38 and R 40 ~R 47 are all H, and R39 If is CD3, R 36 and R 37 are not both D].

[0214] In some embodiments, Q is Q5: [ka] and the structure: [ka] is a single bond, and compounds of formula IA have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 and R 57 is as defined for formula IA, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0215] In some embodiments, Q is Q5: [ka] and the structure: [ka] is a double bond, and compounds of formula IA have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 and R 56 is as defined for formula IA, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0216] In some embodiments, Q is Q6: [ka] and the compound of formula IA has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 58 , R 59 , R 60 , R 61 , R62 and R 63 is as defined for formula IA, any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; provided that the compound of formula IA contains D].

[0217] In some embodiments, R 1 , R 2 , R 2 ', R 2 '', R 3 , R 5 and R 6 are all H, and the compound of formula IA has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 4 and Q is as defined for formula IA; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; with the proviso that when Q is Q6, the compound of formula IA contains D, If Q is Q3 or Q4, then R 5 is H or OCH3, and R 29 or R 39 If is CH3, R 4 , R 26 , R 27 , R 28 , R 30 ~R 35 , R 36 , R 37 , R 38 and R 40 ~R 47 is not all H, Q is Q4 and R 4 , R 38 and R40 ~R 47 are all H, and R 39 If is CD3, R 36 and R 37 are not both D].

[0218] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 and R 6 are all H, and the compound of formula IA has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 5 and Q is as defined for formula IA; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; with the proviso that when Q is Q6, the compound of formula IA contains D, If Q is Q3 or Q4, then R 5 is H or OCH3, and R 29 or R 39 If is CH3, R 26 , R 27 , R 28 , R 30 ~R 35 , R 36 , R 37 , R 38 and R 40 ~R 47 is not all H, Q is Q4 and R 38 and R 40 ~R 47 are all H, and R 39 If is CD3, R 36 and R 37 are not both D].

[0219] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 and R 6 are all H, and the compound of formula IA has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 4 , R 5 and Q is as defined for formula I; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; with the proviso that when Q is Q6, the compound of formula IA contains D, If Q is Q3 or Q4, then R 5 is H or OCH3, and R 29 or R 39 If is CH3, R 4 , R 26 , R 27 , R 28 , R 30 ~R 35 , R 36 , R 37 , R 38 and R 40 ~R 47 is not all H, Q is Q4 and R 4 , R 38 and R 40 ~R 47 are all H, and R 39 If is CD3, R 36 and R 37 are not both D].

[0220] In some embodiments, R 1 , R 1', R 2 and R 2 ' are all H and R 3 , R 4 , R 5 and R 6 are all D, and the compound of formula IA has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: Q is as defined for formula I; All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0221] In some embodiments, R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently H, D, F, Cl, C 1~6 Alkyl, C 1~6 Fluoroalkyl and C 1~6 In some embodiments, R is selected from deuteroalkyl. 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63is independently selected from H, F, D, CH, CDH, CDH, CD, CF, CHF, CHCH, CHCHD, CHCDH, and CDCD. 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 is independently selected from H and D.

[0222] In some embodiments, R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15, R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 and R 57 is independently selected from H and D.

[0223] In some embodiments, R 58 , R 59 , R 62 and R 63 is independently selected from H and D. In some embodiments, R 58 , R 59 , R 62 and R 63 is H. In some embodiments, R 58 , R 59 , R 62 and R 63 is D. In some embodiments, R 58 and R 59 is H and R 62 and R 63 is D. In some embodiments, R 58 and R59 is D and R 62 and R 63 is H.

[0224] In some embodiments, Q has the structure: [ka] If R 28 or R 38 The stereochemistry at the carbon to which is attached is either R or S. Thus, in some embodiments, Q3 has the structure: [ka] and Q4 has the structure: [ka] is.

[0225] In some embodiments, R 28 or R 38 The stereochemistry at the carbon to which is attached is R. In some embodiments, R 28 or R 38 The stereochemistry at the carbon to which is attached is S.

[0226] In some embodiments, Q has the structure: [ka] and the structure: [ka] is a single bond, R 15 , R 25 or R 48 The stereochemistry at the carbon to which is attached is either R or S. Thus, in some embodiments, Q1 has the structure: [ka] and Q2 has the structure: [ka] and Q5 has the structure: [ka] is.

[0227] In some embodiments, R 15 , R 25 or R 48 The stereochemistry at the carbon to which is attached is R. In some embodiments, R 15 , R 25 or R 48 The stereochemistry at the carbon to which is attached is S.

[0228] In some embodiments, Q is selected from one of the following groups: [ka] [ka] [In the formula, R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 are independently H, D, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 In some embodiments, R is selected from deuteroalkyl and C(O)-A'. 12 , R 20 , R 29 and R 39 are independently H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 In some embodiments, R is selected from deuteroalkyl and C(O)-A'. 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R61 is independently selected from H, CH, CD, CDH, CFH, and CF. In some embodiments, R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 is independently selected from H, CH3, and CD3. In some embodiments, R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 is independently selected from CH3 and CD3.

[0229] In some embodiments, Q is selected from one of the following groups: [ka] [In the formula, R 29 H, D, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 In some embodiments, R 29 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 In some embodiments, R is selected from deuteroalkyl and C(O)-A'. 29 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, R is selected from deuteroalkyl. 29 is selected from H, CH, CD, CDH, CFH, and CF. In some embodiments, R 29 is selected from H, CH3 and CD3. In some embodiments, R 29 is selected from CH3 and CD3.

[0230] In some embodiments, R60 and R 61 together with the nitrogen atom to which they are attached, form O, N, and NR 65 and optionally includes one or two additional hetero moieties independently selected from halo, OH, C 1~4 Alkyl and OC 1~4 It forms a 3- to 6-membered heterocyclic ring which may be optionally substituted with one or more substituents independently selected from alkyl.

[0231] In some embodiments, R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 are independently selected from C(O)-A'.

[0232] In some embodiments, R 60 and R 61 One of them is C(O)-A' and the other is H and C 1~6 In some embodiments, R 60 and R 61 One of them is C(O)-A' and the other is H and C 1~4 alkyl.

[0233] In some embodiments, A' is selected from the group consisting of Y, OY, and OC. 1~2 alkylene-OC(O)-Y, where all available hydrogen atoms may be independently optionally replaced with fluorine or deuterium atoms. In some embodiments, A' is selected from Y, OY, and O-C alkylene-OC(O)-Y, where all available hydrogen atoms may be independently optionally replaced with fluorine or deuterium atoms.

[0234] In some embodiments, Y is C 10~25 In some embodiments, Y is alkyl, and all available hydrogen atoms are optionally replaced independently with fluorine or deuterium atoms. 13~21It is alkyl, and all available hydrogen atoms may be independently optionally replaced with fluorine or deuterium atoms.

[0235] In some embodiments, Y is C 10~25 In some embodiments, Y is an alkenyl group, and all available hydrogen atoms are optionally replaced independently with fluorine or deuterium atoms. 13~21 In some embodiments, Y is an alkenyl group, and all available hydrogen atoms are optionally replaced independently with fluorine or deuterium atoms. 10~25 is alkenyl and contains 1, 2, 3, 4, 5 or 6 double bonds;

[0236] In some embodiments, the alkyl or alkene group of Y is an alkyl or alkenyl group present in a fatty acid, and all available hydrogen atoms may be optionally replaced with deuterium atoms. In some embodiments, Y is an alkenyl group present in a fatty acid, and all available hydrogen atoms may be optionally replaced with deuterium atoms. In some embodiments, the fatty acid is an ω-6 fatty acid (i.e., an unsaturated or polyunsaturated fatty acid in which the double bond closest to the terminal methyl is at the sixth carbon atom from the terminal methyl) or an ω-3 fatty acid (i.e., an unsaturated or polyunsaturated fatty acid in which the double bond closest to the terminal methyl is at the third carbon atom from the terminal methyl), and all available hydrogen atoms may be optionally replaced with deuterium atoms. In some embodiments, Y is an alkyl group present in a fatty acid, and all available hydrogen atoms may be optionally replaced with deuterium atoms. In some embodiments, the alkyl or alkene group of Y is an alkyl or alkene group present in a fatty acid, and is selected from the list of fatty acids set forth in Table 1, and all available hydrogen atoms may be optionally replaced with deuterium atoms.

[0237] In some embodiments, the alkene group of Y is an alkyl or alkenyl group present in linoleic acid, eicosadienoic acid, or decosahexanoic acid.

[0238] In some embodiments, Y is an alkyl or alkenyl group of a fatty acid in which 1 to 10, 2 to 8, 2 to 6, or 2 to 4 hydrogen atoms are replaced with deuterium.

[0239] In some embodiments, Y is (CH2)7CH=CH(CH2)7CH3. In some embodiments, Y is (CH2)7CH=CHCH2CH=CH(CH2)4CH3. In some embodiments, Y is (CH2)8CH=CHCH2CH=CH(CH2)4CH3. In some embodiments, Y is (CH2)7CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3. In some embodiments, Y is (CH2)3CH=CHCH2CH=CH(CH2)1CH=CHCH2CH=CH(CH2)3CH3. In some embodiments, Y is (CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3. In some embodiments, Y is (CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3. Thus, in some embodiments, Y is (CH2)7CH=CH(CH2)7CH3, (CH2)7CH=CHCH2CH=CH(CH2)4CH3, (CH2)8CH=CHCH2CH=CH(CH2)4CH3, (CH2)7CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3, (CH2)3CH=CHCH2CH=CH(CH2)1CH=CHCH2CH=CH(CH2)3CH3, or (CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3.

[0240] In some embodiments, A' is Y.

[0241] In some embodiments, A' is -OY.

[0242] In some embodiments, A' is -O-C3 alkylene-OC(O)-Y.

[0243] In some embodiments, R 1 and R 1' is independently H, OH, halo, NH2, C 1~4 Alkyl, C 1~4 Alkoxy, NH(C 1~4 alkyl) and N(C 1~4 In some embodiments, R 1 and R 1 ' are independently H, D, Cl, F, OH, NH2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkyl, C 1~4 Deuteroalkyl, NH(C 1~4 alkyl), NH(C 1~4 Deuteroalkyl), NH(C 1~4 fluoroalkyl), N(C 1~4 alkyl)2, N(C 1~4 Fluoroalkyl)2, N(C 1~4 Deuteroalkyl)2, N(C 1~4 Fluoroalkyl)(C 1~4 alkyl), N(C 1~4 Fluoroalkyl)(C 1~4 Deuteroalkyl) and N(C 1~4 Deuteroalkyl)(C 1~4 In some embodiments, R 1 and R 1 ' are independently H, D, Cl, F, OH, NH2, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Fluoroalkyl and C 1~2 Deuteroalkyl, NH(C 1~2 alkyl), NH(C 1~2 Deuteroalkyl), NH(C 1~2 fluoroalkyl), N(C 1~2 alkyl)2, N(C 1~2 Fluoroalkyl)2, N(C 1~2 Deuteroalkyl)2, N(C 1~2 Fluoroalkyl)(C 1~2 alkyl), N(C 1~2 Fluoroalkyl)(C 1~2 Deuteroalkyl) and N(C 1~2Deuteroalkyl)(C 1~2 In some embodiments, R 1 is selected from H, D, F, NH, CH, CF, H, CD, CH, O, CF, CD, NH(CH), NH(CD), NH(CF), N(CH), N(CF), and N(CD). In some embodiments, R 1 and R 1 R' is independently selected from H, D, F, NH2, CH3, CF2H, CD2H, CH3O, CF3, and CD3. In some embodiments, R 1 and R 1 R' is independently selected from H, D, F, OH, CH, CFH, CDH, CHO, CF, and CD. In some embodiments, R 1 and R 1 is independently selected from H, D, or F. In some embodiments, R 1 and R 1 In some embodiments, R 1 and R 1 ' are both H.

[0244] In some embodiments, R 2 and R 2 ' is independently H, halo, NH2, C 1~4 Alkyl, C 1~4 Alkoxy, NH(C 1~4 alkyl) and N(C 1~4 In some embodiments, R 2 and R 2 ' are independently H, D, Cl, F, NH2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkyl, C 1~4 Deuteroalkyl, NH(C 1~4 alkyl), NH(C 1~4 Deuteroalkyl), NH(C 1~4 fluoroalkyl), N(C 1~4 alkyl)2, N(C 1~4Fluoroalkyl)2, N(C 1~4 Deuteroalkyl)2, N(C 1~4 Fluoroalkyl)(C 1~4 alkyl), N(C 1~4 Fluoroalkyl)(C 1~4 Deuteroalkyl) and N(C 1~4 Deuteroalkyl)(C 1~4 In some embodiments, R 2 and R 2 ' is independently H, D, Cl, F, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Fluoroalkyl, C 1~2 Deuteroalkyl, NH(C 1~2 alkyl), NH(C 1~2 Deuteroalkyl), NH(C 1~2 fluoroalkyl), N(C 1~2 alkyl)2, N(C 1~2 Fluoroalkyl)2, N(C 1~2 Deuteroalkyl)2, N(C 1~2 Fluoroalkyl)(C 1~2 alkyl), N(C 1~2 Fluoroalkyl)(C 1~2 Deuteroalkyl) and N(C 1~2 Deuteroalkyl)(C 1~2 In some embodiments, R 2 and R 2 R' is independently selected from H, D, F, NH, CH, CFH, CDH, CHO, CF, CD, NH(CH), NH(CD), NH(CF), N(CH), N(CF), and N(CD). In some embodiments, R 1 is selected from H, D, F, NH, CH, CF, CD, CH, O, CF, and CD. 2 and R 2 R' is independently selected from H, D, F, CH, CFH, CDH, CHO, CF, and CD. In some embodiments, R 2 and R 2is independently selected from H, D, or F. In some embodiments, R 2 and R 2 In some embodiments, R 2 and R 2 ' are all H's.

[0245] In some embodiments, R 1 , R 1 ', R 2 and R 2 ' is independently H, D, or F. In some embodiments, R 1 , R 1 ', R 2 and R 2 In some embodiments, R 1 , R 1 ', R 2 and R 2 ' are all H's.

[0246] In some embodiments, R 3 and R 6 are independently H, D, Cl, F, OH, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy, C 1~4 Deuteroalkoxy, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, R is selected from deuteroalkyl. 3 and R 6 are independently H, D, Cl, F, OH, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, R is selected from deuteroalkyl. 3 and R 6 are independently H, D, Cl, F, OH, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Fluoroalkoxy, C 1~2 Deuteroalkoxy, C1~2 Fluoroalkyl and C 1~2 In some embodiments, R is selected from deuteroalkyl. 3 and R 6 are independently H, D, Cl, F, OH, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Fluoroalkyl and C 1~2 In some embodiments, R is selected from deuteroalkyl. 3 and R 6 is independently selected from H, D, F, OH, CH, CHO, CFHO, CDHO, CFO, CDO, CFH, CDH, CF and CD. In some embodiments, R 3 and R 6 is independently selected from H, D, F, OH, CH, CHO, CFH, CDH, CF, and CD. In some embodiments, R 3 and R 6 is independently selected from H, D, F, OH, CH, CHO, CFHO, CFO, and CDO. In some embodiments, R 3 and R 6 is independently selected from H and D. In some embodiments, R 3 and R 6 At least one of R is D. In some embodiments, R 3 and R 6 and each is D. In some embodiments, R 3 and R 6 are H respectively.

[0247] In some embodiments, R 4 and R 5 One or both of these may independently be H, D, F, Cl, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 Deuteroalkyl, C 1~6 Alkoxy, C 1~6 Fluoroalkoxy and C 1~6 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy.4 and R 5 Both independently H, D, F, Cl, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Deuteroalkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy and C 1~4 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 4 and R 5 are independently selected from H, D, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, CD3, CH(CH3)2O, CH3CH2CH2O, CH3CHO, CH3O, CF3O, CHF2O, CF2HCH2O, CF3CHO, (CF3)2CHO, and CD3O. 4 and R 5 are independently selected from H, D, F, Cl, CH3, CH(CH3)2, CF3, CF2H, CD3, CH3O, CH(CH3)2O, CF3O, CHF2O, and CD3O.

[0248] In some embodiments, R 4 and R 5 Both D, F, Cl, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 Deuteroalkyl, C 1~6 Alkoxy, C 1~6 Fluoroalkoxy and C 1~6 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 4 and R 5 are both independently selected from H, D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CFO, CHFO, and CDO. 4 and R 5 Both D, F, Cl, C 1~6 Alkyl, C1~6 Fluoroalkyl, C 1~6 Deuteroalkyl, C 1~6 Alkoxy, C 1~6 Fluoroalkoxy and C 1~6 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 4 and R 5 Both independently H, D, F, Cl, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Deuteroalkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy and C 1~4 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 4 and R 5 are both independently selected from H, D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CFO, CHFO, and CDO. 4 and R 5 are both independently selected from D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CFO, CHFO, and CDO. 4 and R 5 are both independently selected from CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 4 and R 5 Both are CD3O or R 4 and R 5 Both are CHO.

[0249] In some embodiments, R 4 is H or D, and R 5 are H, D, F, Cl, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 Deuteroalkyl, C 1~6 Alkoxy, C 1~6 Fluoroalkoxy and C 1~6In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 4 is H or D, and R 5 are H, D, F, Cl, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Deuteroalkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy and C 1~4 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 4 is H or D, and R 5 is selected from H, D, F, Cl, CH(CH3)2, CH3, CF3, CF2H, CD3, CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 4 is H or D, and R 5 is selected from D, F, Cl, CH(CH), CH, CF, CFH, CD, CH(CH)O, CHO, CFO, CHFO, and CDO. 4 is H or D, and R 5 is selected from CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 4 is H and R 5 is selected from CH3O and CD3O.

[0250] In some embodiments, R 5 is H or D, and R 4 are H, D, F, Cl, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 Deuteroalkyl, C 1~6 Alkoxy, C 1~6 Fluoroalkoxy and C 1~6 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 5 is H or D, and R 4is selected from D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CFO, CHFO, and CDO. 5 is H or D, and R 4 is selected from CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 5 is H and R 4 is selected from CH3O and CD3O.

[0251] In some embodiments, R 3 , R 4 , R 5 and R 6 is selected from D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CFO, CHFO, and CDO. 3 , R 4 , R 5 and R 6 are all H, or in some embodiments, R 3 , R 4 , R 5 and R 6 are all D. In some embodiments, R 3 , R 4 , R 5 and R 6 is selected from CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 3 , R 4 , R 5 and R 6 Two of the groups are selected from H or D, and R 3 , R 4 , R 5 and R 6 and the remainder of R is selected from CH(CH)O, CHO, CFO, CHFO, and CDO. 3 , R 4 , R 5 and R 6 Two of the groups are selected from H or D, and R3 , R 4 , R 5 and R 6 and the remainder of R is selected from CHO and CDO. 3 , R 4 , R 5 and R 6 is selected from H or D, and R 3 , R 4 , R 5 and R 6 and the remainder of R is selected from CH(CH)O, CHO, CFO, CHFO, and CDO. 3 , R 4 , R 5 and R 6 is selected from H or D, and R 3 , R 4 , R 5 and R 6 the remainder being selected from CH3O and CD3O.

[0252] In some embodiments, R 4 and R 5 together to form O-CHO.

[0253] In some embodiments, R 4 and R 5 One of them is selected from XLA and R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 Alkoxy is selected from:

[0254] In some embodiments, X is a direct bond and R 4 and R 5 One of the two is selected from LA, and the other is R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 In some embodiments, X is selected from O, C(O), NR a , N.R. aC(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, X is selected from O, C(O), OC(O), C(O)O, and OC(O)O. In some embodiments, X is selected from O, OC(O), and C(O)O. In some embodiments, X is O. In some embodiments, X is selected from OC(O) and C(O)O. In some embodiments, X is NR a , N.R. a C(O), C(O)NR a , N.R. a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, X is selected from NR a C(O), C(O)NR a , N.R. a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, X is selected from NR a C(O) and C(O)NR a In some embodiments, X is selected from NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, X is selected from O, OC(O), C(O)O, NR a C(O) and C(O)NR a is selected from.

[0255] In some embodiments, L is a direct bond, C 1~4 Alkylene, C 2~4 Alkenylene, C 1~4 Alkylene O, C 2~4 Alkenylene O,C 1~4 Alkylene C(O), C 2~4Alkenylene C(O), C 1~4 Alkylene NR b C(O), C 2~4 Alkenylene NR b C(O), C 1~4 AlkyleneC(O)NR b , C 2~4 AlkenyleneC(O)NR b , C 1~4 Alkylene OC(O), C 2~4 Alkenylene OC(O), C 1~4 Alkylene C(O)O, C 2~4 Alkenylene C(O), C 1~4 Alkylene OC(O)NR b , C 2~4 Alkenylene OC(O)NR b , C 1~4 Alkylene NR b C(O)O, C 2~4 Alkenylene NR b C(O)O, C 1~4 Alkylene O-C(O)O, C 2~4 Alkenylene O-C(O)O, C 1~4 Alkylene NR b C(O)NR b and C 2~4 Alkenylene NR b C(O)NR b In some embodiments, L is selected from a direct bond, C 1~2 Alkylene, C 2~4 Alkenylene, C 1~2 Alkylene O, C 2~4 Alkenylene O,C 1~2 Alkylene C(O), C 2~4 Alkenylene C(O), C 1~2 Alkylene NR b C(O), C 2~4 Alkenylene NR b C(O), C 1~2 AlkyleneC(O)NR b , C 2~4 AlkenyleneC(O)NR b , C 1~2 Alkylene OC(O), C 2~4 Alkenylene OC(O), C 1~2 Alkylene C(O)O, C2~4 Alkenylene C(O), C 1~2 Alkylene OC(O)NR b , C 2~4 Alkenylene OC(O)NR b , C 1~2 Alkylene NR b C(O)O, C 2~4 Alkenylene NR b C(O)O, C 1~2 Alkylene O-C(O)O, C 2~4 Alkenylene O-C(O)O, C 1~2 Alkylene NR b C(O)NR b and C 2~4 Alkenylene NR b C(O)NR b In some embodiments, L is selected from a direct bond, C 1~2 Alkylene, C 1~2 Alkylene O, C 1~2 Alkylene C(O), C 1~2 Alkylene NR b C(O), C 1~2 AlkyleneC(O)NR b , C 1~2 Alkylene OC(O), C 1~2 Alkylene C(O)O, C 1~2 Alkylene OC(O)NR b , C 1~2 Alkylene NR b C(O)O, C 1~2 Alkylenes OC(O)O, and C 1~2 Alkylene NR b C(O)NR b In some embodiments, L is selected from a direct bond, CH, CF, CD, CH—O, CF—O, CD—O, CH—C(O), CF—C(O), CD—C(O), CH—NR b C(O), CD2-NR b C(O), CF2-NR b C(O), CH2-C(O)NR b , CF2-C(O)NR b , CD2-C(O)NR b, CH2-OC(O), CD2-OC(O), CF2-OC(O), CH2-C(O)O, CF2-C(O)O, CD2-C(O)O, CH2-OC(O)NR b , CD2-OC(O)NR b , CF2-OC(O)NR b , CH2-NR b C(O)O, CF2-NR b C(O)O, CD2-NR b C(O)O, CH2-OC(O)O, CF2-OC(O)O, CD2-OC(O)O, CH2-NR b C(O)NR b , CF2-NR b C(O)NR b and CD2-NR b C(O)NR b is selected from.

[0256] In some embodiments, X is a direct bond, L is a direct bond, and R 4 and R 5 one of which is selected from A and R 4 and R 5 The other is H, halo, C 1~4 Alkyl and C 1~4 Alkoxy is selected from:

[0257] In some embodiments, X is O, OC(O), C(O)O, NR a C(O) and C(O)NR a Selected from R 4 and R 5 On the other hand, OC 1~2 Alkylene-A, OC 1~2 Alkylene OA, OC 1~2 Alkylene C(O)-A, OC 1~2 Alkylene NR b C(O)-A, OC 1~2 AlkyleneC(O)NR b -A, O.C. 1~2 Alkylene OC(O)-A, OC 1~2 Alkylene C(O)OA, OC 1~2 Alkylene OC(O)NR b -A, O.C.1~2 Alkylene NR b C(O)OA, OC 1~2 Alkylene OC(O)OA, OC 1~2 Alkylene NR b C(O)NR b -A, OC(O)-C 1~2 Alkylene-A, OC(O)-C 1~2 Alkylene OA, OC(O)-C 1~2 Alkylene C(O)-A, O-C(O)-C 1~2 Alkylene NR b C(O)-A, OC(O)-C 1~2 AlkyleneC(O)NR b -A, OC(O)-C 1~2 Alkylene OC(O)-A, OC(O)-C 1~2 Alkylene C(O)OA, OC(O)-C 1~2 Alkylene OC(O)NR b -A, OC(O)-C 1~2 Alkylene NR b C(O)OA, OC(O)-C 1~2 Alkylene OC(O)OA, OC(O)-C 1~2 Alkylene NR b C(O)NR b -A, C(O)OC 1~2 Alkylene-A, C(O)OC 1~2 Alkylene OA, C(O)OC 1~2 Alkylene C(O)-A, C(O)OC 1~2 Alkylene NR b C(O)-A, C(O)OC 1~2 AlkyleneC(O)NR b -A, C(O)OC 1~2 Alkylene OC(O)-A, C(O)OC 1~2 Alkylene C(O)OA, C(O)OC 1~2 Alkylene OC(O)NR b -A, C(O)OC 1~2 Alkylene NR b C(O)OA, C(O)OC 1~2 Alkylene OC(O)OA, C(O)OC 1~2 Alkylene NR b C(O)NRb -A, NR a C(O)-C 1~2 Alkylene-A, NR a C(O)-C 1~2 Alkylene OA, NR a C(O)-C 1~2 Alkylene C(O)-A, NR a C(O)-C 1~2 Alkylene NR b C(O)-A, NR a C(O)-C 1~2 AlkyleneC(O)NR b -A, NR a C(O)-C 1~2 Alkylene OC(O)-A, NR a C(O)-C 1~2 Alkylene C(O)OA, NR a C(O)-C 1~2 Alkylene OC(O)NR b -A, NR a C(O)-C 1~2 Alkylene NR b C(O)OA, NR a C(O)-C 1~2 Alkylene OC(O)OA, NR a C(O)-C 1~2 Alkylene NR b C(O)NR b -A, C(O)NR a -C 1~2 Alkylene-A, C(O)NR a -C 1~2 Alkylene OA, C(O)NR a -C 1~2 Alkylene C(O)-A, C(O)NR a -C 1~2 Alkylene NR b C(O)-A, C(O)NR a -C 1~2 AlkyleneC(O)NR b -A, C(O)NR a -C 1~2 Alkylene OC(O)-A, C(O)NR a -C 1~2 Alkylene C(O)OA, C(O)NR a -C 1~2Alkylene OC(O)NR b -A, C(O)NR a -C 1~2 Alkylene NR b C(O)OA, C(O)NR a -C 1~2 Alkylenes OC(O)OA, and C(O)NR a -C 1~2 Alkylene NR b C(O)NR b - selected from A and R 4 and R 5 The other is H, halo, C 1~4 Alkyl and C 1~4 In some embodiments, X is selected from O, OC(O), C(O)O, NR a C(O) and C(O)NR a Selected from R 4 and R 5 On the other hand, OC 1~2 Alkylene-A, OC 1~2 Alkylene OA, OC 1~2 Alkylene C(O)-A, OC 1~2 Alkylene NR b C(O)-A, OC 1~2 AlkyleneC(O)NR b -A, O.C. 1~2 Alkylene OC(O)-A, OC 1~2 Alkylene C(O)OA, OC 1~2 Alkylene OC(O)NR b -A, O.C. 1~2 Alkylene NR b C(O)OA, OC 1~2 Alkylene OC(O)OA, OC 1~2 Alkylene NR b C(O)NR b -A, OC(O)-C 1~2 Alkylene-A, OC(O)-C 1~2 Alkylene OA, OC(O)-C 1~2 Alkylene C(O)-A, O-C(O)-C 1~2 Alkylene NR bC(O)-A, OC(O)-C 1~2 AlkyleneC(O)NR b -A, OC(O)-C 1~2 Alkylene OC(O)-A, OC(O)-C 1~2 Alkylene C(O)OA, OC(O)-C 1~2 Alkylene OC(O)NR b -A, OC(O)-C 1~2 Alkylene NR b C(O)OA, OC(O)-C 1~2 Alkylene OC(O)OA, OC(O)-C 1~2 Alkylene NR b C(O)NR b -A, C(O)OC 1~2 Alkylene, C(O)OC 1~2 Alkylene OA, C(O)OC 1~2 Alkylene C(O)-A, C(O)OC 1~2 Alkylene NR b C(O)-A, C(O)OC 1~2 AlkyleneC(O)NR b -A, C(O)OC 1~2 Alkylene OC(O)-A, C(O)OC 1~2 Alkylene C(O)OA, C(O)OC 1~2 Alkylene OC(O)NR b -A, C(O)OC 1~2 Alkylene NR b C(O)OA, C(O)OC 1~2 Alkylene OC(O)OA, C(O)OC 1~2 Alkylene NR b C(O)NR b -A, NR a C(O)-C 1~2 Alkylene-A, NR a C(O)-C 1~2 Alkylene OA, NR a C(O)-C 1~2 Alkylene C(O)-A, NR a C(O)-C 1~2 Alkylene NR b C(O)-A, NR a C(O)-C 1~2 AlkyleneC(O)NR b-A, NR a C(O)-C 1~2 Alkylene OC(O)-A, NR a C(O)-C 1~2 Alkylene C(O)OA, NR a C(O)-C 1~2 Alkylene OC(O)NR b -A, NR a C(O)-C 1~2 Alkylene NR b C(O)OA, NR a C(O)-C 1~2 Alkylene OC(O)OA, NR a C(O)-C 1~2 Alkylene NR b C(O)NR b -A, C(O)NR a -C 1~2 Alkylene-A, C(O)NR a -C 1~2 Alkylene OA, C(O)NR a -C 1~2 Alkylene C(O)-A, C(O)NR a -C 1~2 Alkylene NR b C(O)-A, C(O)NR a -C 1~2 AlkyleneC(O)NR b -A, C(O)NR a -C 1~2 Alkylene OC(O)-A, C(O)NR a -C 1~2 Alkylene C(O)OA, C(O)NR a -C 1~2 Alkylene OC(O)NR b -A, C(O)NR a -C 1~2 Alkylene NR b C(O)OA, C(O)NR a -C 1~2 Alkylenes OC(O)OA, and C(O)NR a -C 1~2 Alkylene NR b C(O)NR b - selected from A and R 4 and R 5The other is H, halo, C 1~4 Alkyl and C 1~4 alkoxy, wherein all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0258] In some embodiments, R 4 and R 5 The other is H, F, Cl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Deuteroalkyl and C 1~4 alkoxy, where any available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 4 and R 5 is selected from D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CF, CHF, and CD, where any available hydrogen atom may be independently replaced with a fluorine atom or a deuterium atom, as appropriate; 4 and R 5 The other is H or D.

[0259] In some embodiments, R 4 is XLA and R 5 H, halo, C 1~6 Alkyl and C 1~6 In some embodiments, R is selected from alkoxy. 5 is XLA and R 4 H, halo, C 1~6 Alkyl and C 1~6 Alkoxy is selected from:

[0260] In some embodiments, R a is H and C 1~4 alkyl.

[0261] In some embodiments, R b is H, C 1~4 A is selected from alkyl and A.

[0262] In some embodiments, A is H and R 4 and R 5 One of them is OH, C(O)H, NHR a , NHR a C(O), C(O)NHR a , OC(O)H, C(O)OH, OC(O)OH, NR a C(O)OH, OC(O)NHR a , NHR a C(O)NR a , XC 1~4 Alkylene, XC 2~4 Alkenylene, XC 1~4 Alkylene OH, XC 2~4 Alkenylene OH, XC 1~4 Alkylene C(O)H, XC 2~4 Alkenylene C(O)H, XC 1~4 Alkylene NR b C(O)H, XC 2~4 Alkenylene NR b C(O)H, XC 1~4 AlkyleneC(O)NHR b , XC 2~4 AlkenyleneC(O)NHR b , XC 1~4 Alkylene OC(O)H, XC 2~4 Alkenylene OC(O)H, XC 1~4 Alkylene C(O)OH, C 2~4 Alkenylene C(O)H, XC 1~4 Alkylene OC(O)NHR b , XC 2~4 AlkenyleneOC(O)NHR b , XC 1~4 Alkylene NR b C(O)OH, XC 2~4 Alkenylene NR b C(O)OH, XC 1~4 Alkylene OC(O)OH, XC 2~4 Alkenylene OC(O)OH, XC 1~4 Alkylene NR b C(O)NHR b and XC 2~4Alkenylene NR b C(O)NHR b Selected from R 4 and R 5 The other is H, halo, C 1~4 Alkyl and C 1~4 In some embodiments, A is H and R is selected from the group consisting of alkoxy, wherein all available hydrogen atoms are independently replaced with fluorine or deuterium atoms, as appropriate. 4 and R 5 One of them is OH, C(O)H, NHR a , NHR a C(O), C(O)NHR a , OC(O)H, C(O)OH, OC(O)OH, NR a C(O)OH, OC(O)NHR a , NHR a C(O)NR a , XC 1~2 Alkylene, XC 2~4 Alkenylene, XC 1~2 Alkylene OH, XC 2~4 Alkenylene OH, XC 1~2 Alkylene C(O)H, XC 2~4 Alkenylene C(O)H, XC 1~2 Alkylene NR b C(O)H, XC 2~4 Alkenylene NR b C(O)H, XC 1~2 AlkyleneC(O)NHR b , XC 2~4 AlkenyleneC(O)NHR b , XC 1~2 Alkylene OC(O)H, XC 2~4 Alkenylene OC(O)H, XC 1~2 Alkylene C(O)OH, C 2~4 Alkenylene C(O)H, XC 1~2 Alkylene OC(O)NHR b , XC 2~4 AlkenyleneOC(O)NHR b , XC 1~2 Alkylene NR b C(O)OH, XC 2~4 Alkenylene NR bC(O)OH, XC 1~2 Alkylene OC(O)OH, XC 2~4 Alkenylene OC(O)OH, XC 1~2 Alkylene NR b C(O)NHR b and XC 2~4 Alkenylene NR b C(O)NHR b Selected from R 4 and R 5 The other is H, halo, C 1~4 Alkyl and C 1~4 alkoxy, wherein all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0263] In some embodiments, A is H and X is a direct bond. Thus, in some embodiments, R 4 and R 5 One of them is C 1~4 Alkyl, C 2~4 Alkenyl, C 1~4 Alkylene OH, C 2~6 Alkenylene OH, C 1~4 Alkylene C(O)H, C 2~4 Alkenylene C(O)H, C 1~4 Alkylene NR b C(O)H, C 2~4 Alkenylene NR b C(O)H, C 1~4 AlkyleneC(O)NHR b , C 2~4 AlkenyleneC(O)NHR b , C 1~4 Alkylene OC(O)H, C 2~4 Alkenylene O-C(O)H, C 1~4 Alkylene C(O)OH, C 2~4 Alkenylene C(O)H, C 1~4 Alkylene OC(O)NHR b , C 2~6 AlkenyleneOC(O)NHR b , C 1~4 Alkylene NR b C(O)OH, C 2~4 Alkenylene NRb C(O)OH, C 1~4 Alkylene OC(O)OH, C 2~4 Alkenylene OC(O)OH, C 1~4 Alkylene NR b C(O)NHR b and C 2~4 Alkenylene NR b C(O)NHR b Selected from R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 Alkoxy is selected from:

[0264] In some embodiments, A is H and X is O, C(O), NR a , N.R. a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, A is H and X is selected from O, C(O), OC(O), C(O)O and OC(O)O. In some embodiments, A is H and X is selected from O, OC(O) and C(O)O. In some embodiments, A is H and X is O. In some embodiments, A is H and X is selected from OC(O) and C(O)O. In some embodiments, A is H and X is NR a , N.R. a C(O), C(O)NR a , N.R. a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, A is H and X is selected from NR a C(O), C(O)NR a , N.R. a C(O)O, OC(O)NR a and N.R. a C(O)NR aIn some embodiments, A is H and X is selected from NR a C(O) and C(O)NR a In some embodiments, A is H and X is selected from NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a is selected from.

[0265] In some embodiments, A is H, L is a direct bond, and R 3 and R 4 One of R is selected from XH. Thus, in some embodiments, R 3 and R 4 One of them is OH, C(O)H, NHR a , NHR a C(O), C(O)NHR a , OC(O)H, C(O)OH, OC(O)OH, NR a C(O)OH, OC(O)NHR a and NHR a C(O)NR a wherein all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0266] In some embodiments, when A is H, R b is H and C 1~4 alkyl, where any available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0267] In some embodiments, R 4 and R 5 One side is A, OA, C(O)-A, C(O)-A, C(O)OA, C 1~4 Alkylene-A, C 1~4 Alkylene-C(O)-A,C 1~4 Alkylene-C(O)OA, OC 1~4 Alkylene-A, OC 1~4 Alkylene-C(O)-A, and O-C 1~4alkylene-C(O)OA; R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy, wherein all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0268] In some embodiments, R 4 and R 5 is selected from A, OA, C(O)-A, C(O)-A, and C(O)OA; R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy, wherein all available hydrogen atoms are independently optionally replaced with fluorine or deuterium atoms. 4 and R 5 One of R is A. In some embodiments, R 4 and R 5 One of R is OA. 4 and R 5 One of R is C(O)-A. In some embodiments, R 4 and R 5 One of them is C(O)OA.

[0269] In some embodiments, R 4 and R 5 One of them is C 1~4 Alkylene-A, C 1~4 Alkylene-C(O)-A,C 1~4 Alkylene-C(O)OA, OC 1~4 Alkylene-A, OC 1~4 Alkylene-C(O)-A, and O-C 1~4 alkylene-C(O)OA; R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6alkoxy, wherein all available hydrogen atoms are independently optionally replaced with fluorine or deuterium atoms. 4 and R 5 One of them is C 1~4 In some embodiments, R 4 and R 5 One of them is C 1~4 In some embodiments, R 4 and R 5 One of them is C 1~4 alkylene-C(O)OA. In some embodiments, R 4 and R 5 On the other hand, OC 1~4 In some embodiments, R 4 and R 5 On the other hand, OC 1~4 In some embodiments, R 4 and R 5 On the other hand, OC 1~4 It is alkylene-C(O)OA.

[0270] In some embodiments, R 4 and R 5 One side is A, OA, C(O)-A, C(O)OA, C(O)-A, C(O)OA, C 1~4 Alkylene-A, C 1~4 Alkylene-C(O)-A,C 1~4 Alkylene-C(O)OA, OC 1~4 Alkylene-A, OC 1~4 Alkylene-C(O)-A, and O-C 1~4 alkylene-C(O)OA; R 4 and R 5 The other is H, F, Cl, C 1~4 Alkyl and C 1~4 alkoxy, wherein all available hydrogen atoms are independently optionally replaced with fluorine or deuterium atoms. 4 and R 5One side is A, OA, C(O)-A, C(O)OA, C(O)-A, C(O)OA, C 1~4 Alkylene-A, C 1~4 Alkylene-C(O)-A,C 1~4 Alkylene-C(O)OA, OC 1~4 Alkylene-A, OC 1~4 Alkylene-C(O)-A, and O-C 1~4 alkylene-C(O)OA; R 4 and R 5 The other is H, F, Cl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Deuteroalkyl and C 1~4 alkoxy, where any available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 4 and R 5 One side is A, OA, C(O)-A, C(O)OA, C(O)-A, C(O)OA, C 1~2 Alkylene-A, C 1~2 Alkylene-C(O)-A,C 1~2 Alkylene-C(O)OA, OC 1~2 Alkylene-A, OC 1~2 Alkylene-C(O)-A, and O-C 1~2 alkylene-C(O)OA; R 4 and R 5 and the other is selected from D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CF, CHF, and CD, where any available hydrogen atom may be independently replaced with a fluorine atom or a deuterium atom, as appropriate. 4 and R 5 One side is A, OA, C(O)-A, C(O)OA, C 1~2 Alkylene-A, C 1~2 Alkylene-C(O)-A,C 1~2 Alkylene-C(O)OA, OC 1~2 Alkylene-A, OC 1~2Alkylene-C(O)-A, and O-C 1~2 alkylene-C(O)OA; R 4 and R 5 and the other is H or D, and all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 4 and R 5 One side is A, OA, C(O)-A, C(O)OA, CH2-A, CD2-A, CF2-A, CH2-C(O)-A, CF2-C(O)-A, CD2-C(O)-A, CH2-C(O)OA, CD2-C(O)OA, CF2-C(O)O A, O-CH2A, O-CF2A, O-CD2A, -CH2-C(O)-A, O-CD2-C(O)-A, O-CF2-C(O)-A, O-CH2-C(O)OA, O-CF2-C(O)OA, O-CD2-C(O)OA, R 4 and R 5 The other is H or D.

[0271] In some embodiments, R 4 is A, OA, C(O)-A, C(O)OA, C 1~2 Alkylene-A, C 1~2 Alkylene-C(O)-A,C 1~2 Alkylene-C(O)OA, OC 1~2 Alkylene-A, OC 1~2 Alkylene-C(O)-A, and O-C 1~2 alkylene-C(O)OA; R 5 is H or D, and all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 4are A, OA, C(O)-A, C(O)OA, CH2-A, CD2-A, CF2-A, CH2-C(O)-A, CF2-C(O)-A, CD2-C(O)-A, CH2-C(O)OA, CD2-C(O)OA, CF2-C(O)OA, O- CH2A, O-CF2A, O-CD2A, O-CH2-C(O)-A, O-CD2-C(O)-A, O-CF2-C(O)-A, O-CH2-C(O)OA, O-CF2-C(O)OA, and O-CD2-C(O)OA, R 5 is H or D. In some embodiments, R 5 is A, OA, C(O)-A, C(O)OA, C 1~2 Alkylene-A, C 1~2 Alkylene-C(O)-A,C 1~2 Alkylene-C(O)OA, OC 1~2 Alkylene-A, OC 1~2 Alkylene-C(O)-A, and O-C 1~2 alkylene-C(O)OA; R 4 is H or D, and all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 5 are A, OA, C(O)-A, C(O)OA, CH2-A, CD2-A, CF2-A, CH2-C(O)-A, CF2-C(O)-A, CD2-C(O)-A, CH2-C(O)OA, CD2-C(O)OA, CF2-C(O)OA, O- CH2A, O-CF2A, O-CD2A, O-CH2-C(O)-A, O-CD2-C(O)-A, O-CF2-C(O)-A, O-CH2-C(O)OA, O-CF2-C(O)OA, and O-CD2-C(O)OA, R 4 is H or D.

[0272] In some embodiments, A is C 1~30 Alkyl, C 2~30 Alkenyl, phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 64and 3-6 membered heterocycloalkyl containing 1-3 hetero moieties independently selected from O, S, S(O), SO, N, and NR 64 and wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with F, Cl, OH, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 In some embodiments, A is optionally substituted with one or two substituents independently selected from fluoroalkyl, and all available hydrogen atoms are optionally substituted independently with fluorine or deuterium atoms. 1~30 Alkyl, C 2~30 Alkenyl, phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 64 and 3-6 membered heterocycloalkyl containing 1-3 hetero moieties independently selected from O, S, S(O), SO, N, and NR 64 and wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with F, Cl, OH, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 It may be optionally substituted with one or two substituents independently selected from fluoroalkyl.

[0273] In some embodiments, A is phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 64and 3-6 membered heterocycloalkyl containing 1-3 hetero moieties independently selected from O, S, S(O), SO, N, and NR 64 and wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are F, C, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 In some embodiments, A is optionally substituted with one or two substituents independently selected from phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 64 and 5-6 membered heterocycloalkyl containing 1-2 hetero moieties independently selected from O, S, S(O), SO, N, and NR 64 and wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are F, C, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 It may be optionally substituted with one or two substituents independently selected from fluoroalkyl.

[0274] In some embodiments, C in A 3~6 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. 3~6 Cycloalkyl is F, C, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 and cyclopropyl optionally substituted with one or two substituents independently selected from fluoroalkyl.

[0275] In some embodiments, O, S, S(O), SO, N, and NR in A 64 and 3-6 membered heterocycloalkyl containing 1 to 3 hetero moieties independently selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dixylanyl, azetidinyl, oxetanyl, titanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxathiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithietanyl, selected from oranyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl oxide, tetrahydrothiopyranyl dioxide, dihydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, and dithianyl, which are selected from F, C, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 In some embodiments, A is optionally substituted with one or two substituents independently selected from O, S, S(O), SO, N, and NR 64and 3-6 membered heterocycloalkyl containing 1-3 heteromoieties independently selected from tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, piperidinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, tetrahydropyranyl, tetrahydrothiopyranyl, dihydropyranyl, tetrahydrothiopyranyl oxide, tetrahydrothiopyranyl dioxide, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl, each of which is selected from F, C, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 It may be optionally substituted with one or two substituents independently selected from fluoroalkyl.

[0276] In some embodiments, the 5- to 6-membered heteroaryl in A is selected from furyl, imidazolyl, isothiazolyl, thiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyrrolyl, thienofuryl, triazolyl, and thienyl, each of which is selected from F, C, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 In some embodiments, the 5- to 6-membered heteroaryl in A is selected from furyl, isothiazolyl, thiazolyl, pyridyl, and pyrrolyl, each of which is selected from F, C, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 It may be optionally substituted with one or two substituents independently selected from fluoroalkyl.

[0277] In some embodiments, in A, phenyl, C 3~10 The cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl may be optionally substituted with one or two substituents independently selected from F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, CD3, CH(CH3)2O, CH3CH2CHO, CH3CHO, CHO, CF3O, CHF2O, CF2HCHO, CF3CHO, (CF3)2CHO, and CD3O.

[0278] In some embodiments, A is C 1~30 Alkyl and C 2~30 alkenyl, wherein all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0279] In some embodiments, A is C 10~25 In some embodiments, A is alkyl, and all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms. 13~21 It is alkyl, and all available hydrogen atoms may be independently optionally replaced with fluorine or deuterium atoms.

[0280] In some embodiments, A is C 10~25 In some embodiments, A is C. 13~21 In some embodiments, A is C. 10~25 is alkenyl and contains 1, 2, 3, 4, 5 or 6 double bonds;

[0281] In some embodiments, the alkyl or alkene group of A is an alkyl or alkenyl group present in a fatty acid, and all available hydrogen atoms may be optionally replaced with deuterium atoms. In some embodiments, A is an alkenyl group present in a fatty acid, and all available hydrogen atoms may be optionally replaced with deuterium atoms. In some embodiments, the fatty acid is an ω-6 fatty acid (i.e., an unsaturated or polyunsaturated fatty acid in which the double bond closest to the terminal methyl is at the sixth carbon atom from the terminal methyl) or an ω-3 fatty acid (i.e., an unsaturated or polyunsaturated fatty acid in which the double bond closest to the terminal methyl is at the third carbon atom from the terminal methyl), and all available hydrogen atoms may be optionally replaced with deuterium atoms. In some embodiments, A is an alkyl group present in a fatty acid, and all available hydrogen atoms may be optionally replaced with deuterium atoms. In some embodiments, the alkyl or alkene group of A is an alkyl or alkene group present in a fatty acid, and is selected from the list of fatty acids set forth in Table 1, and all available hydrogen atoms may be optionally replaced with deuterium atoms.

[0282] In some embodiments, the alkene group of A is an alkyl or alkenyl group present in linoleic acid, eicosadienoic acid, or decosahexanoic acid.

[0283] In some embodiments, when A is an alkyl or alkenyl group of a fatty acid, 1 to 10, 2 to 8, 2 to 6, or 2 to 4 hydrogen atoms are replaced with deuterium.

[0284] In some embodiments, A is (CH2)7CH=CH(CH2)7CH3. In some embodiments, A is (CH2)7CH=CHCH2CH=CH(CH2)4CH3. In some embodiments, A is (CH2)8CH=CHCH2CH=CH(CH2)4CH3. In some embodiments, A is (CH2)7CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3. In some embodiments, A is (CH2)3CH=CHCH2CH=CH(CH2)1CH=CHCH2CH=CH(CH2)3CH3. In some embodiments, A is (CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3. In some embodiments, A is (CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3.

[0285] In some embodiments, R 64 and R 65 are independently H, D, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, R is selected from deuteroalkyl. 64 and R 65 is independently selected from H, D, CH, CF, and CD. In some embodiments, R 64 and R 65 is independently selected from CH3 and CD3.

[0286] In some embodiments, the compound of formula IA is defined as follows: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof [In formula: Q is Q1, Q2, Q3, Q4, Q5 and Q6: [ka] Selected from the structure: [ka] is a single or double bond, provided that the structure in Q1: [ka] is a double bond, R 9 and R 15 does not exist, and the structure in Q2: [ka] is a double bond, R 17 and R 25 does not exist, and the structure in Q5: [ka] is a double bond, R 48 and R 57 does not exist; R 1 , R 1 ', R 2 , R 2 ', R 3 and R 6 is independently selected from H, D, and F; R 4 and R 5 One or both of these are H, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy and C 1~4 deuteroalkoxy; or R 4 and R 5 together to form O-(CH2) 1~2 Forming O; R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25, R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 is independently selected from H and D; R 12 , R 20 , R 29 , R 39 and R 51 are independently H, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 is selected from deuteroalkyl; R 60 and R 61 are independently H and C 1~6 alkyl; provided that when Q is Q6, the compound of formula I includes D; If Q is Q3 or Q4, then R 5 is H or OCH3, and R 29 or R 39 If is CH3, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R6 , R 26 , R 27 , R 28 , R 30 ~R 35 , R 36 , R 37 , R 38 and R 40 ~R 47 is not all H, Q is Q4 and R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 6 , R 38 and R 40 ~R 47 are all H, and R 39 If is CD3, R 36 and R 37 are not both D].

[0287] In some embodiments, the compound of formula IA is defined as follows: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof [In formula: R 1 and R 1 ' is independently H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxyl, NH(C 1~6 alkyl) and N(C 1~6 alkyl)2; R 2 and R 2 ' is independently H, halo, NH2, C 1~6 Alkyl, C 1~6 Alkoxyl, NH(C 1~6 alkyl) and N(C 1~6 alkyl)2; Q is Q1, Q2, Q3, Q4, Q5 and Q6: [ka] Selected from the structure: [ka] is a single or double bond, provided that the structure in Q1: [ka] is a double bond, R 9 and R 15 does not exist, and the structure in Q2: [ka] is a double bond, R 17 and R 25 does not exist, and the structure in Q5: [ka] is a double bond, R 48 and R 57 does not exist; R 4 and R 5 One or both of may independently be H, halo, or C 1~6 Alkyl and C 1~6 alkoxy; R 4 and R 5 together to form O-(CH2) 1~2 Form O, or R 4 and R 5 One of them is selected from XLA and R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy; X is a direct bond, O, C(O), or NR a , N.R. a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NRa and N.R. a C(O)NR a Selected from; L is a direct bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 1~6 Alkylene O, C 2~6 Alkenylene O,C 1~6 Alkylene C(O), C 2~6 Alkenylene C(O), C 1~6 Alkylene NR b C(O), C 2~6 Alkenylene NR b C(O), C 1~6 AlkyleneC(O)NR b , C 2~6 AlkenyleneC(O)NR b , C 1~6 Alkylene OC(O), C 2~6 Alkenylene OC(O), C 1~6 Alkylene C(O)O, C 2~6 Alkenylene C(O)O, C 1~6 Alkylene OC(O)NR b , C 2~6 Alkenylene OC(O)NR b , C 1~6 Alkylene NR b C(O)O, C 2~6 Alkenylene NR b C(O)O, C 1~6 Alkylene O-C(O)O, C 2~6 Alkenylene O-C(O)O, C 1~6 Alkylene NR b C(O)NR b and C 2~6 Alkenylene NR b C(O)NR b Selected from; R a is H and C 1~6 alkyl; R b is H, C 1~6 alkyl and A; A is C 1~30 Alkyl, C 2~30 Alkenyl, phenyl, C 3~6Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 64 and 3-6 membered heterocycloalkyl containing 1-4 hetero moieties independently selected from O, S, S(O), SO, N, and NR 64 and wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with halo, C 1~4 Alkyl and OC 1~4 optionally substituted with one or more substituents independently selected from alkyl; R 3 and R 6 are independently H, halo, OH, C 1~6 Alkyl and C 1~6 selected from alkoxy; R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently H, halo, and C 1~6 alkyl; R 12 , R 20 , R 29 , R 39 and R 51 are independently H, C 1~6 Alkyl, C(O)C 1~6 selected from alkyl and C(O)-A'; R 60 and R 61 are independently H and C 1~6 alkyl; or R 60 and R 61 One of them is C(O)-A' and the other is H and C 1~6 alkyl; where A' is Y, OY and OC 1~4 alkylene-OC(O)-Y; Y is C 7~30 Alkyl and C 7~30 alkenyl; or R 60 and R 61 together with the nitrogen atom to which they are attached, form O, S, S(O), SO2, N, and NR 65 and optionally includes one or two additional hetero moieties independently selected from halo, OH, C 1~4 Alkyl and OC 1~4 forming a 3- to 6-membered heterocyclic ring, optionally substituted with one or more substituents independently selected from alkyl; R 64 and R 65 are independently H and C 1~6 alkyl; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; However, R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 one of which is C(O)-A'; or R 4 and R 5 One of them is selected from XLA and R 4 and R 5 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy, provided that when both X and L are direct bonds, A is selected from H, C 1~6 Alkyl or C 1~6 not alkenyl].

[0288] Those skilled in the art will recognize that R 2 and R 2 If ' is different, R 2 and R 2 It will be understood that the carbon to which ' is attached is chiral. Thus, the present application includes all stereoisomers at this carbon center and mixtures thereof.

[0289] Those skilled in the art will recognize that R 1 and R 1 If ' is different, R 1 and R 1 It will be understood that the carbon to which ' is attached is also chiral. Thus, the present application includes all stereoisomers at this carbon center and mixtures thereof.

[0290] In some embodiments, the compound of formula IA is selected from the compounds listed below, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [Table 17] Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29

[0291] In some embodiments, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt.The selection of suitable salt can be performed by those skilled in the art.Suitable salts include acid addition salts, and can be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid (e.g., hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid). Additionally, acids generally considered suitable for forming pharmaceutically useful salts from pharmaceutical base compounds are discussed, for example, in P. Stahl et al., Camille G. (ed.) and Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley VCH; S. Berge et al., Journal of Pharmaceutical Sciences 1977 66(1)1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (website of the U.S. Food and Drug Administration, Washington, D.C.).

[0292] Acid addition salts suitable for or compatible with the treatment of subjects are any non-toxic organic or inorganic acid addition salts for any basic compound.Basic compounds that form acid addition salts include, for example, compounds containing amino groups.Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acid metal salts, such as sodium hydrogen phosphate and potassium hydrogen sulfate.Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids. Examples of such organic acids include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In some embodiments, exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, cinnamate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate ("mesylate"), naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), and the like. In some embodiments, mono- or di-acid salts are formed, and such salts exist in either hydrate, solvate, or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base forms. The criteria for selecting an appropriate salt will be well known to those skilled in the art. Other pharmaceutically unacceptable salts, such as, but not limited to, oxalates, may be used, for example, in the isolation of compounds of the present application for experimental use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0293] The base addition salt suitable for or compatible with the treatment of the subject is any non-toxic organic or inorganic base addition salt of any acidic compound.A compound that forms a base addition salt includes, for example, a compound containing a carbonyl group.Exemplary inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide, and ammonia.Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.Selecting an appropriate salt may be useful, for example, to prevent the ester functional group of another part of the compound, if present, from being hydrolyzed.The criteria for selecting an appropriate salt will be well known to those skilled in the art.In some embodiments, representative basic salts also include ammonium salts, alkali metal salts (e.g., sodium, lithium, and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), salts containing organic bases (e.g., organic amines) (e.g., dicyclohexylamine, butylamine, choline), and salts containing amino acids (e.g., arginine, lysine). Groups containing a basic nitrogen may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfate), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl bromide and phenethyl bromide), and the like.Compounds having an acidic moiety can 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 quaternized ammonium salts. Also, when an acid (—COOH) or alcohol group is present, pharmaceutically acceptable esters can be used to modify the solubility or hydrolysis characteristics of the compound.

[0294] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of this application, and all acid salts and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of this application. Furthermore, when a compound of Formula I or Formula IA, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, contains both a basic moiety (e.g., but not limited to, an aliphatic primary, secondary, tertiary, or cyclic amine, an aromatic amine, or a heteroaryl amine, pyridine, or imidazole) and an acidic moiety (e.g., but not limited to, a tetrazole or a carboxylic acid), zwitterions ("internal salts") may be formed and are included within the scope of the term "salt(s)" as used herein. It is understood that some compounds of Formula I or Formula IA, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, may exist in the form of a zwitterion, having both an anionic and a cationic center in the same compound and having a net neutral charge. Such zwitterions are included within the scope of this application.

[0295] The solvates of the compounds of Formula I or Formula IA, or their pharmaceutically acceptable salts and / or prodrugs, include, for example, those formed using pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvates are called hydrates) and ethanol. Suitable solvents are physiologically acceptable at the dosages administered.

[0296] Prodrugs of the compounds of Formula I or Formula IA, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, include, for example, conventional esters formed with available hydroxy, thiol, amino, or carboxyl groups. Some common esters that have been utilized as prodrugs include phenyl esters, aliphatic (C1-C6) esters, and the like. 24 ) esters, acyloxymethyl esters, carbamates and amino acid esters.

[0297] It is understood and appreciated that in some embodiments, compounds of Formula I or Formula IA, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, may have at least one chiral center and therefore may exist as enantiomers and / or diastereomers. All such isomers and mixtures thereof, in all ratios, are encompassed within the scope of this application. While the stereochemistry of a compound may be as shown in a given compound listed herein, it should be further understood that such compounds may contain a certain amount (e.g., less than 20%, preferably less than 10%, more preferably less than 5%) of a compound of Formula I or Formula IA, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, having an alternative stereochemistry. All optical isomers, as separated, pure, or partially pure optical isomers, or racemic mixtures thereof, are intended to be encompassed within the scope of this application.

[0298] In some embodiments, compounds of Formula I or Formula IA, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, may also include tautomeric forms, such as keto-enol tautomers. Tautomeric forms may be in equilibrium or may be sterically locked into one form by appropriate substitution. Any tautomeric form that a compound forms, as well as mixtures thereof, are intended to be included within the scope of this application.

[0299] Compounds of Formula I or Formula IA, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, may further exist in various amorphous and polymorphic forms, and any amorphous form, polymorph, or mixture thereof is contemplated and included within the scope of this application.

[0300] The compounds of the present application may further be radiolabeled, and therefore all radiolabeled forms of the compounds of Formula I or Formula IA, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, are included within the scope of the present application. Thus, the compounds of Formula I or Formula IA, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, also include compounds having one or more radioactive atoms incorporated into their structure.

[0301] IV. Composition The compounds of Formula I or Formula IA, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, are suitably formulated into compositions using one or more carriers in a conventional manner. Accordingly, the present application also includes compositions comprising one or more compounds of Formula I or Formula IA, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, and a carrier. The compounds of Formula I or Formula IA, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, are suitably formulated into pharmaceutical compositions for administration to a subject in a biologically compatible form suitable for in vivo administration. Accordingly, the present application further includes pharmaceutical compositions comprising one or more compounds of Formula I or Formula IA, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, and a pharmaceutically acceptable carrier. In an embodiment of the present application, the pharmaceutical compositions are used in the treatment of any disease, disorder, or condition described herein.

[0302] As will be understood by those skilled in the art, the compound of Formula I or Formula IA, or its pharmaceutically acceptable salt, solvate and / or prodrug, can be administered to a subject in various forms depending on the selected route of administration.For example, the compound of Formula I or Formula IA, or its pharmaceutically acceptable salt, solvate and / or prodrug, can be administered orally, inhalation, parenteral, buccal, sublingual, insufflation, epidural, nasal, rectal, vaginal, patch, pump, minipump, topical or transdermal, and the pharmaceutical composition can be formulated accordingly.In some embodiments, the compound is administered by 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 (2000-20 edition) and the United States Pharmacopeia: National Formulary, 1999 (USP 24 NF19).

[0303] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, and includes, for example, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary (e.g., using an aerosol), intrathecal, rectal, and topical (including use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0304] In some embodiments, the compound of Formula I or Formula IA, or its pharmaceutically acceptable salt, solvate, and / or prodrug, is orally administered, for example, with an inert diluent or with an absorbable edible carrier, or is enclosed in a hard or soft shell gelatin capsule, or is compressed into a tablet, or is directly ingested with food. In some embodiments, the compound is incorporated with an excipient and used in the form of orally ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powder, syrup, elixir, wafers, aqueous solutions, and suspensions. For tablets, carriers used include lactose, corn starch, sodium citrate, and phosphate salts. Pharmaceutically acceptable excipients include binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), or solvents (e.g., medium-chain triglycerides, ethanol, water). In embodiments, tablets are coated by methods well known in the art. For tablets, capsules, caplets, pellets, or granules for oral administration, pH-sensitive enteric coatings, such as Eudragits™, designed to control the release of active ingredients, may be used as appropriate. Oral dosage forms also include modified release, such as immediate-release and timed-release formulations.Examples of modified release formulations include, for example, sustained release (SR), extended release (ER, XR, or XL), time-release or timed release, controlled release (CR), or continuous release (CR or Contin), and are used, for example, in the form of coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, aggregated particles (e.g., as molecular sieve-type particles), or fine hollow permeable fiber bundles, or chopped hollow permeable fibers assembled or held together in fibrous packets. Timed-release compositions are formulated, for example, as liposomes, or in which the active compound is protected with a differentially degradable coating, for example, by microencapsulation, multilayer coating, etc. Liposomal delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. In some embodiments, liposomes are formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. For oral administration in a capsule form, useful carriers, solvents, or diluents include lactose, medium chain triglycerides, ethanol, and dried corn starch.

[0305] In some embodiments, liquid preparations for oral administration may take the form of, for example, a solution, syrup, or suspension, or may be provided as a dry product that is suitable for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compound of Formula I or Formula IA, or its pharmaceutically acceptable salt, solvate, and / or prodrug, is suitably suspended or dissolved in an oil phase combined with an emulsifier and / or suspending agent. If desired, some sweeteners and / or flavorings and / or coloring agents may be added. Such liquid preparations for oral administration are prepared by conventional means using pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats and oils); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., medium-chain triglycerides, almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0306] For example, it is possible to lyophilize a compound of Formula I or Formula IA, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, and use the resulting lyophilizate for the preparation of an injectable product.

[0307] In some embodiments, a compound of Formula I or Formula IA, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, is administered parenterally. For example, a solution of a compound of Formula I or Formula IA, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, is prepared in water, appropriately mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof (with or without alcohol), and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. Those skilled in the art will know how to prepare appropriate formulations. For parenteral administration, a sterile solution of a compound of Formula I or Formula IA, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, is usually prepared, and the pH of the solution is appropriately adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to make the preparation isotonic. For administration to the eye, ointments or droppable liquids are delivered, for example, by ocular delivery systems (e.g., applicators or eyedroppers) known in the art. In some embodiments, such compositions contain mucosal mimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose, or polyvinyl alcohol, preservatives such as sorbic acid, EDTA, or benzyl chromium chloride, and a conventional amount of diluent or carrier. For administration to the lung, the diluent or carrier will be selected to be suitable for allowing the formation of an aerosol.

[0308] In some embodiments, the compound of Formula I or Formula IA, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, is formulated for parenteral administration by injection, which includes the use of conventional catheterization techniques or infusion. Formulations for injection are provided, for example, in unit dosage form (e.g., in ampoules or multi-dose containers, with an added preservative). In some embodiments, the composition takes the form of a sterile suspension, solution, or emulsion in an oily or aqueous vehicle, and contains formulatory agents such as suspending, stabilizing, and / or dispersing agents. In all cases, it must be sterile and fluid enough to allow easy injectability. Alternatively, the compound of Formula I or Formula IA, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, is preferably in sterile powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0309] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels, and powders.For intranasal administration or inhalation administration, the compound of Formula I or Formula IA, or its pharmaceutically acceptable salts, solvates, and / or prodrugs, is conveniently delivered from a pump spray container that is squeezed or pumped onto the patient, in the form of a solution, dry powder formulation, or suspension, or in the form of an aerosol spray from a pressurized container or nebulizer.Aerosol formulations generally comprise a solution or fine suspension of an active compound in a physiologically acceptable aqueous or non-aqueous solvent, and are usually provided in a single dose or multiple doses in a sterile form in a sealed container (for example, in the form of a cartridge or refill for use with a spray device).Alternatively, the sealed container is a single-dose device, such as a single-dose nasal inhaler, or an aerosol dispenser equipped with a metered-dose valve, which is intended to be disposed of after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant, for example, a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide, or other suitable gases. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound. Capsules and cartridges (e.g., made from gelatin) for use in an inhaler or insufflator are formulated containing, for example, a powder mix of a compound of Formula I or Formula IA, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, and a suitable powder base, such as lactose or starch. The aerosol dosage form can also take the form of a pump-atomizer.

[0310] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, in which the compound of Formula I or Formula IA, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter.

[0311] Suppository formulations of the compound of Formula I or Formula IA, or its pharmaceutically acceptable salts, solvates and / or prodrugs, are useful for vaginal, urethral and rectal administration.Such suppositories will generally be composed of a mixture of materials that are solid at room temperature but melt at body temperature.The materials commonly used to make such vehicles include, but are not limited to, cocoa oil (also known as cocoa butter), glycerin gelatin, other glycerides, hydrogenated vegetable oils, and mixtures of polyethylene glycols with various molecular weights and fatty acid esters of polyethylene glycol.For further description of suppository dosage forms, see, for example, Remington's Pharmaceutical Sciences, 16th edition, Mack Publishing, Easton, PA, 1980, pp.1530-1533.

[0312] In some embodiments, the compound of Formula I or Formula IA, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, is conjugated to a soluble polymer as a targetable drug carrier. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, the compound of Formula I or Formula IA, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, is conjugated to a class of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoester, polyacetal, polydihydropyran, polycyanoacrylic acid, and crosslinked or amphiphilic block copolymers of hydrogels.

[0313] The compounds of Formula I or Formula IA, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, are particularly suitable for administration with nanocarrier systems such as liposomes, micelles, nanoparticles, nanoemulsions, lipid nanosystems, etc. (See, e.g., Bhat, M. et al. Chem. and Phys. of Lipids, 2021, 236, 105053.) Accordingly, the present application includes compositions comprising one or more compounds of Formula I or Formula IA, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, and one or more components of a nanocarrier system.

[0314] Although compounds of Formula I or Formula IA, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, are suitably used per se, they will generally be administered in the form of a pharmaceutical composition in which one or more compounds of Formula I or Formula IA, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof (active ingredients) are combined with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will contain from about 0.05% to about 99% by weight, or from about 0.10% to about 70% by weight, of the active ingredient(s) and from about 1% to about 99.95% by weight, or from about 30% to about 99.90% by weight of the pharmaceutically acceptable carrier (all weight percentages are based on the total weight of the composition).

[0315] In some embodiments, the compounds of Formula I or IA, including their pharmaceutically acceptable salts, solvates and / or prodrugs, are used in and administered in compositions containing additional therapeutic agents. Thus, the present application also includes pharmaceutical compositions comprising one or more compounds of the present application, or pharmaceutically acceptable salts and / or solvates thereof, and additional therapeutic agents, and optionally one or more pharmaceutically acceptable excipients. In some embodiments, the additional therapeutic agent is another known agent useful for treating diseases, disorders, or conditions by activating serotonin receptors, such as those listed in the methods and uses section below. In some embodiments, the additional therapeutic agent is a psychoactive agent.

[0316] In the above, the term "a compound" also includes embodiments in which more than one compound is referenced.

[0317] V. Compound Preparation Compounds of Formula I or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, including compounds of Formula IA or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, can be prepared by a variety of synthetic processes. The selection of certain structural features and / or substituents may influence the selection of one process over another. The selection of a particular process for preparing a given compound of Formula I or its pharmaceutically acceptable salts, solvates, and / or prodrugs is within the skill of one of ordinary skill in the art. Some starting materials for preparing compounds of Formula I or its pharmaceutically acceptable salts, solvates, and / or prodrugs thereof are available from commercial chemical sources or may be extracted from cells, plants, animals, or fungi. Other starting materials are readily prepared from available precursors using facile transformations well known in the art, for example, as described below. In the following schemes illustrating several embodiments of methods for preparing compounds of the present application, all variables are as defined in Formula I unless otherwise specified.

[0318] In some embodiments, Q has the structure: [ka] and R 26 and R 27 is either H or D, and compounds of formula I are prepared as shown in Scheme 1: [ka]

[0319] Thus, in some embodiments, a compound of formula A, wherein R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 and R 6 is as defined in formula I), for example, by reacting a compound of formula B, 28 and R30 ~R 35 is as defined in formula I, and R 29 is as defined in formula I or is a suitable protecting group, and LG is a suitable leaving group, such as chloro or OH, under basic conditions to give a compound of formula C. For example, reduction of the keto group in a compound of formula C with an aluminum reducing agent (e.g., lithium borohydride, lithium aluminum hydride, or lithium aluminum deuteride) can give a compound of formula (I) (wherein R 33 and R 34 is either H or D). 29 When is a protecting group, it is removed in a separate step or, alternatively, is removed during the reduction of the compound of formula C when the protecting group is removed in the presence of an aluminum-based reducing agent.

[0320] Q is the structure: [ka] or Q has the structure: [ka] and R 58 and R 59 is either H or D, the compound of formula I being of the structure: [ka] Those skilled in the art will appreciate that a similar reaction sequence can be used to prepare

[0321] In some embodiments, Q has the structure: [ka] and the structure: [ka] is a single bond, and R 14When is either H or D, compounds of formula I are prepared as shown in Scheme 2: [ka]

[0322] Thus, in some embodiments, a compound of formula A, wherein R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 and R 6 is as defined in formula I) with a keto compound of formula D, 7 ~R 10 , R 12 , R 13 is as defined in formula I, and R 11 is as defined in formula I or is a suitable protecting group in the presence of a suitable reducing agent such as sodium triacetoxyborohydride (STAB) to give a compound of formula (I), 14 is either H or D). 11 If is a protecting group, it is removed in a separate step.

[0323] Q is (Q2) and the structure: [ka] and compounds of formula I where Q is (Q3), (Q4), and compounds of formula I where Q is (Q5) and has the structure: [ka] is a single bond, respectively, with the following keto compounds: [ka] Those skilled in the art will appreciate that a similar reaction sequence can be used to prepare

[0324] In some embodiments, Q is (Q1) and has the structure: [ka] is a single bond, and R 14 is either H or D or Q is (Q2) and the structure: [ka] is a single bond, and R 25 is H or D, or Q is (Q3), or Q is (Q4), or Q is (Q5), and the structure: [ka] is a single bond, the compounds of formula I are prepared using methods known in the art, for example, those described in WO2013122107, US20080234237, US20070099913 and / or Annedi S. C et al., European Journal of Medicinal Chemistry, 55, 94-107, 2012.

[0325] In some embodiments, Q has the structure: [ka]

[0043] When this is the case, compounds of formula I are prepared as shown in Scheme 3: [ka]

[0326] Thus, in some embodiments, a compound of formula A, wherein R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 and R 6is as defined in formula I) in the presence of a suitable base, such as N,N-diisopropylethylamine (DIPEA), to give a compound of formula E (wherein R 26 ~R 28 , R 30 ~R 36 is as defined in formula I, and R 29 is as defined in Formula I or is a suitable protecting group, and LG is a suitable leaving group, such as chloro, bromo, iodo, mesylate, or tosylate, to provide a compound of Formula I. 29 If is a protecting group, it is removed in a separate step.

[0327] Q is Q1, and the structure: [ka] is a single bond, Q is Q2, and the compound of formula I has the structure: [ka] Compounds of formula I where Q is Q4; compounds of formula I where Q is Q5 and have the structure: [ka] and compounds of formula I where Q is a single bond, and compounds of formula I where Q is Q6, are respectively represented by the following structures: [ka] Those skilled in the art will appreciate that a similar reaction sequence can be used to prepare

[0328] In some embodiments, Q is Q1 and has the structure: [ka] is a single bond, Q is Q2, and the structure: [ka] is a single bond, Q is Q3, Q is Q4, Q is Q5, and the structure: [ka] When is a single bond and Q is Q6, the compounds of formula I are prepared using methods known in the art, for example, those described in WO2008153207, Takahashi et al. Chem. Pharm. Bull. (2010) 58(8) 1057-1065 (2010), and / or Mino et al. The Journal of Organic Chemistry (2005), 70, 5, 1937-1940.

[0329] Those skilled in the art will recognize that particular enantiomers or diastereomers of the compounds of the present application may be obtained using the corresponding single enantiomers or diastereomers of the corresponding starting materials.

[0330] It is understood that throughout the processes described herein, appropriate and suitable protecting groups will be added and subsequently removed to the various reactants and intermediates in a manner readily apparent to one skilled in the art. Conventional procedures for using such protecting groups, as well as examples of suitable protecting groups, are described, for example, in "Protective Groups in Organic Synthesis," T.W. Green, P.G.M.Wuts, Wiley-Interscience, New York, (1999).

[0331] It should also be understood that chemical manipulations to transform groups or substituents into other groups or substituents can be performed on any intermediate or final product on the synthetic route toward the final product, with the types of transformations possible being limited only by the inherent incompatibility of other functional groups present on the molecule at that stage with the conditions or reagents used for the transformation. Such inherent incompatibilities and how to overcome them by performing the appropriate transformations and synthetic steps in the proper order will be readily apparent to those skilled in the art. While examples of transformations are provided herein, it should be understood that the transformations described are not limited to only the common groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are provided in "Comprehensive Organic Transformations—A Guide to Functional Group Preparations" by R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions can be found in organic chemistry textbooks, such as "Advanced Organic Chemistry," March, 4th Edition, McGraw Hill (1992) or "Organic Synthesis," Smith, McGraw Hill, (1994).

[0332] Techniques for purifying intermediates and final products include, for example, normal and reverse phase chromatography using columns or rotating plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, and are readily understood by those skilled in the art.

[0333] The products of the processes of the present application may be isolated according to known methods, for example the compounds may be isolated by evaporation of the solvent, filtration, centrifugation, chromatography or other suitable method.

[0334] Generally, the above reactions are carried out in a suitable inert organic solvent, at a suitable temperature, and for a suitable time that maximizes the formation of the desired compound. Examples of suitable inert organic solvents include, but are not limited to, 2-propanol, dimethylformamide (DMF), 1,4-dioxane, methylene chloride, chloroform, tetrahydrofuran (THF), toluene, and the like.

[0335] Formation of a desired compound salt is accomplished using standard techniques, for example, by treating a neutral compound with an acid or base in a suitable solvent and isolating the formed salt by filtration, extraction, or any other suitable method.

[0336] The formation of solvates of the compounds of the present application will vary depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in an appropriate solvent and isolating it by cooling or using an anti-solvent. Solvates are generally dried or lyophilized under amphiphilic conditions. The selection of appropriate conditions for forming a particular solvate can be performed by one skilled in the art.

[0337] Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino, or carboxyl groups. For example, an available hydroxy or amino group may be acylated with an activated acid (e.g., an acid chloride in pyridine) in the presence of a base, optionally in an inert solvent.

[0338] Those skilled in the art will recognize that when reaction steps of the present application are carried out in different solvents or solvent systems, said reaction steps may be carried out in a mixture of suitable solvents or solvent systems. [Example]

[0339] A. Synthesis of Exemplary Compounds of the Present Application Example 1: (R)-1-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)indoline ((R)-I-1) [ka] (R)-2-(2-(indoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ 2 Synthesis of (R)-ethan-1-one ((R)-2): A solution of ((benzyloxy)carbonyl)-D-proline (5.0 g, 20.05 mmol) in anhydrous THF (60 mL) was treated with thionyl chloride (2.92 mL, 40.11 mmol) at room temperature, and the resulting solution was refluxed for an additional 2 h. The reaction was allowed to warm to room temperature, and the solvent was evaporated to give the crude acid chloride as a pale yellow oil.

[0340] A solution of the crude acid chloride from above in CHCl (30 mL) was treated with a solution of indoline (2.25 mL, 20.05 mmol) in CHCl (20 mL) at 0 °C, followed by pyridine (3.24 mL, 40.11 mmol). The reaction was allowed to warm to room temperature and stirred overnight (16 h). The reaction was diluted with CHCl (100 mL), washed with water (100 mL), 1 N HCl solution (50 mL), brine (50 mL), and dried (NaSO). The solvent was evaporated, and the crude product was purified by flash silica gel column chromatography (EtOAc:CHCl, 1:9) to give the title compound (R)-2 (7.0 g, quantitative) as an off-white solid. 1 H NMR (DMSO-d6): δ 8.10,8.06 (2d,1H,J = 3.0,6.0 Hz),7.38-7.23 (m,6H),7.19-6.99 (m,2H),5.11-4.89 (m,2H),4.64-4.60 (m,1H),4.25-3.95 (m,2H),3.51-3.45 (m,2H),3.20-2.94 (m,2H),2.31-2.27 (m,1H),1.99-1.85 (m,3H); ESI-MS (m / z,%): 373 (M+Na),351 (MH + ),277 (100).

[0341] Synthesis of (R)-1-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)indoline ((R)-I-1): (R)-2-(2-(indoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ 2 A solution of (R)-ethan-1-one (1.96 g, 5.89 mmol) in anhydrous THF (50 mL) was treated with LiAlD (1.24 g, 29.48 mmol) at 0 °C over 10 minutes and refluxed overnight (16 hours). The reaction was allowed to warm to room temperature, then cooled to 0 °C and treated with water (1.24 mL), 2N NaOH solution (1.24 mL), and water (1.24 mL). The reaction was allowed to warm to room temperature and stirred for an additional 30 minutes. The solid was filtered off and washed with THF (3 × 25 mL). The solvent was evaporated, and the crude product was purified by silica gel column chromatography (2 M NH in MeOH:CHCl, 5:95) to afford the title compound (R)-I-1 (0.31 g, 24.2%) as a pale yellow oil. 1 H NMR (DMSO-d6): δ 7.02-6.95 (m,2H),6.54 (t,1H,J = 6.0 Hz),6.46 (d,1H,J = 6.0 Hz),3.43-3.31 (m,2H),2.99-2.95 (m,1H),2.88 (t,2H,J = 6.0 Hz), 2.38 (d,2H,J = 6.0 Hz),2.15-2.12 (m,1H),1.95-1.90 (m,1H),1.69-1.52 (m,3H); + ,100).

[0342] Example 2: (R)-6-Methoxy-1-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)indoline ((R)-I-57) [ka] (R)-2-(2-(6-methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ 2Synthesis of (R)-ethan-1-one ((R)-5): A solution of ((benzyloxy)carbonyl)-D-proline (6.0 g, 24.07 mmol) in anhydrous THF (70 mL) was treated with thionyl chloride (3.51 mL, 48.14 mmol) at room temperature, and the resulting solution was refluxed for an additional 2 h. The reaction was allowed to warm to room temperature, and the solvent was evaporated to give the crude acid chloride as a pale yellow oil.

[0343] A solution of the crude acid chloride from above in CHCl (50 mL) was treated with a solution of 6-methoxyindoline (3.6 g, 24.07 mmol) in CHCl (30 mL) at 0 °C, followed by pyridine (3.89 mL, 48.14 mmol). The reaction was allowed to warm to room temperature and stirred overnight (16 h). The reaction was diluted with CHCl (100 mL) and washed with water (2 × 100 mL), 1 N HCl solution (100 mL), brine (50 mL), and dried (NaSO). The solvent was evaporated, and the crude product was purified by flash silica gel column chromatography (EtOAc:CHCl, 1:9) to afford the title compound (R)-5 (8.9 g, 97%) as an off-white solid. 1 H NMR (DMSO-d6): δ 7.77,7.74 (2d,1H,J = 3.0 Hz),7.38-7.36 (m,2H),7.33-7.04 (m,4H),6.61-6.57 (m,1H),5.12-4.89 (m,2H),4.63-4.59 ESI-MS (m / z,%): 403 (M+Na),381 (MH + ).

[0344] Synthesis of (R)-6-methoxy-1-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)indoline ((R)-I-57): A suspension of LiAlD4 (0.83 g, 19.71 mmol) in anhydrous THF (40 mL) was treated with AlCl3 (3.15 g, 23.65 mmol) at 0 °C. The reaction was stirred for 5 min to afford (R)-2-(2-(6-methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ. 2 The reaction mixture was treated with 1.5 g (3.94 mmol) of 1H-ethan-1-one in anhydrous THF (20 mL) and stirred for 15 minutes. The reaction was allowed to warm to room temperature and stirred for an additional 4 hours. The reaction was cooled to 0°C and quenched with water (1.0 mL), 2N NaOH solution (1 mL), and water (1 mL). The reaction was allowed to warm to room temperature and stirred for an additional 30 minutes. The reaction was diluted with THF (50 mL) and filtered through a pad of NaSO followed by silica gel. The solvent was evaporated and the crude product was purified by silica gel column chromatography (2 M NH in MeOH:CHCl, 5:95) to afford the title compound (R)-I-57 (0.92 g, 93%) as an off-white solid. 1 H NMR (DMSO-d6): δ 6.89 (d,1H,J = 3.0 Hz),6.21 (brs,1H),6.13 (dd,1H,3.0,4.5 Hz),3.68 (s,3H),3.49-3.46 (m,1H),3.31-3.16 (m,4H),2.84-2.78 (m,2H),2.12-2.07 (m,1H),1.90-1.80 (m,2H),1.68-1.60 (m,1H); ESI-MS (m / z,%): 252 (MH + ,100).

[0345] Example 3: (R)-6-Methoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-58) [ka] Synthesis of (R)-6-methoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-58): A suspension of LiAlH (0.74 g, 19.71 mmol) in anhydrous THF (40 mL) was treated with AlCl (3.15 g, 23.65 mmol) at 0 °C. The reaction was stirred for 5 min to afford (R)-2-(2-(6-methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ. 2 The reaction mixture was treated with a solution of 1.5 g (3.94 mmol) of 1-ethan-1-one in anhydrous THF (20 mL) and stirred for 15 minutes. The reaction was allowed to warm to room temperature and stirred for an additional 4 hours. The reaction was cooled to 0°C and quenched with water (1.0 mL), 2N NaOH solution (1 mL), and water (1 mL). The reaction was allowed to warm to room temperature and stirred for an additional 30 minutes. The reaction was diluted with THF (50 mL) and filtered through a pad of NaSO followed by silica gel. The solvent was evaporated and the crude product purified by silica gel column chromatography (2 M NH in MeOH:CHCl, 5:95) to afford the title compound (R)-I-58 (0.8 g, 82.5%) as an off-white solid. 1 H NMR (DMSO-d6): δ 6.87 (d,1H,J = 6.0 Hz),6.10-6.08 (m,2H),3.67 (s,3H),3.44-3.39 (m,1H),3.353.33 (m,1H),3.31-3.29 (m,1H),3.20-3.15 (m,1H),2.96-2.91 (m,1H),2.82-2.77 (m,2H),2.60-2.52 (m,1H),2.40 (s,3H),2.30-2.25 (m,1H),2.00-1.92 (m,1H),1.72-1.67 (m,2H),1.59-1.52 (m,1H); ESI-MS (m / z,%): 247 (MH + ,100).

[0346] Example 4: (S)-6-Methoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((S)-I-58) [ka] (S)-2-(2-(6-methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ 2 Synthesis of -ethan-1-one ((S)-8): A solution of ((benzyloxy)carbonyl)-L-proline (2.2 g, 8.82 mmol) in anhydrous THF (30 mL) was treated with thionyl chloride (1.29 mL, 17.65 mmol) at room temperature, and the resulting solution was refluxed for an additional 2 h. The reaction was allowed to warm to room temperature, and the solvent was evaporated to give the crude acid chloride as a pale yellow oil.

[0347] A solution of the crude acid chloride from above in CHCl (20 mL) was treated with a solution of 6-methoxyindoline (1.32 g, 8.82 mmol) in CHCl (10 mL) at 0 °C, followed by pyridine (1.43 mL, 17.65 mmol). The reaction was allowed to warm to room temperature and stirred overnight (16 h). The reaction was diluted with CHCl (100 mL), washed with water (100 mL), 1 N HCl solution (50 mL), brine (50 mL), and dried (NaSO). The solvent was evaporated, and the crude product was purified by flash silica gel column chromatography (EtOAc:CHCl, 1:9) to afford the title compound (S)-8 (3.1 g, 96.8%) as a pale yellow gum. 1 H NMR (DMSO-d6): δ 7.78,7.75 (2d,1H,J = 3.0 Hz),7.39-7.33 (m,2H),7.19-7.05 (m,4H),6.63-6.58 (m,1H),5.13-4.90 (m,2H),4.65-4.60 ESI-MS (m / z,%): 403 (M+Na),381 (MH + ,100).

[0348] Synthesis of (S)-6-methoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((S)-I-58): A suspension of LiAlH (1.34 g, 35.48 mmol) in anhydrous THF (60 mL) was treated with AlCl (5.67 g, 42.58 mmol) at 0 °C. The reaction was stirred for 5 min to afford (S)-2-(2-(6-methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ. 2 The reaction mixture was treated with a solution of 1-ethan-1-one (2.7 g, 7.09 mmol) in anhydrous THF (30 mL) and then stirred for 15 minutes. The reaction was allowed to warm to room temperature and stirred for an additional 4 hours. The reaction was cooled to 0 °C and quenched with water (1.34 mL), 2 N NaOH solution (1.34 mL), and water (1.34 mL). The reaction was allowed to warm to room temperature and stirred for an additional 30 minutes. The reaction was diluted with THF (50 mL) and filtered through a pad of Na2SO4 followed by silica gel filtration. The solvent was evaporated and the crude product was purified by silica gel column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to afford the title compound (S)-I-58 (1.14 g, 65.5%) as an off-white solid. 1 H NMR (DMSO-d6): δ 6.90 (d, 1H, J = 3.0 Hz), 6.27 (brs, 1H), 6.15 (dd, 1H, J = 3.0 Hz), 3.68 (s, 3H), 3.50-3.25 (m, 5H), 3.11-3.09 (m, 1H), 2.87-2.79 (m, 2H), 2.77-2.65 (m, 1H), 2.50 (s, 3H, co-appears with DMSO peaks), 2.15-2.10 (m, 1H), 1.90-1.85 (m, 2H), 1.71-1.63 (m, 1H); ESI-MS (m / z,%): 247 (MH + ,100).

[0349] Example 5: (R)-7-Methoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-46) [ka] (R)-2-(2-(7-methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ 2 Synthesis of (R)-ethan-1-one ((R)-11): A solution of ((benzyloxy)carbonyl)-D-proline (1.67 g, 6.70 mmol) in anhydrous THF (20 mL) was treated with thionyl chloride (0.97 mL, 13.40 mmol) at room temperature, and the resulting solution was stirred for an additional 2 h. The reaction was allowed to warm to room temperature, and the solvent was evaporated to give the crude acid chloride as a pale yellow oil.

[0350] A solution of the crude acid chloride from above in CHCl (20 mL) was treated with a solution of 7-methoxyindoline (1.0 g, 6.70 mmol) in CHCl (10 mL) at 0 °C, followed by pyridine (1.0 mL, 13.40 mmol). The reaction was allowed to warm to room temperature and stirred overnight (16 h). The reaction was diluted with CHCl (100 mL), washed with water (100 mL), 1 N HCl solution (50 mL), brine (50 mL), and dried (NaSO). The solvent was evaporated, and the crude product was purified by flash silica gel column chromatography (EtOAc:CHCl, 1:9) to afford the title compound (R)-11 (2.1 g, 84%) as a purple gum. 1 H NMR (DMSO-d6): δ 7.37-7.30 (m,4H),7.26-7.22 (m,2H),7.11-6.86 (m,2H),5.02-4.85 (m,2H),4.64-4.50 (m,1H),4.30-4.20 ESI-MS (m / z,%): 403 (M+Na,100),381 (MH + ).

[0351] Synthesis of (R)-7-methoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-46): A suspension of LiAlH (0.8 g, 21.02 mmol) in anhydrous THF (50 mL) was treated with AlCl (3.36 g, 25.23 mmol) at 0 °C. The reaction was stirred for 5 min to afford (R)-2-(2-(7-methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ. 2 The reaction mixture was treated with a solution of 1.6 g (4.20 mmol) of 1-ethan-1-one in anhydrous THF (20 mL) and stirred for 15 minutes. The reaction was allowed to warm to room temperature and stirred for an additional 4 hours. The reaction was cooled to 0 °C and quenched with water (0.8 mL), 2 N NaOH solution (0.8 mL), and water (0.8 mL). The reaction was allowed to warm to room temperature and stirred for an additional 30 minutes. The reaction was diluted with THF (50 mL) and filtered through a pad of Na SO followed by silica gel filtration. The solvent was evaporated and the crude product was purified by silica gel column chromatography (2 M NH in MeOH:CHCl, 5:95) to afford the title compound (R)-I-46 (0.77 g, 74.7%) as a colorless oil. 1 H NMR (DMSO-d6): δ 6.71-6.66 (m,2H),6.57 (t,1H,J = 3.0 Hz),3.71 (s,3H),3.51 (dd,1H,J = 3.0,6.0 Hz),3.37-3.28 (m,2H) 3.14 (dd,1H,J = 3.0 Hz),2.97-2.93 (m,1H),2.86 (t,2H,J = 3.0 Hz),2.37-2.34 (m,1H),2.30 (s,3H),2.12-2.08 (m,1H),1.92-1.88 (m,1H),1.67-1.61 (m,3H); ESI-MS (m / z,%): 247 (MH + ,100).

[0352] Example 6: (R)-4-Methoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-47) [ka] (R)-2-(2-(4-methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ 2 Synthesis of (R)-ethan-1-one ((R)-14): A solution of ((benzyloxy)carbonyl)-D-proline (1.67 g, 6.70 mmol) in anhydrous THF (20 mL) was treated with thionyl chloride (0.97 mL, 13.40 mmol) at room temperature, and the resulting solution was refluxed for an additional 2 h. The reaction was allowed to warm to room temperature, and the solvent was evaporated to give the crude acid chloride as a pale yellow oil.

[0353] A solution of the crude acid chloride from above in CHCl (20 mL) was treated with a solution of 4-methoxyindoline (1.0 g, 6.70 mmol) in CHCl (10 mL) at 0 °C, followed by pyridine (1.0 mL, 13.40 mmol). The reaction was allowed to warm to room temperature and stirred overnight (16 h). The reaction was diluted with CHCl (100 mL), washed with water (100 mL), 1 N HCl solution (50 mL), brine (50 mL), and dried (NaSO). The solvent was evaporated, and the crude product was purified by flash silica gel column chromatography (EtOAc:CHCl, 1:9) to afford the title compound (R)-14 (2.4 g, 94%) as a pale purple solid. 1 H NMR (DMSO-d6): δ 7.74,7.69 (2d,1H,J = 6.0 Hz),7.39-7.32 (m,2H),7.20-7.13 (m,3H),7.08-7.04 (m,1H),6.71 (t,1H,J = 6.0 Hz),5.12-4.90 (m,2H),4.63-4.58 (m,1H),4.27-3.97 (m,2H),3.81,3.80 (2s,3H),3.53-3.45 (m,2H),3.09-2.82 (m,2H),2.31-2.27 (m,1H),2.00-1.85 (m,3H); ESI-MS (m / z,%): 403 (M+Na, 100), 381 (MH + ).

[0354] Synthesis of (R)-4-methoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-47): A suspension of LiAlH (1.0 g, 26.28 mmol) in anhydrous THF (50 mL) was treated with AlCl (4.2 g, 31.54 mmol) at 0 °C. The reaction was stirred for 5 min to afford (R)-2-(2-(4-methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ. 2 The reaction mixture was treated with 1.0 g (5.25 mmol) of 1-ethan-1-one in anhydrous THF (30 mL) and stirred for 15 minutes. The reaction was allowed to warm to room temperature and stirred for an additional 4 hours. The reaction was cooled to 0° C. and quenched with water (1.0 mL), 2N NaOH solution (1.0 mL), and water (1.0 mL). The reaction was allowed to warm to room temperature and stirred for an additional 30 minutes. The reaction was diluted with THF (50 mL) and filtered through a pad of NaSO followed by silica gel. The solvent was evaporated and the crude product was purified by silica gel column chromatography (2 M NH in MeOH:CHCl, 5:95) to afford the title compound (R)-I-47 (0.98 g, 76%) as an off-white solid. 1 H NMR (DMSO-d6): δ 7.00 (t, 1H, J = 6.0 Hz), 6.34-6.32 (m, 2H), 3.73 (s, 3H), 3.59-3.12 (m, 6H), 2.87-2.73 (m, 3H), 2.50 (s, 3H, co-appears with DMSO peaks), 2.20-2.10 (m, 1H), 1.95-1.85 (m, 2H), 1.72-1.64 (m, 1H); ESI-MS (m / z, %): 247 (MH + ,100).

[0355] Example 7: (R)-6-Methoxy-1-(pyrrolidin-2-ylmethyl)indoline (R)-6-Methoxy-1-(pyrrolidin-2-ylmethyl)indoline ((R)-I-59) [ka] Synthesis of (R)-6-methoxy-1-prolylindoline (16): (R)-2-(2-(6-methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ 2 A solution of 1.5 g (3.94 mmol) of 1-ethan-1-one in anhydrous methanol (50 mL) was treated with 10% palladium on carbon (1.5 g, dry basis) and hydrogenated overnight (18 h) under partial pressure of hydrogen (40 PSI). The reaction was filtered through a pad of Celite and washed with methanol (2 × 25 mL). The combined methanol layers were evaporated, and the crude product was purified by flash silica gel column chromatography (2 M NH in MeOH:CH2Cl2, 5:95) to give the title compound 16 (0.78 g, 80.4%) as a pale yellow sticky material. 1 H NMR (DMSO-d6): 7.75 (d,1H,J = 3.0 Hz),7.13 (d,1H,J = 6.0 Hz),6.58 (dd,1H,J = 3.0,6.0 Hz),4.30-4.23 (m,1H),4.13-4.04 (m,1H),3.87-3.84 (m,1H),3.72 (s,3H),3.18 (s,1H),3.09-2.97 (m,3H),2.74-2.68 (m,1H),2.10-2.01 (m,1H),1.79-1.61 (m,3H); ESI-MS (m / z,%): 247 (MH + ,100).

[0356] Synthesis of (R)-6-methoxy-1-(pyrrolidin-2-ylmethyl)indoline (R)-I-59): A suspension of LiAlH (0.55 g, 14.61 mmol) in anhydrous THF (20 mL) was treated with AlCl (2.33 g, 17.53 mmol) at 0 °C. The reaction was treated with (R)-6-methoxy-1-prolylindoline (0.72 g, 2.92 mmol) in anhydrous THF (20 mL) over 5 minutes and then stirred for 15 minutes. The reaction was allowed to warm to room temperature and stirred for an additional 4 hours. The reaction was cooled to 0 °C and quenched with water (0.6 mL), 2N NaOH solution (0.6 mL), and water (0.6 mL). The reaction was allowed to warm to room temperature and stirred for an additional 30 minutes. The reaction mixture was diluted with THF (50 mL) and filtered through a pad of NaSO followed by silica gel. The solvent was evaporated and the crude product was purified by silica gel column chromatography (2 M NH in MeOH:CHCl, 5:95) to give the title compound (R)-I-59 (0.6 g, 89.5%) as a pale yellow sticky material. 1 H NMR (DMSO-d6): 6.87 (d,1H,J = 6.0 Hz),6.09-6.05 (m,2H),3.67 (s,3H),3.42-3.36 (m,2H),3.24-3.21 (m,1H),2.98-2.90 (m,2H),2.88-2.71 (m,4H),1.83-1.61 (m,3H),1.36-1.30 (m,1H); ESI-MS (m / z,%): 233 (MH + ,100).

[0357] Example 8: (R)-5,6-Dimethoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-34) [ka] (R)-2-(2-(5,6-dimethoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2l 2Synthesis of -ethan-1-one (19): A solution of ((benzyloxy)carbonyl)-D-proline (1.39 g, 5.57 mmol) in anhydrous THF (20 mL) was treated with thionyl chloride (0.4 mL, 11.16 mmol) at room temperature, and the resulting solution was refluxed for an additional 2 h. The reaction was allowed to warm to room temperature, and the solvent was evaporated to give the crude acid chloride as a pale yellow oil.

[0358] A solution of the crude acid chloride from above in CHCl (10 mL) was treated with a solution of 5,6-dimethoxyindoline (1.0 g, 5.57 mmol) in CHCl (20 mL) at 0 °C, followed by pyridine (0.9 mL, 11.15 mmol). The reaction was allowed to warm to room temperature and stirred overnight (16 h). Workup and purification were performed as described for compound 8 to afford the title compound 19 (2.05 g, 89.5%) as a pale brown solid. ESI-MS (m / z, %): 433 (M+Na), 411 (MH + ,100).

[0359] Synthesis of (R)-5,6-dimethoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-34): A suspension of LiAlH (0.76 g, 20.22 mmol) in anhydrous THF (50 mL) was treated with AlCl (3.2 g, 24.26 mmol) at 0 °C. The reaction was stirred for 5 min to afford (R)-2-(2-(5,6-dimethoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2-indoline. 2 The reaction mixture was treated with a solution of (R)-ethan-1-one (1.66 g, 4.04 mmol) in anhydrous THF (20 mL) and stirred for 15 minutes. The reaction was allowed to warm to room temperature and stirred for an additional 4 hours. The reaction was worked up and purified as described for compound 6 to afford the title compound (R)-I-34 (0.7 g, 63%) as a pale yellow oil. 1H NMR (DMSO-d6): δ 6.75 (s,1H),6.27 (s,1H),3.71 (s,3H),3.63 (s,3H),3.31-3.24 (m,2H),3.07 (dd,1H,J = 3.0,9.0 Hz),3.00-2.95 (m,1H),2.87 (dd,1H,J = 3.0,9.0 Hz),2.78 (t,2H,J = 6.0 Hz),2.38-2.34 (m,4H),2.15-2.13 (m,1H),1.96-1.91 (m,1H),1.70-1.55 (m,3H); ESI-MS (m / z,%): 277 (MH + ,100).

[0360] Example 9: 2-(6-Methoxyindolin-1-yl)-N,N-bis(methyl-d3)ethan-1-amine (I-70) [ka] Synthesis of 2-chloro-1-(6-methoxyindolin-1-yl)ethan-1-one (24): A solution of 6-methoxyindoline (2.0 g, 13.40 mmol) and pyridine (2.38 mL, 29.49 mmol) in anhydrous CHCl (30 mL) was treated with 2-chloroacetyl chloride (2.13 mL, 26.81 mmol) at 0 °C over 10 minutes. The reaction was allowed to warm to room temperature and stirred overnight (16 hours). Workup and purification were performed as described for compound 21 to afford the title compound 24 (3.0 g, quantitative) as an off-white solid.

[0361] Synthesis of 2-(bis(methyl-d3)amino)-1-(6-methoxyindolin-1-yl)ethan-1-one (25): A solution of 2-chloro-1-(6-methoxyindolin-1-yl)ethan-1-one (2.0 g, 8.86 mmol), KCO (3.67 g, 26.58 mmol), bis(methyl-d3)amine hydrochloride (1.16 mL, 13.29 mmol), and DMF (0.3 mL) in anhydrous ACN (50 mL) was stirred overnight (16 h) in a sealed tube at 50 °C. The reaction was cooled to room temperature, worked up, and purified as described for compound 22 to give the title compound 25 (1.7 g, 80%) as a pale brown oil. 1 H NMR (DMSO-d6): δ 7.73 (d,1H,J = 3.0 Hz),7.12 (d,1H,J = 6.0 Hz),6.57 (dd,1H,J = 3.0,6.0 Hz),4.16 (t,2H,J = 6.0 Hz),3.72 (s,3H),3.20 (s,2H),3.05 (t,2H,J = 6.0 Hz); ESI-MS (m / z,%): 241 (MH + ,100).

[0362] Synthesis of 2-(6-methoxyindolin-1-yl)-N,N-bis(methyl-d3)ethan-1-amine (I-70): A suspension of LiAlH4 (0.98 g, 26.01 mmol) in anhydrous THF (50 mL) was treated with AlCl3 (4.2 g, 31.21 mmol) at 0 °C. The reaction was treated with 1-(6-methoxyindolin-1-yl)-2-(dimethylamino)ethan-1-one (1.78 g, 7.43 mmol) in anhydrous THF (20 mL) over 5 minutes and then stirred for 15 minutes. The reaction was allowed to warm to room temperature and stirred for an additional 4 hours. The reaction was worked up and purified as described for compound 6 to afford the title compound I-70 (1.15 g, 68.8%) as a pale yellow oil. 1H NMR (DMSO-d6): δ 6.88-6.86 (m,1H),6.10-6.07 (m,2H),3.67 (s,3H),3.36 (t,2H,J = 6.0 Hz),3.12 (t,2H,J = 6.0 Hz),2.78 (t,2H,J = 6.0 Hz),2.42 (t,2H,J = 6.0 Hz); ESI-MS (m / z,%): 227 (MH + ,100).

[0363] Example 10: 2-(indolin-1-yl)-N,N-bis(methyl-d3)ethan-1-amine (I-71) [ka] Synthesis of 2-chloro-1-(indolin-1-yl)ethan-1-one (27): A solution of indoline (1.0 g, 8.39 mmol) and pyridine (1.49 mL, 18.46 mmol) in anhydrous CHCl (20 mL) was treated with 2-chloroacetyl chloride (1.33 mL, 16.78 mmol) at 0 °C over 10 minutes. The reaction was allowed to warm to room temperature and stirred overnight (16 hours). Workup and purification were carried out as described for compound 21 to afford the title compound 27 (1.6 g, 97.5%) as an off-white solid.

[0364] Synthesis of 2-(bis(methyl-d3)amino)-1-(indolin-1-yl)ethan-1-one (28): A solution of 2-chloro-1-(indolin-1-yl)ethan-1-one (2.0 g, 10.22 mmol), KCO (4.23 g, 30.66 mmol), bis(methyl-d3)amine hydrochloride (1.34 mL, 15.33 mmol), and DMF (0.3 mL) in anhydrous ACN (50 mL) was stirred overnight (16 h) in a sealed tube at 50 °C. The reaction was cooled, worked up, and purified as described for compound 22 to afford the title compound 28 (1.8 g, 83.7%) as a pale yellow oil. 1H NMR (DMSO-d6): δ 8.07 (d,1H,J = 6.0 Hz),7.24 (d,1H,J = 6.0 Hz),7.15 (t,1H,J = 6.0 Hz),7.02-6.98 (m,1H),4.16 (t,2H,J = 6.0 Hz),3.21 (s,2H),3.13 (t,2H,J = 6.0 Hz); ESI-MS (m / z,%): 211 (MH + ,100).

[0365] Synthesis of 2-(indolin-1-yl)-N,N-bis(methyl-d3)ethan-1-amine (I-71): A suspension of LiAlH4 (1.098 g, 28.92 mmol) in anhydrous THF (50 mL) was treated with AlCl3 (4.62 g, 34.71 mmol) at 0 °C. The reaction was treated with 2-(bis(methyl-d3)amino)-1-(indolin-1-yl)ethan-1-one (1.738 g, 8.26 mmol) in anhydrous THF (20 mL) over 5 minutes and then stirred for 15 minutes. The reaction was allowed to warm to room temperature and stirred for an additional 4 hours. The reaction was worked up and purified as described for compound 6 to afford the title compound I-71 (0.96 g, 59.2%) as a light brown oil. 1 H NMR (DMSO-d6): δ 7.02-6.95 (m,2H),6.56-6.47 (m,2H),3.34 (t,2H,J = 6.0 Hz),3.12 (t,2H,J = 6.0 Hz),2.86 (t,2H,J = 60 Hz),2.43 (t,2H,J = 6.0 Hz); ESI-MS (m / z,%): 197 (MH + ,100).

[0366] Example 11: (R)-6-(methoxy-d3)-1-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)indoline ((R)-I-28) [ka] Synthesis of 4-(methoxy-d3)-1-methyl-2-nitrobenzene (31): A solution of 4-methyl-3-nitrophenol (25.3 g, 165.25 mmol) in anhydrous DMF (200 mL) was added to KOH (10.2 g, 181.77 mmol) at room temperature. t The reaction mixture was treated with BuNBr (0.53 g, 1.65 mmol) and CDI (10.8 mL, 173.51 mmol). The reaction was stirred at 60 °C in a sealed tube for 24 h. The reaction mixture was warmed to room temperature, diluted with water (1 L), and the product was extracted into diethyl ether (2 × 300 mL). The combined diethyl ether layers were washed with water (2 × 100 mL), brine (100 mL), and dried (NaSO). The solvent was evaporated to give the crude title compound 31 (28.0 g) as a brown liquid.

[0367] Synthesis of 2-(4-(methoxy-d3)-2-nitrophenyl)-N,N-dimethylethen-1-amine (32): A solution of 4-(methoxy-d3)-1-methyl-2-nitrobenzene (28.0 g, 164.53 mmol) in DMF (150 mL) was treated with DMF.DMA (65.6 mL, 493.59 mmol) at room temperature, and the resulting solution was stirred at 130° C. overnight (16 h). The reaction temperature was lowered to 90° C., and the solvent was evaporated to give the crude title compound 32, which was used in the next step without further purification.

[0368] Synthesis of 6-(methoxy-d3)-1H-indole (33): A solution of the crude product, 2-(4-(methoxy-d3)-2-nitrophenyl)-N,N-dimethylethen-1-amine, in toluene (150 mL) was treated with palladium on carbon (2.1 g, 10% dry basis) and hydrogenated using a Paar apparatus. The reaction was filtered through a pad of Celite and washed with ethyl acetate (3 x 50 mL). The combined organic layers were evaporated, and the crude product was purified by flash silica gel column chromatography (EtOAc:hexane, 1:4) to give the title compound (4.52 g, 18.2% over three steps). 1H NMR (CDCl3): δ 8.03 (brs,1H),7.55 (d,1H,J = 6.0 Hz),7.12 (dd,1H,J = 3.0 Hz),6.90 (d,1H,J = 3.0 Hz),6.84 (dd,1H,J = 3.0,6.0 Hz),6.53-6.51 (m,1H).

[0369] Synthesis of 6-(methoxy-d3)indoline (34): A solution of 6-(methoxy-d3)-1H-indole (1.5 g, 9.98 mmol) in acetic acid (30 mL) was treated portionwise with sodium cyanoborohydride (1.88 g, 29.96 mmol) at 0 °C. The reaction was warmed to room temperature and stirred for an additional 1 h. The reaction was quenched with 4 N NaOH solution at 0 °C, and the product was extracted into ethyl acetate (2 × 50 mL). The combined ethyl acetate layers were washed with brine (25 mL) and dried (Na2SO4). The solvent was evaporated, and the crude product was purified by silica gel column chromatography (EtOAc:hexane, 1:4) to give the title compound 34 (1.27 g, 83.5%) as a brown liquid. 1 H NMR (CDCl3): δ 7.03-7.00 (m,1H),6.29-6.26 (m,2H),3.59 (t,2H,J = 6.0 Hz),2.98 (t,2H,J = 6.0 Hz).

[0370] (R)-2-(2-(6-(methoxy-d3)indoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2l 2 Synthesis of -ethan-1-one (35): A solution of ((benzyloxy)carbonyl)-D-proline (2.08 g, 8.34 mmol) in anhydrous THF (30 mL) was treated with thionyl chloride (1.21 mL, 16.69 mmol) at room temperature, and the resulting solution was refluxed for an additional 2 h. The reaction was allowed to warm to room temperature, and the solvent was evaporated to give the crude acid chloride as a pale yellow oil.

[0371] A solution of the crude acid chloride from above in CHCl (10 mL) was treated with a solution of 6-(methoxy-d)indoline (1.27 g, 8.34 mmol) in CHCl (30 mL) at 0 °C, followed by pyridine (1.35 mL, 16.69 mmol). The reaction was allowed to warm to room temperature and stirred overnight (16 h). The reaction was worked up and purified as described for compound 8 to give the title compound 35 (3.1 g, 96.8%) as a light brown oil. ESI-MS (m / z, %): 406 (M+Na), 384 (MH + ).

[0372] Synthesis of (R)-6-(methoxy-d)-1-((1-(methyl-d)pyrrolidin-2-yl)methyl-d)indoline ((R)-I-28): A suspension of LiAlD (1.42 g, 33.90 mmol) in anhydrous THF (50 mL) was treated with AlCl (5.4 g, 40.68 mmol) at 0 °C. The reaction was stirred for 5 min to afford (R)-2-(2-(6-(methoxy-d)indoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-21 2 The reaction mixture was treated with a solution of (R)-ethan-1-one (2.6 g, 6.78 mmol) in anhydrous THF (30 mL) and stirred for 15 minutes. The reaction was allowed to warm to room temperature and stirred for an additional 4 hours. The reaction mixture was worked up and purified as described for compound 6 to afford the title compound (R)-I-28 (1.26 g, 73%) as a pale yellow oil. 1 H NMR (DMSO-d6): δ 6.88-6.85 (m,1H),6.09-6.03 (m,2H),3.44-3.31 (m,2H),2.99-2.94 (m,1H),2.82-2.78 (m,2H),2.36 (t,1H,J = 6.0 Hz),2.16-2.09 (m,1H),1.94-1.87 (m,1H),1.70-1.50 (m,3H); ESI-MS (m / z,%): 255 (MH + ,100).

[0373] B. Biological Testing Example 12: FLIPR Assay: Human 5-HT2A the purpose: Human 5-HT in agonist mode 2A (h5-HT 2A The effectiveness of exemplary compounds of Formula I in targeting the .ALPHA.) receptor is evaluated. Materials and equipment 1.1 Cell lines [Table 30] 1.2 Compound Preparation and Assay Controls [Table 31] 1.3 Equipment and Consumables [Table 32]

[0374] 2. Experimental Method 2.1 Cell culture HTR2A&Gα15-HEK293 cells were cultured in DMEM medium containing 10% dialyzed FBS, 1x penicillin-streptomycin, 100 μg / mL hygromycin B, and 300 μg / mL G418. Cells were subcultured approximately three times a week and maintained at approximately 30% to 90% confluence.

[0375] 2.2 Cell plating 1. Cell culture medium (DMEM medium containing 10% dialyzed FBS and 1× penicillin-streptomycin, 100 μg / mL hygromycin B, and 300 μg / mL G418), TrypLE™ Express, and DPBS were pre-warmed to room temperature.

[0376] 2. For expression induction, 1 μg / ml tetracycline (final concentration) was added to the cell culture medium and incubated at 37°C, 5% (v / v) CO2 for 48 hours before seeding the cells on plates. The cell culture medium was removed from the flasks. The cells were washed with DPBS.

[0377] 3. 2 mL of TrypLE™ Express was added to the flask, gently shaken to mix well, and the cells were incubated at 37° C. for a few minutes.

[0378] 4. The morphological changes of the cells were confirmed under a microscope, and when most of the cells became round, 4 mL of cell culture medium was added to the flask to stop the digestion.

[0379] 5. The cell suspension was transferred to a 15 mL centrifuge tube and then centrifuged at 1,200 rpm for 5 minutes.

[0380] 6. The supernatant was removed and the cell pellet was resuspended in 2 mL of cell culture medium.

[0381] 7. The cell density was counted using a cell counter. Only cells with a viability of over 85% were used in the assay.

[0382] 8. The cells were diluted to 6.67 x 105 cells / mL using cell culture medium.

[0383] 9. 30 μL / well of the cell suspension was added to a 384-well cell plate (cell density was 20,000 cells per well).

[0384] 10. The cell plates were incubated overnight at 37°C, 5% (v / v) CO2.

[0385] 2.3 Cell handling 1. On the day of the experiment, the culture medium was removed from the cell plates.

[0386] 2. 10 μL of assay buffer (20 mM HEPES in 1×HBSS, pH 7.4) was added to each well of the cell plate.

[0387] 3. 2x dye solution was prepared according to the FLIPR® Calcium 6 Assay Kit manual:

[0388] i. The dye was diluted in assay buffer.

[0389] ii. Probenecid was added to a final concentration of 5 mM.

[0390] iii. Vortex thoroughly for 1-2 minutes.

[0391] 4. 10 μL of 2× dye solution was added to each well of the cell plate.

[0392] 5. The cell plate was placed on a plate shaker and then shaken at 600 rpm for 2 minutes.

[0393] 6. The plate was incubated at 37°C for 2 hours, followed by an additional 15 minutes at 25°C.

[0394] 2.4 Preparation of 3x Compound 1. Serotonin HCl was prepared at a concentration of 10 mM using DMSO.

[0395] 2. Test compounds were prepared at a concentration of 10 mM using DMSO.

[0396] 3. Compounds were added to a 384-well compound source plate.

[0397] 4. A 3-fold dilution series was prepared using DMSO.

[0398] 5. Using the Echo, 90 nL / well of serially diluted compounds was transferred from the source plate to the 384-well compound plate.

[0399] 6. 30 μL / well of assay buffer (20 mM HEPES in 1×HBSS, pH 7.4) was added to the compound plate.

[0400] 7. The plate was mixed on a plate shaker for 2 minutes.

[0401] 2.5 FLIPR assay 1. After incubating the cells with the dye solution, the cell plate, the compound plate containing 3x compound, and the FLIPR chip were subjected to FLIPR.

[0402] 2. 10 μL of 3× compound was transferred from the compound plate to the cell plate by FLIPR.

[0403] 3. The plate was read at 1 second intervals for 160 seconds to obtain agonist mode data.

[0404] 3 2.6 Data Analysis 1. Normalized fluorescence readings (RFU) were calculated as follows: where Fmax and Fmin represent the maximum and minimum values ​​of calcium signal within a given time period. RFU=Fmax-Fmin

[0405] 2. EC 50 was calculated by fitting the RFU to the logarithm of the compound concentration using XLfit with the Hill equation.

[0406] 3.0 Experimental Methods and Procedures: The following steps may also be followed: 1. Culture the cells in cell culture medium (DMEM containing 10% FBS, 1x penicillin-streptomycin, 300 μg / ml G418 and 100 μg / ml hygromycin B) at 37°C and 5% (v / v) CO2.

[0407] 2. The day before the assay, detach the cells using TrypLE™ Express and count the cells using a cell counter. Only cells with viability greater than 85% are used in the assay.

[0408] 3. 20,000 cells are seeded per well into a 384-well cell plate, with 30 μl of culture medium per well, and the cells are incubated overnight at 37° C., 5% (v / v) CO 2 .

[0409] 4. On the day of the assay, prepare a 2x dye solution according to the FLIPR® Calcium 6 Assay Kit manual: i. Dilute the dye in assay buffer (20 mM HEPES in 1x HBSS, pH 7.4); ii. Add probenecid to a final concentration of 5mM; iii. Vortex thoroughly for 1-2 minutes.

[0410] 5. Remove the medium from the cell plate by flicking the cell plate on a paper towel.

[0411] 6. Add 10 μl of assay buffer and 10 μl of 2× dye solution to each well of the cell plate.

[0412] 7. Place the cell plate on a plate shaker and shake the plate gently at 600 rpm for 2 minutes. Incubate the plate at 37°C for 2 hours, followed by an additional 15 minutes at 25°C.

[0413] 8. Prepare 3x compound assay buffer: a. Dilute reference compound to required concentration with DMSO. Add compounds to 384-well compound plate; b. Make dilution series; c. Add 10 mM test compound to compound plate and make 3-fold dilution series; d. Use Echo to transfer 60 nl / well of compound from source plate to 384-well compound plate (Corning, 3657); e. Add 20 μl / well of assay buffer to compound plate; f. Mix plate on plate shaker for 2 minutes;

[0414] 9. Place the cell plate, compound plate and chips into the FLIPR and use the FLIPR to transfer 10 μl of 3× compound to each well of the cell plate.

[0415] Data analysis i. Calculate the normalized fluorescence reading (RFU) as follows, where Fmax and Fmin represent the maximum and minimum values ​​of the calcium signal within a given time period: RFU = Fmax - Fmin

[0416] ii. Calculate the % activation using the following formula:

number

[0417] iii. EC values ​​were calculated by fitting the % activation versus the logarithm of compound concentration to the Hill equation using XLfit. 50 Calculate.

[0418] Results and Discussion Exemplary compounds of Formula I were functionally evaluated for their effect on the 5-HT2A receptor in the agonist mode using a FLIPR assay. The results of potential competitive binding of exemplary compounds of the present application targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A) are summarized in Table 2. The IC values ​​provided in Table 2 50 As such, the results for the exemplary compounds of the present application are presented. [Table 33]

[0419] Exemplary compounds of Formula I were evaluated using a radioligand binding assay for the human 5-HT2A receptor. EC 50 The concentrations (nM) are shown in Table 2. This assay confirms that the compounds of the present application are effective ligands of the target human 5-HT2A receptor.

[0420] Example 13: Human 5-HT2A: Radioligand Binding Assay: the purpose h5-HT in agonist mode using FLIPR assay 2AExemplary compounds of Formula I were functionally evaluated for their effect on the receptor. The purpose of this study was to evaluate the binding of exemplary compounds of Formula I to the 5-hydroxytryptamine receptor 2A (5-HT2A). Human 5-HT 2A Radioligand binding assay: 1 Materials and equipment [Table 34] [Table 35]

[0421] 2. Experimental Procedure i. Assay buffer was prepared according to the table below. [Table 36]

[0422] ii. Eight doses of reference and test compounds were prepared by making a 5-fold dilution series from the required 10 mM stock solutions using 100% (v / v) DMSO.

[0423] iii. UniFilter-96GF / B plates were pretreated:

[0424] 50 μl of 0.5% (v / v) PEI was added to each well of a UniFilter-96GF / C plate. The plate was sealed and incubated at 4°C for 3 hours.

[0425] b. After incubation, the plates were washed three times with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0426] iv. Assay plates were prepared:

[0427] a. Cell membranes were diluted in assay buffer and 330 μl / well was added to a 96 deep-well round-bottom plate to give a concentration of 20 μg / well.

[0428] b. Eight concentrations of reference or test compounds were prepared and 110 μl / well was added to a 96 deep-well round-bottom plate.

[0429] c. [3H]-Ketanserin was diluted in assay buffer to 5 nM (5x final concentration) and 110 μl / well was added to a 96 deep well round bottom plate.

[0430] v. The plate was centrifuged at 1000 rpm for 30 seconds and then shaken at 600 rpm for 5 minutes at room temperature.

[0431] vi. The plate was sealed and the plate was incubated at 27°C for 90 minutes.

[0432] vii. The incubation was terminated by suction filtration onto GF / B filter plates, followed by four washes with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0433] viii. The plates were dried at 37°C for 45 minutes.

[0434] ix. The filter plate was sealed and 40 μl / well of scintillation cocktail was added.

[0435] x.Microbeta 2 The plates were read using a microplate counter.

[0436] 3. Data analysis 1. For reference and test compounds, results were expressed as % inhibition using the normalization formula: N=100-100×(U-C2) / (C1-C2), where U is the unknown, C1 is the mean value of the high control, and C2 is the mean value of the low control.

[0437] 2. Calculate IC by fitting % inhibition as a function of compound concentration to the Hill equation using XLfit. 50 It was decided that:

[0438] Results and Discussion The results of the potential competitive binding of exemplary compounds of the present application targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A) are summarized in Table 3. The results of exemplary compounds of the present application are summarized in Table 3. 50 is presented as. [Table 37]

[0439] II. Results and Discussion Exemplary compounds of Formula I were evaluated using a radioligand binding assay for the human 5-HT2A receptor. IC 50 The concentrations (nM) are shown in Table 3. This assay confirms that the compounds of the present application are effective ligands of the target human 5-HT2A receptor.

[0440] Example 14: Human 5-HT1A: Functional FLIPR Assay 1 purpose The potential excitatory effects of compounds targeting the 5-hydroxytryptamine receptor 1A (5-HT1A) in the agonist mode were evaluated. 2 Materials and equipment [Table 38] [Table 39] [Table 40]

[0441] 3 Experimental Method 3.1 Cell culture HTR1A&Gα15-CHO cells were cultured in DMEM / F12 medium containing 10% dialyzed FBS, 1x penicillin-streptomycin, and 600 μg / mL hygromycin B. Cells were subcultured approximately three times a week and maintained at approximately 30% to 90% confluence.

[0442] 3.2 Cell plating 1. Cell culture medium (DMEM / F12 medium containing 10% dialyzed FBS, 1× penicillin-streptomycin, and 600 μg / mL hygromycin B), TrypLE™ Express, and DPBS were pre-warmed to room temperature.

[0443] 2. The cell culture medium was removed from the flask. The cells were washed with DPBS.

[0444] 3. 1 mL of TrypLE™ Express was added to the flask, gently shaken to mix well, and the cells were incubated at 37°C for a few minutes.

[0445] 4. The morphological changes of the cells were confirmed under a microscope, and when the majority of the cells had become round, 2 mL of cell culture medium was added to the flask to stop the digestion.

[0446] 5. The cell suspension was transferred to a 15 mL centrifuge tube and then centrifuged at 1,200 rpm for 5 minutes.

[0447] 6. The supernatant was removed and the cell pellet was resuspended in 2 mL of cell culture medium.

[0448] 7. The cell density was counted using a cell counter. Only cells with a viability of over 85% were used in the assay.

[0449] 8. The cells were diluted to 4 x 105 / mL using cell culture medium.

[0450] 9. 30 μL / well of the cell suspension was added to a 384-well cell plate (cell density was 12,000 cells per well).

[0451] 10. The cell plates were incubated overnight at 37°C, 5% (v / v) CO2.

[0452] 3.3 Cell handling 1. On the day of the experiment, the culture medium was removed from the cell plates.

[0453] 2. 10 μL of assay buffer (20 mM HEPES in 1×HBSS, pH 7.4) was added to each well of the cell plate.

[0454] 3. Prepare 2x dye solution according to the FLIPR® Calcium 6 Assay Kit product instructions:

[0455] i. The dye was diluted in assay buffer.

[0456] ii. Probenecid was added to a final concentration of 5 mM.

[0457] iii. Vortex thoroughly for 1-2 minutes and adjust the pH to 7.4.

[0458] 4. 10 μL of 2× dye solution was added to each well of the cell plate.

[0459] 5. The cell plate was placed on a plate shaker and then shaken at 600 rpm for 2 minutes.

[0460] 6. The plate was incubated at 37°C for 2 hours, followed by an additional 15 minutes at 25°C.

[0461] 3.4 Preparation of 3x Compound 1. Serotonin was prepared at a concentration of 10 mM using DMSO, and a 3-fold dilution series was prepared using DMSO.

[0462] 2. A test compound was prepared at a concentration of 10 mM using DMSO, and a 3-fold dilution series was prepared using DMSO.

[0463] 3. Compounds were added to a 384-well compound source plate.

[0464] 4. Using the Echo, 90 nL / well of serially diluted compounds was transferred from the source plate to the 384-well compound plate.

[0465] 5. 30 μL / well of assay buffer was added to the compound plate.

[0466] 6. The plate was mixed on a plate shaker for 2 minutes.

[0467] 3.5 FLIPR assay 1. After incubating the cells with the dye solution, the cell plate, the compound plate containing 3x compound, and the FLIPR chip were subjected to FLIPR.

[0468] 2. 10 μL of 3× compound was transferred from the compound plate to the cell plate by FLIPR.

[0469] 3. The plate was read at 1 second intervals for 160 seconds to obtain agonist mode data.

[0470] 4. Data analysis 1. Normalized fluorescence readings (RFU) were calculated as follows, where Fmax and Fmin represent the maximum and minimum values ​​of calcium signal within a given time period: RFU=Fmax-Fmin

[0471] 2. Calculate the EC by fitting the RFU to the logarithm of the compound concentration using XLfit. 50 was calculated.

[0472] Results and Discussion The results of the potential competitive binding of exemplary compounds of the present application targeting the human 5-hydroxytryptamine receptor 1A (5-HT1A) are summarized in Table 4. The results of exemplary compounds of the present application are summarized in Table 4. 50 is presented as. [Table 41]

[0473] Exemplary compounds of Formula I were evaluated using a functional FLIPR assay against the human 5-HT1A receptor. EC 50 The concentrations (nM) are shown in Table 4. This assay confirms that the compounds of the present application have moderate functional activity at the target human 5-HT1A receptor.

[0474] Example 15: Human 5-HT1A: Radioligand Binding Assay: 1 purpose The purpose of this study was to evaluate the binding of test compounds to the 5-hydroxytryptamine receptor 1A (5-HT1A). 2 Materials and equipment [Table 42] [Table 43]

[0475] 3 Experimental Method 1. Assay buffer was prepared according to the table below. [Table 44]

[0476] 2. Eight doses of reference and test compounds were prepared by making 5-fold serial dilutions from the required 10 mM stock solutions using 100% (v / v) DMSO.

[0477] 3. UniFilter-96GF / B plates were prepared:

[0478] i. 50 μl / well of 0.5% (v / v) PEI was added to the UniFilter-96GF / B plate. The plate was sealed and incubated at 4° C. for 3 hours.

[0479] ii. After incubation, the plates were washed three times with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0480] 4. Assay plates were prepared:

[0481] i. Cell membranes were diluted in assay buffer and 100 μl / well was added to a 96-well round-bottom plate to give a concentration of 20 μg / well.

[0482] ii. Eight concentrations of reference or test compounds were prepared and 50 μl / well was added to a 96 deep-well round-bottom plate.

[0483] iii. [3H]-8-hydroxy-DPAT was diluted in assay buffer to 2 nM (4x final concentration) and 50 μl / well was added to a 96-well round-bottom plate.

[0484] 5. The plate was centrifuged at 1000 rpm for 30 seconds, then gently shaken at 600 rpm for 5 minutes at room temperature.

[0485] 6. The plate was sealed and incubated at 27°C for 90 minutes.

[0486] 7. The incubation was stopped by vacuum filtration onto GF / B filter plates, followed by four washes with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0487] 8. The plates were dried at 37°C for 45 minutes.

[0488] 9. The filter plate was sealed and 40 μl / well of scintillation cocktail was added.

[0489] 10. Microbeta 2 The plates were read using a microplate counter.

[0490] 4. Data analysis 1. For reference and test compounds, results were expressed as % inhibition using the normalization formula: N=100-100×(U-C2) / (C1-C2), where U is the unknown, C1 is the mean value of the high control, and C2 is the mean value of the low control.

[0491] 2. Calculate the IC by fitting the % inhibition as a function of bound compound concentration to the Hill equation using XLfit. 50 It was decided that:

[0492] result The results of the competitive binding potential of exemplary compounds of the present application targeting the human 5-hydroxytryptamine receptor (5-HT1A) are summarized in Table 5. The results of exemplary compounds of the present application are shown in the IC 50 is presented as. [Table 45]

[0493] Consideration Exemplary compounds of Formula I were evaluated using a radioligand binding assay for the human 5-HT1A receptor. IC 50 The concentrations (nM) are shown in Table 5. This assay confirms that the compounds of the present application are effective ligands of the target human 5-HT1A receptor.

[0494] Example 16: Human, rat and mouse liver microsome stability the purpose The purpose of this study is to estimate the in vitro metabolic stability of an exemplary compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, in pooled liver microsomes from humans, male rats, and male mice. To estimate stability in pooled liver microsomes from humans, male rats, and male mice, the compound concentration in the reaction system is assessed by LC-MS / MS. The in vitro intrinsic clearance of the test compound is also determined.

[0495] protocol Prepare a master solution containing phosphate buffer, ultrapure water, MgCl2 solution, and liver microsomes in an "incubation plate" according to Table 6. Pre-warm the mixture in a 37°C water bath for 5 minutes. [Table 46]

[0496] Add 40 μL of 10 mM NADPH solution to each well. The final concentration of NADPH is 1 mM. Prepare a negative control sample by replacing the NADPH with 40 μL of ultrapure water. Prepare samples in duplicate. Prepare one negative control.

[0497] The reaction is initiated by adding 4 μL of 200 μM of an exemplary test compound of the present application or a control compound to each master solution to give a final concentration of 2 μM. The test is performed in duplicate.

[0498] At 0, 15, 30, 45, and 60 minutes, 50 μL aliquots were removed from the reaction mixture. The reaction mixture was stopped by adding four volumes of cold methanol containing 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. A 90 μL aliquot of the supernatant was mixed with 90 μL of ultrapure water and then used for LC-MS / MS analysis.

[0499] LC / MS analysis was performed on all samples in this study using a Shimadzu liquid chromatographic separation system equipped with a degasser DGU-20A5R, a solvent delivery unit LC-30AD, a system controller SIL-30AC, a column oven CTO-30A, and a CTC analytical HTC PAL system. Mass spectrometry was performed using a Triple Quad™ 5500 instrument.

[0500] All calculations are performed using Microsoft Excel. Peak area ratios of test compounds to internal standards (listed in the table below) are determined from extracted ion chromatograms.

[0501] All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The slope k was determined by linear regression of the curve of the natural logarithm of the percentage of parent drug remaining versus incubation time.

[0502] Determine the in vitro half-life (in vitro t) from the slope value: In vitro 1 / 2 =-(0.693 / k)

[0503] Conversion of in vitro t (min) to in vitro intrinsic clearance (In vitro CLint, μL / min / mg protein) is performed using the following formula (mean of duplicate determinations):

number

[0504] For exemplified compounds or control compounds of this application that exhibit an initial rapid elimination followed by a slower elimination, only time points within the initial rate are included in the calculation.

[0505] Results and Discussion Human, rat, and mouse liver microsomes contain various drug-metabolizing enzymes and are commonly used to support in vitro ADME (absorption, distribution, metabolism, and excretion) studies. These microsomes are used to investigate potential first-pass metabolic byproducts of orally administered drugs. Representative compounds of the present application are evaluated for their stability in human, rat, and mouse liver microsomes.

[0506] Example 17: Human, rat, mouse and dog: plasma stability 1. Preparation of Stock Solutions

[0507] Stock solutions of test compounds were prepared in DMSO and diluted to a final concentration of 200 μM. 1 mM working solutions of lovastatin and propantheline were prepared in DMSO and acetonitrile, respectively. Lovastatin was used as a positive control for plasma stability assays in rats and dogs. Propantheline was used as a positive control in plasma stability assays in humans, mice, and monkeys.

[0508] 2. Plasma Stability Procedure

[0509] 2.5 μL of test compound or control compound solution (200 μM or 1 mM) was mixed with 497.5 μL of plasma to give a final concentration of 1 μM or 5 μM. The final concentration of organic solvent was 0.5%. Assays were performed in duplicate.

[0510] b. The reaction samples were incubated in a water bath at 37° C. at approximately 600 rpm.

[0511] c. 50 μL aliquots were removed from the reaction samples at 0, 30, 60, 120, 180, and 240 min. The reactions were stopped by adding 7 volumes of cold acetonitrile containing internal standards (IS: 100 nM alprazolam, 200 nM imipramine, 200 nM labetalol, and 2 μM ketoprofen).

[0512] d. All samples were vortexed for 2 minutes, then centrifuged at 3,220 g for 30 minutes to precipitate proteins. 100 μL of the supernatant was transferred to a new plate. Depending on the LC-MS signal response and peak shape, the supernatant was diluted with ultrapure water.

[0513] 3. Sample Analysis

[0514] The samples were analyzed by LC-MS / MS. LC system: Shimadzu MS analysis: Triple Quad™ 6500+ with ESI interface manufactured by AB Inc (Canada) Column temperature: 40℃ Column: Xselect® Hss T3 2.5μ (2.1 x 30 mm) with pre-guard column Mobile phase: water containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B) [Table 47]

[0515] 4. Data Analysis

[0516] All calculations were performed using Microsoft Excel. The percentage of parent compound remaining at each time point was estimated by determining peak area ratios from extracted ion chromatograms. [Table 48]

[0517] Example 18: Hallucinogen-like effects of exemplary compounds of Formula I The effects of various doses of exemplary compounds of Formula I are assessed based on the head-twitch response (HTR) and other behavioral responses as a behaviorally based model of hallucinogen activity.

[0518] protocol Mouse swing C57BL / 6J male mice (weight: 20-30 g) were administered the appropriate dose of the test substance, followed by a 1-minute pretreatment period and then placed in individual observation chambers. Animals were visually assessed for head-shaking events continuously over a 1-hour period. Head-shaking is defined as a rapid reflex response of the neck that is not elicited by external tactile stimuli (Corne and Pickering, Psychopharmacologia, 1967, 11(1):65-78). Each head-shaking event was counted independently by a trained observer, and data are presented as the mean ± standard error of the mean for 6-10 mice per group. Mice were used for a single experiment only.

[0519] Rat behavioral tests Male Sprague-Dawley rats (weight: 250-400 g) were administered the appropriate dose of the test substance, followed by a 1-minute pretreatment period, and then placed in a locomotor activity box (dimensions: 17"W x 17"L x 12"H). 5-HT activity was continuously monitored for 1 hour, with data collected every 10 minutes. 2A Behaviors characteristic of receptor activation (wet dog shakes, back muscle contractions), 5-HT 2A Receptor activation (yawning, penile grooming) and 5-HT 1A Animals are visually assessed for overt behavioral signs, including forepaw treading and hindlimb abduction (Halberzettl et al., Behav Brain Res. 256:328-345, 2013). Additional behavioral and physical signs characteristic of 5-HT syndrome (e.g., shivering, salivation, flat posture, and changes in core body temperature) are also measured. Concurrently, rats' spontaneous activity is measured using an automated tracking system (Med Associates, VT, USA). Activity data collected include total distance traveled, number of rearings, and walking episodes. All data are expressed as the mean ± standard error of mean values ​​for 6–10 rats per group.

[0520] Drug discrimination in rats Male Sprague-Dawley rats were initially food-restricted (single-housed) with 18–20 g of food at the end of each day. After 7 days of acclimation to the food-restriction procedure, they were trained daily for 1 week to press the lever for food (45 mg Bioserve pellets) in a standard two-lever operant conditioning chamber controlled by Med-PC software (Med. Associates Ins., St. Albans, VT). Rats were trained to press the lever for food at an FR ...

Claims

1. Formula IA: 【Chemical 1】 or a pharmaceutically acceptable salt, solvate and / or prodrug thereof [In the formula: R １ and R １ ' is independently H, halo, OH, NH ２ , C １～６ Alkyl, C １～６ Alkoxyl, NH(C １～６ alkyl) and N(C １～６ alkyl) ２ Selected from: R ２ and R ２ ' is independently H, halo, NH ２ , C １～６ Alkyl, C １～６ Alkoxyl, NH(C １～６ alkyl) and N(C １～６ alkyl) ２ Selected from: Q is Q1, Q2, Q3, Q4, Q5 and Q6: 【Chemistry 2】 and having the structure: 【Chemistry 3】 is a single or double bond, provided that the structure: 【Chemistry 4】 is a double bond, R ９ and R １５ does not exist, and the structure in Q2: 【Chemistry 5】 is a double bond, R １７ and R ２５ does not exist, and the structure in Q5: 【Chemistry 6】 is a double bond, R ４８ and R ５７ does not exist; R ４ and R ５ One or both of the groups may independently be H, halo, C １～６ Alkyl and C １～６ alkoxy; R ４ and R ５ are combined to form O-(CH ２ ) １～２ Form O, or R ４ and R ５ is selected from X-L-A, and R ４ and R ５ The other is H, halo, C １～６ Alkyl and C １～６ alkoxy; X is a direct bond, O, C(O), NR ａ , N.R. ａ C(O), C(O)NR ａ , OC(O), C(O)O, OC(O)O, NR ａ C(O)O, OC(O)NR ａ and N.R. ａ C(O)NR ａ Selected from: L is a direct bond, C １～６ Alkylene, C ２～６ Alkenylene, C １～６ Alkylene O, C ２～６ Alkenylene O, C １～６ Alkylene C(O), C ２～６ Alkenylene C(O), C １～６ Alkylene NR ｂ C(O), C ２～６ Alkenylene NR ｂ C(O), C １～６ AlkyleneC(O)NR ｂ , C ２～６ AlkenyleneC(O)NR ｂ , C １～６ Alkylene OC(O), C ２～６ Alkenylene OC(O), C １～６ Alkylene C(O)O,C ２～６ Alkenylene C(O)O,C １～６ AlkyleneOC(O)NR ｂ , C ２～６ Alkenylene OC(O)NR ｂ , C １～６ Alkylene NR ｂ C(O)O,C ２～６ Alkenylene NR ｂ C(O)O,C １～６ Alkylene OC(O)O,C ２～６ Alkenylene OC(O)O,C １～６ Alkylene NR ｂ C(O)NR ｂ and C ２～６ Alkenylene NR ｂ C(O)NR ｂ Selected from: R ａ is H and C １～６ alkyl; R ｂ is H, C １～６ alkyl and A; A is H, C １～３０ Alkyl, C ２～３０ Alkenyl, phenyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N and NR ６４ and 3-6 membered heterocycloalkyl containing 1-4 hetero moieties independently selected from O, S, S(O), SO ２ , N and NR ６４ wherein said phenyl, C ３～１０ Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with halo, C １～４ Alkyl and OC １～４ optionally substituted with one or more substituents independently selected from alkyl; R ３ and R ６ H, halo, OH, C １～６ Alkyl and C １～６ independently selected from alkoxy; R ８ , R ９ , R １０ , R １１ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , R ２７ , R ２８ , R ３０ , R ３１ , R ３２ , R ３３ , R ３４ , R ３５ , R ３６ , R ３７ , R ３８ , R ４０ , R ４１ , R ４２ , R ４３ , R ４４ , R ４５ , R ４６ , R ４７ , R ４８ , R ４９ , R ５０ , R ５２ , R ５３ , R ５４ , R ５５ , R ５６ , R ５７ , R ５８ , R ５９ , R ６２ and R ６３ are independently H, halo, and C １～６ alkyl; R １２ , R ２０ , R ２９ , R ３９ and R ５１ are independently H, C １～６ Alkyl, C(O)C １～６ selected from alkyl and C(O)-A'; R ６０ and R ６１ are independently H and C １～６ alkyl; or R ６０ and R ６１ One of the groups is C(O)-A', and the other is H and C １～６ alkyl; where A' is Y, O-Y and O-C １～４ alkylene-O-C(O)-Y; Y is C ７～３０ Alkyl and C ７～３０ alkenyl; or R ６０ and R ６１ together with the nitrogen atom to which they are attached, form O, S, S(O), SO ２ , N, and NR ６５ and optionally includes one or two additional hetero moieties selected from halo, OH, C １～４ Alkyl and OC １～４ forming a 3- to 6-membered heterocyclic ring optionally substituted with one or more substituents independently selected from alkyl; R ６４ and R ６５ are independently H and C １～６ alkyl; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; with the proviso that when Q is Q6, the compound of formula I includes D, When Q is Q3 or Q4, R ５ is H or OCH ３ and R ２９ or R ３９ is CH ３ If R １ , R １ ', R ２ , R ２ ', R ３ , R ４ , R ６ , R ２６ , R ２７ , R ２８ , R ３０ ~R ３５ , R ３６ , R ３７ , R ３８ and R ４０ ~R ４７ is not all H; Q is Q4 and R １ , R １ ', R ２ , R ２ ', R ３ , R ４ , R ６ , R ３８ and R ４０ ~R ４７ are all H, and R ３９ CD ３ If R ３６ and R ３７ are not both D].

2. R ８ , R ９ , R １０ , R １１ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , R ２７ , R ２８ , R ３０ , R ３１ , R ３２ , R ３３ , R ３４ , R ３５ , R ３６ , R ３７ , R ３８ , R ４０ , R ４１ , R ４２ , R ４３ , R ４４ , R ４５ , R ４６ , R ４７ , R ４８ , R ４９ , R ５０ , R ５２ , R ５３ , R ５４ , R ５５ , R ５６ , R ５７ , R ５８ , R ５９ , R ６２ and R ６３ is independently selected from H and D.

3. Q is the following group: 【Chemistry 7】 【Chemistry 8】 and R １２ , R ２０ , R ２９ , R ３９ , R ５１ , R ６０ and R ６１ are independent, H, D, C １～６ Alkyl, C １～６ Fluoroalkyl, C １～６ The compound of claim 1, wherein the compound is selected from deuteroalkyl and C(O)-A'.

4. R １２ , R ２０ , R ２９ , R ３９ , R ５１ , R ６０ and R ６１ are independent, H, C １～４ Alkyl, C １～４ Fluoroalkyl and C １～４ 4. The compound of claim 3, wherein the compound is selected from deuteroalkyl.

5. R ６０ and R ６１ together with the nitrogen atom to which they are attached, O, N and NR ６５ and optionally includes one or two additional hetero moieties independently selected from halo, OH, C １～４ Alkyl and OC １～４ The compound of claim 3, which forms a 3- to 6-membered heterocyclic ring optionally substituted with one or more substituents independently selected from alkyl.

6. Q is the following group: 【Chemistry 9】 and R ２９ But H, D, C １～６ Alkyl, C １～６ Fluoroalkyl, C １～６ The compound of claim 3, wherein the compound is selected from deuteroalkyl and C(O)-A'.

7. R ２９ But H, CH ３ , CDs ３ , C.F. ２ H and CF ３ 7. The compound of claim 6, selected from:

8. R １２ , R ２０ , R ２９ , R ３９ , R ５１ , R ６０ and R ６１ is independently selected from C(O)-A'.

9. R ６０ and R ６１ One of the groups is C(O)-A', and the other is H and C １～６ 4. The compound of claim 1 or claim 3, wherein the alkyl is selected from the group consisting of aryl, aryl, arylsulfonyl ...

10. 10. The compound of claim 8 or claim 9, wherein A' is selected from Y, O-Y and O-C1 alkylene-O-C(O)-Y, and all available hydrogen atoms may be independently optionally replaced with fluorine or deuterium atoms.

11. Y is C １０～２５ 11. The compound of claim 10, wherein the alkyl is alkyl and all available hydrogen atoms are optionally independently replaced with fluorine or deuterium atoms.

12. Y is C １０～２５ 11. The compound of claim 10, which is alkenyl, and all available hydrogen atoms may be independently and optionally replaced with fluorine or deuterium atoms.

13. 13. The compound of claim 12, wherein Y is an alkenyl group present in a fatty acid, and all available hydrogen atoms may optionally be replaced with deuterium atoms.

14. 12. The compound of claim 11, wherein Y is an alkyl group present on a fatty acid, and all available hydrogen atoms may optionally be replaced with deuterium.

15. 11. The compound of claim 10, wherein Y is an alkyl or alkenyl group present in linoleic acid, eicosadienoic acid, or decosahexanoic acid.

16. 11. The compound of claim 10, wherein Y is an alkyl or alkenyl group of a fatty acid in which 1 to 10, 2 to 8, 2 to 6, or 2 to 4 hydrogen atoms are replaced with deuterium.

17. Y is (CH ２ ), ７ CH=CH(CH ２ ), ７ CH ３ , (CH ２ ), ７ CH=CHCH ２ CH=CH(CH ２ ), ４ CH ３ , (CH ２ ), ８ CH=CHCH ２ CH=CH(CH ２ ), ４ CH ３ , (CH ２ ), ７ CH=CHCH ２ CH=CHCH ２ CH=CH(CH ２ ), １ CH ３ , (CH ２ ), ３ CH=CHCH ２ CH=CH(CH ２ ), １ CH=CHCH ２ CH=CH(CH ２ ), ３ CH ３ , or (CH ２ ), ２ [[ID=七十]]CH=CHCH ２ CH=CHCH ２ [[ID=七十四]]CH=CHCH ２ [[ID=七十六]]CH=CHCH ２ CH=CHCH ２ CH=CH(CH ２ ), １ CH ３ , the compound according to claim 10.

18. R １ and R １ ' are independently H, D and CH ３ The compound according to any one of claims 1 to 17, selected from:

19. R ２ and R ２ 19. The compound of any one of claims 1 to 18, wherein:

20. R ３ and R ６ are independently H, D, Cl, F, OH, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Fluoroalkoxy, C １～４ Deuteroalkoxy, C １～４ Fluoroalkyl and C １～４ The compound of any one of claims 1 to 19, selected from deuteroalkyl.

21. R ３ and R ６ are independently H, D, F, OH, CH ３ , C.H. ３ O.C.F. ２ HO, CD ２ H.O., C.F. ３ O, CD ３ O.C.F. ２ H, CD ２ H, C.F. ３ and CDs ３ 21. The compound of claim 20 selected from:

22. R ３ and R ６ is independently selected from H and D.

23. R ４ and R ５ One or both of these independently represent H, D, F, Cl, C １～６ Alkyl, C １～６ Fluoroalkyl, C １～６ Deuteroalkyl, C １～６ Alkoxy, C １～６ Fluoroalkoxy and C １～６ 23. The compound of any one of claims 1 to 22, selected from deuteroalkoxy.

24. R ４ and R ５ Both are independent of H, D, F, Cl, C １～６ Alkyl, C １～６ Fluoroalkyl, C １～６ Deuteroalkyl, C １～６ Alkoxy, C １～６ Fluoroalkoxy and C １～６ 23. The compound of any one of claims 1 to 22, selected from deuteroalkoxy.

25. R ４ is H or D, and R ５ But H, D, F, Cl, C １～６ Alkyl, C １～６ Fluoroalkyl, C １～６ Deuteroalkyl, C １～６ Alkoxy, C １～６ Fluoroalkoxy and C １～６ 23. The compound of any one of claims 1 to 22, selected from deuteroalkoxy.

26. R ５ is H or D, and R ４ But H, D, F, Cl, C １～６ Alkyl, C １～６ Fluoroalkyl, C １～６ Deuteroalkyl, C １～６ Alkoxy, C １～６ Fluoroalkoxy and C １～６ 23. The compound of any one of claims 1 to 22, selected from deuteroalkoxy.

27. R ４ and R ５ Together, O-CH ２ 23. The compound according to any one of claims 1 to 22, wherein the compound forms O.

28. R ４ and R ５ is selected from X-L-A, and R ４ and R ５ The other is H, halo, C １～６ Alkyl and C １～６ 23. The compound of any one of claims 1 to 22, selected from alkoxy.

29. X is a direct bond, and R ４ and R ５ is selected from L-A, and R ４ and R ５ The other is H, halo, C １～６ Alkyl and C １～６ 29. The compound of claim 28, wherein the compound is selected from alkoxy.

30. X is O, C(O), NR ａ , N.R. ａ C(O), C(O)NR ａ , OC(O), C(O)O, OC(O)O, NR ａ C(O)O, OC(O)NR ａ and N.R. ａ C(O)NR ａ 29. The compound of claim 28, selected from:

31. X is O, NR ａ , N.R. ａ C(O), C(O)NR ａ , N.R. ａ C(O)O, OC(O)NR ａ and N.R. ａ C(O)NR ａ 29. The compound of claim 28, selected from:

32. L is a direct bond, C １～４ Alkylene, C ２～４ Alkenylene, C １～４ Alkylene O, C ２～４ Alkenylene O, C １～４ Alkylene C(O), C ２～４ Alkenylene C(O), C １～４ Alkylene NR ｂ C(O), C ２～４ Alkenylene NR ｂ C(O), C １～４ AlkyleneC(O)NR ｂ , C ２～４ AlkenyleneC(O)NR ｂ , C １～４ Alkylene OC(O), C ２～４ Alkenylene OC(O), C １～４ Alkylene C(O)O,C ２～４ Alkenylene C(O)O,C １～４ AlkyleneOC(O)NR ｂ , C ２～４ Alkenylene OC(O)NR ｂ , C １～４ Alkylene NR ｂ C(O)O,C ２～４ Alkenylene NR ｂ C(O)O,C １～４ Alkylene OC(O)O,C ２～４ Alkenylene OC(O)O,C １～４ Alkylene NR ｂ C(O)NR ｂ and C ２～４ Alkenylene NR ｂ C(O)NR ｂ The compound according to any one of claims 28 to 31, selected from:

33. R ４ and R ５ The other is H, F, Cl, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Deuteroalkyl and C １～４ 33. The compound of any one of claims 28 to 32, selected from alkoxy.

34. The compound of any one of claims 28 to 33, wherein A is H.

35. A is C １～３０ Alkyl, C ２～３０ Alkenyl, phenyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N and NR ６３ and 3-6 membered heterocycloalkyl containing 1-3 hetero moieties independently selected from O, S, S(O), SO ２ , N and NR ５３ and wherein said phenyl, C ３～１０ Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are selected from the group consisting of F, Cl, OH, C １～４ Alkyl, C １～４ Deuteroalkyl, C １～４ Fluoroalkyl, OC １～４ Alkyl, OC １～４ Deuteroalkyl and OC １～４ 34. The compound of any one of claims 28 to 33, optionally substituted with one or two substituents independently selected from fluoroalkyl, wherein all available hydrogen atoms are optionally substituted independently with fluorine atoms or deuterium atoms.

36. A is phenyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N and NR ６４ and 5-6 membered heterocycloalkyl containing 1-2 hetero moieties independently selected from O, S, S(O), SO ２ , N and NR ４８ and wherein said phenyl, C ３～１０ Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are selected from F, C, C １～４ Alkyl, C １～４ Deuteroalkyl, C １～４ Fluoroalkyl, OC １～４ Alkyl, OC １～４ Deuteroalkyl and OC １～４ 36. The compound of claim 35, optionally substituted with one or two substituents independently selected from fluoroalkyl.

37. R ６４ But H, D, C １～４ Alkyl, C １～４ Fluoroalkyl and C １～４ 37. The compound of claim 36, wherein the compound is selected from deuteroalkyl.

38. A is C １～３０ Alkyl and C ２～３０ 36. The compound of claim 35, wherein the compound is selected from alkenyl, wherein all available hydrogen atoms are independently optionally replaced with fluorine or deuterium atoms.

39. A is C １０～２５ 39. The compound of claim 38, wherein the alkyl is alkyl and all available hydrogen atoms are optionally independently replaced with fluorine or deuterium atoms.

40. A is C １０～２５ 39. The compound of claim 38, which is alkenyl, wherein all available hydrogen atoms are optionally independently replaced with fluorine or deuterium atoms.

41. 41. The compound of claim 40, wherein A is an alkenyl group present in a fatty acid, where all available hydrogen atoms may optionally be replaced with deuterium atoms.

42. 39. The compound of claim 38, wherein A is an alkyl group present on a fatty acid, and all available hydrogen atoms may optionally be replaced with deuterium atoms.

43. 39. The compound of claim 38, wherein A is an alkyl or alkenyl group present in linoleic acid, eicosadienoic acid, or decosahexanoic acid.

44. 39. The compound of claim 38, wherein A is an alkyl or alkenyl group of a fatty acid in which 1 to 10, 2 to 8, 2 to 6, or 2 to 4 hydrogen atoms are replaced with deuterium.

45. A is (CH ２ ), ７ CH=CH(CH ２ ), ７ CH ３ , (CH ２ ), ７ CH=CHCH ２ CH=CH(CH ２ ), ４ CH ３ , (CH ２ ), ８ CH=CHCH ２ CH=CH(CH ２ ), ４ CH ３ , (CH ２ ), ７ CH=CHCH ２ CH=CHCH ２ CH=CH(CH ２ ), １ CH ３ , (CH ２ ), ３ CH=CHCH ２ CH=CH(CH ２ ), １ CH=CHCH ２ CH=CH(CH ２ ), ３ CH ３ , or (CH ２ ), ２ CH=CHCH ２ CH=CHCH ２ CH=CHCH ２ CH=CHCH ２ CH=CHCH ２ CH=CH(CH ２ ), １ CH ３ ; the compound according to claim 38.

46. Formula IA: 【Chemistry 10】 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, wherein the compound of formula (I) is defined as follows: [In the formula: R １ , R １ ', R ２ , R ２ ', R ３ and R ６ is independently selected from H, D, and F; Q is Q1, Q2, Q3, Q4, Q5 and Q6: 【Chemistry 11】 Selected from: structure: 【Chemistry 12】 is a single bond or a double bond, provided that the structure: 【Chemistry 13】 is a double bond, R ９ and R １５ does not exist, and the structure in Q2: 【Chemistry 14】 is a double bond, R １７ and R ２５ does not exist, and the structure in Q5: 【Chemistry 15】 is a double bond, R ４８ and R ５７ does not exist R ４ and R ５ One or both of １～４ Alkoxy, C １～４ Fluoroalkoxy and C １～４ selected from deuteroalkoxy; or R ４ and R ５ Together, O-(CH ２ ) １～２ Forming O; R ８ , R ９ , R １０ , R １１ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , R ２７ , R ２８ , R ３０ , R ３１ , R ３２ , R ３３ , R ３４ , R ３５ , R ３６ , R ３７ , R ３８ , R ４０ , R ４１ , R ４２ , R ４３ , R ４４ , R ４５ , R ４６ , R ４７ , R ４８ , R ４９ , R ５０ , R ５２ , R ５３ , R ５４ , R ５５ , R ５６ , R ５７ , R ５８ , R ５９ , R ６２ and R ６３ is independently selected from H and D; R １２ , R ２０ , R ２９ , R ３９ and R ５１ are independent, H, C １～４ Alkyl, C １～４ Fluoroalkyl and C １～４ is selected from deuteroalkyl; R ６０ and R ６１ are independently H and C １～６ alkyl, with the proviso that when Q is Q6, the compound of formula I includes D, When Q is Q3 or Q4, R ５ is H or OCH ３ and R ２９ or R ３９ is CH ３ If R １ , R １ ', R ２ , R ２ ', R ３ , R ４ , R ６ , R ２６ , R ２７ , R ２８ , R ３０ ~R ３５ , R ３６ , R ３７ , R ３８ and R ４０ ~R ４７ is not all H].

47. Formula IA: 【Chemistry 16】 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, wherein the compound of formula (I) is defined as follows: [In the formula: R １ and R １ ' is independently H, halo, OH, NH ２ , C １～６ Alkyl, C １～６ Alkoxyl, NH(C １～６ alkyl) and N(C １～６ alkyl) ２ Selected from: R ２ and R ２ ' is independently H, halo, NH ２ , C １～６ Alkyl, C １～６ Alkoxyl, NH(C １～６ alkyl) and N(C １～６ alkyl) ２ Selected from: Q is Q1, Q2, Q3, Q4, Q5 and Q6: 【Chemistry 17】 Selected from: structure: 【Chemistry 18】 is a single or double bond, provided that the structure: 【Chemistry 19】 is a double bond, R ９ and R １５ does not exist, and the structure in Q2: 【Chemistry 20】 is a double bond, R １７ and R ２５ does not exist, and the structure in Q5: 【Chemical 21】 is a double bond, R ４８ and R ５７ does not exist; R ４ and R ５ One or both of the groups may independently be H, halo, C １～６ Alkyl and C １～６ alkoxy; or R ４ and R ５ Together, O-(CH ２ ) １～２ Forming O, or R ４ and R ５ is selected from X-L-A, and R ４ and R ５ The other is H, halo, C １～６ Alkyl and C １～６ alkoxy; X is a direct bond, O, C(O), NR ａ , N.R. ａ C(O), C(O)NR ａ , OC(O), C(O)O, OC(O)O, NR ａ C(O)O, OC(O)NR ａ and N.R. ａ C(O)NR ａ Selected from: L is a direct bond, C １～６ Alkylene, C ２～６ Alkenylene, C １～６ Alkylene O, C ２～６ Alkenylene O, C １～６ Alkylene C(O), C ２～６ Alkenylene C(O), C １～６ Alkylene NR ｂ C(O), C ２～６ Alkenylene NR ｂ C(O), C １～６ AlkyleneC(O)NR ｂ , C ２～６ AlkenyleneC(O)NR ｂ , C １～６ Alkylene OC(O), C ２～６ Alkenylene OC(O), C １～６ Alkylene C(O)O,C ２～６ Alkenylene C(O)O,C １～６ AlkyleneOC(O)NR ｂ , C ２～６ Alkenylene OC(O)NR ｂ , C １～６ Alkylene NR ｂ C(O)O,C ２～６ Alkenylene NR ｂ C(O)O,C １～６ Alkylene OC(O)O,C ２～６ Alkenylene OC(O)O,C １～６ Alkylene NR ｂ C(O)NR ｂ and C ２～６ Alkenylene NR ｂ C(O)NR ｂ Selected from: R ａ However, H and C １～６ alkyl; R ｂ But H, C １～６ alkyl and A; A is H, C １～３０ Alkyl, C ２～３０ Alkenyl, phenyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N and NR ６４ and 3-6 membered heterocycloalkyl containing 1-4 hetero moieties independently selected from O, S, S(O), SO ２ , N and NR ６４ and wherein said phenyl, C ３～１０ Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with halo, C １～４ Alkyl and OC １～４ optionally substituted with one or more substituents independently selected from alkyl; R ３ and R ６ H, halo, OH, C １～６ Alkyl and C １～６ independently selected from alkoxy; R ８ , R ９ , R １０ , R １１ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , R ２７ , R ２８ , R ３０ , R ３１ , R ３２ , R ３３ , R ３４ , R ３５ , R ３６ , R ３７ , R ３８ , R ４０ , R ４１ , R ４２ , R ４３ , R ４４ , R ４５ , R ４６ , R ４７ , R ４８ , R ４９ , R ５０ , R ５２ , R ５３ , R ５４ , R ５５ , R ５６ , R ５７ , R ５８ , R ５９ , R ６２ and R ６３ is H, halo and C １～６ independently selected from alkyl; R １２ , R ２０ , R ２９ , R ３９ and R ５１ is H, C １～６ Alkyl, C(O)C １～６ independently selected from alkyl and C(O)-A'; R ６０ and R ６１ is H and C １～６ independently selected from alkyl; or R ６０ and R ６１ One of the groups is C(O)-A', and the other is H and C １～６ alkyl; where A' is Y, O-Y and O-C １～４ alkylene-O-C(O)-Y; Y is C ７～３０ Alkyl and C ７～３０ alkenyl; or R ６０ and R ６１ together with the nitrogen atom to which they are attached, form O, S, S(O), SO ２ , N, and NR ６５ and optionally includes one or two additional hetero moieties independently selected from halo, OH, C １～４ Alkyl and OC １～４ forming a 3- to 6-membered heterocyclic ring, optionally substituted with one or more substituents independently selected from alkyl; R ６４ and R ６５ is H and C １～６ independently selected from alkyl; any available hydrogen atom may be independently optionally replaced by a fluorine or chlorine atom, any available atom may be optionally replaced by its alternative isotope; However, R １２ , R ２０ , R ２９ , R ３９ , R ５１ , R ６０ and R ６１ is C(O)-A'; or R ４ and R ５ One of them is H, halo, C １～６ Alkyl and C １～６ alkoxy, provided that when both X and L are direct bonds, A is selected from H, C １～６ Alkyl or C １～６ not alkenyl].

48. R ２ and R ２ ' is different, R ２ and R ２ 48. The compound of any one of claims 1 to 47, wherein the carbon to which ' is attached is chiral.

49. R １ and R １ ' is different, R １ and R １ 49. The compound of any one of claims 1 to 48, wherein the carbon to which ' is attached is chiral.

50. The table below: 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 【Table 12】 【Table 13】 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, selected from:

51. A composition comprising one or more compounds according to any one of claims 1 to 50 and a carrier.

52. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 50 and a pharmaceutically acceptable carrier.

53. A method of treating a disease, disorder, or condition by activating a serotonin receptor, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula I or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: 【Chemical 22】 [In the formula: R １ and R １ ' is independently H, halo, OH, NH ２ , C １～６ Alkyl, C １～６ Alkoxyl, NH(C １～６ alkyl) and N(C １～６ alkyl) ２ Selected from: R ２ and R ２ ' is independently H, halo, NH ２ , C １～６ Alkyl, C １～６ Alkoxyl, NH(C １～６ alkyl) and N(C １～６ alkyl) ２ Selected from: Q is Q1, Q2, Q3, Q4, Q5 and Q6: 【Chemical 23】 is selected from structure: 【Chemistry 24】 is a single or double bond, provided that the structure: 【Chemistry 25】 is a double bond, R ９ and R １５ does not exist, and the structure in Q2: 【Chemical 26】 is a double bond, R １７ and R ２５ does not exist, and the structure in Q5: 【Chemical 27】 is a double bond, R ４８ and R ５７ does not exist; R ４ and R ５ One or both of the groups may independently be H, halo, C １～６ Alkyl and C １～６ alkoxy; or R ４ and R ５ are combined to form O-(CH ２ ) １～２ Forming O, or R ４ and R ５ is selected from X-L-A, and R ４ and R ５ The other is H, halo, C １～６ Alkyl and C １～６ alkoxy; X is a direct bond, O, C(O), NR ａ , N.R. ａ C(O), C(O)NR ａ , OC(O), C(O)O, OC(O)O, NR ａ C(O)O, OC(O)NR ａ and N.R. ａ C(O)NR ａ Selected from: L is a direct bond, C １～６ Alkylene, C ２～６ Alkenylene, C １～６ Alkylene O, C ２～６ Alkenylene O, C １～６ Alkylene C(O), C ２～６ Alkenylene C(O), C １～６ Alkylene NR ｂ C(O), C ２～６ Alkenylene NR ｂ C(O), C １～６ AlkyleneC(O)NR ｂ , C ２～６ AlkenyleneC(O)NR ｂ , C １～６ Alkylene OC(O), C ２～６ Alkenylene OC(O), C １～６ Alkylene C(O)O,C ２～６ Alkenylene C(O)O,C １～６ AlkyleneOC(O)NR ｂ , C ２～６ Alkenylene OC(O)NR ｂ , C １～６ Alkylene NR ｂ C(O)O,C ２～６ Alkenylene NR ｂ C(O)O,C １～６ Alkylene OC(O)O,C ２～６ Alkenylene OC(O)O,C １～６ Alkylene NR ｂ C(O)NR ｂ and C ２～６ Alkenylene NR ｂ C(O)NR ｂ Selected from: R ａ is H and C １～６ alkyl; R ｂ is H, C １～６ alkyl and A; A is H, C １～３０ Alkyl, C ２～３０ Alkenyl, phenyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N and NR ６４ and 3-6 membered heterocycloalkyl containing 1-4 hetero moieties independently selected from O, S, S(O), SO ２ , N and NR ６４ and wherein said phenyl, C ３～１０ Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with halo, C １～４ Alkyl and OC １～４ optionally substituted with one or more substituents independently selected from alkyl; R ３ and R ６ are independently H, halo, OH, C １～６ Alkyl and C １～６ alkoxy; R ８ , R ９ , R １０ , R １１ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , R ２７ , R ２８ , R ３０ , R ３１ , R ３２ , R ３３ , R ３４ , R ３５ , R ３６ , R ３７ , R ３８ , R ４０ , R ４１ , R ４２ , R ４３ , R ４４ , R ４５ , R ４６ , R ４７ , R ４８ , R ４９ , R ５０ , R ５２ , R ５３ , R ５４ , R ５５ , R ５６ , R ５７ , R ５８ , R ５９ , R ６２ and R ６３ are independently H, halo, and C １～６ alkyl; R １２ , R ２０ , R ２９ , R ３９ and R ５１ are independently H, C １～６ Alkyl, C(O)C １～６ selected from alkyl and C(O)-A'; R ６０ and R ６１ are independently H and C １～６ alkyl; or R ６０ and R ６１ One of the groups is C(O)-A', and the other is H and C １～６ alkyl; where A' is Y, O-Y and O-C １～４ alkylene-O-C(O)-Y; Y is C ７～３０ Alkyl and C ７～３０ alkenyl; or R ６０ and R ６１ together with the nitrogen atom to which they are attached, form O, S, S(O), SO ２ , N, and NR ６５ and optionally includes one or two additional hetero moieties independently selected from halo, OH, C １～４ Alkyl and OC １～４ forming a 3- to 6-membered heterocyclic ring which may be optionally substituted with one or more substituents independently selected from alkyl; R ６４ and R ６５ are independently H and C １～６ alkyl; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; provided that when Q is Q6, the compound of formula I includes D.

54. 54. A method for treating a psychiatric disorder, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula I as defined in claim 53.

55. 55. The method of claim 54, wherein the psychiatric disorder is selected from hallucinations and delusions, and combinations thereof.

56. 55. The method of claim 54, wherein the psychiatric disorder is selected from anxiety disorders; depression; mood disorders; psychotic disorders; impulse control and addictions; substance dependence; obsessive-compulsive disorder (OCD); post-traumatic stress disorder (PTSD); stress response syndromes; dissociative disorders; depersonalization disorder; factitious disorder; sex and gender disorders; and somatic symptom disorders, and combinations thereof.

57. 54. A method for treating psychosis or psychotic symptoms, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula I as defined in claim 53.

58. 54. A method for treating a central nervous system (CNS) disease, disorder or condition, and / or a neurological disease, disorder or condition, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula I as defined in claim 53.

59. The CNS disease, disorder or condition, and / or neurological disease, disorder or condition is a neurological disease, including neurodevelopmental and neurodegenerative diseases, such as Alzheimer's disease; presenile dementia; senile dementia; vascular dementia; dementia with Lewy bodies; cognitive impairment, Parkinson's disease and Parkinson's disease-related disorders (e.g., Parkinsonism, corticobasal degeneration), and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disorders; Fragile X syndrome; Angelman syndrome; hereditary ataxias; neuro-otologic and oculomotor disorders; neurodegenerative diseases of the retina; amyotrophic lateral sclerosis; tardive dyskinesia; hyperactivity disorder; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette's syndrome; schizophrenia; autism spectrum disorder; tuberous sclerosis complex; Rett syndrome; cerebral palsy; 59. The method of claim 58, wherein the condition is selected from disorders of the reward system, including eating disorders such as anorexia nervosa ("AN") and bulimia nervosa ("BN"); and binge eating disorder ("BED"), trichotillomania, excoriation disorder, onychophagia; migraine; fibromyalgia; and peripheral neuropathy of any cause, and combinations thereof.

60. 54. A method for treating a behavioral disorder, comprising administering to a non-human subject in need thereof a therapeutically effective amount of one or more compounds of formula I as defined in claim 53.

61. 61. The method of claim 60, wherein the non-human subject is a dog or cat suffering from a neurological disease, a behavioral disorder, a trainability problem, and / or a combination thereof.

62. 62. The method of claim 61 , wherein the neurological disease, behavioral disorder, trainability problem includes, but is not limited to, anxiety, fear and stress, sleep disorders, cognitive disorders, aggression, and / or combinations thereof.

63. A method for treating a disease, disorder, or condition by activating a serotonin receptor, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula I as defined in claim 53 in combination with other known agents useful in treating diseases, disorders, or conditions via activation of serotonin receptors.

64. R ８ , R ９ , R １０ , R １１ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , R ２７ , R ２８ , R ３０ , R ３１ , R ３２ , R ３３ , R ３４ , R ３５ , R ３６ , R ３７ , R ３８ , R ４０ , R ４１ , R ４２ , R ４３ , R ４４ , R ４５ , R ４６ , R ４７ , R ４８ , R ４９ , R ５０ , R ５２ , R ５３ , R ５４ , R ５５ , R ５６ , R ５７ , R ５８ , R ５９ , R ６２ and R ６３ 64. The method of any one of claims 53 to 63, wherein is as defined in claim 2.

65. R １２ , R ２０ , R ２９ , R ３９ , R ５１ , R ６０ and R ６１ is as defined in any one of claims 4, 5 and 8.

66. 65. The method of any one of claims 53 to 64, wherein Q is as defined in claim 3 or claim 6.

67. 67. The method of any one of claims 53 to 66, wherein A' is as defined in claim 10.

68. 67. The method of any one of claims 53 to 66, wherein Y is as defined in any one of claims 11 to 17.

69. R １ and R １ 69. The method of any one of claims 53 to 68, wherein ' is as defined in claim 18.

70. R ２ and R ２ 70. The method of any one of claims 53 to 69, wherein ' is as defined in claim 19.

71. R ３ and R ６ The method of any one of claims 53 to 70, wherein is as defined in any one of claims 20 to 22.

72. R ４ and R ５ The method of any one of claims 53 to 71, wherein is as defined in any one of claims 23 to 28.

73. 73. The method of any one of claims 53 to 72, wherein A is as defined in any one of claims 34, 35, 36, 38 to 45.

74. The compounds of formula I are listed in the following table: 【Table 14】 【Table 15】 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 54. The method of claim 53, wherein the compound is selected from:

75. 51. A pharmaceutical composition comprising a compound of any one of claims 1 to 50 and an additional therapeutic agent.

76. 76. The composition of claim 75, wherein the additional therapeutic agent is a psychoactive agent.

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