Indoline derivatives as serotonergic agents for treatment of related conditions

Abstract

The present application relates to methods of activating intracellular serotonin receptors using indoline derivatives of general formula (I) or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, and to the treatment of diseases, disorders or conditions by activating intracellular serotonin receptors. The diseases, disorders, or conditions include, for example, psychosis, mental disorders, and CNS disorders. The invention also relates to a novel indoline derivative as well as a composition and application thereof. Wherein Q is selected from (Q1), (Q2), (Q3), (Q4), (Q5) and (Q6). # imgabs0 #

Description

[0001] Related applications

[0002] This application claims priority to co-pending U.S. Provisional Patent Application No. 63 / 401,847, filed on August 29, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present application relates to methods for activating intracellular serotonin receptors using indoline derivatives of Formula I or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, as well as methods for treating various conditions, such as mental illness and neurological diseases, that are treated by activating serotonin receptors in the fields of psychiatry, neurobiology, and pharmacotherapy. The present application also relates to indoline derivatives of Formula IA, compositions, and uses thereof. Background Art

[0004] Mental health disorders, or mental illnesses, refer to a broad range of conditions that include, but are not limited to, depression, anxiety and panic disorders, schizophrenia, eating disorders, substance abuse disorders, post-traumatic stress disorder, attention-deficit / hyperactivity disorder, and obsessive-compulsive disorder. Many mental health disorders, as well as neurological conditions, are influenced by alterations, dysfunction, degeneration, and / or damage to the brain's serotonergic system, which may partially explain the common endophenotypes and comorbidities seen in neuropsychiatric and neurological disorders.

[0005] After decades of research limited by its legal status, the field of psychedelic neuroscience has recently experienced a resurgence. Hallucinogens (serotonergic hallucinogens) are potent psychoactive substances that alter perception and mood and affect numerous cognitive processes. It is now generally accepted that hallucinogens are agonists or partial agonists of brain serotonin 5-hydroxytryptamine 2A (5-HT2A) receptors.

[0006] Hallucinogens have rapid onset and long-lasting effects beyond their acute effects, including changes in mood and brain function. The persistent effects may arise from their unique receptor affinity, which affects neurotransmission through neuromodulatory systems that are responsible for regulating brain activity, i.e., neuroplasticity, and promoting cell survival, having neuroprotective effects, and regulating the brain neuroimmune system. The mechanisms leading to these long-term neuromodulatory changes are related to epigenetic modifications, changes in gene expression, and regulation of pre- and postsynaptic receptor density. These previously understudied hallucinogens may potentially provide the next generation of neurotherapeutics, in which refractory psychiatric and neurological disorders, such as depression, post-traumatic stress disorder, dementia, and addiction, may become treatable with a reduced pharmacological risk profile.

[0007] Despite widespread perception that hallucinogens are dangerous, they are among the safest known classes of CNS medications from a physiological safety perspective. Preliminary data suggest that administration of hallucinogens in humans results in a unique profile of effects and potential adverse reactions, which need to be appropriately managed to maximize safety. In practice, the primary safety concerns are primarily psychological, rather than physiological. Physical effects vary, but even at doses that produce strong psychological effects, they are relatively minor. Psilocybin, when administered under controlled conditions, is frequently reported to cause a transient, delayed headache, with the incidence, duration, and severity increasing in a dose-related manner [Johnson et al., Drug Alcohol Depend (2012) 123(1-3):132–140]. Repeated administration of hallucinogens has been shown to lead to the very rapid development of tolerance, known as tachyphylaxis, a phenomenon believed to be mediated in part by the 5-HT2A receptor. Indeed, several studies have shown that tachyphylaxis to hallucinogens is associated with downregulation of the 5-HT2A receptor. For example, daily administration of LSD selectively reduces 5-HT2 receptor density in rat brain [Buckholtz et al., Eur. J. Pharmacol. 1990, 109:421-425. 1985; Buckholtz et al., Life Sci. 1985, 42:2439-2445].

[0008] Classical hallucinogens and dissociative hallucinogens are known to have rapid-onset antidepressant and anti-addictive effects that are unlike any currently available treatment. Randomized controlled clinical studies have confirmed the antidepressant and anxiolytic effects of classical hallucinogens in humans.

[0009] Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) has the chemical formula C 12 H 17N2O4P. It is a tryptamine and one of the main psychoactive components of psilocybe mushrooms. Psilocybin was first isolated from Psilocybe mushrooms by Hofmann in 1957 and later synthesized by him in 1958 [Passie et al. Addict Biol., 2002, 7(4):357-364] and used in psychiatric and psychological research and in psychotherapy in the early to mid-1960s until it was regulated in the United States in 1970 and in Germany in the 1980s [Passie 2005; Passie et al. Addict Biol., 2002, 7(4):357-364]. In the mid-1990s, research on the effects of psilocybin resumed, and it is now the preferred compound used in studies of the effects of serotonergic hallucinogens [Carter et al. J. Cogn. Neurosci., 2005 17(10):1497–1508; Gouzoulis-Mayfrank et al. Neuropsychopharmacology 1999, 20(6):565–581; Hasler et al. Psychopharmacology (Berl) 2004, 172(2):145–156], probably because its effects are shorter-lasting than those of LSD and it has a lesser reputation. Like other members of this class, psilocybin sometimes causes profound changes in perception, cognition, and mood, including mood lability.

[0010] In humans and other mammals, psilocybin is converted to the active metabolite, psilocin (4-hydroxy-N,N-dimethyltryptamine). Psilocybin likely partially or completely produces most of the subjective and physiological effects of psilocybin in humans and non-human animals. Recent human psilocybin studies have confirmed the 5-HT2A activity of psilocybin and psilocin and provide some support for indirect effects on dopamine via 5-HT2A activity and possible activity at other serotonin receptors. Indeed, the most consistent finding regarding the involvement of other receptors in the effects of hallucinogens is the 5-HT1A receptor. This is particularly true for tryptamines and LSD, which typically have significant affinity and functional potency for this receptor. It is known that 5-HT1A receptors colocalize with 5-HT2A receptors on cortical pyramidal cells [Martín-Ruiz et al. J Neurosci. 2001, 21(24):9856–986], with the two receptor types having opposing functional effects [Araneda et al. Neuroscience 1991, 40(2):399–412].

[0011] Although the precise role of the 5-HT2A receptor and other 5-HT2 receptor family members in the amygdala remains unclear, it is clear that the 5-HT2A receptor plays an important role in emotional responses and is an important target to consider in the hallucinogenic effects of 5-HT2A agonists. In fact, most known 5-HT2A agonists produce psychedelic effects in humans, and in rodents, this extends from one 5-HT2A agonist to other agonists, such as psilocybin and 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 the human 5-HT2A receptor than for the rat receptor, and its K(i) for both the 5-HT2A and 5-HT2C receptors is lower than that of LSD. Furthermore, a series of drug recognition studies in rats found that a 5HT2A antagonist, but not a 5-HT1A antagonist, prevented rats from recognizing psilocybin [Winter et al., Pharmacol Biochem Behav., 2007, 87(4):472–480]. Daily administration of LSD and psilocybin reduced 5-HT2 receptor density in the rat brain.

[0012] Currently, psilocybin is one of the most widely used hallucinogens in human research due to its relative safety, moderate duration of activity, and good absorption by subjects. Psilocybin still has strong research and therapeutic potential, as recent studies have shown varying degrees of success in neurotic disorders, alcoholism, depression in advanced cancer patients, obsessive-compulsive disorder, addiction, anxiety disorders, post-traumatic stress disorder, and even cluster headaches. It can also be used as a psychotic model for the development of new treatments for psychotic disorders [Dubovyk and Monahan-Vaughn, ACS Chem. Neurosci. (2018), 9(9):2241-2251].

[0013] Recent advances in this area have emerged in clinical research, with several double-blind, placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with treatment-resistant major depressive disorder and cancer-related psychosocial distress demonstrating unprecedented positive improvements in anxiety and depression. Two recent small pilot studies of psilocybin-assisted psychotherapy have also demonstrated positive benefits in the treatment of alcohol and nicotine addiction. Recently, blood oxygen level-dependent functional magnetic resonance imaging and magnetoencephalography have been used to image the human brain in vivo after administration of hallucinogens, demonstrating that intravenously administered psilocybin and LSD induce a decrease in oscillatory power in the default mode network region of the brain [Nichols DE. Pharmacol Rev., 2016, 68(2):264–355].

[0014] Preliminary studies using positron emission tomography (PET) have shown that psilocybin ingestion (15 mg or 20 mg orally) increases the absolute metabolic rate of glucose in frontal regions and, to a lesser extent, in other cortical regions and striatum and limbic subcortical structures in healthy participants, suggesting that some of the key behavioral effects of psilocybin involve the frontal cortex [Gouzoulis-Mayfrank et al., Neuropsychopharmacology, 1999, 20(6):565-581; Vollenweider et al., Brain Res. Bull. 2001, 56(5):495–507]. Although 5-HT2A agonism is widely considered the primary effect of classic hallucinogens, psilocybin has lower affinity for a wide range of other pre- and postsynaptic serotonin and dopamine receptors and serotonin reuptake transporters [Tyls et al., Eur. Neuropsychopharmacol., 2014, 24(3):342–356]. Psilocybin activates 5-HT1A receptors, which may contribute to the antidepressant / anxiety effects.

[0015] Depression and anxiety are two of the most common psychiatric disorders worldwide. Depression is a multifaceted condition characterized by episodes of mood disturbance accompanied by other symptoms such as anhedonia, psychomotor complaints, guilt, attention deficits, and suicidality, all of which can vary in severity. Similarly, anxiety disorders are a class of conditions with complex etiologies characterized by intense psychosocial distress and, depending on the subtype, other symptoms. Anxiety disorders associated with life-threatening illnesses are the only subtype of anxiety disorders that have been studied in terms of hallucinogen-assisted therapy. Pharmacological and psychosocial interventions are commonly used to manage this type of anxiety disorder, but their efficacy is variable and limited, making them often unable to provide satisfactory mood relief. Recent interest in the use of hallucinogen-assisted therapy may represent a promising alternative for patients with depression and anxiety disorders who cannot be effectively managed by conventional methods.

[0016] Typically, the hallucinogen treatment model involves administering an orally active drug to induce a mystical experience that lasts 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 resolve and integrate difficult emotions and situations, producing lasting antidepressant and antianxiety effects. Classical hallucinogens, such as psilocybin and LSD, are being studied as potential candidates. In a study using classic hallucinogens to treat depression and anxiety associated with life-threatening illnesses, it was found that psilocybin and LSD consistently produced significant and lasting antidepressant and antianxiety effects in a supportive environment.

[0017] Treatment with hallucinogens is generally well tolerated, with no persistent adverse effects. Regarding their mechanism of action, they mediate their primary therapeutic effects biochemically through serotonin receptor agonism and psychologically by producing meaningful psychospiritual experiences that contribute to mental flexibility. Given the limited success of current treatments for anxiety and mood disorders, and the high morbidity associated with these conditions, hallucinogens have the potential to provide symptomatic relief for patients who cannot be managed with conventional methods.

[0018] Further emerging clinical research and evidence suggest that hallucinogen-assisted therapy also shows potential as an alternative treatment approach for refractory substance use disorders and mental health conditions and may therefore be an important tool in times of crisis where existing approaches have had limited success [dos Santos et al., Ther Adv Psychopharmacol., 2016, 6(3):193-213]. Similarly, encouraging are the findings from a recent pilot study of psilocybin-assisted therapy for tobacco use disorder, which demonstrated abstinence rates of 80% at six months and 67% at 12 months [Johnson et al., https: / / www.ncbi.nlm.nih.gov / pubmed / 27441452 J Drug Alcohol Abuse, 2017, 43(1):55-60; Johnson et al., Psychopharmacol. 2014, 28(11):983-992], rates significantly higher than any recorded in the smoking cessation literature. Notably, mystical experiences during psilocybin therapy were significantly associated with positive treatment outcomes. These results are consistent with rapidly developing evidence from recent clinical trials supporting the effectiveness of psilocybin-assisted therapy for treatment-resistant depression and end-of-life anxiety [Carhart-Harris et al. Neuropsychopharmacology, 2017, 42(11):2105-2113]. Research on the potential benefits of hallucinogen-assisted therapy for opioid use disorder (OUD) is beginning to emerge, and increasing evidence supports the need to advance such investigations. Available evidence from early randomized clinical trials suggests promise for treating OUD: at long-term follow-up, higher abstinence rates were observed in participants receiving high-dose LSD- and ketamine-assisted therapy for heroin addiction compared with controls. Recently, a large US population-based study of 44,000 individuals found that hallucinogen use was associated with a 40% lower risk of opioid abuse and a 27% lower risk of opioid dependence in the next year, as defined by DSM-IV criteria [Pisano et al. J Psychopharmacol., 2017, 31(5):606-613]. Similarly, a protective moderating effect of hallucinogen use on the relationship between prescription opioid use and suicide risk among marginalized women was found [Argento et al., J Psychopharmacol., 2018, 32(12):1385-1391]. Although these preliminary findings with classic hallucinogens are promising, further research is necessary to determine their potential contribution to the opioid crisis response given their potential toxicity. In the meantime, the growing evidence on the safety and efficacy of psilocybin for the treatment of mental and substance use disorders should help promote further clinical research into its use as a novel OUD intervention.

[0019] Regular doses of hallucinogens also improve sleep disturbances, which are highly prevalent among depressed patients, with over 80% complaining of poor sleep quality. Sleep symptoms often fail to resolve with first-line treatments and are associated with a higher risk of relapse and recurrence. Interestingly, sleep problems often precede the onset of other depressive symptoms, and subjective sleep quality deteriorates before recurrent depressive episodes. Two other studies evaluating electroencephalogram (EEG) brain activity during sleep have shown that hallucinogens, such as LSD, positively affect sleep patterns. Furthermore, partial or full nights of sleep deprivation have been suggested to alleviate depressive symptoms by resetting circadian rhythms through alterations in circadian clock gene expression. It has further been proposed that a single dose of hallucinogens induces a resetting of the circadian clock within the sleep / wake cycle, thereby enhancing cognitive-emotional processing in depressed individuals while also improving well-being and elevating mood in healthy individuals [Kuypers, Medical Hypotheses, 2019, 125:21–24].

[0020] In a systematic meta-analysis of clinical trials from 1960 to 2018 investigating the therapeutic use of hallucinogens in patients with severe or terminal illness and associated psychiatric disorders, it was found that hallucinogen therapy (primarily LSD) may improve cancer-related depression, anxiety, and fear of death. Four randomized controlled clinical trials (primarily psilocybin) were published between 2011 and 2016, which showed that hallucinogen-assisted therapy can rapidly, significantly, and sustainably improve cancer-related psychological and existential distress [Ross S, Int Rev Psychiatry, 2018, 30(4):317-330]. Therefore, the use of hallucinogens in oncology and palliative care is intriguing 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 may be associated with hopelessness, depression, powerlessness, a sense of encumbrance, and a desire for a hastened death. These characteristics are also often at the core of clinically significant anxiety and depression, and they may significantly reduce the quality of life in this patient population. Alleviating these forms of distress should be a core goal of palliative care. Therefore, several programmed psychotherapies for cancer-related existential distress have been developed in recent years, focusing on dignity and meaning-making. However, there are currently no pharmacological interventions for existential distress itself, and available pharmacological treatments for depressive symptoms in cancer patients have not shown an advantage over placebo. There is still a need for additional effective treatments for these conditions [Rosenbaum et al., Curr. Oncol., 2019, 26(4): 225–226].

[0021] Recently, there has been growing interest in new modes of administration for hallucinogens such as psilocybin and LSD, often referred to as "microdosing." In this mode, subperceptual doses of serotonergic hallucinogens, approximately 10% or less of the full dose, are taken on a more consistent basis, such as once a day, every other day, or every third day. This mode of administration is not only more consistent with current standards of pharmacological care, but may also be particularly beneficial for certain conditions, such as Alzheimer's disease and other neurodegenerative diseases, attention deficit disorder, attention deficit hyperactivity disorder, and for certain patient populations, such as the elderly, adolescents, and patients who are fearful of or averse to hallucinogen-assisted therapy. Furthermore, this approach may be particularly suitable for managing cognitive deficits and preventing neurodegeneration. For example, after a dose of psilocybin below the threshold for eliciting the classic wet-dog shake behavioral response associated with psychedelic doses, subpopulations of rats with low attention and low motivation showed improved performance in a 5-choice serial reaction time and progressive ratio task, respectively (Blumstock et al., WO 2020 / 157569 A1, Higgins et al., Front. Pharmacol., 2001, DOI: 10.3389). Similarly, treatment of patients with psychedelic doses of 5HT2A agonists was associated with increased BDNF and activation of the mTOR pathway, which is thought to promote neuroplasticity and is hypothesized to serve as a molecular target for the treatment of dementia and other neurodegenerative disorders (Ly et al., Cell Rep., 2018, 23(11): 3170-3182). In addition, several groups have demonstrated that low, non-psychedelic and non-psychotometic doses of 5HT2A agonists also show similar neuroprotective effects and increased neuroplasticity effects (neuroplastogens) and reduced neuroinflammation, which may be beneficial for neurodegenerative and neurodevelopmental diseases and chronic conditions (Manfredi et al., WO 2020 / 181194, Flanagan et al., Int. Rev. Psychiatry, 2018, 13: 1-13; Nichols et al., 2016, Psychedelics as medicines; an emerging new paradigm). This repeated, lower dose pattern can extend the utility of these compounds to additional indications and may prove useful for health applications.

[0022] Psychosis is often referred to as an abnormal mental state, which is characterized by hallucinations, delusional thinking and confusion. In addition, this state is accompanied by social cognitive impairment, inappropriate emotional expression and bizarre behavior. Typically, psychosis develops into a part of psychotic disorder, in which it represents the basic part of schizophrenia. It corresponds to the most significant stage of the disease. The first time a patient experiences psychotic symptoms is called first-episode psychosis. It reflects the key transition stage of the disease to chronic development, which may be mediated by the progressive structural and functional abnormalities observed in diagnosed patients. [ACS Chem.Neurosci., 2018, 9, 2241-2251]. Anecdotal evidence shows that regular administration of low, non-psychedelic doses (micro-dosing) of hallucinogens can reduce the symptoms of schizophrenia and psychosis. Summary of the Invention

[0023] Applicants have discovered that indoline derivatives modulate the activity of serotonin receptor subtypes, particularly 5-HT2A, by directly binding to these receptors.

[0024] Therefore, the present application includes a method for treating a disease, condition or disorder 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 a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0025]

[0026] in:

[0027] R 1 and R 1' Independently selected from H, halo, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2;

[0028] R 2 and R 2' independently selected from H, halo, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2;

[0029] Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6:

[0030]

[0031] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 Does not exist, when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q5 When it is a double bond, R 48 and R 57 does not exist;

[0032] R 4 and R 5 One or both of them are independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, or

[0033] R 4 and R 5 Linked together to form O-(CH2) 1-2 O, or

[0034] R 4 and R 5 One of them is selected from XLA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy,

[0035] X is selected from direct bond, O, C(O), NR a NR 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 NR a C(O)NR a ;

[0036] L is selected from 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 Alkylene C(O)NR b 、C 2-6 Alkenylene C(O)NR b 、C1-6 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 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 ;

[0037] R a Selected from H and C 1-6 alkyl;

[0038] R b Selected from H, C 1-6 Alkyl and A;

[0039] A is selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 64 The heterocyclic alkyl group of the heterocyclic alkyl group is 3 to 6 members and contains 1 to 4 independently selected from O, S, S (O), SO2, N and NR 64 The 5-membered to 6-membered heteroaryl group of the hetero part, wherein phenyl, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted by one or more independently selected from halo, C 1-4 Alkyl and OC 1-4 Substitution of alkyl groups;

[0040] R 3 and R 6 are independently selected from H, halo, OH, C 1-6 Alkyl and C 1-6 alkoxy;

[0041] 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 selected from H, halo and C 1-6 alkyl;

[0042] R 12 、R 20 、R 29 、R 39 and R 51 Independently selected from H, C 1-6 Alkyl, C(O)C 1-6 Alkyl and C(O)-A';

[0043] R 60 and R 61 Independently selected from H and C 1-6 alkyl; or

[0044] R 60 and R 61One of them is C(O)-A' and the other is selected from H and C 1-6 alkyl;

[0045] wherein A' is selected from Y, OY and OC 1-4 Alkylene-OC(O)-Y; and

[0046] Y is selected from C 7-30 Alkyl and C 7-30 alkenyl; or

[0047] R 60 and R 61 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered heterocyclic ring optionally comprising one or two independently selected from O, S, S(O), SO2, N and NR 65 and optionally substituted by one or more independently selected from halo, OH, C 1-4 Alkyl and OC 1-4 Substitution of alkyl groups;

[0048] R 64 and R 65 Independently selected from H and C 1-6 alkyl; and

[0049] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof,

[0050] Provided that when Q is Q6, then the compound of formula I comprises D.

[0051] The present application also includes a method of treating a psychotic disorder or psychotic symptoms comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application.

[0052] The present application also includes a method for treating a mental 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.

[0053] The present application also includes methods of treating CNS diseases, disorders or conditions and / or nervous system diseases, 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.

[0054] The present application includes one or more compounds of formula IA or pharmaceutically acceptable salts, solvates and / or prodrugs thereof,

[0055]

[0056] in:

[0057] R 1 and R 1' Independently selected from H, halo, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2;

[0058] R 2 and R 2' independently selected from H, halo, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2;

[0059] Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6:

[0060]

[0061]

[0062] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 Does not exist, when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q5 When it is a double bond, R 48 and R 57 does not exist;

[0063] R 4 and R 5 One or both of them are independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, or

[0064] R 4 and R 5 Linked together to form O-(CH2) 1-2 O, or

[0065] R 4 and R 5 One of them is selected from XLA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy,

[0066] X is selected from direct bond, O, C(O), NR a NR 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 NR a C(O)NR a ;

[0067] L is selected from 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 Alkylene C(O)NR b 、C 2-6 Alkenylene C(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 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 ;

[0068] R a Selected from H and C 1-6 alkyl;

[0069] R b Selected from H, C 1-6 Alkyl and A;

[0070] A is selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 64 The heterocyclic alkyl group of the heterocyclic alkyl group is 3 to 6 members and contains 1 to 4 independently selected from O, S, S (O), SO2, N and NR 64 The 5-membered to 6-membered heteroaryl group of the hetero part, wherein phenyl, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted by one or more independently selected from halo, C 1-4 Alkyl and OC 1-4 Substitution of alkyl groups;

[0071] R 3 and R 6 are independently selected from H, halo, OH, C 1-6 Alkyl and C 1-6 alkoxy;

[0072] 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 selected from H, halo and C 1-6 alkyl;

[0073] R 12 、R 20 、R 29 、R 39 and R 51 Independently selected from H, C 1-6 Alkyl, C(O)C 1-6 Alkyl and C(O)-A';

[0074] R 60 and R 61 Independently selected from H and C 1-6 alkyl; or

[0075] R 60 and R 61 One of them is C(O)-A' and the other is selected from H and C 1-6 alkyl;

[0076] wherein A' is selected from Y, OY and OC 1-4 Alkylene-OC(O)-Y; and

[0077] Y is selected from C 7-30 Alkyl and C 7-30 alkenyl; or

[0078] R 60 and R 61 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered heterocyclic ring optionally contains one or two independently selected from O, S, S(O), SO2, N and NR 65 and optionally substituted by one or more independently selected from halo, OH, C 1-4 Alkyl and OC 1-4 Substitution of alkyl groups;

[0079] R 64 and R 65 Independently selected from H and C 1-6 alkyl; and

[0080] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof,

[0081] Provided that when Q is Q6, then the compound of formula I comprises D,

[0082] When Q is Q3 or Q4, when R 5 is H or OCH3, and R 29 or R 39 When it is CH3, R 1 、R 1' 、R 2 、R 2’ 、R 3 、R 4 、R 6 、R 26 、R 27 、R 28 、R 30 to R 35 、R 36 、R 37 、R 38 and R 40 to R 47 Not all are H.

[0083] When Q is Q4 and R 1 、R 1' 、R 2 、R 2' 、R 3 、R 4 、R 6 、R 38 and R 40 to R 47 When all are H, then when R 39 When it is CD3, R 36 and R 37 Not all are D.

[0084] The present application further provides processes for preparing the compounds of the present application. General and specific processes will be discussed in more detail below and illustrated in the following examples.

[0085] Other features and advantages of the present application will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, although indicating embodiments of the present application, are given only by way of illustration, and the scope of the claims should not be limited by these embodiments, but should be given the broadest interpretation consistent with the entirety of this specification. DETAILED DESCRIPTION

[0086] I. Definition

[0087] Unless otherwise stated, the definitions and embodiments described in this section and elsewhere are intended to apply to all embodiments and aspects of the application described herein, as will be understood by those skilled in the art.

[0088] As used herein, the term "compound(s) of the application" or "compound(s) of the present application" and the like refer to compounds of Formula I and Formula IA, and include pharmaceutically acceptable salts, solvates and / or prodrugs thereof, as well as all stereoisomers and regioisomers.

[0089] As used herein, the term "composition(s) of the application" or "composition(s) of the present application" and the like refer to a composition, such as a pharmaceutical composition, comprising one or more compounds of the present application.

[0090] As used herein, the term "and / or" means the presence or use of the listed items, alone or in combination. In practice, this term means the use or presence of "at least one" or "one or more" of the listed items. The term "and / or" with respect to pharmaceutically acceptable salts, solvates, and / or prodrugs thereof means that the compounds of the present application are present as individual salts, solvates, and / or prodrugs, as well as combinations of salts or solvates of the compounds of the present application, for example.

[0091] As used herein, the singular forms "a", "an", and "the" include plural references unless the context clearly indicates otherwise. For example, an embodiment including "a compound" should be understood to refer to certain embodiments with one compound or two or more additional compounds.

[0092] As used in this application and in the claims, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”), or “containing” (and any form of containing, such as “contain” and “contains”) are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0093] As used herein, the term "consisting of" and its derivatives are closed terms that specify the presence of stated features, elements, components, groups, integers and / or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and / or steps.

[0094] As used herein, the term "consisting essentially of" is intended to specify the presence of the recited features, elements, components, groups, integers and / or steps, as well as the presence of those that do not materially affect the basic and novel characteristics of such features, elements, components, groups, integers and / or steps.

[0095] In embodiments comprising an "additional" or "second" component (e.g., an additional or second compound), the second component, as used herein, is chemically different from the other components or the first component. The "third" component is different from the other components, and the first and second components and other listed components or "additional" components are similarly different.

[0096] As used herein, the term "suitable" means that the selection of specific compounds or conditions will depend on the specific synthetic operation to be performed, the identity of the molecule to be converted, and / or the specific use of the compound, but that the selection is well within the skill of those skilled in the art. All process / method steps described herein will be carried out under conditions sufficient to provide the products shown. It will be understood by those skilled in the art that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio, and whether the reaction should be carried out under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product, and that doing so is well within the skill of those skilled in the art.

[0097] As used herein, the terms "about," "substantially," and "approximately" mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be interpreted as including a deviation of at least ±5% of the modified term where such deviation would not negate the meaning of the word it modifies, or unless the context suggests otherwise to one skilled in the art.

[0098] This specification refers to many chemical terms and abbreviations used by those skilled in the art. However, for the sake of clarity and consistency, definitions of selected terms are provided.

[0099] As used herein, the term "solvate" means a compound, or salt and / or prodrug of a compound, wherein molecules of a suitable solvent are incorporated into the crystal lattice.

[0100] As used herein, the term "prodrug" means a compound or salt of a compound that is converted to an active drug after administration.

[0101] As used herein, whether used alone or as part of another group, the term "alkyl" means a straight or branched chain saturated alkyl group. The number of carbon atoms possible in a reference to an alkyl group is indicated by the prefix "C n1-n2 ”. Thus, for example, the term “C 1-6 Alkyl (or "C 1-6 "alkyl") means an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0102] As used herein, whether used alone or as part of another group, the term "alkenyl" means a straight or branched saturated alkenyl group containing at least one double bond. The number of carbon atoms possible in the 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.

[0103] As used herein, the term "alkenylene" whether used alone or as part of another group, means a straight or branched unsaturated alkylene group, i.e., an unsaturated carbon chain containing substituents at both ends and at least one double bond. The number of carbon atoms possible in a reference to an alkenylene group is indicated by the prefix "C n1-n2 " means. For example, the term C 2-6 The alkenylene group means an alkenylene group having 2, 3, 4, 5 or 6 carbon atoms.

[0104] As used herein, the term "alkoxy," when used herein, alone or in combination, includes an alkyl group attached to an oxygen linking atom.

[0105] As used herein, the term "cycloalkyl" whether used alone or as part of another group, means a saturated carbocyclic group containing 3 to 6 carbon atoms and one or more rings. The number of carbon atoms in a cycloalkyl group is indicated by the numerical prefix "C n1-n2 " means. For example, the term C 3-6 The cycloalkyl group means a cycloalkyl group having 3, 4, 5 or 6 carbon atoms.

[0106] As used herein, the term "heterocycloalkyl" whether used alone or as part of another group, refers to a cyclic group containing at least one non-aromatic ring and containing 3 to 6 atoms, one or more of which is selected from O, S, S(O), SO2, NH, NC 1-6 The heterocyclic portion of an alkyl group and N, and the remaining atoms are C. Heterocycloalkyl groups are saturated or unsaturated (i.e., contain one or more double bonds). When a heterocycloalkyl group contains the prefix C n1-n2or "n1-n2", this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, wherein one or more, suitably 1-4 ring atoms are selected from O, S, S(O), SO2, NH, NC 1-6 The alkyl group and the N group are heteroatom substituted, and the remaining atoms are C.

[0107] As used herein, the term "aryl," whether used alone or as part of another group, refers to a carbocyclic group containing at least one aromatic ring and containing 6 to 10 carbon atoms.

[0108] As used herein, whether used alone or as part of another group, the term "heteroaryl" refers to a cyclic group containing at least one heteroaromatic ring and containing 5-6 atoms, one or more of which is a heteroatom selected from O, S and N, and the remaining atoms are C. When the heteroaryl group contains the prefix C n1-n2 When , this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, wherein one or more, suitably 1 to 4, ring atoms are replaced by heteroatoms as defined above.

[0109] The term "halogen" (or "halo"), whether used alone or as part of another group, refers to a halogen atom and includes fluorine, chlorine, bromine, and iodine.

[0110] As used herein, the term "haloalkyl" refers to an alkyl group as defined above in which one or more available hydrogen atoms are replaced by 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.

[0111] As used herein, the term "deuterated alkyl" refers to an alkyl group as defined above in which one or more available hydrogen atoms are replaced by deuterium. Thus, for example, "C 1-6 "Deuterated alkyl" refers to a C1 to C6 straight or branched chain alkyl group as defined above having one or more deuterium substituents.

[0112] In "available hydrogen atom" or "available atom", the term "available" refers to an atom known by those skilled in the art to be capable of being replaced by a substituent.

[0113] As used herein, the term "one or more" items includes a single item selected from the list as well as a mixture of two or more items selected from the list.

[0114] As used herein, the term "alternative isotopes thereof" refers to isotopes of an element other than the most abundant isotope in nature. In the compounds of Formula I and Formula IA and pharmaceutically acceptable salts, solvates and / or prodrugs thereof, atoms may have their natural isotopic abundance, or one or more atoms may be artificially enriched with a specific isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. This application is intended to include all suitable isotopic variants of the compounds of Formula I and Formula IA and pharmaceutically acceptable salts, solvates and / or prodrugs thereof. For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H). Protium is the major isotope of hydrogen found in nature.

[0115] The term "compound" refers to the compound, and in certain embodiments, refers to any hydrate or solvate thereof with respect to its degree of stability. A hydrate is a compound complexed with water, and a solvate is a compound complexed with a solvent, and the solvent may be an organic solvent or an inorganic solvent. A "stable" compound is a compound that can be prepared and separated, and its structure and properties are maintained or can result in maintaining substantially unchanged within a certain time period sufficient to allow the use of the compound for purposes described herein (e.g., therapeutic administration to a subject). The compound of the present application is limited to a stable compound encompassed by general formula (IA) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

[0116] The term "pharmaceutically acceptable" means compatible with the treatment of the subject.

[0117] The term "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant or other substance that is mixed with the active ingredient to allow for formation of a pharmaceutical composition (ie, a dosage form that can be administered to a subject).

[0118] The term "pharmaceutically acceptable salt" means an acid addition salt or a base addition salt that is suitable for or compatible with the treatment of a subject.

[0119] Acid addition salts suitable for or compatible with the treatment of a subject are any non-toxic organic or inorganic acid addition salts of any basic compound.

[0120] Base addition salts suitable for or compatible with the treatment of a subject are any non-toxic organic or inorganic base addition salt of any acidic compound.

[0121] As used herein, the term "protecting group" or "PG" refers to a group that protects or masks the reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule while manipulating different portions of the molecule or reacting the chemical portion thereof. After the manipulation or reaction is complete, the protecting group is removed without degrading or decomposing the remainder of the molecule. A person skilled in the art can select a suitable protecting group. Many conventional protecting groups are known in the art, for example, as described in "Protective Groups in Organic Chemistry" McOmie, JFW, ed., Plenum Press, 1973; 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).

[0122] As used herein, the term "subject" includes all members of the animal kingdom, including mammals, and appropriately refers to humans. Thus, the methods of the present application are suitable for both human therapy and veterinary applications.

[0123] As used herein and as known in the art, the term "treating / treatment" means a method for obtaining a beneficial or desired result (including clinical outcome). Beneficial or desired clinical outcome includes, but is not limited to, alleviating or improving one or more symptoms or illnesses, alleviating the extent of the disease, stabilizing (i.e., not worsening) the disease state, preventing the spread of the disease, delaying or slowing the progression of the disease, alleviating or relieving the disease state, reducing disease recurrence, and alleviating (whether partially or completely), whether detectable or undetectable. "Treatment" can also mean prolonging survival compared to the expected survival when not receiving treatment. As used herein, "treatment" also includes preventive 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 the compound or composition of the present application to prevent recurrence. The method of treatment includes administering a therapeutically effective amount of one or more compounds of the present application to the subject, and is optionally composed of a single administration, or alternatively includes a series of administrations.

[0124] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of one or more compounds of the present invention effective at the dosage and for the period of time necessary to achieve the desired result. For example, in the context of treating a disease, condition, or disorder mediated or treated by agonizing or activating serotonergic receptors and downstream second messengers, an effective amount is, for example, an amount that increases such activation compared to activation without administration of the compound(s).

[0125] By "alleviating" a disease, disorder or condition, it is meant that the extent and / or adverse clinical manifestations of the disease, disorder or condition are reduced and / or the time course of progression is slowed or prolonged, as compared to not treating the disorder.

[0126] As used herein, the term "administering" means administering a therapeutically effective amount of one or more compounds or compositions of the present application to a cell, tissue, organ or subject.

[0127] As used herein, the terms "prevention" and "prophylaxis" or their synonyms refer to reducing the risk or probability that a patient will develop a disease, condition, or disorder, or exhibit symptoms associated with a disease, condition, or disorder.

[0128] As used herein, a "disease, condition, or disorder" refers to a disorder or condition that is caused by activation of serotonin receptors (e.g., 5-HT 2A ), particularly diseases, conditions or disorders that are treated or treatable using a serotonin receptor agonist (e.g., one or more of the compounds of the present application as described herein). The disease, condition or disorder may also be treated by alternative mechanisms, such as by modulating, inactivating, antagonizing or inversely agonizing serotonin receptors (including 5-HT 2A and / or 5-HT 1A ) to treat or be treatable.

[0129] As used herein, the term "treating a disease, condition, or disorder by activating a serotonin receptor" means that the disease, condition, or disorder to be treated is directly or indirectly affected by, regulated by, and / or has a biological basis that includes serotonergic activity, particularly an increase in serotonergic activity. Diseases, conditions, or disorders associated with the disease, condition, or disorder respond favorably when the serotonergic activity is modulated (e.g., agonized) by one or more compounds or compositions of the present application.

[0130] As used herein, the term "activation" includes agonism, partial agonism, and positive allosteric modulation of serotonin receptors.

[0131] The term "5-HT 1A ” and “5-HT 2A "5-HT" is used herein to refer to the 5-HT serotonin receptor, 1A and 5-HT 2AReceptor subtype.

[0132] As used herein, the term "therapeutic agent" refers to any drug or active agent that has a pharmacological effect when administered to a subject.

[0133] II. Methods and Uses of the Present Application

[0134] The applicant has found that indoline derivatives can be used to treat diseases, disorders or conditions by regulating (e.g., activating) serotonin receptors. Therefore, indoline derivatives can be used as medicines. Therefore, the application also includes indoline derivatives used as medicines.

[0135] Therefore, the present application includes a method for treating a disease, condition or disorder 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 a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0136]

[0137] in:

[0138] R 1 and R 1’ Independently selected from H, halo, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2;

[0139] R 2 and R 2' independently selected from H, halo, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2;

[0140] Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6:

[0141]

[0142]

[0143] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 Does not exist, when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q5 When it is a double bond, R48 and R 57 does not exist;

[0144] R 4 and R 5 One or both of them are independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, or

[0145] R 4 and R 5 Linked together to form O-(CH2) 1-2 O, or

[0146] R 4 and R 5 One of them is selected from XLA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 alkoxy;

[0147] X is selected from direct bond, O, C(O), NR a NR 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 NR a C(O)NR a ;

[0148] L is selected from 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 Alkylene C(O)NR b 、C 2-6 Alkenylene C(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 2-6Alkenylene 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 ;

[0149] R a Selected from H and C 1-6 alkyl;

[0150] R b Selected from H, C 1-6 Alkyl and A;

[0151] A is selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 64 The heterocyclic alkyl group of the heterocyclic alkyl group is 3 to 6 members and contains 1 to 4 independently selected from O, S, S (O), SO2, N and NR 64 The 5-membered to 6-membered heteroaryl group of the hetero part, wherein phenyl, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted by one or more independently selected from halo, C 1-4 Alkyl and OC 1-4 Substitution of alkyl groups;

[0152] R 3 and R 6 are independently selected from H, halo, OH, C 1-6 Alkyl and C 1-6 alkoxy;

[0153] 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 selected from H, halo and C 1-6 alkyl;

[0154] R 12 、R 20 、R 29 、R 39 and R 51 Independently selected from H, C 1-6 Alkyl, C(O)C 1-6 Alkyl and C(O)-A';

[0155] R 60 and R 61 Independently selected from H and C 1-6 alkyl; or

[0156] R 60 and R 61 One of them is C(O)-A' and the other is selected from H and C 1-6 alkyl;

[0157] wherein A' is selected from Y, OY and OC 1-4 Alkylene-OC(O)-Y; and

[0158] Y is selected from C 7-30Alkyl and C 7-30 alkenyl; or

[0159] R 60 and R 61 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered heterocyclic ring optionally contains one or two independently selected from O, S, S(O), SO2, N and NR 65 and optionally substituted by one or more independently selected from halo, OH, C 1-4 Alkyl and OC 1-4 Substitution of alkyl groups;

[0160] R 64 and R 65 Independently selected from H and C 1-6 alkyl; and

[0161] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof,

[0162] Provided that when Q is Q6, then the compound of formula I comprises D.

[0163] 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 diseases, conditions and / or disorders by activating serotonin receptors, and 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 diseases, conditions or disorders by activating serotonin receptors. The present application also includes one or more compounds of Formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof for treating diseases, conditions or disorders by activating serotonin receptors.

[0164] In some embodiments, the serotonin receptor is 5-HT 2A Thus, the present application includes methods for activating 5-HT in cells of a biological sample or patient. 2A The present invention also includes one or more compounds of formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof for activating 5-HT in cells. 2A Use of one or more compounds of formula I or their pharmaceutically acceptable salts, solvates and / or prodrugs for preparing 5-HT activating cells 2A The present application also includes one or more compounds of formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof for activating 5-HT in cells. 2A .

[0165] In some embodiments, the serotonin receptor is 5-HT 1A Thus, the present application includes methods for activating 5-HT in cells of a biological sample or patient. 1A The present invention also includes one or more compounds of formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof for activating 5-HT receptors in cells. 1A The use of one or more compounds of formula I or their pharmaceutically acceptable salts, solvates and / or prodrugs for the preparation of 5-HT receptors for activating cells 1A The present application also includes one or more compounds of formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof for activating 5-HT in cells. 1A receptor.

[0166] The present application also includes activation of 5-HT 2A A method for treating a disease, condition or illness comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. The present application also includes one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof for use in activating 5-HT 2A to treat a disease, condition or disorder, and one or more compounds of formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof for use in the preparation of a pharmaceutical composition for treating a disease, condition or disorder by activating 5-HT 2A The present application also includes one or more compounds of formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof for use in treating diseases, disorders or conditions by activating 5-HT 2A To treat a disease, condition or illness.

[0167] The present application also includes activation of 5-HT 1A A method for treating a disease, condition or illness comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. The present application also includes one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof for use in activating 5-HT 1A to treat a disease, condition or disorder, and one or more compounds of formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof for use in the preparation of a pharmaceutical composition for treating a disease, condition or disorder by activating 5-HT 1A The present application also includes one or more compounds of formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof for use in treating diseases, disorders or conditions by activating 5-HT1A To treat a disease, condition or illness.

[0168] Diseases, conditions or disorders may also be mediated through alternative mechanisms, such as by modulation, inactivation, antagonism or inverse agonism of serotonin receptors, including 5-HT 2A and / or 5-HT 1A ) to treat or be treatable.

[0169] In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, solvate and / or prodrug can be used to prevent, treat and / or alleviate the severity of the subject's mental illness and / or illness. Therefore, in some embodiments, the disease, illness or illness treated by activating serotonin receptors is a mental illness. Therefore, the application also includes a method for treating mental illness, which includes administering a therapeutically effective amount of one or more compounds of formula I or its pharmaceutically acceptable salt, solvate and / or prodrug to a subject in need. The application also includes the use of one or more compounds of formula I or its pharmaceutically acceptable salt, solvate and / or prodrug for treating mental illness, and the use of one or more compounds of formula I or its pharmaceutically acceptable salt, solvate and / or prodrug for the preparation of a medicine for treating mental illness. The application also includes one or more compounds of formula I or its pharmaceutically acceptable salt, solvate and / or prodrug for treating mental illness.

[0170] 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 disorders, such as hopelessness, loss of pleasure, fatigue, and suicidal thoughts; mood disorders, such as depression, bipolar disorder, cancer-related depression, anxiety disorders, and cyclothymic disorder; psychotic disorders, such as hallucinations, delusions, schizophrenia; impulse control and addiction disorders, such as pyromania (fire setting), kleptomania (stealing), and compulsive gambling; alcohol addiction; drug addiction, such as opioid addiction; personality disorders, such as antisocial personality disorder, obsessive-compulsive personality disorder, and paranoid personality disorder; obsessive-compulsive disorder (OCD), and psychotic disorder. disorder (OCD), such as thoughts or fears that lead the subject to perform certain rituals or routines; post-traumatic stress disorder (PTSD); stress response syndrome (formerly known as adjustment disorder); dissociative disorder, formerly known as multiple personality disorder, or "split personality," and depersonalization disorder; factitious disorder; sex and gender disorders, such as hypersexuality, gender identity disorder, and paraphilia; somatic symptom disorder, formerly known as psychosomatic disorder or somatoform disorder; and combinations thereof.

[0171] In some embodiments, the diseases, disorders, or conditions treated by activating serotonin receptors include cognitive impairment; ischemia, including stroke; neurodegeneration; refractory substance use disorder; sleep disorders; pain, such as social pain, acute pain, cancer pain, chronic pain, breakthrough pain, bone pain, soft tissue pain, neuralgia, referred pain, phantom limb pain, neuropathic pain, cluster headache, and migraine; obesity and eating disorders; epilepsy and spastic disorders; neuronal cell death; excitotoxic cell death; or a combination thereof.

[0172] In some embodiments, the psychiatric disorder is selected from the group consisting of hallucinations and delusions, and combinations thereof.

[0173] In some embodiments, the hallucination is selected from the group consisting of visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, balance-sensory hallucinations, nociceptive hallucinations, thermal-sensory hallucinations, and temporal-sensory hallucinations, and combinations thereof.

[0174] In some embodiments, the disease, condition or disorder treated by activating serotonin receptors is a psychotic disorder or a psychotic symptom. Therefore, the present application also includes a method for treating a psychotic disorder or a psychotic symptom, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

[0175] The present application also includes the use of one or more compounds of Formula I or their pharmaceutically acceptable salts, solvates and / or prodrugs for treating psychosis or psychotic symptoms, and the use of one or more compounds of Formula I or their pharmaceutically acceptable salts, solvates and / or prodrugs for preparing a medicament for treating psychosis or psychotic symptoms. The present application also includes one or more compounds of Formula I or their pharmaceutically acceptable salts, solvates and / or prodrugs for treating psychosis or psychotic symptoms.

[0176] 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 a subject in need thereof does not result in worsening of 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 a subject in need thereof results in improvement of 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 a subject in need thereof results in improvement of psychosis or psychotic symptoms.

[0177] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof can be used to treat a central nervous system (CNS) disorder in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0178] Therefore, in some embodiments, the disease, disorder or illness treated by activating serotonin receptors is a central nervous system (CNS) disease, disorder or illness and / or neurological disease, disorder or illness. Therefore, the application also includes a method for treating CNS disease, disorder or illness and / or neurological disease, disorder or illness, which includes administering a therapeutically effective amount of one or more compounds of formula I or its pharmaceutically acceptable salts, solvates and / or prodrugs to a subject in need. The application also includes one or more compounds of formula I or its pharmaceutically acceptable salts, solvates and / or prodrugs for the treatment of CNS disease, disorder or illness and / or neurological disease, disorder or illness, and one or more compounds of formula I or its pharmaceutically acceptable salts, solvates and / or prodrugs for the preparation of a drug for the treatment of CNS disease, disorder or illness and / or neurological disease, disorder or illness. The application also includes one or more compounds of formula I or its pharmaceutically acceptable salts, solvates and / or prodrugs for the treatment of CNS disease, disorder or illness and / or neurological disease, disorder or illness. In some embodiments, the CNS disease, disorder or condition and / or nervous system disease, disorder or condition is selected from the group consisting of: a nervous system disease, including neurodevelopmental and neurodegenerative diseases, such as Alzheimer's disease; precocious dementia; Alzheimer's disease; vascular dementia; dementia with Lewy bodies; cognitive impairment, Parkinson's disease and Parkinson-related diseases, such as Parkinson's disease, corticobasal degeneration and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disease; fragile X syndrome; Angelman syndrome; hereditary ataxias; neurotological and oculomotor disorders; retinal neurodegenerative diseases; amyotrophic lateral sclerosis; tardive dyskinesia; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette's syndrome syndrome); schizophrenia; autism spectrum disorder; tuberous sclerosis complex; Rett syndrome; cerebral palsy; reward system disorders, including eating disorders such as anorexia nervosa ("AN") and bulimia nervosa ("BN"); and binge eating disorder ("BED"), trichotillomania, dermotillomania, nail biting; migraine headaches; fibromyalgia; and peripheral neuropathies of any etiology, and combinations thereof.

[0179] In some embodiments, the subject is a mammal. In another embodiment, the subject is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a canine. In some embodiments, the subject is a feline. Thus, the compounds, methods, and uses of the present application are directed to both human and veterinary diseases, disorders, and conditions.

[0180] In some embodiments, compounds of Formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, are useful for treating behavioral problems in feline or canine subjects.

[0181] Therefore, in some embodiments, the disease, disorder or illness treated by activating serotonin receptors is a behavioral problem in a feline or canine subject. Therefore, the present application also includes a method for treating behavioral problems, comprising administering a therapeutically effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof to a non-human subject in need. The present application also includes the use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof for treating behavioral problems in non-human subjects, and the use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof for the preparation of a medicament for treating behavioral problems in non-human subjects. The present application also includes one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof for treating behavioral problems in non-human subjects.

[0182] In some embodiments, the behavioral problem is selected from, but not limited to, anxiety, fear, stress, sleep disturbances, cognitive dysfunction, aggressive behavior, excessive noise making, scratching, biting, and combinations thereof.

[0183] In some embodiments, the non-human subject is a canine. In some embodiments, the non-human subject is a feline.

[0184] The present application also includes a method for treating a disease, condition, or illness by activating serotonin receptors, comprising administering to a subject in need thereof a therapeutically effective amount of a combination of one or more compounds of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, and another agent known to be useful for treating a disease, condition, or illness by activating serotonin receptors. The present application also includes the use of a combination of one or more compounds of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, and another agent known to be useful for treating a disease, condition, or illness by activating serotonin receptors, as well as the use of a combination of one or more compounds of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, and another agent known to be useful for treating a disease, condition, or illness by activating serotonin receptors for the preparation of a medicament for treating a disease, condition, or illness by activating serotonin receptors. The present application also includes a combination of one or more compounds of Formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof with another known agent that can be used to treat a disease, condition or disorder by activating serotonin receptors, for use in treating a disease, condition or disorder by activating serotonin receptors.

[0185] In some embodiments, the disease, condition or illness treated by activating serotonin receptors is a mental illness. In some embodiments, the mental illness is selected from hallucinations and delusions and combinations thereof. In some embodiments, the disease, condition or illness treated by activating serotonin receptors is a central nervous system (CNS) disorder. In some embodiments, the disease, condition or illness treated by activating serotonin receptors is a psychotic disorder or a psychotic symptom. In some embodiments, the disease, condition or illness treated by activating serotonin receptors is a behavioral problem in a non-human subject.

[0186] In some embodiments, the disease, condition, or disorder 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 antipsychotics, including typical antipsychotics and atypical antipsychotics; antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and monoamine oxidase inhibitors (MAOIs) (e.g., bupropion); antianxiety drugs, including benzodiazepines (such as alprazolam); mood stabilizers, such as lithium, and anticonvulsants (such as carbamazepine, divalproex sodium (valproic acid), lamotrigine, gabapentin, and topiramate).

[0187] In some embodiments, the disease, condition or illness treated by activating serotonin receptors is selected from attention deficit hyperactivity disorder and attention deficit disorder and a combination thereof. In some embodiments, the disease, condition or illness treated by activating serotonin receptors is attention deficit hyperactivity disorder and / or attention deficit disorder and a combination thereof, 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 other treatments for attention deficit hyperactivity disorder and / or attention deficit disorder and a combination thereof. In some embodiments, the other treatments for attention deficit hyperactivity disorder and / or attention deficit disorder and a combination thereof are selected from methylphenidate, atomoxetine and amphetamine and a combination thereof.

[0188] In some embodiments, the disease, condition, or disorder 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, additional treatments for dementia and Alzheimer's disease are selected acetylcholinesterase inhibitors, NMDA antagonists, and muscarinic agonists and antagonists, and nicotinic agonists.

[0189] In some embodiments, the acetylcholinesterase inhibitor is selected from donepezil, galantamine, rivastigmine, and phenserine, and combinations thereof.

[0190] In some embodiments, the NMDA antagonist is selected from MK-801, ketamine, phencyclidine, and memantine, and combinations thereof.

[0191] 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.

[0192] In some embodiments, the muscarinic agonist is a muscarinic M1 agonist or a muscarinic M4 agonist, or a combination thereof.

[0193] In some embodiments, the muscarinic antagonist is a muscarinic M2 antagonist.

[0194] In some embodiments, the disease, condition, or disorder treated by activating serotonin receptors is a psychotic disorder 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 psychotic disorder or psychotic symptom. In some embodiments, the additional treatment for the psychotic disorder or psychotic symptom is selected from a typical antipsychotic and an atypical antipsychotic.

[0195] In some embodiments, the typical antipsychotic is selected from the group consisting of acepromazine, acetophenazine, benperidol, bromperidol, butaperazine, carfenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, ne), dixyrazine, droperidol, fluanisone, flupentixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, lenperone, loxapine, mesoridazine, metitepine, molindone, Moperone, oxypertine, oxyprotepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, piperacetazine, pipotiazine, prochlorperazine, promazine, prothiopentyl hipendyl, spiperone, sulforidazine, thiopropazate, thioproperazine, thioridazine, thiothixene, timiperone, trifluoperazine, trifluperidol, triflupromazine, and zuclopenthixol, and combinations thereof.

[0196] In some embodiments, the atypical antipsychotic is selected from amoxapine, amisulpride, aripiprazole, asenapine, blonanserin, brexpiprazole, cariprazine, carpipramine, clocapramine, clorotepine, clotiapine, clozapine, iloperidone, levosulpiride, lurasidone, metoprolol, thiazolidinone ... melperone, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpiride, sultopride, tiapride, veralipride, ziprasidone and zotepine, and combinations thereof.

[0197] In some embodiments, the disease, condition, or disorder 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.

[0198] In some embodiments, the 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 one or more given compounds that would correspond to an effective amount will vary depending on a variety of factors, such as the given drug or compound, the drug formulation, the route of administration, the type of disorder, disease, or condition, the identity of the subject to be treated, etc., but can still be routinely determined by one skilled in the art.

[0199] In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, solvate and / or prodrug is administered once, twice, three times or four times per year. In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, solvate and / or prodrug is administered at least once per week. However, in another embodiment, the compound is administered to the subject at a frequency of about once every two weeks, three weeks or a month. In another embodiment, the compound is administered once a week to once a day. In another embodiment, the compound is administered 1, 2, 3, 4, 5 or 6 times a day. The length of the treatment period depends on various factors, such as the severity of the disease, condition or illness, the age of the subject, the concentration and / or activity of the compound of formula I or its pharmaceutically acceptable salt, solvate and / or prodrug and / or its combination. It should also be understood that the effective dose of the compound for treatment can increase or decrease during the course of a specific treatment regimen. By standard diagnostic assays known in the art, changes in dosage may occur and become apparent. In some cases, long-term administration is required. For example, the compound is administered to the subject in an amount and duration sufficient to treat the subject.

[0200] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, is administered at a psychedelic or psychotomimetic dose and is taken in conjunction with psychotherapy or therapy and may occur once, twice, three times, or four times a year. However, in some embodiments, the compound is administered to a subject at a non-psychedelic or psychotomimetic dose once daily, once every two days, once every three days, once a week, once every two weeks, once a month, once every two months, or once every three months.

[0201] The compound of formula I or its pharmaceutically acceptable salt, solvate and / or prodrug is used alone or in combination with other known agents (such as compounds of the present application) that can be used to treat diseases, disorders or illnesses by activating serotonin receptors. When used in combination with other known agents that can be used to treat diseases, disorders by activating serotonin receptors, one embodiment is to administer the compound of formula I or its pharmaceutically acceptable salt, solvate and / or prodrug simultaneously with those agents. As used herein, "administering" two substances to a subject "simultaneously" means providing each of the two substances so that they are active in the individual at the same time. The exact details of administration will depend on the pharmacokinetics of the two substances when they are present in each other, and may include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of administering another substance if the pharmacokinetics are suitable. The design of a suitable dosing regimen is conventional for those skilled in the art. In a specific embodiment, the two substances will be administered substantially simultaneously, i.e., a few minutes apart from each other, or administered in a single composition containing the two substances. Another embodiment of the application is to administer a combination of agents to a subject in a non-simultaneous manner. In some embodiments, the compound of the present application and another therapeutic agent are administered simultaneously or sequentially in different unit dosage forms, or are administered together in a single unit dosage form. Therefore, the present application provides a single unit dosage form, which comprises one or more compounds of the present application, another therapeutic agent and a pharmaceutically acceptable carrier.

[0202] The dosage of a compound of formula I or a pharmaceutically acceptable salt thereof, a solvate and / or a prodrug varies according to many factors, such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of treatment and the type of concurrent treatment (if any), and the clearance rate of the compound in the subject to be treated. One skilled in the art can determine a suitable dosage based on the above factors. In some embodiments, one or more compounds of formula I or a pharmaceutically acceptable salt thereof, a solvate and / or a prodrug are initially administered at a suitable dosage, which is adjusted as needed based on the clinical response. The dosage is typically selected to maintain a serum level of one or more compounds of formula I or a pharmaceutically acceptable salt thereof, a solvate and / or a prodrug of about 0.01 μg / cc to about 1000 μg / cc, or about 0.1 μg / cc to about 100 μg / cc. As a representative example, for adults, the oral dosage of one or more compounds of Formula I or its pharmaceutically acceptable salt, solvate and / or prodrug will be in the range of about 10 μg / day to about 1000 mg / day, suitably about 10 μg / day to about 500 mg / day, more suitably about 10 μg / day to about 200 mg / day. For parenteral administration, representative amounts are about 0.0001 mg / kg to about 10 mg / kg, about 0.0001 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg or about 0.0001 mg / kg to about 0.01 mg / kg. For oral administration, representative 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 as a suppository, a representative amount is from about 0.1 mg / kg to about 10 mg / kg or from about 0.1 mg / kg to about 1 mg / kg. In some embodiments of the present application, the composition is formulated for oral administration, and the compound(s) are suitably in tablet form, each tablet containing 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 5.0 mg, 10.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 40.0 mg, 50.0 mg, 60.0 mg, 70.0 mg, 75.0 mg, 80.0 mg, 90.0 mg, 100.0 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg of the active ingredient (one or more compounds of 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 dose daily, weekly or monthly, or the total daily dose is divided into two, three or four daily doses.

[0203] 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 that includes administering a dose or dosage regimen that has no clinically significant hallucinogenic / psychotomimetic effects. 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 that includes administering a dose or dosage regimen that provides a clinical effect similar to a human plasma psilocybin Cmax of 4 ng / mL or less and / or a human 5-HT Cmax of 40% or less. 2A Clinical efficacy demonstrated by human CNS receptor occupancy, or human plasma psilocybin Cmax of 1 ng / mL or less and / or 30% or less of human 5-HT 2A 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 that includes administering a dose or a dosage regimen that provides a clinical effect similar to that exhibited by a human plasma psilocybin Tmax of greater than 60 minutes, greater than 120 minutes, or greater than 180 minutes.

[0204] For the sake of clarity, in the above text, the term "compound" also includes embodiments that mention one or more compounds. Likewise, the term "compound of the present application" also includes embodiments that mention only one compound.

[0205] In some embodiments, all available hydrogen atoms in a group are optionally replaced with deuterium, when all available atoms are optionally replaced with their alternative isotopes.

[0206] In some embodiments, Q is Q1 and is a single bond, and the compound of formula I has the following structure:

[0207]

[0208] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0209] in:

[0210] R 1 、R 1' 、R 2 、R 2' 、R 3 、R4 、R 5 、R 6 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 As defined in Formula I, and

[0211] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0212] In some embodiments, Q is Q1 and is a double bond, and the compound of formula I has the following structure:

[0213]

[0214] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0215] in:

[0216] 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 As defined in Formula I, and

[0217] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0218] In some embodiments, Q is Q2 and is a single bond, and the compound of formula I has the following structure:

[0219]

[0220] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0221] in:

[0222] 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 As defined in Formula I, and

[0223] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0224] In some embodiments, Q is Q2 and is a double bond, and the compound of formula I has the following structure:

[0225]

[0226] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0227] in:

[0228] 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 As defined in Formula I, and

[0229] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0230] In some embodiments, Q is Q3 And the compound of formula I has the following structure:

[0231]

[0232] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0233] in:

[0234] 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 As defined in Formula I, and

[0235] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0236] In some embodiments, Q is Q4 And the compound of formula I has the following structure:

[0237]

[0238] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0239] in:

[0240] 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 As defined in Formula I, and

[0241] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0242] In some embodiments, Q is Q5 and is a single bond, and the compound of formula I has the following structure:

[0243]

[0244] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0245] in:

[0246] 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 As defined in Formula I, and

[0247] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0248] In some embodiments, Q is Q5 and is a double bond, and the compound of formula I has the following structure:

[0249]

[0250] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0251] in:

[0252] R 1 、R 1’ 、R 2 、R 2’ 、R 3 、R 4 、R 5 、R 6 、R 48 、R 50 、R51 、R 52 、R 53 、R 54 、R 55 and R 56 As defined in Formula I, and

[0253] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0254] In some embodiments, Q is Q6 And the compound of formula I has the following structure:

[0255]

[0256] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0257] in:

[0258] 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 As defined in Formula I, and

[0259] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof,

[0260] Provided that the compound of formula I comprises D.

[0261] In some embodiments, R 1 、R 2 、R 2’ 、R 2” 、R 3 、R 5 and R 6 All are H, and the compound of formula I has the following structure:

[0262]

[0263] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0264] in:

[0265] R 4 and Q are as defined in Formula I, and

[0266] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0267] In some embodiments, R 1 、R 1’ 、R 2 、R 2’ 、R 3 、R 4 and R 6 All are H, and the compound of formula I has the following structure:

[0268]

[0269] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0270] in:

[0271] R 5 and Q are as defined in Formula I, and

[0272] wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0273] In some embodiments, R 1 、R 1' 、R 2 、R 2' 、R 3 and R 6 All are H, and the compound of formula I has the following structure:

[0274]

[0275] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0276] in:

[0277] R 4 、R 5 and Q are as defined in Formula I, and

[0278] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0279] In some embodiments, R 1 、R 1' 、R 2 and R 2’ All H and R3 、R 4 、R 5 and R 6 All are D, and the compound of formula I has the following structure:

[0280]

[0281] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0282] in:

[0283] Q is as defined in Formula I, and

[0284] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0285] 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 、R57 、R 58 、R 59 、R 62 and R 63 Independently selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl and C 1-6 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 is independently selected from H, F, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. 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 Independently selected from H and D.

[0286] 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 Independently selected from H and D.

[0287] In some embodiments, R 58 、R 59 、R 62 and R 63 are 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 R 59 is D, and R 62 and R 63 For H.

[0288] In some embodiments, when Q is When R 28 or R 38 The stereochemistry at the bonded carbon is R or S. Thus, in some embodiments, Q3 is And Q4 is

[0289] In some embodiments, R 28 or R 38 The stereochemistry at the bonded carbon is R. In some embodiments, R 28 or R 38 The stereochemistry at the bonded carbon is S.

[0290] In some embodiments, when Q is and When it is a single bond, R 15 、R 25 or R 48 The stereochemistry at the bonded carbon is R or S. Thus, in some embodiments, Q1 is Q2 is And Q5 is

[0291] In some embodiments, R 15 、R 25 or R 48 The stereochemistry at the bonded carbon is R. In some embodiments, R 15 、R 25 or R 48 The stereochemistry at the bonded carbon is S.

[0292] In some embodiments, Q is selected from one of the following groups:

[0293]

[0294]

[0295] where R 12 、R 20 、R 29 、R 39 、R 51 、R 60 and R 61 Independently selected from H, D, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl and C(O)-A'. In some embodiments, R 12 、R 20 、R 29 and R 39 Independently selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl and C(O)-A'. In some embodiments, R 12 、R 20 、R 29 、R 39、R 51 、R 60 and R 61 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 Independently selected from CH3 and CD3.

[0296] In some embodiments, Q is selected from one of the following groups:

[0297]

[0298] where R 29 Selected from H, D, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl and C(O)-A'. In some embodiments, R 29 Selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl and C(O)-A'. In some embodiments, R 29 Selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 In some embodiments, R 29 is selected from the group consisting of H, CH3, CD3, CD2H, CF2H, and CF3. In some embodiments, R 29 In some embodiments, R 29 Selected from CH3 and CD3.

[0299] In some embodiments, R 60 and R 61 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered heterocyclic ring optionally contains one or two independently selected from O, N and NR 65 and optionally substituted by one or more independently selected from halo, OH, C 1-4 Alkyl and OC 1-4The alkyl group is substituted with a substituent.

[0300] In some embodiments, R 12 、R 20 、R 29 、R 39 、R 51 、R 60 and R 61 Independently selected from C(O)-A'.

[0301] In some embodiments, R 60 and R 61 One of them is C(O)-A' and the other is selected from H and C 1-6 In some embodiments, R 60 and R 61 One of them is C(O)-A' and the other is selected from H and C 1-4 alkyl.

[0302] In some embodiments, A' is selected from Y, OY and OC 1-2 Alkylene-OC(O)-Y, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, A' is selected from Y, OY and O-C1alkylene-OC(O)-Y, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0303] In some embodiments, Y is C 10-25 In some embodiments, Y is C 13-21 An alkyl group in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0304] In some embodiments, Y is C 10-25 In some embodiments, Y is C 13-21 In some embodiments, Y is C 10-25 alkenyl and contain 1, 2, 3, 4, 5 or 6 double bonds.

[0305] In some embodiments, the alkyl or alkene groups of Y are alkyl or alkene groups present in fatty acid, and wherein all available H atoms are optionally substituted by deuterium. In some embodiments, Y is the alkene groups present in fatty acid, and wherein all available H atoms are optionally substituted by deuterium. In some embodiments, fatty acid is ω-6 fatty acid (i.e. unsaturated or polyunsaturated fatty acid, wherein the nearest double bond from the molecular methyl end is positioned on the 6th carbon starting from the terminal methyl) or ω-3 fatty acid (i.e. unsaturated or polyunsaturated fatty acid, wherein the nearest double bond from the molecular methyl end is positioned on the 3rd carbon starting from the terminal methyl), wherein all available H atoms are optionally substituted by deuterium. In some embodiments, Y is the alkyl or alkene groups present in fatty acid, and wherein all available H atoms are optionally substituted by deuterium. In some embodiments, the alkyl or alkene groups of Y are alkyl or alkene groups present in fatty acid, and this fatty acid is selected from the fatty acid list in table 1:

[0306] Table 1

[0307]

[0308]

[0309] wherein all available H atoms are optionally replaced by deuterium.

[0310] In some embodiments, the olefinic group of Y is an alkyl or alkenyl group present in linoleic acid, eicosadienoic acid, or docosahexaenoic acid.

[0311] In some embodiments, Y is an alkyl or alkenyl group of a fatty acid in which 1-10, 2-8, 2-6, or 2-4 H atoms are replaced by deuterium.

[0312] 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=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=CH(CH2)1CH3.

[0313] In some embodiments, A' is Y.

[0314] In some embodiments, A' is -OY.

[0315] In some embodiments, A' is -O-C3 alkylene-OC(O)-Y.

[0316] In some embodiments, R 1 and R 1’ Independently selected from 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' Independently selected from H, D, Cl, F, OH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, NH(C 1-4 alkyl), NH(C 1-4Deuterated alkyl), NH(C 1-4 Fluoroalkyl), N(C 1-4 alkyl)2, N(C 1-4 Fluoroalkyl)2, N(C 1-4 Deuterated alkyl)2, N(C 1-4 Fluoroalkyl)(C 1-4 alkyl), N(C 1-4 Fluoroalkyl)(C 1-4 Deuterated alkyl) and N(C 1-4 Deuterated alkyl)(C 1-4 In some embodiments, R 1 and 'R 1' Independently selected from H, D, Cl, F, OH, NH2, C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Fluoroalkyl and C 1-2 Deuterated alkyl, NH(C 1-2 alkyl), NH(C 1-2 Deuterated alkyl), NH(C 1-2 Fluoroalkyl), N(C 1-2 alkyl)2, N(C 1-2 Fluoroalkyl)2, N(C 1-2 Deuterated alkyl)2, N(C 1-2 Fluoroalkyl)(C 1-2 alkyl), N(C 1-2 Fluoroalkyl)(C 1-2 Deuterated alkyl) and N(C 1-2 Deuterated alkyl)(C 1-2 In some embodiments, R 1 is selected from the group consisting of H, D, F, NH2, CH3, CF2H, CD2H, CH3O, CF3, CD3, NH(CH3), NH(CD3), NH(CF3), N(CH3)2, N(CF3)2, and N(CD3)2. In some embodiments, R 1 and 'R 1' is independently selected from H, D, F, NH2, CH3, CF2H, CD2H, CH3O, CF3 and CD3. In some embodiments, R 1 and R 1' is independently selected from H, D, F, OH, CH3, CF2H, CD2H, CH3O, CF3 and CD3. In some embodiments, R 1 and R 1’ are independently H, D or F. In some embodiments, R 1 and R 1' All are H or all are D. In some embodiments, R 1 and R 1'Both are H.

[0317] In some embodiments, R 2 and R 2’ independently selected from 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’ Independently selected from H, D, Cl, F, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, NH(C 1-4 alkyl), NH(C 1-4 Deuterated alkyl), NH(C 1-4 Fluoroalkyl), N(C 1-4 Alkyl)2, N(C 1-4 Fluoroalkyl)2, N(C 1-4 Deuterated alkyl)2, N(C 1-4 Fluoroalkyl)(C 1-4 alkyl), N(C 1-4 Fluoroalkyl)(C 1-4 Deuterated alkyl) and N(C 1-4 Deuterated alkyl)(C 1-4 In some embodiments, R 2 and R 2’ Independently selected from H, D, Cl, F, C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Fluoroalkyl, C 1-2 Deuterated alkyl, NH(C 1-2 alkyl), NH(C 1-2 Deuterated alkyl), NH(C 1-2 Fluoroalkyl), N(C 1-2 Alkyl)2, N(C 1-2 Fluoroalkyl)2, N(C 1-2 Deuterated alkyl)2, N(C 1-2 Fluoroalkyl)(C 1-2 alkyl), N(C 1-2 Fluoroalkyl)(C 1-2 Deuterated alkyl) and N(C 1-2 Deuterated alkyl)(C 1-2 In some embodiments, R 2 and R 2’is independently selected from H, D, F, NH2, CH3, CF2H, CD2H, CH3O, CF3, CD3, NH(CH3), NH(CD3), NH(CF3), N(CH3)2, N(CF3)2, and N(CD3)2. In some embodiments, R 1 is selected from the group consisting of H, D, F, NH2, CH3, CF2H, CD2H, CH3O, CF3 and CD3. In some embodiments, R 2 and R 2’ is independently selected from H, D, F, CH3, CF2H, CD2H, CH3O, CF3 and CD3. In some embodiments, R 2 and R 2' are independently H, D or F. In some embodiments, R 2 and R 2' All are H or all are D. In some embodiments, R 2 and R 2’ All are H.

[0318] In some embodiments, R 1 、R 1' 、R 2 and R 2’ are independently H, D or F. In some embodiments, R 1 、R 1' 、R 2 and R 2’ All are H or all are D. In some embodiments, R 1 、R 1' 、R 2 and R 2’ All are H.

[0319] In some embodiments, R 3 and R 6 Independently selected from H, D, Cl, F, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluoroalkyl and C 1-4 In some embodiments, R 3 and R 6 Independently selected from 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 3 and R 6 Independently selected from H, D, Cl, F, OH, C1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Fluoroalkoxy, C 1-2 Deuterated alkoxy, C 1-2 Fluoroalkyl and C 1-2 In some embodiments, R 3 and R 6 Independently selected from 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 3 and R 6 is independently selected from H, D, F, OH, CH3, CH3O, CF2HO, CD2HO, CF3O, CD3O, CF2H, CD2H, CF3, and CD3. In some embodiments, R 3 and R 6 is independently selected from H, D, F, OH, CH3, CH3O, CF2H, CD2H, CF3 and CD3. In some embodiments, R 3 and R 6 is independently selected from H, D, F, OH, CH3, CH3O, CF2HO, CF3O, and CD3O. In some embodiments, R 3 and R 6 are independently selected from H and D. In some embodiments, R 3 and R 6 At least one of is D. In some embodiments, R 3 and R 6 Each of is D. In some embodiments, R 3 and R 6 Each of is H.

[0320] In some embodiments, R 4 and R 5 One or both of them are independently selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 In some embodiments, R 4 and R 5 Two of them are independently selected from H, D, F, Cl, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 In some embodiments, R 4 and R 5 One or both of 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, CH3CH2O, CH3O, CF3O, CHF2O, CF2HCH2O, CF3CH2O, (CF3)2CHO, and CD3O. In some embodiments, R 4 and R 5 One or both are independently selected from H, D, F, Cl, CH3, CH(CH3)2, CF3, CF2H, CD3, CH3O, CH(CH3)2O, CF3O, CHF2O and CD3O.

[0321] In some embodiments, R 4 and R 5 Two of them are independently selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 In some embodiments, R 4 and R 5 Two of them are independently selected from D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 In some embodiments, R 4 and R 5 Two of them are independently selected from H, D, F, Cl, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 In some embodiments, R 4 and R 5In some embodiments, R 4 and R 5 In some embodiments, R 4 and R 5 In some embodiments, R 4 and R 5 Both of them are CD3O, or R 4 and R 5 Both of them are CH3O.

[0322] In some embodiments, R 4 H or D and R 5 Selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 In some embodiments, R 4 H or D and R 5 Selected from H, D, F, Cl, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 In some embodiments, R 4 H or D and R 5 is selected from the group consisting of H, D, F, Cl, CH(CH3)2, CH3, CF3, CF2H, CD3, CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 4 H or D and R 5 is selected from the group consisting of D, F, Cl, CH(CH3)2, CH3, CF3, CF2H, CD3, CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 4 H or D and R 5is selected from CH(CH3)2O, CH3O, CF3O, CHF2O and CD3O. In some embodiments, R 4 H and R 5 Selected from CH3O and CD3O.

[0323] In some embodiments, R 5 H or D and R 4 Selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 In some embodiments, R 5 H or D and R 4 Selected from H, D, F, Cl, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 In some embodiments, R 5 H or D and R 4 is selected from the group consisting of D, F, Cl, CH3, CH(CH3)2, CF3, CF2H, CD3, CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 5 H or D and R 4 is selected from CH(CH3)2O, CH3O, CF3O, CHF2O and CD3O. In some embodiments, R 5 H and R 4 Selected from CH3O and CD3O.

[0324] In some embodiments, R 4 and R 5 Connect together to form O-CH2O.

[0325] In some embodiments, R 3 、R 4 、R 5 and R 6 is selected from the group consisting of D, F, Cl, CH3, CH(CH3)2, CF3, CF2H, CD3, CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 3 、R 4 、R 5 and R 6All H, or in some embodiments, R 3 、R 4 、R 5 and R 6 All are 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 selected from H or D, and R 3 、R 4 、R 5 and R 6 The remaining groups in are 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 selected from H or D, and R 3 、R 4 、R 5 and R 6 The remaining groups in are selected from CH3O and CD3O. In some embodiments, R 3 、R 4 、R 5 and R 6 One of is selected from H or D, and R 3 、R 4 、R 5 and R 6 The remaining groups in are selected from CH(CH3)2O, CH3O, CF3O, CHF2O and CD3O. In some embodiments, R 3 、R 4 、R 5 and R 6 One of is selected from H or D, and R 3 、R 4 、R 5 and R 6 The remaining groups in are selected from CH3O and CD3O.

[0326] In some embodiments, R 4 and R 5 One of them is selected from XLA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6Alkoxy.

[0327] In some embodiments, X is a direct bond, R 4 and R 5 One of them is selected from LA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 In some embodiments, X is selected from O, C(O), NR a NR 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 NR 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 selected from O, NR a NR a C(O), C(O)NR a NR a C(O)O、OC(O)NR a and NR a C(O)NR a In some embodiments, X is selected from NR a C(O), C(O)NR a NR a C(O)O、OC(O)NR a and NR 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 NR 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 .

[0328] In some embodiments, L is selected from a direct bond, C 1-4 Alkylene, C 2-4 Alkenylene, C1-4 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 Alkylene C(O)NR b 、C 2-4 Alkenylene C(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)OC 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 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 Alkylene C(O)NR b 、C 2-4 Alkenylene C(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), C1-2 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 OC(O)O, C 2-4 Alkenylene OC(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 Alkylene C(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 Alkylene OC(O)O and C 1-2 Alkylene NR b C(O)NR b In some embodiments, L is selected from a direct bond, CH2, CF2, CD2, CH2-O, CF2-O, CD2-O, CH2-C(O), CF2-C(O), CD2-C(O), CH2-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 .

[0329] In some embodiments, X is a direct bond, L is a direct bond, and R 4 and R 5 One of them is selected from A, and R 4 and R 5 The other one is selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy.

[0330] In some embodiments, X is selected from O, OC(O), C(O)O, NR a C(O) and C(O)NR a , R 4 and R 5 One of them is selected from 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 Alkylene C(O)NR b -A, OC 1-2 Alkylene OC(O)-A, OC 1-2 Alkylene C(O)OA, OC 1-2 Alkylene OC(O)NR b -A, OC 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, OC(O)-C 1-2 Alkylene NRb C(O)-A, OC(O)-C 1-2 Alkylene C(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 Alkylene C(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 Alkylene C(O)NR b -A, NR a C(O)-C1-2 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 Alkylene C(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 Alkylene OC(O)OA and C(O)NR a -C 1-2 Alkylene NR b C(O)NR b -A, and R 4 and R 5 The other one is selected from H, halogen, C 1-4 Alkyl and C 1-4Alkoxy, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, X is selected from O, OC(O), C(O)O, NR a C(O) and C(O)NR a , R 4 and R 5 One of them is selected from 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 Alkylene C(O)NR b -A, OC 1-2 Alkylene OC(O)-A, OC 1-2 Alkylene C(O)OA, OC 1-2 Alkylene OC(O)NR b -A, OC 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, OC(O)-C 1-2 Alkylene NR b C(O)-A, OC(O)-C 1-2 Alkylene C(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 1-2Alkylene C(O)-A, C(O)OC 1-2 Alkylene NR b C(O)-A, C(O)OC 1-2 Alkylene C(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 Alkylene C(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 1-2Alkylene 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 Alkylene C(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 Alkylene OC(O)OA and C(O)NR a -C 1-2 Alkylene NR b C(O)NR b -A, and R 4 and R 5 The other one is selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy groups in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0331] In some embodiments, R 4 and R 5 The other one is selected from H, F, Cl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl and C 1-4 Alkoxy, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, R 4 and R 5 The other of is selected from D, F, Cl, CH3, CH(CH3)2, CF3, CF2H, CD3, CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms, and R 4 and R 5 The other one is H or D.

[0332] In some embodiments, R4 For XLA and R 5 Selected from H, halogen, C 1-6 Alkyl and C 1-6 In some embodiments, R 5 For XLA and R 4 Selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy.

[0333] In some embodiments, R a Selected from H and C 1-4 alkyl.

[0334] In some embodiments, R b Selected from H, C 1-4 Alkyl and A.

[0335] In some embodiments, A is H, R 4 and R 5 One of 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 Alkylene C(O)NHR b 、XC 2-4 Alkenylene C(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 AlkyleneOC(O)NHR b 、XC 2-4Alkenylene OC(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 , and R 4 and R 5 The other one is selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, A is H, R 4 and R 5 One of 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 Alkylene C(O)NHR b 、XC 2-4 Alkenylene C(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, XC1-2 AlkyleneOC(O)NHR b 、XC 2-4 Alkenylene OC(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 , and R 4 and R 5 The other one is selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy groups in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0336] In some embodiments, A is H and X is a direct bond. Thus, in some embodiments, and R 4 and R 5 One of them is selected from 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 Alkylene C(O)NHR b 、C 2-4 Alkenylene C(O)NHR b 、C 1-4 Alkylene OC(O)H, C 2-4 Alkenylene OC(O)H, C 1-4 Alkylene C(O)OH, C 2-4 Alkenylene C(O)H, C 1-4 AlkyleneOC(O)NHR b 、C 2-6 Alkenylene OC(O)NHR b 、C 1-4 Alkylene NR bC(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 , and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy.

[0337] In some embodiments, A is H and X is selected from O, C(O), NR a NR 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 NR 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 selected from NR a NR a C(O), C(O)NR a NR a C(O)O、OC(O)NR a and NR a C(O)NR a In some embodiments, A is H and X is selected from NR a C(O), C(O)NR a NR a C(O)O、OC(O)NR a and NR 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 aand NR a C(O)NR a .

[0338] In some embodiments, A is H, and L is a direct bond, R 3 and R 4 One of is selected from XH. Thus, in some embodiments, and R 3 and R 4 One of 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 are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0339] In some embodiments, when A is H, R b Selected from H and C 1-4 An alkyl group in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0340] In some embodiments, R 4 and R 5 One of 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 OC 1-4 Alkylene-C(O)OA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy groups in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0341] In some embodiments, R 4 and R 5 One of is selected from A, OA, C(O)-A, C(O)-A and C(O)OA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6Alkoxy, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, R 4 and R 5 In some embodiments, one of R 4 and R 5 In some embodiments, one of R 4 and R 5 In some embodiments, one of R 4 and R 5 One of them is C(O)OA.

[0342] In some embodiments, R 4 and R 5 One of them is selected from 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 OC 1-4 Alkylene-C(O)OA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, R 4 and R 5 One of them is C 1-4 Alkylene-A. In some embodiments, R 4 and R 5 One of them is C 1-4 Alkylene-C(O)-A. 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 OC 1-4 Alkylene-A. In some embodiments, R 4 and R 5 One of them is OC 1-4 Alkylene-C(O)-A. In some embodiments, R 4 and R 5 One of them is OC 1-4 Alkylene-C(O)OA.

[0343] In some embodiments, R 4and R 5 One of 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 OC 1-4 Alkylene-C(O)OA, and R 4 and R 5 The other one is selected from H, F, Cl, C 1-4 Alkyl and C 1-4 Alkoxy, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, R 4 and R 5 One of 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 OC 1-4 Alkylene-C(O)OA, and R 4 and R 5 The other one is selected from H, F, Cl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl and C 1-4 Alkoxy, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, R 4 and R 5 One of 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 OC 1-2 Alkylene-C(O)OA, and R 4 and R 5The other of is selected from D, F, Cl, CH3, CH(CH3)2, CF3, CF2H, CD3, CH(CH3)2O, CHO, CF3O, CHF2O, and CD3O, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, R 4 and R 5 One of 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 OC 1-2 Alkylene-C(O)OA, and R 4 and R 5 The other of is H or D, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, R 4 and R 5 One of them is selected from 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, -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, and R 4 and R 5 The other one is H or D.

[0344] In some embodiments, R 4 Selected from 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 OC 1-2 Alkylene-C(O)OA, and R 5 is H or D, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. 4Selected from 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, 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, and R 5 is H or D. In some embodiments, R 5 Selected from 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 OC 1-2 Alkylene-C(O)OA, and R 4 is H or D, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. 5 Selected from 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, 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, and R 4 It is H or D.

[0345] In some embodiments, A is selected from C 1-30 Alkyl, C 2-30 Alkenyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 64 The heterocyclic alkyl group of the heterocyclic alkyl group is 3 to 6 members and contains 1 to 3 independently selected from O, S, S (O), SO2, N and NR 64 The 5- to 6-membered heteroaryl group of the hetero portion, wherein the phenyl group, C 3-10Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, OH, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 In some embodiments, A is selected from C 1-30 Alkyl, C 2-30 Alkenyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 64 The heterocyclic alkyl group of the heterocyclic alkyl group is 3 to 6 members and contains 1 to 3 independently selected from O, S, S (O), SO2, N and NR 64 The 5- to 6-membered heteroaryl group of the hetero portion, wherein the phenyl group, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, OH, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 Fluoroalkyl.

[0346] In some embodiments, A is selected from phenyl, C 3-6 Cycloalkyl, containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 64 The heterocyclic alkyl group of the heterocyclic alkyl group is 3 to 6 members and contains 1 to 3 independently selected from O, S, S (O), SO2, N and NR 64 The 5- to 6-membered heteroaryl group of the hetero portion, wherein the phenyl group, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 In some embodiments, A is selected from phenyl, C 3-6 Cycloalkyl, containing 1 to 2 independently selected from O, S, S(O), SO2, N and NR 48The heterocyclic 5- to 6-membered alkyl group of the heterocyclic group and containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 64 The 5- to 6-membered heteroaryl group of the hetero portion, wherein the phenyl group, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 Fluoroalkyl.

[0347] In some embodiments, C in A 3-6 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In some embodiments, C in A 3-6 Cycloalkyl is cyclopropyl optionally substituted by one or two substituents independently selected from the group consisting of F, Cl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 Fluoroalkyl.

[0348] In some embodiments, A comprises 1 to 3 independently selected from O, S, S(O), SO2, N and NR 64The 3- to 6-membered heterocycloalkyl group of the hetero portion is selected from aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, thitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl , isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl oxide, tetrahydrothiopyranyl dioxide, dihydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, and dithianyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of F, C, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 In some embodiments, A comprises 1 to 3 independently selected from O, S, S(O), SO2, N and NR 64 The 3- to 6-membered heterocycloalkyl group of the hetero portion is selected from tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, dioxolane, piperidinyl, thiomorpholinyl, thiomorpholinylsulfoxide, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl oxide, tetrahydrothiopyran dioxide, dihydropyranyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of F, C, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 Fluoroalkyl.

[0349] In some embodiments, the 5- to 6-membered heteroaryl in A is selected from furanyl, imidazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyrrolyl, thienofuranyl, triazolyl, and thienyl, each of which is optionally substituted with one or two substituents independently selected from F, C, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 In some embodiments, the 5- to 6-membered heteroaryl in A is selected from furanyl, isothiazolyl, thiazolyl, pyridinyl, and pyrrolyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of F, C, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 Fluoroalkyl.

[0350] In some embodiments, the phenyl group in A, C 3-10 The cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl groups are optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, CD3, CH(CH3)2O, CH3CH2CH2O, CH3CH2O, CH3O, CF3O, CHF2O, CF2HCH2O, CF3CH2O, (CF3)2CHO, and CD3O.

[0351] In some embodiments, A is selected from C 1-30 Alkyl and C 2-30 alkenyl groups in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0352] In some embodiments, A is C 10-25 In some embodiments, A is C 13-21 An alkyl group in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0353] In some embodiments, A is C 10-25 In some embodiments, A is C 13-21In some embodiments, A is C 10-25 alkenyl and contain 1, 2, 3, 4, 5 or 6 double bonds.

[0354] In some embodiments, the alkyl or alkene groups of A are alkyl or alkene groups present in fatty acid, and wherein all available H atoms are optionally substituted by deuterium. In some embodiments, A is the alkene groups present in fatty acid, and wherein all available H atoms are optionally substituted by deuterium. In some embodiments, fatty acid is ω-6 fatty acid (i.e. unsaturated or polyunsaturated fatty acid, wherein the double bond nearest to the molecular methyl end is positioned on the 6th carbon starting from the terminal methyl) or ω-3 fatty acid (i.e. unsaturated or polyunsaturated fatty acid, wherein the double bond nearest to the molecular methyl end is positioned on the 3rd carbon starting from the terminal methyl), wherein all available H atoms are optionally substituted by deuterium. In some embodiments, A is the alkyl or alkene groups present in fatty acid, and wherein all available H atoms are optionally substituted by deuterium. In some embodiments, A is the alkyl or alkene groups present in fatty acid, and this fatty acid is selected from the fatty acid list in table 1, and wherein all available H atoms are optionally substituted by deuterium.

[0355] In some embodiments, the olefinic group of A is an alkyl or alkenyl group present in linoleic acid, eicosadienoic acid, or docosahexaenoic acid.

[0356] In some embodiments, when A is an alkyl or alkenyl group of a fatty acid, 1-10, 2-8, 2-6, or 2-4 H atoms are replaced by deuterium.

[0357] 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=CH(CH2)1CH3.

[0358] In some embodiments, R 64 and R 65 Independently selected from H, D, C 1-4 Alkyl, C 1-4Fluoroalkyl and C 1-4 In some embodiments, R 64 and R 65 is independently selected from H, D, CH3, CF3 and CD3. In some embodiments, R 64 and R 65 Independently selected from CH3 and CD3.

[0359] In some embodiments, the compound of Formula I is defined as follows:

[0360]

[0361] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0362] in:

[0363] Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6:

[0364]

[0365] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 Does not exist, when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q5 When it is a double bond, R 48 and R 57 does not exist;

[0366] R 1 、R 1' 、R 2 、R 2' 、R 3 and R 6 independently selected from H, D and F;

[0367] R 4 and R 5 One or both of them are selected from H, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 deuterated alkoxy, or

[0368] R 4 and R 5 Linked together to form O-(CH2) 1-2 O;

[0369] R 8 、R 9 、R10 、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 independently selected from H and D;

[0370] R 12 、R 20 、R 29 、R 39 and R 51 Independently selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 deuterated alkyl, and

[0371] R 60 and R 61 Independently selected from H and C 1-6 alkyl,

[0372] Provided that when Q is Q6, then the compound of formula I comprises D.

[0373] In some embodiments, the compound of Formula I is defined as follows:

[0374]

[0375] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0376] in:

[0377] R 1 and R 1’ Independently selected from H, halo, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2;

[0378] R 2 and R 2' independently selected from H, halo, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2;

[0379] Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6:

[0380]

[0381]

[0382] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 Does not exist, when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q5 When it is a double bond, R 48 and R 57 does not exist;

[0383] R 4 and R 5 One or both of them are independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, or

[0384] R 4 and R 5 Linked together to form O-(CH2) 1-2 O, or

[0385] R 4 and R 5 One of them is selected from XLA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy,

[0386] X is selected from direct bond, O, C(O), NR a NR 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 NR a C(O)NR a ;

[0387] L is selected from 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 Alkylene C(O)NR b 、C 2-6 Alkenylene C(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)OC 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 NRb C(O)NR b ;

[0388] R a Selected from H and C 1-6 alkyl;

[0389] R b Selected from H, C 1-6 Alkyl and A;

[0390] A is selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 64 The heterocyclic alkyl group of the heterocyclic alkyl group is 3 to 6 members and contains 1 to 4 independently selected from O, S, S (O), SO2, N and NR 64 The 5-membered to 6-membered heteroaryl group of the hetero part, wherein phenyl, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted by one or more independently selected from halo, C 1-4 Alkyl and OC 1-4 Substitution of alkyl groups;

[0391] R 3 and R 6 are independently selected from H, halo, OH, C 1-6 Alkyl and C 1-6 alkoxy;

[0392] 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 、R40 、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 selected from H, halo and C 1-6 alkyl;

[0393] R 12 、R 20 、R 29 、R 39 and R 51 Independently selected from H, C 1-6 Alkyl, C(O)C 1-6 Alkyl and C(O)-A';

[0394] R 60 and R 61 Independently selected from H and C 1-6 alkyl; or

[0395] R 60 and R 61 One of them is C(O)-A' and the other is selected from H and C 1-6 alkyl;

[0396] wherein A' is selected from Y, OY and OC 1-4 Alkylene-OC(O)-Y; and

[0397] Y is selected from C 7-30 Alkyl and C 7-30 alkenyl; or

[0398] R 60 and R 61 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered heterocyclic ring optionally contains one or two independently selected from O, S, S(O), SO2, N and NR 65 and optionally substituted by one or more independently selected from halo, OH, C 1-4 Alkyl and OC 1-4 Substitution of alkyl groups;

[0399] R 64 and R 65 Independently selected from H and C 1-6 alkyl; and

[0400] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof,

[0401] The condition is R 12 、R 20 、R 29 、R 39 、R 51 、R 60 and R 61 one of which is C(O)-A'; or

[0402] R 4 and R 5 One of them is selected from XLA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, provided that when X and L are direct bonds, A is not H, C 1-6 Alkyl or C 1-6 alkenyl.

[0403] Those skilled in the art will understand that when R 2 and R 2’ At different times, R 2 and R 2’ The carbon to which it is bonded is chiral. Therefore, the present application includes all stereoisomers at this carbon center and mixtures thereof.

[0404] Those skilled in the art will understand that when R 1 and R 1’ At different times, R 1 and R 1’ The carbon to which it is bonded is also chiral. Therefore, the present application includes all stereoisomers at this carbon center and mixtures thereof.

[0405] In some embodiments, the compound of Formula I is selected from the compounds listed below, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof:

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415] III. New compounds of the present application

[0416] Certain compounds of Formula I are novel, and thus the present application includes these compounds and compositions comprising these compounds and their uses. Thus, in some embodiments, the compound of Formula I is a compound of Formula IA. Thus, the present application includes a compound of Formula IA or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof,

[0417]

[0418] in:

[0419] R 1 、R 1' 、R 2 、R 2' 、R 3 、R 4 、R 5 、R 5 and Q are as defined above for Formula I, and

[0420] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof,

[0421] Provided that when Q is Q6, then the compound of formula IA comprises D,

[0422] When Q is Q3 or Q4, then when R 5 is H or OCH3, and R 29 or R 39 When it is CH3, R 1 、R 1' 、R 2 、R 2' 、R 3 、R 4 、R 6 、R 26 、R 27 、R 28 、R 30 to R 35 、R36 、R 37 、R 38 and R 40 to R 47 Not all are H; and

[0423] When Q is Q4 and R 1 、R 1' 、R 2 、R 2' 、R 3 、R 4 、R 6 、R 38 and R 40 to R 47 When all are H, then when R 39 When it is CD3, R 36 and R 37 Not all are D.

[0424] In some embodiments, all available hydrogen atoms are optionally and independently replaced with fluorine atoms, and all available atoms are optionally replaced with alternative isotopes thereof.

[0425] In some embodiments, Q is Q1 and is a single bond, and the compound of Formula IA has the following structure:

[0426]

[0427] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0428] in:

[0429] 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 As defined in Formula IA, and

[0430] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0431] In some embodiments, Q is Q1 and is a double bond, and the compound of Formula IA has the following structure:

[0432]

[0433] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0434] in:

[0435] 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 As defined in Formula IA, and

[0436] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0437] In some embodiments, when all available hydrogen atoms in a group are optionally replaced by halogen atoms, the halogen atoms are F, Cl, or Br. In some embodiments, when all available hydrogen atoms in a group are optionally replaced by halogen atoms, the halogen atoms are F or Br. In some embodiments, when all available hydrogen atoms in a group are optionally replaced by halogen atoms, the halogen atoms are F or Cl. In some embodiments, when all available hydrogen atoms in a group are optionally replaced by halogen atoms, the halogen atoms are F.

[0438] In some embodiments, all available hydrogen atoms in a group are optionally replaced with deuterium, when all available atoms are optionally replaced with their alternative isotopes.

[0439] In some embodiments, Q is Q2 and is a single bond, and the compound of Formula IA has the following structure:

[0440]

[0441] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0442] in:

[0443] R 1 、R 1' 、R2 、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 As defined in Formula IA, and

[0444] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0445] In some embodiments, Q is Q2 and is a double bond, and the compound of Formula IA has the following structure:

[0446]

[0447] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0448] in:

[0449] 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 As defined in Formula IA, and

[0450] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0451] In some embodiments, Q is Q3 And the compound of formula IA has the following structure:

[0452]

[0453] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0454] in:

[0455] 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 As defined in Formula IA, and

[0456] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof,

[0457] The condition is that when R 5 is H or OCH3, and R 29 When it is CH3, R 1 、R 1' 、R 2 、R 2’ 、R 3 、R 4 、R 6 、R 26 、R 27 、R 28 、R 30 to R 35 、R 36 、R 37 、R 38 and R 40 to R 47 Not all are H.

[0458] In some embodiments, Q is Q4 And the compound of formula IA has the following structure:

[0459]

[0460] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0461] in:

[0462] R 1 、R1' 、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 As defined in Formula IA, and

[0463] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof, provided that when R 5 is H or OCH3, and R 39 When it 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 to R 47 Not all H, and

[0464] When R 1 、R 1' 、R 2 、R 2' 、R 3 、R 4 、R 6 、R 38 and R 40 to R 47 When all are H, then when R 39 When it is CD3, R 36 and R 37 Not all are D.

[0465] In some embodiments, Q is Q5 and is a single bond, and the compound of Formula IA has the following structure:

[0466]

[0467] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0468] in:

[0469] 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 As defined in Formula IA, and

[0470] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0471] In some embodiments, Q is Q5 and is a double bond, and the compound of Formula IA has the following structure:

[0472]

[0473] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0474] in:

[0475] 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 As defined in Formula IA, and

[0476] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0477] In some embodiments, Q is Q6 And the compound of formula IA has the following structure:

[0478]

[0479] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0480] in:

[0481] 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 As defined in Formula IA, and

[0482] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof,

[0483] with the proviso that the compound of formula IA comprises D.

[0484] In some embodiments, R 1 、R 2 、R 2’ 、R 2” 、R 3 、R 5 and R 6 All are H, and the compound of formula IA has the following structure:

[0485]

[0486] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0487] in:

[0488] R 4 and Q are as defined in Formula IA, and

[0489] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof,

[0490] Provided that when Q is Q6, then the compound of formula IA comprises D,

[0491] When Q is Q3 or Q4, then when R 5 is H or OCH3, and R 29 or R 39 When it is CH3, R 4 、R 26 、R 27 、R 28 、R 30 to R 35 、R 36 、R 37 、R 38 and R 40 to R 47 Not all H, and

[0492] When Q is Q4 and R 4 、R 38 and R 40 to R 47 When all are H, then when R 39 When it is CD3, R 36 and R 37 Not all are D.

[0493] In some embodiments, R 1 、R 1' 、R 2 、R 2' 、R 3 、R 4 and R 6 All are H, and the compound of formula I has the following structure:

[0494]

[0495] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0496] in:

[0497] R 5 and Q are as defined in Formula IA, and

[0498] wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof,

[0499] Provided that when Q is Q6, then the compound of formula IA comprises D,

[0500] When Q is Q3 or Q4, then when R 5 is H or OCH3, and R 29 or R 39 When it is CH3, R 26 、R 27 、R 28、R 30 to R 35 、R 36 、R 37 、R 38 and R 40 to R 47 Not all H, and

[0501] When Q is Q4 and R 38 and R 40 to R 47 When all are H, then when R 39 When it is CD3, R 36 and R 37 Not all are D.

[0502] In some embodiments, R 1 、R 1' 、R 2 、R 2' 、R 3 and R 6 All are H, and the compound of formula IA has the following structure:

[0503]

[0504] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0505] in:

[0506] R 4 、R 5 and Q are as defined in Formula I, and

[0507] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof,

[0508] Provided that when Q is Q6, then the compound of formula IA comprises D,

[0509] When Q is Q3 or Q4, then when R 5 is H or OCH3, and R 29 or R 39 When it is CH3, R 4 、R 26 、R 27 、R 28 、R 30 to R 35 、R 36 、R 37 、R 38 and R 40 to R 47 Not all H, and

[0510] When Q is Q4 and R 4 、R 38 and R 40 to R 47 When all are H, then when R 39 When it is CD3, R 36 and R 37 Not all are D.

[0511] In some embodiments, R 1 、R 1' 、R 2 and R 2’ All H and R 3 、R 4 、R 5 and R 6 All are D, and the compound of formula IA has the following structure:

[0512]

[0513] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0514] in:

[0515] Q is as defined in Formula I, and

[0516] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0517] 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 Independently selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl and C 1-6 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 、R54 、R 55 、R 56 、R 57 、R 58 、R 59 、R 62 and R 63 is independently selected from H, F, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. 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 Independently selected from H and D.

[0518] 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 Independently selected from H and D.

[0519] In some embodiments, R 58 、R 59 、R 62 and R 63 are 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 For H.

[0520] In some embodiments, when Q is When R 28 or R 38 The stereochemistry at the bonded carbon is R or S. Thus, in some embodiments, Q3 is And Q4 is

[0521] In some embodiments, R 28 or R 38 The stereochemistry at the bonded carbon is R. In some embodiments, R 28 or R 38 The stereochemistry at the bonded carbon is S.

[0522] In some embodiments, when Q is and When it is a single bond, R 15 、R 25 or R 48 The stereochemistry at the bonded carbon is R or S. Thus, in some embodiments, Q1 is Q2 is And Q5 is

[0523] In some embodiments, R 15 、R 25 or R 48 The stereochemistry at the bonded carbon is R. In some embodiments, R 15 、R 25 or R 48 The stereochemistry at the bonded carbon is S.

[0524] In some embodiments, Q is selected from one of the following groups:

[0525]

[0526]

[0527] where R 12 、R 20 、R 29 、R 39 、R 51 、R 60 and R 61 Independently selected from H, D, C 1-6 Alkyl, C1-6 Fluoroalkyl, C 1-6 Deuterated alkyl and C(O)-A'. In some embodiments, R 12 、R 20 、R 29 and R 39 Independently selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl and C(O)-A'. In some embodiments, R 12 、R 20 、R 29 、R 39 、R 51 、R 60 and R 61 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 Independently selected from CH3 and CD3.

[0528] In some embodiments, Q is selected from one of the following groups:

[0529]

[0530] where R 29 Selected from H, D, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl and C(O)-A'. In some embodiments, R 29 Selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl and C(O)-A'. In some embodiments, R 29 Selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 In some embodiments, R 29 is selected from the group consisting of H, CH3, CD3, CD2H, CF2H, and CF3. In some embodiments, R29 In some embodiments, R 29 Selected from CH3 and CD3.

[0531] In some embodiments, R 60 and R 61 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered heterocyclic ring optionally contains one or two independently selected from O, N and NR 65 and optionally substituted by one or more independently selected from halo, OH, C 1-4 Alkyl and OC 1-4 The alkyl group is substituted with a substituent.

[0532] In some embodiments, R 12 、R 20 、R 29 、R 39 、R 51 、R 60 and R 61 Independently selected from C(O)-A'.

[0533] In some embodiments, R 60 and R 61 One of them is C(O)-A' and the other is selected from H and C 1-6 In some embodiments, R 60 and R 61 One of them is C(O)-A' and the other is selected from H and C 1-4 alkyl.

[0534] In some embodiments, A' is selected from Y, OY and OC 1-2 Alkylene-OC(O)-Y, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, A' is selected from Y, OY and O-C1alkylene-OC(O)-Y, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0535] In some embodiments, Y is C 10-25 In some embodiments, Y is C 13-21 An alkyl group in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0536] In some embodiments, Y is C 10-25 In some embodiments, Y is C 13-21In some embodiments, Y is C 10-25 alkenyl and contain 1, 2, 3, 4, 5 or 6 double bonds.

[0537] In some embodiments, the alkyl or alkene groups of Y are alkyl or alkene groups present in fatty acid, and wherein all available H atoms are optionally substituted by deuterium. In some embodiments, Y is the alkene groups present in fatty acid, and wherein all available H atoms are optionally substituted by deuterium. In some embodiments, fatty acid is ω-6 fatty acid (i.e. unsaturated or polyunsaturated fatty acid, wherein the nearest double bond from the molecular methyl end is positioned on the 6th carbon starting from the terminal methyl) or ω-3 fatty acid (i.e. unsaturated or polyunsaturated fatty acid, wherein the nearest double bond from the molecular methyl end is positioned on the 3rd carbon starting from the terminal methyl), wherein all available H atoms are optionally substituted by deuterium. In some embodiments, Y is the alkyl or alkene groups present in fatty acid, and wherein all available H atoms are optionally substituted by deuterium. In some embodiments, Y is the alkyl or alkene groups present in fatty acid, and this fatty acid is selected from the fatty acid list in table 1, and wherein all available H atoms are optionally substituted by deuterium.

[0538] In some embodiments, the olefinic group of Y is an alkyl or alkenyl group present in linoleic acid, eicosadienoic acid, or docosahexaenoic acid.

[0539] In some embodiments, Y is an alkyl or alkenyl group of a fatty acid in which 1-10, 2-8, 2-6, or 2-4 H atoms are replaced by deuterium.

[0540] 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=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=CH(CH2)1CH3.

[0541] In some embodiments, A' is Y.

[0542] In some embodiments, A' is -OY.

[0543] In some embodiments, A' is -O-C3 alkylene-OC(O)-Y.

[0544] In some embodiments, R 1 and R 1’ Independently selected from 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' Independently selected from H, D, Cl, F, OH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, NH(C 1-4 alkyl), NH(C 1-4Deuterated alkyl), NH(C 1-4 Fluoroalkyl), N(C 1-4 Alkyl)2, N(C 1-4 Fluoroalkyl)2, N(C 1-4 Deuterated alkyl)2, N(C 1-4 Fluoroalkyl)(C 1-4 alkyl), N(C 1-4 Fluoroalkyl)(C 1-4 Deuterated alkyl) and N(C 1-4 Deuterated alkyl)(C 1-4 In some embodiments, R 1 and R 1' Independently selected from H, D, Cl, F, OH, NH2, C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Fluoroalkyl and C 1-2 Deuterated alkyl, NH(C 1-2 alkyl), NH(C 1-2 Deuterated alkyl), NH(C 1-2 Fluoroalkyl), N(C 1-2 Alkyl)2, N(C 1-2 Fluoroalkyl)2, N(C 1-2 Deuterated alkyl)2, N(C 1-2 Fluoroalkyl)(C 1-2 alkyl), N(C 1-2 Fluoroalkyl)(C 1-2 Deuterated alkyl) and N(C 1-2 Deuterated alkyl)(C 1-2 In some embodiments, R 1 is selected from the group consisting of H, D, F, NH2, CH3, CF2H, CD2H, CH3O, CF3, CD3, NH(CH3), NH(CD3), NH(CF3), N(CH3)2, N(CF3)2, and N(CD3)2. In some embodiments, R 1 and R 1' In some embodiments, R 1 and R 1' is independently selected from H, D, F, OH, CH3, CF2H, CD2H, CH3O, CF3 and CD3. In some embodiments, R 1 and R 1' are independently H, D or F. In some embodiments, R 1 and R 1' All are H or all are D. In some embodiments, R 1 and R 1'Both are H.

[0545] In some embodiments, R 2 and R 2’ independently selected from 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’ Independently selected from H, D, Cl, F, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, NH(C 1-4 alkyl), NH(C 1-4 Deuterated alkyl), NH(C 1-4 Fluoroalkyl), N(C 1-4 alkyl)2, N(C 1-4 Fluoroalkyl)2, N(C 1-4 Deuterated alkyl)2, N(C 1-4 Fluoroalkyl)(C 1-4 alkyl), N(C 1-4 Fluoroalkyl)(C 1-4 Deuterated alkyl) and N(C 1-4 Deuterated alkyl)(C 1-4 In some embodiments, R 2 and R 2’ Independently selected from H, D, Cl, F, C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Fluoroalkyl, C 1-2 Deuterated alkyl, NH(C 1-2 alkyl), NH(C 1-2 Deuterated alkyl), NH(C 1-2 Fluoroalkyl), N(C 1-2 alkyl)2, N(C 1-2 Fluoroalkyl)2, N(C 1-2 Deuterated alkyl)2, N(C 1-2 Fluoroalkyl)(C 1-2 alkyl), N(C 1-2 Fluoroalkyl)(C 1-2 Deuterated alkyl) and N(C 1-2 Deuterated alkyl)(C 1-2 In some embodiments, R 2 and R 2’is independently selected from H, D, F, NH2, CH3, CF2H, CD2H, CH3O, CF3, CD3, NH(CH3), NH(CD3), NH(CF3), N(CH3)2, N(CF3)2, and N(CD3)2. In some embodiments, R 1 is selected from the group consisting of H, D, F, NH2, CH3, CF2H, CD2H, CH3O, CF3 and CD3. In some embodiments, R 2 and R 2’ is independently selected from H, D, F, CH3, CF2H, CD2H, CH3O, CF3 and CD3. In some embodiments, R 2 and R 2' are independently H, D or F. In some embodiments, R 2 and R 2' All are H or all are D. In some embodiments, R 2 and R 2’ All are H.

[0546] In some embodiments, R 1 、R 1' 、R 2 and R 2' are independently H, D or F. In some embodiments, R 1 、R 1' 、R 2 and R 2' All are H or all are D. In some embodiments, R 1 、R 1' 、R 2 and R 2' All are H.

[0547] In some embodiments, R 3 and R 6 Independently selected from H, D, Cl, F, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluoroalkyl and C 1-4 In some embodiments, R 3 and R 6 Independently selected from 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 3 and R 6 Independently selected from H, D, Cl, F, OH, C1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Fluoroalkoxy, C 1-2 Deuterated alkoxy, C 1-2 Fluoroalkyl and C 1-2 In some embodiments, R 3 and R 6 Independently selected from 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 3 and R 6 is independently selected from H, D, F, OH, CH3, CH3O, CF2HO, CD2HO, CF3O, CD3O, CF2H, CD2H, CF3, and CD3. In some embodiments, R 3 and R 6 is independently selected from H, D, F, OH, CH3, CH3O, CF2H, CD2H, CF3 and CD3. In some embodiments, R 3 and R 6 is independently selected from H, D, F, OH, CH3, CH3O, CF2HO, CF3O, and CD3O. In some embodiments, R 3 and R 6 are independently selected from H and D. In some embodiments, R 3 and R 6 At least one of is D. In some embodiments, R 3 and R 6 Each of is D. In some embodiments, R 3 and R 6 Each of is H.

[0548] In some embodiments, R 4 and R 5 One or both of them are independently selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 In some embodiments, R 4 and R 5 Two of them are independently selected from H, D, F, Cl, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 In some embodiments, R 4 and R 5 One or both of 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, CH3CH2O, CH3O, CF3O, CHF2O, CF2HCH2O, CF3CH2O, (CF3)2CHO, and CD3O. In some embodiments, R 4 and R 5 One or both are independently selected from H, D, F, Cl, CH3, CH(CH3)2, CF3, CF2H, CD3, CH3O, CH(CH3)2O, CF3O, CHF2O and CD3O.

[0549] In some embodiments, R 4 and R 5 Two of them are independently selected from D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 In some embodiments, R 4 and R 5 In some embodiments, R 4 and R 5 Two of them are independently selected from D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 In some embodiments, R 4 and R 5 Two of them are independently selected from H, D, F, Cl, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4In some embodiments, R 4 and R 5 In some embodiments, R 4 and R 5 In some embodiments, R 4 and R 5 In some embodiments, R 4 and R 5 Both of them are CD3O, or R 4 and R 5 Both of them are CH3O.

[0550] In some embodiments, R 4 H or D and R 5 Selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 In some embodiments, R 4 H or D and R 5 Selected from H, D, F, Cl, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 In some embodiments, R 4 H or D and R 5 is selected from the group consisting of H, D, F, Cl, CH(CH3)2, CH3, CF3, CF2H, CD3, CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 4 H or D and R 5 is selected from the group consisting of D, F, Cl, CH(CH3)2, CH3, CF3, CF2H, CD3, CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 4 H or D and R5 is selected from CH(CH3)2O, CH3O, CF3O, CHF2O and CD3O. In some embodiments, R 4 H and R 5 Selected from CH3O and CD3O.

[0551] In some embodiments, R 5 H or D and R 4 Selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 In some embodiments, R 5 H or D and R 4 is selected from the group consisting of D, F, Cl, CH3, CH(CH3)2, CF3, CF2H, CD3, CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 5 H or D and R 4 is selected from CH(CH3)2O, CH3O, CF3O, CHF2O and CD3O. In some embodiments, R 5 H and R 4 Selected from CH3O and CD3O.

[0552] In some embodiments, R 3 、R 4 、R 5 and R 6 is selected from the group consisting of D, F, Cl, CH3, CH(CH3)2, CF3, CF2H, CD3, CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 3 、R 4 、R 5 and R 6 All H, or in some embodiments, R 3 、R 4 、R 5 and R 6 All are 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 6Two of them are selected from H or D, and R 3 、R 4 、R 5 and R 6 The remaining groups in are 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 selected from H or D, and R 3 、R 4 、R 5 and R 6 The remaining groups in are selected from CH3O and CD3O. In some embodiments, R 3 、R 4 、R 5 and R 6 One of is selected from H or D, and R 3 、R 4 、R 5 and R 6 The remaining groups in are selected from CH(CH3)2O CH3O, CF3O, CHF2O and CD3O. In some embodiments, R 3 、R 4 、R 5 and R 6 One of is selected from H or D, and R 3 、R 4 、R 5 and R 6 The remaining groups in are selected from CH3O and CD3O.

[0553] In some embodiments, R 4 and R 5 Connect together to form O-CH2O.

[0554] In some embodiments, R 4 and R 5 One of them is selected from XLA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy.

[0555] In some embodiments, X is a direct bond, R 4 and R 5 One of them is selected from LA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6In some embodiments, X is selected from O, C(O), NR a NR 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 NR 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 selected from NR a NR a C(O), C(O)NR a NR a C(O)O、OC(O)NR a and NR a C(O)NR a In some embodiments, X is selected from NR a C(O), C(O)NR a NR a C(O)O、OC(O)NR a and NR 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 NR 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 .

[0556] In some embodiments, L is selected from 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), C1-4 Alkylene C(O)NR b 、C 2-4 Alkenylene C(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)OC 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 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 Alkylene C(O)NR b 、C 2-4 Alkenylene C(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、C1-2 Alkylene OC(O)O, C 2-4 Alkenylene OC(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 Alkylene C(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 Alkylene OC(O)O and C 1-2 Alkylene NR b C(O)NR b In some embodiments, L is selected from a direct bond, CH2, CF2, CD2, CH2-O, CF2-O, CD2-O, CH2-C(O), CF2-C(O), CD2-C(O), CH2-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-NRb C(O)NR b and CD2-NR b C(O)NR b .

[0557] In some embodiments, X is a direct bond, L is a direct bond, and R 4 and R 5 One of them is selected from A, and R 4 and R 5 The other one is selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy.

[0558] In some embodiments, X is selected from O, OC(O), C(O)O, NR a C(O) and C(O)NR a , R 4 and R 5 One of them is selected from 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 Alkylene C(O)NR b -A, OC 1-2 Alkylene OC(O)-A, OC 1-2 Alkylene C(O)OA, OC 1-2 Alkylene OC(O)NR b -A, OC 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, OC(O)-C 1-2 Alkylene NR b C(O)-A, OC(O)-C 1-2 Alkylene C(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)NRb -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 Alkylene C(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 Alkylene C(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 1-2Alkylene 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 Alkylene C(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 Alkylene OC(O)OA and C(O)NR a -C 1-2 Alkylene NR b C(O)NR b -A, and R 4 and R 5 The other one is selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, X is selected from O, OC(O), C(O)O, NR a C(O) and C(O)NR a , R 4 and R 5 One of them is selected from OC 1-2 Alkylene-A, OC 1-2 Alkylene OA, OC 1-2 Alkylene C(O)-A, OC1-2 Alkylene NR b C(O)-A、OC 1-2 Alkylene C(O)NR b -A, OC 1-2 Alkylene OC(O)-A, OC 1-2 Alkylene C(O)OA, OC 1-2 Alkylene OC(O)NR b -A, OC 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, OC(O)-C 1-2 Alkylene NR b C(O)-A, OC(O)-C 1-2 Alkylene C(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 Alkylene C(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 Alkylene C(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 Alkylene C(O)NR b -A、C(O)NR a -C 1-2Alkylene 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 Alkylene OC(O)OA and C(O)NR a -C 1-2 Alkylene NR b C(O)NR b -A, and R 4 and R 5 The other one is selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy groups in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0559] In some embodiments, R 4 and R 5 The other one is selected from H, F, Cl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl and C 1-4 Alkoxy, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, R 4 and R 5 The other of is selected from D, F, Cl, CH3, CH(CH3)2, CF3, CF2H, CD3, CH(CH3)2O, CH3O, CF3O, CHF2O and CD3O, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. And R 4 and R 5 The other one is H or D.

[0560] In some embodiments, R 4 For XLA and R 5 Selected from H, halogen, C 1-6 Alkyl and C 1-6 In some embodiments, R 5 For XLA and R 4 Selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy.

[0561] In some embodiments, Ra Selected from H and C 1-4 alkyl.

[0562] In some embodiments, R b Selected from H, C 1-4 Alkyl and A.

[0563] In some embodiments, A is H, R 4 and R 5 One of 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 Alkylene C(O)NHR b 、XC 2-4 Alkenylene C(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 AlkyleneOC(O)NHR b 、XC 2-4 Alkenylene OC(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 bC(O)NHR b and XC 2-4 Alkenylene NR b C(O)NHR b , and R 4 and R 5 The other one is selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, A is H, R 4 and R 5 One of 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 Alkylene C(O)NHR b 、XC 2-4 Alkenylene C(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 AlkyleneOC(O)NHR b 、XC 2-4 Alkenylene OC(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 2-4Alkenylene OC(O)OH, XC 1-2 Alkylene NR b C(O)NHR b and XC 2-4 Alkenylene NR b C(O)NHR b , and R 4 and R 5 The other one is selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy groups in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0564] In some embodiments, A is H and X is a direct bond. Thus, in some embodiments, and R 4 and R 5 One of them is selected from 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 Alkylene C(O)NHR b 、C 2-4 Alkenylene C(O)NHR b 、C 1-4 Alkylene OC(O)H, C 2-4 Alkenylene OC(O)H, C 1-4 Alkylene C(O)OH, C 2-4 Alkenylene C(O)H, C 1-4 AlkyleneOC(O)NHR b 、C 2-6 Alkenylene OC(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, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy.

[0565] In some embodiments, A is H and X is selected from O, C(O), NR a NR 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 NR 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 selected from NR a NR a C(O), C(O)NR a NR a C(O)O、OC(O)NR a and NR a C(O)NR a In some embodiments, A is H and X is selected from NR a C(O), C(O)NR a NR a C(O)O、OC(O)NR a and NR 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 NR a C(O)NR a .

[0566] In some embodiments, A is H, and L is a direct bond, R 3 and R 4 One of is selected from XH. Thus, in some embodiments, and R 3 and R 4 One of OH, C(O)H, NHR a 、NHRa 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 are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0567] In some embodiments, when A is H, R b Selected from H and C 1-4 An alkyl group in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0568] In some embodiments, R 4 and R 5 One of 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 OC 1-4 Alkylene-C(O)OA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy groups in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0569] In some embodiments, R 4 and R 5 One of is selected from A, OA, C(O)-A, C(O)-A and C(O)OA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, R 4 and R 5 In some embodiments, one of R 4 and R 5 In some embodiments, one of R 4 and R 5 In some embodiments, one of R 4 and R 5One of them is C(O)OA.

[0570] In some embodiments, R 4 and R 5 One of them is selected from 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 OC 1-4 Alkylene-C(O)OA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, R 4 and R 5 One of them is C 1-4 Alkylene-A. In some embodiments, R 4 and R 5 One of them is C 1-4 Alkylene-C(O)-A. 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 OC 1-4 Alkylene-A. In some embodiments, R 4 and R 5 One of them is OC 1-4 Alkylene-C(O)-A. In some embodiments, R 4 and R 5 One of them is OC 1-4 Alkylene-C(O)OA.

[0571] In some embodiments, R 4 and R 5 One of them is selected from 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 OC 1-4 Alkylene-C(O)OA, and R4 and R 5 The other one is selected from H, F, Cl, C 1-4 Alkyl and C 1-4 Alkoxy, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, R 4 and R 5 One of them is selected from 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 OC 1-4 Alkylene-C(O)OA, and R 4 and R 5 The other one is selected from H, F, Cl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl and C 1-4 Alkoxy, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, R 4 and R 5 One of them is selected from 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 OC 1-2 Alkylene-C(O)OA, and R 4 and R 5 The other of is selected from D, F, Cl, CH3, CH(CH3)2, CF3, CF2H, CD3, CH(CH3)2O, CHO, CF3O, CHF2O, and CD3O, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, R 4 and R 5 One of 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, OC1-2 Alkylene-C(O)-A and OC 1-2 Alkylene-C(O)OA, and R 4 and R 5 The other of is H or D, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. In some embodiments, R 4 and R 5 One of them is selected from 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, -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, and R 4 and R 5 The other one is H or D.

[0572] In some embodiments, R 4 Selected from 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 OC 1-2 Alkylene-C(O)OA, and R 5 is H or D, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. 4 Selected from 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, 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, and R 5 is H or D. In some embodiments, R 5 Selected from A, OA, C(O)-A, C(O)OA, C 1-2Alkylene-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 OC 1-2 Alkylene-C(O)OA, and R 4 is H or D, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. 5 Selected from 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, 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, and R 4 It is H or D.

[0573] In some embodiments, A is selected from C 1-30 Alkyl, C 2-30 Alkenyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 64 The heterocyclic alkyl group of the heterocyclic alkyl group is 3 to 6 members and contains 1 to 3 independently selected from O, S, S (O), SO2, N and NR 64 The 5- to 6-membered heteroaryl group of the hetero portion, wherein the phenyl group, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, OH, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 In some embodiments, A is selected from C 1-30 Alkyl, C 2-30 Alkenyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 64The heterocyclic alkyl group of the heterocyclic alkyl group is 3 to 6 members and contains 1 to 3 independently selected from O, S, S (O), SO2, N and NR 64 The 5- to 6-membered heteroaryl group of the hetero portion, wherein the phenyl group, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, OH, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 Fluoroalkyl.

[0574] In some embodiments, A is selected from phenyl, C 3-6 Cycloalkyl, containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 64 The heterocyclic alkyl group of the heterocyclic alkyl group is 3 to 6 members and contains 1 to 3 independently selected from O, S, S (O), SO2, N and NR 64 The 5- to 6-membered heteroaryl group of the hetero portion, wherein the phenyl group, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of F, C, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 In some embodiments, A is selected from phenyl, C 3-6 Cycloalkyl, containing 1 to 2 independently selected from O, S, S(O), SO2, N and NR 64 The heterocyclic 5- to 6-membered alkyl group of the heterocyclic group and containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 64 The 5- to 6-membered heteroaryl group of the hetero portion, wherein the phenyl group, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of F, C, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 Fluoroalkyl.

[0575] In some embodiments, C in A 3-6Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In some embodiments, C in A 3-6 Cycloalkyl is cyclopropyl optionally substituted by one or two substituents independently selected from the group consisting of F, C, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 Fluoroalkyl.

[0576] In some embodiments, A comprises 1 to 3 independently selected from O, S, S(O), SO2, N and NR 64 The 3- to 6-membered heterocycloalkyl group of the hetero portion is selected from aziridinyl, oxirane, thiirane, oxaziridinyl, dioxirane, azetidinyl, oxetanyl, thitanyl, diazetidinyl, dioxetanyl, dithitanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxathianyl, thiazolidinyl, isothiazolidinyl, dioxolane, dithiolanyl, alkyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl oxide, tetrahydrothiopyran dioxide, dihydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, and dithianyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of F, C, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 In some embodiments, A comprises 1 to 3 independently selected from O, S, S(O), SO2, N and NR 64 The 3- to 6-membered heterocycloalkyl group of the hetero portion is selected from tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, dioxolane, piperidinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, tetrahydropyranyl, tetrahydrothiopyranyl, dihydropyranyl, tetrahydrothiopyran oxide, tetrahydrothiopyran dioxide, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of F, C, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 Fluoroalkyl.

[0577] In some embodiments, the 5- to 6-membered heteroaryl in A is selected from furanyl, imidazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyrrolyl, thienofuranyl, triazolyl, and thienyl, each of which is optionally substituted with one or two substituents independently selected from F, C, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 In some embodiments, the 5- to 6-membered heteroaryl in A is selected from furanyl, isothiazolyl, thiazolyl, pyridinyl, and pyrrolyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of F, C, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 Fluoroalkyl.

[0578] In some embodiments, the phenyl group in A, C 3-10 The cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl groups are optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, CD3, CH(CH3)2O, CH3CH2CH2O, CH3CH2O, CH3O, CF3O, CHF2O, CF2HCH2O, CF3CH2O, (CF3)2CHO, and CD3O.

[0579] In some embodiments, A is selected from C 1-30 Alkyl and C 2-30 alkenyl groups in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0580] In some embodiments, A is C 10-25 In some embodiments, A is C 13-21 An alkyl group in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0581] In some embodiments, A is C 10-25 In some embodiments, A is C13-21 In some embodiments, A is C 10-25 alkenyl and contain 1, 2, 3, 4, 5 or 6 double bonds.

[0582] In some embodiments, the alkyl or alkene groups of A are alkyl or alkene groups present in fatty acid, and wherein all available H atoms are optionally substituted by deuterium. In some embodiments, A is the alkene groups present in fatty acid, and wherein all available H atoms are optionally substituted by deuterium. In some embodiments, fatty acid is ω-6 fatty acid (i.e. unsaturated or polyunsaturated fatty acid, wherein the double bond nearest to the molecular methyl end is positioned on the 6th carbon starting from the terminal methyl) or ω-3 fatty acid (i.e. unsaturated or polyunsaturated fatty acid, wherein the double bond nearest to the molecular methyl end is positioned on the 3rd carbon starting from the terminal methyl), wherein all available H atoms are optionally substituted by deuterium. In some embodiments, A is the alkyl or alkene groups present in fatty acid, and wherein all available H atoms are optionally substituted by deuterium. In some embodiments, A is the alkyl or alkene groups present in fatty acid, and this fatty acid is selected from the fatty acid list in table 1, and wherein all available H atoms are optionally substituted by deuterium.

[0583] In some embodiments, the olefinic group of A is an alkyl or alkenyl group present in linoleic acid, eicosadienoic acid, or docosahexaenoic acid.

[0584] In some embodiments, when A is an alkyl or alkenyl group of a fatty acid, 1-10, 2-8, 2-6, or 2-4 H atoms are replaced by deuterium.

[0585] 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=CH(CH2)1CH3.

[0586] In some embodiments, R 64 and R 65 Independently selected from H, D, C 1-4 Alkyl, C1-4 Fluoroalkyl and C 1-4 In some embodiments, R 64 and R 65 is independently selected from H, D, CH3, CF3 and CD3. In some embodiments, R 64 and R 65 Independently selected from CH3 and CD3.

[0587] In some embodiments, the compound of Formula IA is defined as follows:

[0588]

[0589] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0590] in:

[0591] Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6:

[0592]

[0593] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 Does not exist, when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q5 When it is a double bond, R 48 and R 57 does not exist;

[0594] R 1 、R 1' 、R 2 、R 2' 、R 3 and R 6 independently selected from H, D and F;

[0595] R 4 and R 5 One or both of them are selected from H, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 deuterated alkoxy, or

[0596] R 4 and R 5 Linked together to form O-(CH2) 1-2 O;

[0597] 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 independently selected from H and D;

[0598] R 12 、R 20 、R 29 、R 39 and R 51 Independently selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 deuterated alkyl, and

[0599] R 60 and R 61 Independently selected from H and C 1-6 alkyl;

[0600] Provided that when Q is Q6, then the compound of formula I comprises D;

[0601] When Q is Q3 or Q4, then when R 5 is H or OCH3, and R 29 or R 39 When it is CH3, R 1 、R 1' 、R 2 、R 2' 、R 3 、R 4 、R 6 、R 26 、R 27 、R 28 、R 30 to R 35 、R 36 、R 37 、R 38 and R 40 to R 47 Not all are H; and

[0602] When Q is Q4 and R 1 、R 1' 、R 2 、R 2' 、R 3 、R 4 、R 6 、R 38 and R 40 to R 47 When all are H, then when R 39 When it is CD3, R 36 and R 37 Not all are D.

[0603] In some embodiments, the compound of Formula IA is defined as follows:

[0604]

[0605] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,

[0606] in:

[0607] R 1 and R 1’ Independently selected from H, halo, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2;

[0608] R 2 and R 2'independently selected from H, halo, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2;

[0609] Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6:

[0610]

[0611] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 Does not exist, when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q5 When it is a double bond, R 48 and R 57 It is existence;

[0612] R 4 and R 5 One or both of them are independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, or

[0613] R 4 and R 5 Linked together to form O-(CH2) 1-2 O, or

[0614] R 4 and R 5 One of them is selected from XLA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy,

[0615] X is selected from direct bond, O, C(O), NR a NR 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 NR a C(O)NR a ;

[0616] L is selected from direct bond, C 1-6 Alkylene, C 2-6 Alkenylene, C1-6 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 Alkylene C(O)NR b 、C 2-6 Alkenylene C(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)OC 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 ;

[0617] R a Selected from H and C 1-6 alkyl;

[0618] R b Selected from H, C 1-6 Alkyl and A;

[0619] A is selected from C 1-30 Alkyl, C 2-30 Alkenyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 64 The heterocyclic alkyl group of the heterocyclic alkyl group is 3 to 6 members and contains 1 to 4 independently selected from O, S, S (O), SO2, N and NR 64 The 5-membered to 6-membered heteroaryl group of the hetero part, wherein phenyl, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted by one or more independently selected from halo, C1-4 Alkyl and OC 1-4 Substitution of alkyl groups;

[0620] R 3 and R 6 are independently selected from H, halo, OH, C 1-6 Alkyl and C 1-6 alkoxy;

[0621] 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 selected from H, halo and C 1-6 alkyl;

[0622] R 12 、R 20 、R 29 、R39 and R 51 Independently selected from H, C 1-6 Alkyl, C(O)C 1-6 Alkyl and C(O)-A';

[0623] R 60 and R 61 Independently selected from H and C 1-6 alkyl; or

[0624] R 60 and R 61 One of them is C(O)-A' and the other is selected from H and C 1-6 alkyl;

[0625] wherein A' is selected from Y, OY and OC 1-4 Alkylene-OC(O)-Y; and

[0626] Y is selected from C 7-30 Alkyl and C 7-30 alkenyl; or

[0627] R 60 and R 61 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered heterocyclic ring optionally contains one or two independently selected from O, S, S(O), SO2, N and NR 65 and optionally substituted by one or more independently selected from halo, OH, C 1-4 Alkyl and OC 1-4 Substitution of alkyl groups;

[0628] R 64 and R 65 Independently selected from H and C 1-6 alkyl; and

[0629] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof,

[0630] The condition is R 12 、R 20 、R 29 、R 39 、R 51 、R 60 and R 61 one of which is C(O)-A'; or

[0631] R 4 and R 5 One of them is selected from XLA, and R 4 and R 5 The other one is selected from H, halogen, C1-6 Alkyl and C 1-6 Alkoxy, provided that when X and L are direct bonds, A is not H, C 1-6 Alkyl or C 1-6 Alkenyl.

[0632] Those skilled in the art will understand that when R 2 and R 2’ At different times, R 2 and R 2’ The carbon to which it is bonded is chiral. Therefore, the present application includes all stereoisomers at this carbon center and mixtures thereof.

[0633] Those skilled in the art will understand that when R 1 and R 1’ At different times, R 1 and R 1’ The carbon to which it is bonded is also chiral. Therefore, the present application includes all stereoisomers at this carbon center and mixtures thereof.

[0634] In some embodiments, the compound of Formula IA is selected from the compounds listed below, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof:

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645] In some embodiments, pharmaceutically acceptable salts are acid addition salts or base addition salts. Suitable salts can be selected by those skilled in the art. Suitable salts include acid addition salts, which can be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid (such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or benzoic acid). In addition, acids generally considered suitable for forming pharmaceutically useful salts from basic drug compounds are discussed, for example, by P. Stahl et al., Camille G. (ed.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley VCH; S. Berge et al., Journal of Pharmaceutical Sciences 1977 66(1)1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC, on their website).

[0646] Acid addition salts suitable for subject treatment or compatible with subject treatment are any non-toxic organic acid or inorganic acid addition salts of any basic compound. The basic compound forming the acid addition salt includes, for example, a compound comprising an amine group. Exemplary inorganic acids forming suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and acidic metal salts, such as sodium monohydrogen phosphate and potassium hydrogen sulfate. Exemplary organic acids forming suitable salts include monocarboxylic acids, dicarboxylic acids and tricarboxylic acids. Examples of such organic acids are, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid and other sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid. In some embodiments, exemplary acid addition salts also include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor salt, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate (methanesulfonate) (" mesylate "), naphthenate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (toluenesulfonate) (also known as tosylate) and the like. In some embodiments, monoacid or diacid salts are formed, and such salts exist in hydrated, solvated or substantially anhydrous forms. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents and, compared with their free base forms, typically exhibit higher melting points. The selection criteria for suitable salts are well known to those skilled in the art. Other non-pharmaceutically acceptable salts, such as but not limited to oxalates, may be used, for example, to isolate the compounds of the present application for laboratory use or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0647] Suitable for subject treatment or with subject treatment compatible base addition salt is any nontoxic organic or inorganic base addition salt of any acidic compound.The acidic compound forming basic addition salt includes, for example, a compound comprising a carboxylic acid group.The exemplary inorganic base forming suitable salt includes hydroxide and ammonia of lithium, sodium, potassium, calcium, magnesium or barium.The exemplary organic base forming suitable salt includes aliphatic, alicyclic or aromatic organic amine, for example 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 resin etc. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. It may be useful to select a suitable salt, for example, so that the ester functional group (if any) elsewhere in the compound is not hydrolyzed. The selection criteria for suitable salts are well known to those skilled in the art. In some embodiments, exemplary basic salts also include ammonium salts, alkali metal salts (such as sodium salts, lithium salts and potassium salts), alkaline earth metal salts (such as calcium salts and magnesium salts), salts formed with organic bases (such as organic amines) (such as dicyclohexylamine, amide, choline) and salts formed with amino acids (such as arginine, lysine, etc.). Basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl halides (such as methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (such as dimethyl, diethyl and dibutyl sulfates), long chain halides (such as decyl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halides (such as benzyl and phenethyl bromides). Compounds carrying acidic moieties can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands (e.g., quaternary ammonium salts). In addition, in the presence of an acid (-COOH) or alcohol group, pharmaceutically acceptable esters can be used to modify the solubility or hydrolysis characteristics of the compound.

[0648] 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 the purposes of this application. In addition, when a compound of Formula I or Formula IA, or a pharmaceutical salt, solvate, and / or prodrug thereof, contains both a basic moiety (such as, but not limited to, aliphatic primary, secondary, tertiary, or cyclic amines, aromatic or heteroarylamines, pyridine, or imidazole) and an acidic moiety (such as, but not limited to, a tetrazole or a carboxylic acid), zwitterions ("inner salts") may be formed and are included in the term "salt" as used herein. It should be understood that certain compounds of Formula I or Formula IA, or pharmaceutical salts, solvates, and / or prodrugs thereof, may exist as zwitterions, having anionic and cationic centers and a net neutral charge in the same compound. Such zwitterions are included in this application.

[0649] Solvates of the compounds of Formula I or Formula IA, or pharmaceutically salts and / or prodrugs thereof, include, for example, those prepared with pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvates are referred to as hydrates) and ethanol, among others. Suitable solvents are physiologically tolerable at the administered dose.

[0650] Prodrugs of the compounds of Formula I or Formula IA, or pharmaceutically salts, solvates and / or prodrugs thereof, include, for example, conventional esters formed with available hydroxyl, thiol, amino or carboxyl groups. Some common esters that have been used as prodrugs are phenyl esters, aliphatic (C1-C 24 ) esters, acyloxymethyl esters, carbamates and amino acid esters.

[0651] It will be understood and appreciated that, in some embodiments, a compound of Formula I or Formula IA, or a pharmaceutical salt, solvate, and / or prodrug thereof, may have at least one chiral center and, therefore, may exist as enantiomers and / or diastereomers. It will be understood that all such isomers and mixtures thereof in any proportion are included within the scope of the present application. It will also be understood that, while the stereochemistry of a compound may be as shown for any given compound listed herein, such compounds may also contain an amount (e.g., less than 20%, suitably less than 10%, more suitably less than 5%) of a compound of Formula I or Formula IA, or a pharmaceutical salt, solvate, and / or prodrug thereof, having an alternative stereochemistry. It is contemplated that any optical isomer, such as an isolated, pure, or partially purified optical isomer, or a racemic mixture thereof, is included within the scope of the present application.

[0652] In some embodiments, the compounds of Formula I or Formula IA, or pharmaceutically salts, solvates, and / or prodrugs thereof, may also include tautomeric forms, such as keto-enol tautomers, etc. By appropriate substitution, tautomers may be in equilibrium or sterically locked into one form. Any tautomeric forms and mixtures thereof formed by the compounds are contemplated to be within the scope of this application.

[0653] Compounds of Formula I or Formula IA, or pharmaceutical salts, solvates, and / or prodrugs thereof, may also exist in various amorphous and polymorphic forms, and it is contemplated that any amorphous form, polymorphic form, or mixture thereof, is within the scope of this application.

[0654] The compounds of the present application may further be radiolabeled, and thus all radiolabeled forms of the compounds of Formula I, Formula II, or Formula IA, or pharmaceutically salts, solvates, and / or prodrugs thereof, are included within the scope of the present application. Thus, the compounds of Formula I, Formula II, or Formula IA, or pharmaceutically salts, solvates, and / or prodrugs thereof, also include those that have one or more radioactive atoms incorporated into their structure.

[0655] IV. Composition

[0656] The compound of formula I or formula IA or its pharmaceutical salt, solvate and / or prodrug is suitably formulated into a composition using one or more carriers in a conventional manner. Therefore, the application also includes a composition comprising one or more compounds of formula I or formula IA or its pharmaceutical salt, solvate and / or prodrug and a carrier. The compound of formula I or formula IA or its pharmaceutical salt, solvate and / or prodrug is suitably formulated into a pharmaceutical composition for administration to a subject in a biocompatible form suitable for in vivo administration. Therefore, the application also includes a pharmaceutical composition comprising one or more compounds of formula I or formula IA or its pharmaceutical salt, solvate and / or prodrug and a pharmaceutically acceptable carrier. In an embodiment of the present application, the pharmaceutical composition is used to treat any disease, condition or illness described herein.

[0657] As will be appreciated by those skilled in the art, a compound of Formula I or Formula IA, or a pharmaceutical salt, solvate, and / or prodrug thereof, is administered to a subject in a variety of forms, depending on the route of administration selected. For example, a compound of Formula I or Formula IA, or a pharmaceutical salt, solvate, and / or prodrug thereof, is administered orally, by inhalation, parenterally, buccal, sublingually, insufflated, epidurally, intranasally, rectally, vaginally, by patch, pump, mini-pump, topically, or transdermally, and the pharmaceutical composition is formulated accordingly. In some embodiments, administration is performed by regular or continuous delivery via a pump. Conventional procedures and ingredients for selecting and preparing suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000-20th Edition) and the United States Pharmacopoeia published in 1999: The National Formulary (USP 24NF19).

[0658] Parenteral administration includes systemic routes of delivery other than the gastrointestinal (GI) tract, and includes, for example, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary (e.g., by use of an aerosol), intrathecal, rectal, and topical (including use of a patch or other transdermal delivery device) modes of administration. Parenteral administration can be performed by continuous infusion over a selected period of time.

[0659] In some embodiments, the compound of Formula I or Formula IA, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, is administered orally, for example, with an inert diluent or an assimilable edible carrier, or encapsulated in a hard or soft shell gelatin capsule, or compressed into a tablet, or incorporated directly into the food of the diet. In some embodiments, the compound is mixed with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pills, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions, and suspensions. In the case of tablets, carriers used include lactose, corn starch, sodium citrate, and phosphates. 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 silicon dioxide); 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 an embodiment, the tablets are coated by methods well known in the art. For tablets, capsules, caplets, pills, or granules for oral administration, a pH-sensitive enteric coating, such as Eudragits, designed to control the release of the active ingredient, may be used. TM Oral dosage forms also include improved release, such as immediate release and timed release. Examples of improved release include, for example, sustained release (SR), extended release (ER, XR or XL), timed release (time-release / timed-release), controlled release (CR) or continuous release (CR or Contin), for example, in the form of coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, agglomerated particles (such as molecular sieve type particles) or fine hollow permeable fiber bundles or short-cut hollow permeable fibers (agglomerated or maintained in fiber bags). Timed-release compositions are formulated into, for example, liposomes or compositions in which the active compound is protected by different degradable coatings (such as by microencapsulation, multilayer coatings, etc.). Liposomal delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. In some embodiments, liposomes are formed by a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine. For oral administration in capsule form, useful carriers, solvents or diluents include lactose, medium-chain triglycerides, ethanol and dry corn starch.

[0660] In some embodiments, the liquid preparation for oral administration takes the form of, for example, a solution, syrup or suspension, or they are suitable for being present as a dry product for use with water or other suitable vehicle structures before use. When an aqueous suspension and / or emulsion is administered orally, Formula I or Formula IA compound or its pharmaceutical salt, solvate and / or prodrug are suitably suspended or dissolved in an oil phase combined with an emulsifier and / or suspending agent. If necessary, certain sweeteners and / or flavorings and / or coloring agents can be added. Such liquid preparations for oral administration are prepared by conventional methods with pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous vehicles (e.g., medium-chain triglycerides, almond oil, oily esters or ethanol); and preservatives (e.g., methylparaben or propylparaben or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycol.

[0661] It is also possible to freeze-dry the compound of formula I or formula IA or a pharmaceutical salt, solvate and / or prodrug thereof and use the lyophilizate obtained, for example, for the preparation of an injectable product.

[0662] In some embodiments, the compound of Formula I or Formula IA, or a pharmaceutically salt, solvate, and / or prodrug thereof, is administered parenterally. For example, a solution of the compound of Formula I or Formula IA, or a pharmaceutically salt, solvate, and / or prodrug thereof, is prepared in water with a surfactant such as hydroxypropylcellulose, as appropriate. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, as well as in oil. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth. One skilled in the art will know how to prepare suitable formulations. For parenteral administration, a sterile solution of the compound of Formula I or Formula IA, or a pharmaceutically salt, solvate, and / or prodrug thereof, is typically prepared, and the pH of the solution is appropriately adjusted and buffered. For intravenous use, the total concentration of the solute should be controlled to make the formulation isotonic. For ophthalmic administration, for example, an ophthalmic delivery system known in the art, such as an applicator or eye dropper, is used to deliver the ophthalmic ointment or dropperable liquid. In some embodiments, such compositions include a mucus mimetic (such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol), a preservative (such as sorbic acid, EDTA or benzylchromium chloride) and a conventional amount of a diluent or carrier. For pulmonary administration, the diluent or carrier will be selected to be suitable for forming an aerosol.

[0663] In some embodiments, the compound of Formula I or Formula IA or its pharmaceutical salt, solvate and / or prodrug is formulated for parenteral administration by injection, including the use of conventional catheter insertion techniques or infusion. Injectable formulations are, for example, present in unit dosage form (e.g., in ampoules or multidose containers) and are supplemented with preservatives. In some embodiments, the composition takes the form of a sterile suspension, solution or emulsion in an oily or aqueous vehicle and contains a preparaton such as a suspending agent, a stabilizer and / or a dispersant. In all cases, the dosage form must be sterile and must be a fluid that is easy to inject. Alternatively, the compound of Formula I or Formula IA or its pharmaceutical salt, solvate and / or prodrug is suitably in the form of a sterile powder for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

[0664] In some embodiments, the composition for intranasal administration is conveniently formulated into aerosols, drops, gels and powders. For intranasal administration or inhalation administration, Formula I or Formula IA compound or its pharmaceutical salt, solvate and / or prodrug are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that the patient squeezes or pumps, or delivered as an aerosol spray from a pressurized container or a sprayer. Aerosol formulations typically comprise a solution or fine suspension of active substance in a physiologically acceptable aqueous or non-aqueous solvent, and are typically present in a sealed container in a sterile form with a single dose or multiple doses, the container being, for example, in the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container is an integral dispensing device, such as a single dose nasal inhaler or an aerosol dispenser equipped with a metering valve, which is expected to be discarded after use. When the dosage form includes an aerosol dispenser, it will contain a propellant, such as a compressed gas (such as compressed air) or an organic propellant (such as a fluorochlorocarbon). Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkane, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve that delivers a metered amount. In some embodiments, the pressurized container or sprayer contains a solution or suspension of the active compound. Capsules and cartridges for inhalers or insufflators (e.g., made of gelatin) are, for example, formulated into a powder mixture containing a compound of Formula I, Formula I or Formula IA, or a pharmaceutically salt, solvate and / or prodrug thereof, and a suitable powder base (such as lactose or starch). Aerosol dosage forms can also be in the form of a pump nebulizer.

[0665] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles in which a compound of Formula I or Formula IA, or a pharmaceutically 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.

[0666] Suppositories of compounds of Formula I or Formula IA or pharmaceutically salts, solvates and / or prodrugs thereof can be used for vaginal, urethral and rectal administration. Such suppositories are generally composed of a mixture of substances that are solid at room temperature but melt at body temperature. Materials commonly used to produce such vehicles include, but are not limited to, mixtures of polyethylene glycols of various molecular weights and polyethylene glycol fatty acid esters. See, for example, Remington's Pharmaceutical Sciences, 16th edition, Mack Publishing, Easton, PA, 1980, pages 1530-1533 for further discussion of suppository dosage forms.

[0667] In some embodiments, a compound of Formula I or Formula IA, or a pharmaceutically salt, solvate, and / or prodrug thereof, is coupled to a soluble polymer as a targetable drug carrier. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, in some embodiments, a compound of Formula I or Formula IA, or a pharmaceutically salt, solvate, and / or prodrug thereof, is coupled to a class of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymers of hydrogels.

[0668] The compounds of Formula I or Formula IA, or pharmaceutically salts, solvates, and / or prodrugs thereof, are particularly suitable for administration with the air of a nanocarrier system, such as liposomes, micelles, nanoparticles, nanoemulsions, lipid nanosystems, and the like (see, for example, Bhat, M. et al., Chem. and Phys. of Lipids, 2021, 236, 105053). Therefore, the present application includes compositions comprising one or more compounds of Formula I or Formula IA, or pharmaceutically salts, solvates, and / or prodrugs thereof, and one or more components of a nanocarrier system.

[0669] The compounds of Formula I or Formula IA, or pharmaceutically salts, solvates, and / or prodrugs thereof, including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, are suitable for use alone, but are typically administered as pharmaceutical compositions comprising one or more compounds of Formula I or Formula IA, or pharmaceutically salts, solvates, and / or prodrugs thereof (active ingredient), in combination 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 and from about 1% to about 99.95% or from about 30% to about 99.90% by weight of a pharmaceutically acceptable carrier, all weight percentages being based on the total composition.

[0670] In some embodiments, the compounds of Formula I or Formula IA, including pharmaceutically acceptable salts, solvates and / or prodrugs thereof, are used or administered in a composition comprising an additional therapeutic agent. Thus, the present application also includes pharmaceutical compositions comprising one or more compounds of Formula I or Formula IA, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, and an additional therapeutic agent, and optionally one or more pharmaceutically acceptable excipients. In some embodiments, the additional therapeutic agent is another known agent that can be used to treat a disease, condition, or disorder by activating serotonin receptors, such as those listed in the methods and uses section below. In some embodiments, the additional therapeutic agent is a psychoactive drug.

[0671] In the above, the term "compound" also includes embodiments referring to one or more compounds.

[0672] V. Preparation of Compounds

[0673] The compound of formula I or its pharmaceutical salt, solvate and / or prodrug, including the compound of formula IA or its pharmaceutical salt, solvate and / or prodrug, can be prepared by various synthetic methods. The selection of specific structural features and / or substituents may affect the selection of one method relative to another method. It is within the knowledge of those skilled in the art to select a specific method for preparing a given compound of formula I or its pharmaceutically acceptable salt, solvate and / or prodrug. Some starting materials for preparing the compound of formula I or its pharmaceutical salt, solvate and / or prodrug can be obtained from commercial chemical sources or can be extracted from cells, plants, animals or fungi. Other starting materials are easily prepared from available precursors using direct conversions well known in the art, for example as described below. In the schemes of some embodiments of the preparation methods of the compounds of the present application shown below, all variables are as defined in formula I unless otherwise indicated.

[0674] In some embodiments, when Q is And R 26 and R 27When is H or D, the compound of formula I is prepared as shown in Scheme 1:

[0675]

[0676] Solution 1

[0677] Thus, in some embodiments, the compound of formula A (wherein R 1 、R 1' 、R 2 、R 2' 、R 3 、R 4 、R 5 and R 6 As defined in formula I) under basic conditions using, for example, pyridine and a compound of formula B (wherein R 28 and R 30 -R 35 As defined in Formula I, R 29 As defined in Formula I or is a suitable protecting group, and LG is a suitable leaving group, such as chloro or OH) to provide a compound of Formula C. Reduction of the ketone group in the compound of Formula C, for example using an Al-based reducing agent (such as lithium borohydride, lithium aluminum hydride or lithium aluminum deuteride), provides a compound of Formula (I), wherein R 33 and R 34 is H or D. If R 29 is a protecting group, it is removed in a single step, or wherein the protecting group is removed in the presence of an Al-based reducing agent, during the reduction of the compound of formula C.

[0678] Those skilled in the art will appreciate that a similar reaction sequence can be used to prepare compounds of formula I, wherein Q is Or when Q is And R 58 and R 59 Use when it is H or D

[0679] In some embodiments, when Q is and is a single bond and R 14 When is H or D, the compound of formula I is prepared as shown in Scheme 2:

[0680]

[0681] Option 2

[0682] Thus, in some embodiments, the compound of formula A (wherein R 1 、R 1' 、R 2 、R 2' 、R 3 、R 4、R 5 and R 6 As defined in formula I) in the presence of a suitable reducing agent such as sodium triacetoxyborohydride (STAB) with a ketone compound of formula D (wherein R 7 -R 10 、R 12 、R 13 As defined in Formula I, R 11 as defined in Formula I or a suitable protecting group) to provide a compound of formula (I), wherein R 14 is H or D. If R 11 is a protecting group, it is removed in a single step.

[0683] Those skilled in the art will appreciate that a similar reaction sequence can be used to prepare compounds of formula I wherein Q is (Q2) and is a single bond, Q is (Q3), (Q4) and (Q5) and Is a single bond, use the following ketone compounds

[0684]

[0685] In some embodiments, when Q is (Q1) and is a single bond and R 14 is H or D, Q is (Q2) and is a single bond and R 25 is H or D, Q is (Q3), Q is (Q4) or Q is (Q5) and When is a single bond, the compound of formula I is prepared as shown using methods known in the art (eg, methods described in WO2013122107, US20080234237, US20070099913 and / or Annedi SC et al., European Journal of Medicinal Chemistry, 55, 94-107, 2012).

[0686] In some embodiments, when Q is When, the compound of formula I is prepared as shown in Scheme 3:

[0687]

[0688] Option 3

[0689] Thus, in some embodiments, the compound of formula A (wherein R 1 、R 1' 、R 2 、R 2' 、R 3 、R 4 、R5 and R 6 As defined in formula I) in the presence of a suitable base (such as N,N-diisopropylethylamine (DIPEA)) and a compound of formula E (wherein R 26 -R 28 、R 30 -R 36 As defined in Formula I, R 29 As defined in Formula I or is a suitable protecting group, and LG is a suitable leaving group (such as chloro, bromo, iodo, mesyl or tosyl)) to provide a compound of Formula I. If R 29 is a protecting group, it is removed in a single step.

[0690] Those skilled in the art will appreciate that a similar reaction sequence can be used to prepare compounds of formula I wherein Q is Q1 and is a single bond, Q is Q2 and is a single bond, Q is Q4, Q5 and is a single bond, Q is Q6, use

[0691] In some embodiments, wherein Q is Q1 and is a single bond, Q is Q2 and is a single bond, Q is Q3, Q4, Q5 and is a single bond, Q is Q6, and compounds of formula I are prepared as shown using methods known in the art (e.g., methods 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).

[0692] It will be understood by those skilled in the art that a specific enantiomer or diastereomer of a compound of the present application can be obtained by using the corresponding single enantiomer or diastereomer of the corresponding starting material.

[0693] Throughout the processes described herein, it will be understood that, where appropriate, suitable protecting groups will be added to the various reactants and intermediates and subsequently removed therefrom in a manner readily understood by those skilled in the art. Conventional procedures using such protecting groups and examples of suitable protecting groups are described, for example, in "Protective Groups in Organic Synthesis", TW Green, PGM Wuts, Wiley-Interscience, New York, (1999).

[0694] It should also be understood that by chemical operations, a group or substituent is converted into another group or substituent and can be carried out on any intermediate or final product on the synthetic path towards the final product, wherein the possible conversion type is limited to the inherent incompatibility of other functional groups carried by the molecule at this stage with the conditions or reagents used in the conversion. Such inherent incompatibility and the method for overcoming them by carrying out appropriate conversion and synthesis steps in appropriate order are readily understood by those skilled in the art. Examples of conversions are provided herein, and it should be understood that the conversions described are not limited to the general groups or substituents as examples of conversions. References and descriptions of other suitable conversions are provided in " Comprehensive Organic Transformations – A Guide to Functional Group Preparations " RCLarock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in organic chemistry textbooks, such as " Advanced Organic Chemistry ", March, 4th edition McGraw Hill (1992) or " Organic Synthesis ", Smith, McGraw Hill, (1994).

[0695] Techniques for purification of intermediates and final products include, for example, normal and reverse phase chromatography on columns or spinning plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, which are readily apparent to those skilled in the art.

[0696] The products of the process of the present application can be isolated according to known methods, for example, the compounds can be separated by evaporation of the solvent, filtration, centrifugation, chromatography or other suitable methods.

[0697] Typically, the above reaction is carried out in a suitable inert organic solvent and at a temperature and time that will optimize the yield of the desired compound. Examples of suitable inert organic solvents include, but are not limited to, 2-propanol, dimethylformamide (DMF), 1,4-dioxane, dichloromethane, chloroform, tetrahydrofuran (THF), toluene, and the like.

[0698] Formation of salts of the desired compounds is achieved using standard techniques, for example, by treating the neutral compound with an acid or base in a suitable solvent and isolating the salt formed by filtration, extraction, or any other suitable method.

[0699] The formation of the solvate of the compound of the present application will vary according to the compound and the solvate. Usually, the solvate is formed by dissolving the compound in a suitable solvent and separating the solvate by cooling or using an anti-solvent. Usually the solvate is dried or azeotropic under ambient conditions. Those skilled in the art can select the suitable conditions for forming a specific solvate.

[0700] The prodrugs of the compounds of the present invention can be conventional esters formed, for example, with available hydroxyl, thiol, amino or carboxyl groups. For example, available hydroxyl or amino groups can be acylated (e.g., acyl chlorides in pyridine) using activated acids in the presence of a base and optionally in an inert solvent.

[0701] Those skilled in the art will recognize that when a reaction step of the present application is carried out in a variety of solvents or solvent systems, the reaction step can also be carried out in a mixture of suitable solvents or solvent systems.

[0702] Example

[0703] Synthesis of Exemplary Compounds of the Present Application

[0704] Example 1: (R)-1-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)indoline ((R)-I- 1)

[0705]

[0706] Synthesis of (R)-2-(2-(indoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ2-ethan-1-one ((R)-2): A solution of ((benzyloxy)carbonyl)-D-proline (5.0 g, 20.05 mmol) in dry 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 warmed to room temperature, and the solvent was evaporated to afford the crude acid chloride as a light yellow oil.

[0707] At 0 DEG C, by above-mentioned crude acyl chloride in CH cl 2 (30mL) in solution with indoline (2.25mL, 20.05mmol) in CH cl 2 (20mL) in solution process, then use pyridine (3.24mL, 40.11mmol) process.Reactant is warming up to room temperature and stirred overnight (16h).By reactant CH cl 2 (100mL) dilution, water (100mL), 1N HCl solution (50mL), salt solution (50mL) washed and dried (Na sO 4).Evaporating solvent and by flash column chromatography (EtOAc:CH cl 2, 1:9) crude material is purified on silica gel, obtains title compound (R) -2 (7.0g, quantitative) as pale solid. 1 H NMR(DMSO-d6): δ8.10,8.06(2d,1H,J=3.0,6.0Hz),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).

[0708] 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 To the solution of -2- ketone (1.96g, 5.89mmol) in dry THF (50mL) LiAlD4(1.24g, 29.48mmol) is treated for 10min, and refluxed overnight (16h). The reactant is warmed to room temperature, then cooled to 0 DEG C, processed with water (1.24mL), 2N NaOH solution (1.24mL) and water (1.24mL). The reactant is warmed to room temperature and stirred for 30min. Solid is filtered out and washed with THF (3x 25mL). The solvent is evaporated and purified on silica gel by column chromatography (MeOH:CH containing 2M NH3, 5:95) crude product is obtained as light yellow oily title compound (R)-I-1 (0.31g, 24.2%). 1H NMR (DMSO-d6): δ7.02-6.95(m,2H),6.54(t,1H,J=6.0Hz),6.46(d,1H,J=6.0Hz),3.43-3.31(m,2H),2.99-2.95(m,1H),2.8 8(t,2H,J=6.0Hz),2.38(d,2H,J=6.0Hz),2.15-2.12(m,1H),1.95-1.90(m,1H),1.69-1.52(m,3H); ESI-MS(m / z,%):222(MH + ,100).

[0709] Example 2: (R)-6-methoxy-1-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)indoline ((R)-I-57)

[0710]

[0711] (R)-2-(2-(6-methoxyindolin-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ 2 Synthesis of ((R)-5): A solution of ((benzyloxy)carbonyl)-D-proline (6.0 g, 24.07 mmol) in dry 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 warmed to room temperature and the solvent evaporated to afford the crude acid chloride as a light yellow oil.

[0712] At 0 ℃, by above-mentioned crude acyl chloride in CH cl 2 (50mL) solution in 6-methoxyindoline (3.6g, 24.07mmol) in CH cl 2 (30mL) solution process, then use pyridine (3.89mL, 48.14mmol) process.Reactant is warming up to room temperature and stirred overnight (16h).By reactant CH cl 2 (100mL) dilution, water (2x 100mL), 1N HCl solution (100mL), salt solution (50mL) washing and dry (Na sO 4).Evaporated solvent and by flash column chromatography (EtOAc:CH cl 2, 1: 9) crude material is purified on silica gel, obtain title compound (R) -5 (8.9g, 97%) as pale white solid. 1H NMR(DMSO-d6): δ7.77,7.74(2d,1H,J=3.0Hz),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(m,1H),4.24 -3.97(m,2H),3.72,3.71(2s,3H),3.51-3.32(m,2H),3.11-2.86(m,2H), 2.30-2.30(m,1H),1.97-1.85(m,3H); ESI-MS(m / z,%):403(M+Na),381(MH + ).

[0713] 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 dry THF (40 mL) was treated with AlCl3 (3.15 g, 23.65 mmol) at 0°C. The reaction was then reacted with (R)-2-(2-(6-methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ in dry THF (20 mL). 2 -2- ketone (1.5g, 3.94mmol) is processed for 5min. After stirring for 15min, the reactant is warmed to room temperature and stirred for another 4h. The reactant is cooled to 0 DEG C, quenched with water (1.0mL), 2N NaOH solution (1mL) and water (1mL). The reactant is warmed to room temperature and stirred for another 30min. The reactant is diluted with THF (50mL), passed through Na2SO4 pad is filtered, then filtered through silica gel pad. The solvent is evaporated and the crude product is purified on silica gel by column chromatography (MeOH:CH containing 2M NH3, 5:95), obtain the title compound (R) -I-57 (0.92g, 93%) as off-white solid. 1 H NMR (DMSO-d6): δ6.89 (d, 1H, J = 3.0Hz), 6.21 (brs, 1H), 6.13 (dd, 1H, 3.0, 4.5Hz), 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).

[0714] Example 3: (R)-6-methoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-58)

[0715]

[0716] Synthesis of (R)-6-methoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-58): A suspension of LiAlH4 (0.74 g, 19.71 mmol) in dry THF (40 mL) was treated with AlCl3 (3.15 g, 23.65 mmol) at 0°C. The reaction was then reacted with (R)-2-(2-(6-methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ in dry THF (20 mL). 2 -2- ketone (1.5g, 3.94mmol) is processed for 5min. After stirring for 15min, the reactant is warmed to room temperature and stirred for another 4h. The reactant is cooled to 0 DEG C, quenched with water (1.0mL), 2N NaOH solution (1mL) and water (1mL). The reactant is warmed to room temperature and stirred for another 30min. The reactant is diluted with THF (50mL), passed through Na2SO4 pad is filtered, then filtered through silica gel pad. The solvent is evaporated and the crude product is purified on silica gel by column chromatography (MeOH:CH containing 2M NH3, 5:95), obtain the title compound (R)-I-58 (0.8g, 82.5%) as off-white solid. 1 H NMR(DMSO-d6): δ6.87(d,1H,J=6.0Hz),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).

[0717] Example 4: (S)-6-methoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((S)-I-58)

[0718]

[0719] (S)-2-(2-(6-methoxyindolin-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 dry 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 warmed to room temperature, and the solvent was evaporated to afford the crude acid chloride as a light yellow oil.

[0720] At 0 ℃, by above-mentioned crude acyl chloride in CH cl 2 (20mL) solution in 6-methoxyindoline (1.32g, 8.82mmol) in CH cl 2 (10mL) solution process, then use pyridine (1.43mL, 17.65mmol) process.Reactant is warmed to room temperature and stirred overnight (16h).Reactant is diluted with CH cl 2 (100mL), washed with water (100mL), 1N HCl solution (50mL), brine (50mL) and dried (Na sO 4).Evaporated solvent and purified crude material on silica gel by flash column chromatography (EtOAc:CH cl 2, 1: 9), obtain title compound (S) -8 (3.1g, 96.8%) as light yellow jelly. 1 H NMR(DMSO-d6): δ7.78,7.75(2d,1H,J=3.0Hz),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(m,1H),4.25 -3.98(m,2H),3.73,3.72(2s,3H),3.53-3.45(m,2H),3.13-2.87(m,2H), 2.31-2.29(m,1H),2.00-1.86(m,3H); ESI-MS(m / z,%):403(M+Na),381(MH + ,100).

[0721] Synthesis of (S)-6-methoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((S)-I-58): A suspension of LiAlH4 (1.34 g, 35.48 mmol) in dry THF (60 mL) was treated with AlCl3 (5.67 g, 42.58 mmol) at 0°C. The reaction was then reacted with (S)-2-(2-(6-methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ in dry THF (30 mL). 2To 4- ethyl -1- ketone (2.7g, 7.09mmol) was added to the mixture of 4- ethyl -1- ketone (2.7g, 7.09mmol) for 5min. After stirring for 15min, the reactant was warmed to room temperature and stirred for another 4h. The reactant was cooled to 0 DEG C, quenched with water (1.34mL), 2N NaOH solution (1.34mL) and water (1.34mL). The reactant was warmed to room temperature and stirred for another 30min. The reactant was diluted with THF (50mL), filtered through Na2SO4 pad, then filtered through silica gel pad. The solvent was evaporated and the crude product was purified on silica gel by column chromatography (MeOH:CH containing 2M NH3, 5:95) to obtain the title compound (S) -I-58 (1.14g, 65.5%) as a pale 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, overlapped with DMSO peak), 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).

[0722] Example 5: (R)-7-methoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-46)

[0723]

[0724] (R)-2-(2-(7-methoxyindolin-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ 2 Synthesis of -ethan-1-one ((R)-11): A solution of ((benzyloxy)carbonyl)-D-proline (1.67 g, 6.70 mmol) in dry 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 warmed to room temperature and the solvent evaporated to afford the crude acid chloride as a light yellow oil.

[0725] At 0 ℃, by above-mentioned crude acyl chloride in CH2Cl2 (20mL) solution in 7-methoxyindoline (1.0g, 6.70mmol) in CH2Cl2 (10mL) solution process, then use pyridine (1.0mL, 13.40mmol) process.Reactant is warmed to room temperature and stirred overnight (16h).Reactant is diluted with CH2Cl2 (100mL), washed with water (100mL), 1N HCl solution (50mL), brine (50mL) and dried (Na2SO4).Evaporated solvent and purified crude material on silica gel by flash column chromatography (EtOAc:CH2Cl2, 1:9), obtain title compound (R) -11 (2.1g, 84%) as purple jelly. 1 H NMR(DMSO-d6): δ7.37-7.30(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(m,1H),3.81,3.77( 2s,3H),3.50-3.31(m,3H),3.05-2.70(m,1H),2.65-2.55(m,1H),2.23- 2.21(m,1H),2.04-1.81(m,3H); ESI-MS(m / z,%):403(M+Na,100),381(MH + ).

[0726] Synthesis of (R)-7-methoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-46): A suspension of LiAlH4 (0.8 g, 21.02 mmol) in dry THF (50 mL) was treated with AlCl3 (3.36 g, 25.23 mmol) at 0°C. The reaction was then reacted with (R)-2-(2-(7-methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ in dry THF (20 mL). 2 -2- ketone (1.6g, 4.20mmol) is processed for 5min. After stirring for 15min, the reactant is warmed to room temperature and stirred for another 4h. The reactant is cooled to 0 DEG C, quenched with water (0.8mL), 2N NaOH solution (0.8mL) and water (0.8mL). The reactant is warmed to room temperature and stirred for another 30min. The reactant is diluted with THF (50mL), passed through Na2SO4 pad is filtered, then filtered through silica gel pad. The solvent is evaporated and the crude material is purified on silica gel by column chromatography (MeOH:CH2Cl2 containing 2M NH3, 5:95) to obtain the title compound (R)-I-46 (0.77g, 74.7%) as colorless oil. 1H NMR (DMSO-d6): δ6.71-6.66(m,2H),6.57(t,1H,J=3.0Hz),3.71(s,3H),3.51(dd,1H,J=3.0,6.0Hz),3.37-3.28(m,2H)3.14(dd,1H,J=3.0Hz),2.97- 2.93(m,1H),2.86(t,2H,J=3.0Hz),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).

[0727] Example 6: (R)-4-methoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-47)

[0728]

[0729] (R)-2-(2-(4-methoxyindolin-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ 2 Synthesis of -ethan-1-one ((R)-14): A solution of ((benzyloxy)carbonyl)-D-proline (1.67 g, 6.70 mmol) in dry 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 warmed to room temperature and the solvent evaporated to afford the crude acid chloride as a light yellow oil.

[0730] At 0 ℃, by above-mentioned crude acyl chloride in CH cl 2 (20mL) solution in 4-methoxyindoline (1.0g, 6.70mmol) in CH cl 2 (10mL) solution process, then use pyridine (1.0mL, 13.40mmol) process.Reactant is warmed to room temperature and stirred overnight (16h).Reactant is diluted with CH cl 2 (100mL), washed with water (100mL), 1N HCl solution (50mL), brine (50mL) and dried (Na sO 4).Evaporated solvent and purified crude material on silica gel by flash column chromatography (EtOAc:CH cl 2, 1: 9), obtain title compound (R) -14 (2.4g, 94%) as lavender solid. 1H NMR(DMSO-d6): δ7.74,7.69(2d,1H,J=6.0Hz),7.39-7.32(m,2H),7.20-7.13(m, 3H),7.08-7.04(m,1H),6.71(t,1H,J=6.0Hz),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 + ).

[0731] Synthesis of (R)-4-methoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-47): A suspension of LiAlH4 (1.0 g, 26.28 mmol) in dry THF (50 mL) was treated with AlCl3 (4.2 g, 31.54 mmol) at 0°C. The reaction was then reacted with (R)-2-(2-(4-methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ in dry THF (30 mL). 2 -2- ketone (2.0g, 5.25mmol) is processed for 5min. After stirring for 15min, the reactant is warmed to room temperature and stirred for another 4h. The reactant is cooled to 0 DEG C, quenched with water (1.0mL), 2N NaOH solution (1.0mL) and water (1.0mL). The reactant is warmed to room temperature and stirred for another 30min. The reactant is diluted with THF (50mL), passed through Na2SO4 pad is filtered, then filtered through silica gel pad. The solvent is evaporated and the crude product is purified on silica gel by column chromatography (MeOH:CH containing 2M NH3, 5:95), obtain the title compound (R) -I-47 (0.98g, 76%) as off-white solid. 1 H NMR (DMSO-d6): δ7.00 (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, overlapped with DMSO peak), 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).

[0732] Example 7: (R)-6-methoxy-1-(pyrrolidin-2-ylmethyl)indoline (R)-6-methoxy-1-(pyrrolidin-2-ylmethyl)indoline ((R)-I-59)

[0733]

[0734] Synthesis of (R)-6-methoxy-1-prolyl indoline (16): (R)-2-(2-(6-methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ 2 A solution of -2-ethyl-1-one (1.5 g, 3.94 mmol) in dry methanol (50 mL) was treated with 10% palladium on carbon (1.5 g, dry basis) and hydrogenated overnight (18 h) under a hydrogen atmosphere (40 PSI). The reactant was filtered through a celite pad and washed with methanol (2 x 25 mL). The combined methanol layer was evaporated and the crude product was purified on silica gel by flash column chromatography (MeOH:CH2Cl2 containing 2M NH3, 5:95) to obtain the title compound 16 (0.78 g, 80.4%) as a light yellow gum. 1 H NMR (DMSO-d6): 7.75 (d, 1H, J = 3.0Hz), 7.13 (d, 1H, J = 6.0Hz), 6.58 (dd, 1H, J = 3.0, 6.0Hz), 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).

[0735] Synthesis of (R)-6-methoxy-1-(pyrrolidin-2-ylmethyl)indoline (R)-I-59): A suspension of LiAlH4 (0.55 g, 14.61 mmol) in dry THF (20 mL) was treated with AlCl3 (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 dry THF (20 mL) for a period of 5 minutes. After stirring for 15 minutes, the reaction was warmed 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 warmed 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 and then through a pad of silica gel. The solvent was evaporated and the crude was purified by column chromatography on silica gel (2M NH 3 in MeOH:CH 2 Cl 2 , 5:95) to obtain the title compound (R)-I-59 (0.6 g, 89.5%) as a light yellow gum. 1 H NMR(DMSO-d6):6.87(d,1H,J=6.0Hz),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).

[0736] Example 8: (R)-5,6-dimethoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-34)

[0737]

[0738] (R)-2-(2-(5,6-dimethoxyindolin-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2- 2 Synthesis of -ethan-1-one (19): A solution of ((benzyloxy)carbonyl)-D-proline (1.39 g, 5.57 mmol) in dry 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 warmed to room temperature and the solvent was evaporated to afford the crude acid chloride as a light yellow oil.

[0739] At 0 ° C, a solution of the above crude acid chloride in CHCl (10 mL) was treated with a solution of 5,6-dimethoxyindoline (1.0 g, 5.57 mmol) in CHCl (20 mL) and subsequently treated with pyridine (0.9 mL, 11.15 mmol). The reaction was warmed to room temperature and stirred overnight (16 h). The reaction was treated and purified as described for compound 8 to obtain the title compound 19 (2.05 g, 89.5%) as a tan solid. ESI-MS (m / z, %): 433 (M+Na), 411 (MH + ,100).

[0740] Synthesis of (R)-5,6-dimethoxy-1-((1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-34): A suspension of LiAlH4 (0.76 g, 20.22 mmol) in dry THF (50 mL) was treated with AlCl3 (3.2 g, 24.26 mmol) at 0°C. The reaction was reacted with (R)-2-(2-(5,6-dimethoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2-yl in dry THF (20 mL). 2 -Ethan-1-one (1.66 g, 4.04 mmol) was added over a period of 5 min. After stirring for 15 min, the reaction was warmed to room temperature and stirred for an additional 4 h. The reaction was processed and purified as described for compound 6 to obtain the title compound (R)-I-34 (0.7 g, 63%) as a light yellow oil. 1 H NMR(DMSO-d6): δ6.75(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=3.0,9.0Hz),3.00-2.95(m,1H),2.87(d d,1H,J=3.0,9.0Hz),2.78(t,2H,J=6.0Hz),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).

[0741] Example 9: 2-(6-methoxyindolin-1-yl)-N,N-bis(methyl-d3)ethan-1-amine (I-70)

[0742]

[0743] 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 dry CH2Cl2 (30 mL) was treated with 2-chloroacetyl chloride (2.13 mL, 26.81 mmol) at 0°C for a period of 10 min. The reaction was warmed to room temperature and stirred overnight (16 h). The reaction was processed and purified as described for compound 21 to obtain the title compound 24 (3.0 g, quantitative) as an off-white solid.

[0744] 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), K2CO3 (3.67 g, 26.58 mmol), bis(methyl-d3)amine hydrochloride (1.16 mL, 13.29 mmol) and DMF (0.3 mL) in dry ACN (50 mL) was stirred in a sealed tube at 50°C overnight (16 h). The reaction was cooled to room temperature, worked up and purified as described for compound 22 to afford the title compound 25 (1.7 g, 80%) as a light brown oil. 1 H NMR (DMSO-d6): δ7.73(d,1H,J=3.0Hz), 7.12(d,1H,J=6.0Hz), 6.57(dd,1H,J=3.0,6.0Hz), 4. 16(t,2H,J=6.0Hz),3.72(s,3H),3.20(s,2H),3.05(t,2H,J=6.0Hz); ESI-MS(m / z,%):241(MH + ,100).

[0745] Synthesis of 2-(6-methoxyindolin-1-yl)-N,N-bis(methyl-d3)ethyl-1-amine (I-70): A suspension of LiAlH4 (0.98 g, 26.01 mmol) in dry THF (50 mL) was treated with AlCl3 (4.2 g, 31.21 mmol) at 0 ° C. The reactant was treated with 1-(6-methoxyindolin-1-yl)-2-(dimethylamino)ethyl-1-one (1.78 g, 7.43 mmol) in dry THF (20 mL) for a period of 5 min. After stirring for 15 min, the reactant was warmed to room temperature and stirred for another 4 h. The reactant was treated and purified as described for compound 6 to obtain the title compound I-70 (1.15 g, 68.8%) as a light yellow oil. 1H NMR(DMSO-d6): δ6.88-6.86(m,1H),6.10-6.07(m,2H),3.67(s,3H),3.36(t,2H,J=6.0Hz), 3.12 (t, 2H, J = 6.0Hz), 2.78 (t, 2H, J = 6.0Hz), 2.42 (t, 2H, J = 6.0Hz); ESI-MS (m / z, %): 227 (MH + ,100).

[0746] Example 10: 2-(Indolin-1-yl)-N,N-bis(methyl-d3)ethan-1-amine (I-71)

[0747]

[0748] 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 dry CH2Cl2 (20 mL) was treated with 2-chloroacetyl chloride (1.33 mL, 16.78 mmol) at 0°C for a period of 10 min. The reaction was warmed to room temperature and stirred overnight (16 h). The reaction was worked up and purified as described for compound 21 to give the title compound 27 (1.6 g, 97.5%) as an off-white solid.

[0749] 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), K2CO3 (4.23 g, 30.66 mmol), bis(methyl-d3)amine hydrochloride (1.34 mL, 15.33 mmol) and DMF (0.3 mL) in dry ACN (50 mL) was stirred in a sealed tube at 50° C. overnight (16 h). The reaction was cooled to room temperature, worked up and purified as described for compound 22 to afford the title compound 28 (1.8 g, 83.7%) as a light yellow oil. 1 H NMR (DMSO-d6): δ8.07 (d, 1H, J = 6.0Hz), 7.24 (d, 1H, J = 6.0Hz), 7.15 (t, 1H, J = 6.0Hz), 7.02-6. 98 (m, 1H), 4.16 (t, 2H, J = 6.0Hz), 3.21 (s, 2H), 3.13 (t, 2H, J = 6.0Hz); ESI-MS (m / z, %): 211 (MH + ,100).

[0750] Synthesis of 2-(indolin-1-yl)-N,N-bis(methyl-d3)ethyl-1-amine (I-71): A suspension of LiAlH4 (1.098 g, 28.92 mmol) in dry THF (50 mL) was treated with AlCl3 (4.62 g, 34.71 mmol) at 0 ° C. The reactant was treated with 2-(bis(methyl-d3)amino)-1-(indolin-1-yl)ethyl-1-one (1.738 g, 8.26 mmol) in dry THF (20 mL) for a period of 5 min. After stirring for 15 min, the reactant was warmed to room temperature and stirred for another 4 h. The reactant was treated and purified as described for compound 6 to obtain the title compound I-71 (0.96 g, 59.2%) as a light brown oil. 1 H NMR(DMSO-d6): δ7.02-6.95(m,2H),6.56-6.47(m,2H),3.34(t,2H,J=6.0Hz),3.12( t, 2H, J = 6.0Hz), 2.86 (t, 2H, J = 60Hz), 2.43 (t, 2H, J = 6.0Hz); ESI-MS (m / z, %): 197 (MH + ,100).

[0751] Example 11: (R)-6-(methoxy-d3)-1-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)indoline ((R)-I-28)

[0752]

[0753] Synthesis of 4-(methoxy-d3)-1-methyl-2-nitrobenzene (31): A solution of 4-methyl-3-nitrophenol (25.3 g, 165.25 mmol) in dry DMF (200 mL) was stirred at room temperature with KOH (10.2 g, 181.77 mmol), t Bu4NBr (0.53g, 1.65mmol) and CD3I (10.8mL, 173.51mmol) are processed. The reactant is stirred in a sealed tube at 60°C for 24h. The reactant is warmed to room temperature, diluted with water (1L), and the product is extracted into diethyl ether (2x 300mL). The combined diethyl ether layer is washed with water (2x 100mL), brine (100mL) and dried (Na2SO4). The solvent is evaporated to obtain the crude title compound 31 (28.0g) as a brown liquid.

[0754] Synthesis of 2-(4-(methoxy-d3)-2-nitrophenyl)-N,N-dimethylethan-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 distilled off to obtain the crude title compound 32, which was used in the next step without any further purification.

[0755]

[00155] Synthesis of 6-(methoxy-d3)-1H-indole (33): A solution of the above crude 2-(4-(methoxy-d3)-2-nitrophenyl)-N,N-dimethylethan-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 material was purified on silica gel by flash column chromatography (EtOAc:hexanes, 1:4) to afford the title compound (4.52 g, 18.2% over three steps). 1 H NMR (CDCl3): δ8.03 (brs, 1H), 7.55 (d, 1H, J = 6.0Hz), 7.12 (dd, 1H, J = 3.0Hz), 6.90 (d, 1H, J = 3.0Hz), 6.84 (dd, 1H, J = 3.0, 6.0Hz), 6.53-6.51 (m, 1H).

[0756] 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 in batches with sodium cyanoborohydride (1.88 g, 29.96 mmol) at 0 ° C. The reactant was warmed to room temperature and stirred for 1 h. At 0 ° C, the reactant was quenched with 4N NaOH solution, and the product was extracted into ethyl acetate (2x 50 mL). The combined ethyl acetate layer was washed with brine (25 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified on silica gel by column chromatography (EtOAc: hexane, 1: 4) to obtain the title compound 34 (1.27 g, 83.5%) as a brown liquid. 1 H NMR (CDCl3): δ7.03-7.00 (m, 1H), 6.29-6.26 (m, 2H), 3.59 (t, 2H, J = 6.0Hz), 2.98 (t, 2H, J = 6.0Hz).

[0757] (R)-2-(2-(6-(methoxy-d3)indoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2- 2 Synthesis of -ethan-1-one (35): A solution of ((benzyloxy)carbonyl)-D-proline (2.08 g, 8.34 mmol) in dry 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 warmed to room temperature and the solvent evaporated to afford the crude acid chloride as a light yellow oil.

[0758] At 0 ° C, a solution of the above crude acid chloride in CHCl (10 mL) was treated with a solution of 6-(methoxy-d3)indoline (1.27 g, 8.34 mmol) in CHCl (30 mL) and subsequently treated with pyridine (1.35 mL, 16.69 mmol). The reaction was warmed to room temperature and stirred overnight (16 h). The reaction was treated and purified as described for compound 8 to obtain the title compound 35 (3.1 g, 96.8%) as a light brown oil. ESI-MS (m / z, %): 406 (M+Na), 384 (MH + ).

[0759] Synthesis of (R)-6-(methoxy-d3)-1-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)indoline ((R)-I-28): A suspension of LiAlD4 (1.42 g, 33.90 mmol) in dry THF (50 mL) was treated with AlCl3 (5.4 g, 40.68 mmol) at 0°C. The reaction was reacted with (R)-2-(2-(6-(methoxy-d3)indoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2-yl in dry THF (30 mL). 2 -Ethan-1-one (2.6 g, 6.78 mmol) was added over a 5 min period. After stirring for 15 min, the reaction was warmed to room temperature and stirred for an additional 4 h. The reaction was processed and purified as described for compound 6 to obtain the title compound (R)-I-28 (1.26 g, 73%) as a light yellow oil. 1 H NMR(DMSO-d6): δ6.88-6.85(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 = 6.0Hz), 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).

[0760] B. Biological Testing

[0761] Example 12: FLIPR Assay: Human 5-HT2A

[0762] Target:

[0763] Evaluation of exemplary Formula I compounds targeting human 5-HT in agonist mode 2A (h5-HT 2A ) receptor effects.

[0764] Materials and instruments

[0765] 1.1 Cell lines

[0766]

[0767] 1.2 Compound preparation and assay control

[0768] Reagents and materials:

[0769]

[0770] 1.3 Instruments and consumables

[0771]

[0772]

[0773] 2 Experimental methods

[0774] 2.1 Cell culture

[0775] HTR2A&Gα15-HEK293 cells were cultured in DMEM medium containing 10% dialyzed FBS, 1× penicillin-streptomycin, 100 μg / mL hygromycin B, and 300 μg / mL G418. Cells were passaged approximately three times a week to maintain a confluence of approximately 30% to approximately 90%.

[0776] 2.2 Cell plating

[0777] 1. Cell culture medium (DMEM medium containing 10% dialyzed FBS, 1× penicillin-streptomycin, 100 μg / mL hygromycin B, and 300 μg / mL G418), TrypLE TM Express and DPBS are warmed to room temperature in advance.

[0778] 2. For induction, add 1 μg / ml tetracycline (final concentration) to the cell culture medium and incubate for 48 hours, then seed the cells into plates at 37°C, 5% (v / v) CO2. Remove the cell culture medium from the flask. Wash the cells with DPBS.

[0779] 3. Add 2 mL of TrypLE TM Express was added to the flask, mixed thoroughly by gentle shaking, and the cells were incubated at 37°C for several minutes.

[0780] 4. Check the morphological changes of the cells under a microscope. When most of the cells become round, stop the digestion by adding 4 mL of cell culture medium to the flask.

[0781] 5. Transfer the cell suspension to a 15 mL centrifuge tube and centrifuge at 1,200 rpm for 5 minutes.

[0782] 6. Remove the supernatant and resuspend the cell pellet in 2 mL of cell culture medium.

[0783] 7. Count the cell density using a cell counter. Only cells with a viability > 85% were used for the assay.

[0784] 8. Dilute the cells to 6.67×10 5 / mL.

[0785] 9. Add 30 μL / well of the cell suspension to a 384-well cell plate (cell density is 20,000 cells / well).

[0786] 10. Incubate the cell plate at 37°C, 5% (v / v) CO2 overnight.

[0787] 2.3 Cell treatment

[0788] 1. On the day of the experiment, remove the culture medium from the cell plates.

[0789] 2. Add 10 μL of assay buffer (20 mM HEPES in 1× HBSS, pH 7.4) to each well of the cell plate.

[0790] 3. Follow Prepare 2x dye solution according to the instruction manual of the Calcium 6 Assay Kit:

[0791] i. Dilute the dye in assay buffer.

[0792] ii. Add probenecid to a final concentration of 5 mM.

[0793] iii. Vortex vigorously for 1-2 minutes.

[0794] 4. Add 10 μL of 2x dye solution to each well of the cell plate.

[0795] 5. Place the cell plate on a plate shaker and shake at 600 rpm for 2 minutes.

[0796] 6. Incubate the plate at 37°C for 2 hours, followed by incubation at 25°C for 15 minutes.

[0797] 2.4 Preparation of 3-fold Compounds

[0798] 1. Prepare serotonin HCl in DMSO to a concentration of 10 mM.

[0799] 2. Prepare the test compound in DMSO to a concentration of 10 mM.

[0800] 3. Add compounds to a 384-well compound source plate.

[0801] 4. Perform 3-fold serial dilutions with DMSO.

[0802] 5. Transfer 90 nL / well of the serially diluted compounds from the source plate to the 384-well compound plate by using Echo.

[0803] 6. Add 30 μL / well of assay buffer (20 mM HEPES in 1×HBSS, pH 7.4) to the compound plate.

[0804] 7. Mix the plate on a plate shaker for 2 minutes.

[0805] 2.5 FLIPR assay

[0806] 1. After incubating the cells with the dye solution, place the cell plate, compound plate containing 3x compounds, and FLIPR tips into the FLIPR.

[0807] 2. Transfer 10 μL of 3x compound from the compound plate to the cell plate using FLIPR.

[0808] 3. Read the plate at 1 second intervals for 160 seconds and acquire data for the agonist mode.

[0809] 2.6 Data Analysis

[0810] 1. The normalized fluorescence reading (RFU) is calculated as follows, where Fmax and Fmin represent the maximum and minimum values of the calcium signal within the defined time window:

[0811] RFU=Fmax–Fmin

[0812] 2. Using XLfit, calculate EC by fitting the RFU agonist to the logarithm of the compound concentration using the Hill equation50 .

[0813] 3.0 Experimental Methods and Procedures:

[0814] You can also follow the following procedure:

[0815] 1. Cells were cultured in cell culture medium (DMEM containing 10% FBS, 1× penicillin-streptomycin, 300 μg / ml G418, and 100 μg / ml hygromycin B) at 37° C. and 5% (v / v) CO 2 .

[0816] 2. One day before the assay, use TrypLE TM Express cells were detached and counted using a cell counter. Only cells with a viability > 85% were used in the assay.

[0817] 3. 20,000 cells / well were seeded into 384-well cell plates in 30 μl / well culture medium and the cells were incubated overnight at 37°C, 5% (v / v) CO2.

[0818] 4. On the day of measurement, Prepare 2x dye solution according to the instruction manual of the Calcium 6 Assay Kit: i. Dilute the dye with assay buffer (20 mM HEPES in 1x HBSS, pH 7.4); ii. Add probenecid to a final concentration of 5 mM; iii. Vortex vigorously for 1-2 minutes.

[0819] 5. Remove the culture medium from the cell plate by flicking the plate on a paper towel.

[0820] 6. Add 10 μl of assay buffer and 10 μl of 2x dye solution to each well of the cell plate.

[0821] 7. Place the cell plate on a plate shaker and agitate the plate at 600 rpm for 2 minutes. Incubate the plate at 37°C for 2 hours, then at 25°C for 15 minutes.

[0822] 8. Prepare 3x compounds in assay buffer: a. Dilute the reference compound to the desired concentration in DMSO. Add the compound to a 384-well compound plate. b. Perform a serial dilution. c. Add 10 mM test compound to the compound plate and perform a 3x serial dilution. d. Transfer 60 nl / well of compound from the source plate to a 384-well compound plate (Corning, 3657) using an Echo. e. Add 20 μl / well of assay buffer to the compound plate. f. Mix the plate on a plate shaker for 2 minutes.

[0823] 9. Place the cell plate, compound plate, and pipette tips into the FLIPR. Transfer 10 μl of the 3x compound to each well of the cell plate using the FLIPR.

[0824] Data Analysis

[0825] i. The normalized fluorescence reading (RFU) is calculated as follows, where Fmax and Fmin represent the maximum and minimum values of the calcium signal within the defined time window: RFU = Fmax – Fmin

[0826] ii. Calculate the activation percentage using the following equation:

[0827]

[0828] iii. Using XLfit, calculate EC by fitting the activation percentage to the logarithm of compound concentration using the Hill equation 50 .

[0829] Results and discussion

[0830] The effects of the exemplary compounds of Formula I on the h5-HT2A receptor in agonist mode were functionally evaluated using the FLIPR assay. Table 2 summarizes the results of the potential competitive binding properties of the exemplary compounds of the present application targeting human 5-hydroxytryptamine receptor 2A (5-HT2A). The results of the exemplary compounds of the present application are presented in the IC values provided in Table 2. 50 Present.

[0831] Table 2: Effects of exemplary compounds of Formula I on human 5-HT2A receptor using FLIPR functional assay

[0832] Compound ID# <![CDATA[h5-HT2A,EC 50 [nM]]]> <![CDATA[RFU@10μM (1) ]]> Psilocybin <![CDATA[ND (2) ]]> 257 Psilocin 72.5 308 (R)-I-1 3551 386 <![CDATA[ (R)-I-57 ]]> 422 749 (R)-I-58 322 796 (S)-I-58 ND 203 (R)-I-46 1137 487 (R)-I-47 ND 174 (R)-I-59 1211 801 (R)-I-34 ND 268 I-70 ND 303 I-71 ND 280 (R)-I-28 1,093 3744

[0833] (1) Curve fitting using activation (%) and RFU at 10 mM

[0834] (2)ND: Not Detected

[0835] Exemplary compounds of Formula I were evaluated using a radioligand binding assay at the human 5-HT2A receptor. 50 The (nM) concentrations are shown in Table 2. This assay demonstrates that the compounds of the present application are potent ligands for the target human 5-HT2A receptor.

[0836] Example 13: Human 5-HT2A: Radioligand Binding Assay:

[0837] Target

[0838] The FLIPR assay was used to functionally evaluate the effects of exemplary compounds of Formula I on h5-HT in agonist mode. 2AThe goal of this study was to evaluate the binding properties of exemplary compounds of formula I to the serotonin receptor 2A (5-HT2A).

[0839] Human 5-HT 2A : Radioligand binding assay:

[0840] 1 Materials and Instruments

[0841] 1.1 Reagents

[0842]

[0843] 1.2 Instruments and consumables

[0844]

[0845] 2 Experimental procedures

[0846] i. Prepare the assay buffer according to the table below.

[0847]

[0848] The pH was adjusted to 7.4 and then sterile filtered through 0.2 μM.

[0849] ii. Starting from 10 mM stock solutions, 8 doses of reference and test compounds were prepared as required by 5-fold serial dilutions with 100% (v / v) DMSO.

[0850] iii. Pre-treat the UniFilter-96 GF / B plate:

[0851] a. Add 50 μl / well of 0.5% (v / v) PEI to a UniFilter-96 GF / C plate. Seal the plate and incubate at 4°C for 3 hours.

[0852] b. After incubation, the plates were washed three times with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0853] iv. Prepare assay plates:

[0854] a. Cell membranes were diluted with assay buffer and 330 μl / well were added to a 96-round deep-well plate to achieve a concentration of 20 μg / well.

[0855] b. Prepare 8 concentrations of reference or test compound and add 110 μl / well to a 96-round deep-well plate.

[0856] c. [3H]-ketanserin was diluted to 5 nM (5-fold final concentration) with assay buffer, and 110 μl / well was added to a 96-round deep-well plate.

[0857] v. Centrifuge the plate at 1000 rpm for 30 seconds and then agitate at 600 rpm for 5 minutes at room temperature.

[0858] vi. Seal the plate and incubate the plate at 27°C for 90 min.

[0859] vii. Stop the incubation by vacuum filtration onto GF / B filter plates, followed by four washes with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0860] viii. Dry the plate at 37°C for 45 min.

[0861] ix. Seal the filter plate and add 40 μl / well of scintillation cocktail.

[0862] x. By using Microbeta 2 The plate is read with a microplate counter.

[0863] 3 Data Analysis

[0864] 1. For reference and test compounds, express the results as % inhibition using the normalization equation: N = 100 - 100 x (U - C2) / (C1 - C2), where U is the unknown value, C1 is the high control mean, and C2 is the low control mean.

[0865] 2.IC 50 The percent inhibition was determined by fitting the Hill equation as a function of compound concentration using XLfit.

[0866] Results and discussion

[0867] Table 3 summarizes the results of potential competitive binding properties of the exemplary compounds of the present application targeting human 5-hydroxytryptamine receptor 2A (5-HT2A). The results of the exemplary compounds of the present application are presented in the form of IC 50 Present.

[0868] Table 3: Effects of exemplary compounds of Formula I on the human 5-HT2A receptor using a radioligand binding assay

[0869] Compound ID# h5-HT2A,IC50[nM] Psilocybin 4248 Psilocin 187.2 (R)-I-1 4528 (R)-I-57 7955 (R)-I-58 6525 (S)-I-58 >30000 (R)-I-46 2460 (R)-I-47 >30000 (R)-I-59 15253 (R)-I-34 >30000 I-70 25794 I-71 14972 (R)-I-28 8483

[0870] II. Results and Discussion

[0871] Exemplary compounds of Formula I were evaluated using a radioligand binding assay for the human 5-HT2A receptor. 50 The (nM) concentrations are shown in Table 3. This assay demonstrates that the compounds of the present application are potent ligands for the target human 5-HT2A receptor.

[0872] Example 14: Human 5-HT1A: Functional FLIPR Assay

[0873] 1 goal

[0874] Compounds targeting 5-hydroxytryptamine receptor 1A (5-HT1A) were evaluated in agonist mode for their potential excitatory effects.

[0875] 2 Materials and instruments

[0876] 2.1 Cell lines

[0877]

[0878] 2.2 Materials

[0879]

[0880]

[0881] 2.3 Instruments and consumables

[0882]

[0883] 3 Experimental methods

[0884] 3.1 Cell culture

[0885] HTR1A&Gα15-CHO cells were cultured in DMEM / F12 medium containing 10% dialyzed FBS, 1× penicillin-streptomycin, and 600 μg / mL hygromycin B. The cells were passaged approximately three times a week, maintaining a confluence of approximately 30% to approximately 90%.

[0886] 3.2 Cell plating

[0887] 1. Cell culture medium (DMEM / F12 medium containing 10% dialyzed FBS, 1× penicillin-streptomycin and 600 μg / mL hygromycin B), TrypLE TM Express and DPBS are warmed to room temperature in advance.

[0888] 2. Remove the cell culture medium from the flask and wash the cells with DPBS.

[0889] 3. Add 1 mL of TrypLE TM Express was added to the flask, mixed thoroughly by gentle shaking, and the cells were incubated at 37°C for several minutes.

[0890] 4. Check the morphological changes of the cells under a microscope. When most of the cells become round, stop the digestion by adding 2 mL of cell culture medium to the flask.

[0891] 5. Transfer the cell suspension to a 15 mL centrifuge tube and centrifuge at 1,200 rpm for 5 minutes.

[0892] 6. Remove the supernatant and resuspend the cell pellet in 2 mL of cell culture medium.

[0893] 7. Count the cell density using a cell counter. Only cells with a viability > 85% were used for the assay.

[0894] 8. Dilute the cells to 4 × 10 5 / mL.

[0895] 9. Add 30 μL / well of the cell suspension to a 384-well cell plate (cell density is 12,000 cells / well).

[0896] 10. Incubate the cell plate at 37°C, 5% (v / v) CO2 overnight.

[0897] 3.3 Cell treatment

[0898] 1. On the day of the experiment, remove the culture medium from the cell plates.

[0899] 2. Add 10 μL of assay buffer (20 mM HEPES in 1× HBSS, pH 7.4) to each well of the cell plate.

[0900] 3. Follow Prepare 2x dye solution according to the manufacturer's instructions of the Calcium 6 Assay Kit:

[0901] i. Dilute the dye with assay buffer.

[0902] ii. Add probenecid to a final concentration of 5 mM.

[0903] iii. Vortex vigorously for 1-2 minutes and adjust pH to 7.4.

[0904] 4. Add 10 μL of 2x dye solution to each well of the cell plate.

[0905] 5. Place the cell plate on a plate shaker and shake at 600 rpm for 2 minutes.

[0906] 6. Incubate the plate at 37°C for 2 hours, followed by incubation at 25°C for 15 minutes.

[0907] 3.4 Preparation of 3-fold compounds

[0908] 1. Prepare serotonin in DMSO to a concentration of 10 mM and make three-fold serial dilutions in DMSO.

[0909] 2. Prepare the test compound in DMSO to a concentration of 10 mM and perform 3-fold serial dilutions in DMSO.

[0910] 3. Add compounds to a 384-well compound source plate.

[0911] 4. Transfer 90 nL / well of the serially diluted compounds from the source plate to the 384-well compound plate by using Echo.

[0912] 5. Add 30 μL / well of assay buffer to the compound plate.

[0913] 6. Mix the plate on a plate shaker for 2 minutes.

[0914] 3.5 FLIPR assay

[0915] 1. After incubating the cells with the dye solution, place the cell plate, compound plate containing 3x compounds, and FLIPR tips into the FLIPR.

[0916] 2. Transfer 10 μL of 3x compound from the compound plate to the cell plate using FLIPR.

[0917] 3. Read the plate at 1 second intervals for 160 seconds to obtain data in agonist mode.

[0918] 4 Data Analysis

[0919] 1. The normalized fluorescence reading (RFU) is calculated as follows, where Fmax and Fmin represent the maximum and minimum values of the calcium signal within the defined time window:

[0920] RFU=Fmax–Fmin

[0921] 2. Using XLfit, calculate EC by fitting the RFU agonist to the logarithm of the compound concentration using the Hill equation 50 .

[0922] Results and discussion

[0923] Table 4 summarizes the results of potential competitive binding properties of the exemplary compounds of the present application targeting human 5-hydroxytryptamine receptor 1A (5-HT1A). The results of the exemplary compounds of the present application are presented in the form of EC 50 Present.

[0924] Table 4: Effects of exemplary compounds of Formula I on human 5-HT1A receptor using FLIPR functional assay

[0925] Compound ID# <![CDATA[h5-HT1A,EC 50 [nM]]]> <![CDATA[RFU@10μM (1) ]]> Psilocybin <![CDATA[ND (2) ]]> 143 Psilocin ND 140 (R)-I-1 ND 84 (R)-I-57 1264 2081 (R)-I-58 2042 2444 (R)-I-46 ND 373 (R)-I-47 ND 70 (R)-I-59 ND 521 (R)-I-34 ND 155 I-70 ND 161 I-71 ND 145 (R)-I-28 2339 1981

[0926] (1) Curve fitting using activation (%) and RFU at 10 mM

[0927] (2) Not detected

[0928] Exemplary compounds of Formula I were evaluated using a functional FLIPR assay for the human 5-HT1A receptor. 50 The (nM) concentrations are shown in Table 4. This assay demonstrates that the compounds of the present application have moderate functional activity at the target human 5-HT1A receptor.

[0929] Example 15: Human 5-HT1A: Radioligand Binding Assay:

[0930] 1 goal

[0931] The goal of this study was to evaluate the binding properties of test compounds to the serotonin receptor 1A (5-HT1A).

[0932] 2 Materials and Instruments

[0933] 2.1 Reagents

[0934]

[0935] 2.2 Instruments and consumables

[0936]

[0937] 3 Experimental methods

[0938] 1. Prepare the assay buffer according to the table below.

[0939]

[0940] The pH was adjusted to 7.4 and then sterile filtered through 0.2 μM.

[0941] 2. Starting from 10 mM stock solutions, 8 doses of reference and test compounds were prepared as required by 5-fold serial dilutions with 100% (v / v) DMSO.

[0942] 3. Pre-treat the UniFilter-96 GF / B plate:

[0943] i. Add 50 μl / well of 0.5% (v / v) PEI to the UniFilter-96 GF / B plate. Seal the plate and incubate at 4°C for 3 hours.

[0944] ii. After incubation, the plate was washed three times with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0945] 4. Prepare the assay plate:

[0946] i. Dilute the cell membranes with assay buffer and add 100 μl / well to a 96-well round-well plate to achieve a concentration of 20 μg / well.

[0947] ii. Prepare 8 concentrations of reference or test compound and add 50 μl / well to a 96-round deep-well plate.

[0948] iii. [3H]-8-hydroxy-DPAT was diluted to 2 nM (4 times the final concentration) with assay buffer, and 50 μl / well was added to a 96-well round-well plate.

[0949] 5. Centrifuge the plate at 1000 rpm for 30 seconds and then agitate at 600 rpm for 5 minutes at room temperature.

[0950] 6. Seal the plate and incubate the plate at 27°C for 90 min.

[0951] 7. Stop the incubation by vacuum filtration onto GF / B filter plates, followed by four washes with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0952] 8. Dry the plate at 37°C for 45 min.

[0953] 9. Seal the filter plate and add 40 μl / well of scintillation cocktail.

[0954] 10. By using Microbeta 2 The plate is read with a microplate counter.

[0955] 4 Data Analysis

[0956] 1. For reference and test compounds, express the results as % inhibition using the normalization equation: N = 100 - 100 x (U - C2) / (C1 - C2), where U is the unknown value, C1 is the high control mean, and C2 is the low control mean.

[0957] 2.IC 50 The percent inhibition of binding as a function of compound concentration was determined by fitting with the Hill equation using XLfit.

[0958] result

[0959] Table 5 summarizes the results of potential competitive binding properties of the exemplary compounds of the present application targeting human 5-hydroxytryptamine receptor (5-HT1A). The results of the exemplary compounds of the present application are presented in the form of IC 50 Present.

[0960] Table 5: Effects of exemplary compounds of Formula I on the human 5-HT1A receptor using a radioligand binding assay

[0961] Compound ID# <![CDATA[h5-HT1A,IC 50 [nM]]]> Psilocybin 4785 Psilocin 195.7 (R)-I-1 444.13 (R)-I-57 10.00 (R)-I-58 13.00 (R)-I-46 211.41 (R)-I-47 15320.57 (R)-I-59 85 (R)-I-34 7750.56 I-70 193.00 I-71 1623.00 (R)-I-28 5.04

[0962] discuss

[0963] Exemplary compounds of Formula I were evaluated using a radioligand binding assay for the human 5-HT1A receptor. 50 The (nM) concentrations are shown in Table 5. This assay demonstrates that the compounds of the present application are potent ligands for the target human 5-HT1A receptor.

[0964] Example 16: Human, Rat and Mouse Liver Microsome Stability

[0965] Target

[0966] The goal of this research is to assess the in vitro metabolic stability of exemplary Formula I compounds or their pharmaceutically acceptable salts, solvates and / or prodrugs in the human, male rat and male mouse liver microsomes that merge. The concentration of the compound in the reaction system is evaluated by LC-MS / MS for stability in the human, male rat and male mouse liver microsomes that merge. The in vitro intrinsic clearance of the test compound is also measured.

[0967] plan

[0968] Prepare the stock solution in the "incubation plate" containing phosphate buffer, ultrapure H2O, MgCl2 solution and liver microsomes according to Table 6. Preheat the mixture in a 37°C water bath for 5 minutes.

[0969] Table 6: Preparation of mother liquor

[0970]

[0971]

[0972] 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 NADPH with 40 μL of ultrapure HO. Prepare samples in duplicate. Prepare a negative control in a single aliquot.

[0973] To start the reaction, 4 μL of 200 μM of an exemplary test compound or control compound of the present application was added to each stock solution to obtain a final concentration of 2 μM. This study was performed in duplicate.

[0974] 50 μL aliquots were removed from the reaction solution at 0, 15, 30, 45, and 60 minutes. The reaction solution was terminated by adding 4 volumes of cold methanol containing IS (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol, and 2 μM ketoprofen). The sample was centrifuged at 3,220 g for 40 minutes. A 90 μL aliquot of the supernatant was mixed with 90 μL of ultrapure HO and then used for LC-MS / MS analysis.

[0975] All samples in this study were analyzed by LC / MS using a Shimadzu liquid chromatography system equipped with a degasser DGU-20A5R, a solvent delivery device LC-30AD, a system controller SIL-30AC, a column oven CTO-30A, and a CTC analysis HTC PAL system. Mass spectrometry analysis was performed using a Triple Quad™ 5500 instrument.

[0976] All calculations were performed using Microsoft Excel.The peak area ratios of the test compounds to the internal standards (listed in the table below) were determined from the extracted ion chromatograms.

[0977] All calculations were performed using Microsoft Excel. Peak areas were determined from the extracted ion chromatograms. The slope value, k, was determined by linear regression of the percent parent drug remaining versus the natural logarithm of the incubation time curve.

[0978] In vitro half-life (in vitro t 1 / 2 ) is determined by the slope value:

[0979] in vitro t / 2 =-(0.693 / k)

[0980] In vitro 1 / 2 The conversion of the in vitro intrinsic clearance (CLint in vitro, in μL / min / mg protein) was performed using the following equation (average of two determinations):

[0981]

[0982] For exemplary compounds of the present application or control compounds that showed an initial rapid disappearance followed by a slow disappearance, only time points within the initial rate were included in the calculations.

[0983] Results and discussion

[0984] Human, rat and mouse liver microsomes contain a variety of drug metabolizing enzymes and are commonly used to support in vitro ADME (absorption, distribution, metabolism and excretion) studies. These microsomes are used to examine potential first-pass metabolic byproducts of orally administered drugs. The stability of representative compounds of the present application in human, rat and mouse liver microsomes was evaluated.

[0985] Example 17: Humans, rats, mice, and dogs: Plasma stability

[0986] 1. Preparation of Stock Solutions

[0987] Stock solutions of the test compounds were prepared in DMSO and diluted to a final concentration of 200 μM. 1 mM working solutions of lovastatin and propantheline were pre-prepared in DMSO and acetonitrile, respectively. Lovastatin was used as a positive control for the stability assays in rat and dog plasma. Propantheline was used as a positive control for the stability assays in human, mouse, and monkey plasma.

[0988] 2. Plasma Stability Procedure

[0989] a. Add 2.5 μL of a 200 μM or 1 mM solution of test compound or control compound to 497.5 μL of plasma to achieve a final concentration of 1 μM or 5 μM. The final concentration of organic solvent is 0.5%. This assay is performed in duplicate.

[0990] b. Incubate the reaction sample in a water bath at 37°C at approximately 60 rpm.

[0991] c. Remove 50 μL aliquots from the reaction samples at 0, 30, 60, 120, 180, and 240 minutes. Terminate the reaction by adding 7 volumes of cold acetonitrile containing internal standards (IS: 100 nM alprazolam, 200 nM imipramine, 200 nM labetalol, and 2 μM ketoprofen).

[0992] d. Vortex all samples for 2 minutes, then centrifuge at 3,220 g for 30 minutes to precipitate proteins. Transfer 100 μL of the supernatant to a new plate. Dilute the supernatant with ultrapure water based on the LC-MS signal response and peak shape.

[0993] 3. Sample Analysis

[0994] Samples were analyzed by LC-MS / MS.

[0995] LC system: Shimadzu

[0996] MS analysis: Triple Quad™ 6500+ with ESI interface from AB Inc (Canada)

[0997] Column temperature: 40°C

[0998] Column: connected with pre-guard column Hss T3 2.5μ(2.1×30mm)

[0999] Mobile phase: Water containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B)

[1000]

[1001] 4. Data Analysis

[1002] All calculations were performed using Microsoft Excel. The percentage of parent compound remaining at each time point was estimated by determining the peak area ratios from the extracted ion chromatograms.

[1003] Table 7. Stability results of exemplary compounds in plasma of different species

[1004]

[1005] Note:

[1006] 1. If the remaining percentage at 60 minutes is greater than 85%, then T 1 / 2 Reported as >255.85min.

[1007] 2. For compounds that showed an initial rapid disappearance followed by a slow disappearance, only time points within the initial rate were included in the calculations.

[1008] Example 18: Hallucinogenic Effects of Exemplary Compounds of Formula I

[1009] The effects of various doses of exemplary compounds of Formula I on the head twitch response (HTR) and other behavioral responses were evaluated as a behaviorally based model of hallucinogenic activity.

[1010] plan

[1011] Mouse head twitching

[1012] The test article of appropriate dose is administered to male C57BL / 6J mice (body weight range is 20-30g) and after 1 minute pre-treatment time, is placed in a separate observation chamber. Visual assessment animal continuous head twitching incidence in 1 hour time period. Head twitching is defined as the rapid twitching of the head that is not caused by external tactile stimulation (Corne and Pickering, Psychopharmacologia, 1967, 11 (1): 65-78). Each head twitch is counted separately by a well-trained observer, and data are expressed as mean ± SEM of 6-10 mice per group. Mice are used in only single experiment.

[1013] Rat behavioral testing

[1014] Male Sprague-Dawley rats (weight range 250-400 g) were administered the appropriate dose of the test article and, after a 1 minute pretreatment period, were placed in a locomotor activity box (dimensions 17" W x 17" L x 12" H) and continuously monitored for a period of 1 hour, with data collected in 10 minute time segments. The animals were visually assessed for overt behavioral signs, including 5-HT 2A Receptor activation (wet dog shake, back muscle contraction), 5-HT 2A Receptor activation (yawning, penile grooming) and 5-HT 1A Behavioral characteristics of behavior (forepaw stepping, hind limb abduction) (Halberzettl et al., Behav Brain Res. 256: 328-345, 2013). Other behavioral and somatic signs characteristic of serotonin syndrome (such as tremor, salivation, flat posture, core body temperature changes) were also measured. At the same time, ...

Claims

1. A compound of formula IA or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, in: R 1 and R 1' Independently selected from H, halo, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2; R 2 and R 2' independently selected from H, halo, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2; Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6: is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 Does not exist, when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q5 When it is a double bond, R 48 and R 57 does not exist; R 4 and R 5 One or both of them are independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, or R 4 and R 5 Linked together to form O-(CH2) 1-2 O, or R 4 and R 5 One of them is selected from XLA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, X is selected from direct bond, O, C(O), NR a NR 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 NR a C(O)NR a ; L is selected from 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 Alkylene C(O)NR b 、C 2-6 Alkenylene C(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 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 ; R a Selected from H and C 1-6 alkyl; R b Selected from H, C 1-6 Alkyl and A; A is selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 64 The heterocyclic alkyl group of the heterocyclic alkyl group is 3 to 6 members and contains 1 to 4 independently selected from O, S, S (O), SO2, N and NR 64 The 5-membered to 6-membered heteroaryl group of the hetero part, wherein phenyl, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted by one or more independently selected from halo, C 1-4 Alkyl and OC 1-4 Substitution of alkyl groups; R 3 and R 6 are independently selected from 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 selected from H, halo and C 1-6 alkyl; R 12 、R 20 、R 29 、R 39 and R 51 Independently selected from H, C 1-6 Alkyl, C(O)C 1-6 Alkyl and C(O)-A'; R 60 and R 61 Independently selected from H and C 1-6 alkyl; or R 60 and R 61 One of them is C(O)-A' and the other is selected from H and C 1-6 alkyl; wherein A' is selected from Y, OY and OC 1-4 Alkylene-OC(O)-Y; and Y is selected from 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, they form a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered heterocyclic ring optionally contains one or two independently selected from O, S, S(O), SO2, N and NR 65 and optionally substituted by one or more independently selected from halo, OH, C 1-4 Alkyl and OC 1-4 Substitution of alkyl groups; R 64 and R 65 Independently selected from H and C 1-6 alkyl; and All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof, Provided that when Q is Q6, then the compound of formula I comprises D, When Q is Q3 or Q4, when R 5 is H or OCH3, and R 29 or R 39 When it is CH3, R 1 、R 1' 、R 2 、R 2' 、R 3 、R 4 、R 6 、R 26 、R 27 、R 28 、R 30 to R 35 、R 36 、R 37 、R 38 and R 40 to R 47 Not all are H; and When Q is Q4 and R 1 、R 1' 、R 2 、R 2' 、R 3 、R 4 、R 6 、R 38 and R 40 to R 47 When all are H, then when R 39 When it is CD3, R 36 and R 37 Not all are D.

2. The compound of claim 1, wherein 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 Independently selected from H and D.

3. The compound of claim 1, wherein Q is selected from one of the following groups: where R 12 、R 20 、R 29 、 R 39 、R 51 、R 60 and R 61 Independently selected from H, D, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl and C(O)-A'.

4. The compound of claim 3, wherein R 12 、R 20 、R 29 、R 39 、R 51 、R 60 and R 61 Independently selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 Deuterated alkyl.

5. The compound of claim 3, wherein R 60 and R 61 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered heterocyclic ring optionally contains one or two independently selected from O, N and NR 65 and optionally substituted by one or more independently selected from halo, OH, C 1-4 Alkyl and OC 1-4 The alkyl group is substituted with a substituent.

6. The compound of claim 3, wherein Q is selected from one of the following groups: where R 29 Selected from H, D, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl and C(O)-A'.

7. The compound of claim 6, wherein R 29 Selected from H, CH3, CD3, CF2H and CF3.

8. The compound of claim 1 or claim 3, wherein R 12 、R 20 、R 29 、R 39 、R 51 、R 60 and R 61 Independently selected from C(O)-A'.

9. The compound of claim 1 or claim 3, wherein R 60 and R 61 One of them is C(O)-A' and the other is selected from H and C 1-6 alkyl.

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

11. The compound of claim 10, wherein Y is C 10-25 An alkyl group in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

12. The compound of claim 10, wherein Y is C 10-25 alkenyl groups in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

13. The compound of claim 12, wherein Y is an alkenyl group present in a fatty acid wherein all available H atoms are optionally replaced by deuterium.

14. The compound of claim 11, wherein Y is an alkyl group present in a fatty acid wherein all available H atoms are optionally replaced by deuterium.

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

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

17. The compound of claim 10, wherein 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=CH(CH2)1CH3.

18. A compound as claimed in any one of claims 1 to 17, wherein R 1 and R 1’ Independently selected from H, D and CH3.

19. The compound of any one of claims 1 to 18, wherein R 2 and R 2’ are independently H, D or F.

20. The compound of any one of claims 1 to 19, wherein R 3 and R 6 Independently selected from H, D, Cl, F, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluoroalkyl and C 1-4 Deuterated alkyl.

21. The compound of claim 20, wherein R 3 and R 6 Independently selected from H, D, F, OH, CH3, CH3O, CF2HO, CD2HO, CF3O, CD3O, CF2H, CD2H, CF3 and CD3.

22. The compound of claim 21, wherein R 3 and R 6 Independently selected from H and D.

23. A compound as described in any one of claims 1 to 22, wherein R 4 and R 5 One or both of them are independently selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 Deuterated alkoxy.

24. The compound of any one of claims 1 to 22, wherein R 4 and R 5 Two of them are independently selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 Deuterated alkoxy.

25. The compound of any one of claims 1 to 22, wherein R 4 is H or D, and R 5 Selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 Deuterated alkoxy.

26. A compound as described in any one of claims 1 to 22, wherein R 5 is H or D, and R 4 Selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 Deuterated alkoxy.

27. A compound as described in any one of claims 1 to 22, wherein R 4 and R 5 Connect together to form O-CH2O.

28. A compound as described in any one of claims 1 to 22, wherein R 4 and R 5 One of them is selected from XLA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy.

29. The compound of claim 28, wherein X is a direct bond, R 4 and R 5 One of them is selected from LA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy.

30. The compound of claim 28, wherein X is selected from O, C(O), NR a NR 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 NR a C(O)NR a .

31. The compound of claim 28, wherein X is selected from O, NR a NR a C(O), C(O)NR a NR a C(O)O、OC(O)NR a and NR a C(O)NR a .

32. The compound of any one of claims 28 to 31, wherein L is selected from 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 Alkylene C(O)NR b 、C 2-4 Alkenylene C(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 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 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 .

33. A compound as described in any one of claims 28 to 32, wherein R 4 and R 5 The other one is selected from H, F, Cl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl and C 1-4 Alkoxy.

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

35. The compound of any one of claims 28 to 33, wherein A is selected from C 1-30 Alkyl, C 2-30 Alkenyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 63 The heterocyclic alkyl group of the heterocyclic alkyl group is 3 to 6 members and contains 1 to 3 independently selected from O, S, S (O), SO2, N and NR 53 The 5- to 6-membered heteroaryl group of the hetero portion, wherein the phenyl group, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, OH, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 A fluoroalkyl group wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

36. The compound of claim 35, wherein A is selected from the group consisting of phenyl, C 3-6 Cycloalkyl, containing 1 to 2 independently selected from O, S, S(O), SO2, N and NR 64 The heterocyclic 5- to 6-membered alkyl group of the heterocyclic group and containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 48 The 5- to 6-membered heteroaryl group of the hetero portion, wherein the phenyl group, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of F, C, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 Fluoroalkyl.

37. The compound of claim 36, wherein R 64 Selected from H, D, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 Deuterated alkyl.

38. The compound of claim 35, wherein A is selected from C 1-30 Alkyl and C 2-30 alkenyl groups in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

39. The compound of claim 38, wherein A is C 10-25 An alkyl group in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

40. The compound of claim 38, wherein A is C 10-25 alkenyl groups in which all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

41. The compound of claim 40, wherein A is an alkenyl group present in a fatty acid, wherein all available H atoms are optionally replaced by deuterium.

42. The compound of claim 38, wherein A is an alkyl group present in a fatty acid wherein all available H atoms are optionally replaced by deuterium.

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

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

45. The compound of claim 38, wherein A 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=CH(CH2)1CH3.

46. The compound of claim 1, wherein the compound of formula IA is defined as follows: or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, in: R 1 、R 1’ 、R 2 、R 2’ 、R 3 and R 6 independently selected from H, D and F; Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6: is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 Does not exist, when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q5 When it is a double bond, R 48 and R 57 does not exist; R 4 and R 5 One or both of them are selected from H, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 deuterated alkoxy, or R 4 and R 5 Linked together to form O-(CH2) 1-2 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 are independently selected from H and D; R 12 、R 20 、R 29 、R 39 and R 51 Independently selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 deuterated alkyl, and R 60 and R 61 Independently selected from H and C 1-6 alkyl, Provided that when Q is Q6, then the compound of formula I comprises D, When Q is Q3 or Q4, when R 5 is H or OCH3, and R 29 or R 39 When it is CH3, R 1 、R 1' 、R 2 、R 2' 、R 3 、R 4 、R 6 、R 26 、R 27 、R 28 、R 30 to R 35 、R 36 、R 37 、R 38 and R 40 to R 47 Not all are H.

47. The compound of claim 1, wherein the compound of formula IA is defined as follows: or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, in: R 1 and R 1’ Independently selected from H, halo, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2; R 2 and R 2’ independently selected from H, halo, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2; Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6: is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 Does not exist, when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q5 When it is a double bond, R 48 and R 57 does not exist; R 4 and R 5 One or both of them are independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, or R 4 and R 5 Linked together to form O-(CH2) 1-2 O, or R 4 and R 5 One of them is selected from XLA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, X is selected from direct bond, O, C(O), NR a NR 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 NR a C(O)NR a ; L is selected from 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 Alkylene C(O)NR b 、C 2-6 Alkenylene C(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 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 ; R a Selected from H and C 1-6 alkyl; R b Selected from H, C 1-6 Alkyl and A; A is selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 64 The heterocyclic alkyl group of the heterocyclic alkyl group is 3 to 6 members and contains 1 to 4 independently selected from O, S, S (O), SO2, N and NR 64 The 5-membered to 6-membered heteroaryl group of the hetero part, wherein phenyl, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted by one or more independently selected from halo, C 1-4 Alkyl and OC 1-4 Substitution of alkyl groups; R 3 and R 6 are independently selected from 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 Independently selected from H, alkyl and C 1-6 alkyl; R 12 、R 20 、R 29 、R 39 and R 51 Independently selected from H, C 1-6 Alkyl, C(O)C 1-6 Alkyl and C(O)-A'; R 60 and R 61 Independently selected from H and C 1-6 alkyl; or R 60 and R 61 One of them is C(O)-A' and the other is selected from H and C 1-6 alkyl; wherein A' is selected from Y, OY and OC 1-4 Alkylene-OC(O)-Y; and Y is selected from 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, they form a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered heterocyclic ring optionally contains one or two independently selected from O, S, S(O), SO2, N and NR 65 and optionally substituted by one or more independently selected from halo, OH, C 1-4 Alkyl and OC 1-4 Substitution of alkyl groups; R 64 and R 65 Independently selected from H and C 1-6 alkyl; and All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof, The condition is R 12 、R 20 、R 29 、R 39 、R 51 、R 60 and R 61 One of them is C(O)-A'; or R 4 and R 5 One of which is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, provided that when X and L are direct bonds, A is not H, C 1-6 Alkyl or C 1-6 Alkenyl.

48. A compound as described in any one of claims 1 to 47, wherein R 2 and R 2’ Different and R 2 and R 2’ The bonded carbon is chiral.

49. A compound as described in any one of claims 1 to 48, wherein R 1 and R 1’ Different and R 1 and R 1’ The bonded carbon is chiral.

50. The compound of claim 1 , selected from: or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

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, condition or disorder 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 a pharmaceutically acceptable salt, solvate and / or prodrug thereof, in: R 1 and R 1’ Independently selected from H, halo, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2; R 2 and R 2' independently selected from H, halo, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl)2; Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6: is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 Does not exist, when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q5 When it is a double bond, R 48 and R 57 does not exist; R 4 and R 5 One or both of them are independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, or R 4 and R 5 Linked together to form O-(CH2) 1-2 O, or R 4 and R 5 One of them is selected from XLA, and R 4 and R 5 The other one is selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, X is selected from direct bond, O, C(O), NR a NR 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 NR a C(O)NR a ; L is selected from 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 Alkylene C(O)NR b 、C 2-6 Alkenylene C(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 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 ; R a Selected from H and C 1-6 alkyl; R b Selected from H, C 1-6 Alkyl and A; A is selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 64 The heterocyclic alkyl group of the heterocyclic alkyl group is 3 to 6 members and contains 1 to 4 independently selected from O, S, S (O), SO2, N and NR 64 The 5-membered to 6-membered heteroaryl group of the hetero part, wherein phenyl, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted by one or more independently selected from halo, C 1-4 Alkyl and OC 1-4 Substitution of alkyl groups; R 3 and R 6 are independently selected from 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 selected from H, halo and C 1-6 alkyl; R 12 、R 20 、R 29 、R 39 and R 51 Independently selected from H, C 1-6 Alkyl, C(O)C 1-6 Alkyl and C(O)-A'; R 60 and R 61 Independently selected from H and C 1-6 alkyl; or R 60 and R 61 One of them is C(O)-A' and the other is selected from H and C 1-6 alkyl; wherein A' is selected from Y, OY and OC 1-4 Alkylene-OC(O)-Y; and Y is selected from 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, they form a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered heterocyclic ring optionally contains one or two independently selected from O, S, S(O), SO2, N and NR 65 and optionally substituted by one or more independently selected from halo, OH, C 1-4 Alkyl and OC 1-4 Substitution of alkyl groups; R 64 and R 65 Independently selected from H and C 1-6 alkyl; and All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof, Provided that when Q is Q6, then the compound of formula I comprises D.

54. A method of treating a psychotic 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. The method of claim 54, wherein the psychiatric disorder is selected from the group consisting of hallucinations and delusions, and combinations thereof.

56. The method of claim 54, wherein the psychiatric disorder is selected anxiety disorder; depression; mood disorders; psychotic disorders; impulse control and addiction disorders; drug addiction; obsessive-compulsive disorder (OCD); post-traumatic stress disorder (PTSD); stress response syndrome; dissociative disorders; depersonalization disorder; factitious disorder; sexual and gender disorders; and somatic symptom disorder, and combinations thereof.

57. A method of treating a psychotic disorder 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. A method of treating a central nervous system (CNS) disease, condition or disorder and / or a neurological disease, condition or 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.

59. The method of claim 58, wherein the CNS disease, disorder or condition and / or nervous system disease, disorder or condition is selected from the group consisting of: a nervous system disease, including neurodevelopmental and neurodegenerative diseases, such as Alzheimer's disease; precocious dementia; Alzheimer's disease; vascular dementia; dementia with Lewy bodies; cognitive impairment, Parkinson's disease and Parkinson's-related diseases, such as Parkinson's disease, corticobasal degeneration and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disease; fragile X syndrome; Angelman syndrome; hereditary Ataxia; neurootological and oculomotor disorders; retinal neurodegenerative diseases; amyotrophic lateral sclerosis; tardive dyskinesia; ADHD; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette syndrome; schizophrenia; autism spectrum disorder; tuberous sclerosis complex; Rett syndrome; cerebral palsy; reward system disorders, including eating disorders such as anorexia nervosa ("AN") and bulimia nervosa ("BN"); and binge eating disorder ("BED"), trichotillomania, ringworm, nail biting; migraine; fibromyalgia; and peripheral neuropathies of any etiology, and combinations thereof.

60. A method of treating a behavioral problem 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. The method of claim 60, wherein the non-human subject is a canine or feline suffering from a neurological disease, behavioral problems, trainability problems, and / or combinations thereof.

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

63. A method of treating a disease, condition or disorder 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 another agent known to be useful for treating a disease, condition or disorder by activating a serotonin receptor.

64. The method of any one of claims 53 to 63, wherein 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 As defined in claim 2.

65. The method of any one of claims 53 to 63, wherein R 12 、R 20 、R 29 、R 39 、R 51 、R 60 and R 61 As defined in any one of claims 4, 5 and 8.

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

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

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

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

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

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

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

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 method of claim 53, wherein the compound of formula I is selected from: or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

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

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

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