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

Abstract

The present application relates to indazole derivatives of general formula I, their preparation processes, compositions containing them, and their use for activating intracellular serotonin receptors, and for treating diseases, disorders, or conditions by activating intracellular serotonin receptors. The diseases, disorders, or conditions include, for example, psychosis, psychiatric disorders, and CNS disorders. In formula (I), Q is selected from (Q1), (Q2), (Q3), (Q4), (Q5), and (Q6).

Description

[Technical Field]

[0001] (Related Applications) This application claims priority to co-pending U.S. Provisional Patent Application No. 63 / 401,856, filed August 29, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present application relates to indazole compounds for the treatment of various conditions, such as psychiatric and neurological disorders, that are treated by activation of serotonin receptors in the fields of psychiatry, neurobiology and pharmacotherapy. [Background technology]

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

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

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

[0006] Although hallucinogens are generally perceived as dangerous, from a physiological safety perspective, they are one of the safest known classes of central nervous system (CNS) drugs. Preliminary data indicate that administration of hallucinogens to humans results in a unique profile of potential adverse responses that must be appropriately addressed to maximize efficacy and safety. Primary safety concerns are primarily psychological rather than physiological in nature. Physical effects vary, but are relatively minor, even at potent psychoactive doses. When administered in a controlled environment, psilocybin has often been reported to produce a transient, delayed headache with dose-related increases in incidence, duration, and severity [Johnson et al., Drug Alcohol Depend (2012) 123(1-3):132-140]. Repeated administration of hallucinogens has been found to result in the very rapid development of tolerance known as tachyphylaxis, a phenomenon thought to be partially mediated by 5-HT2A receptors. Indeed, several studies have shown that rapid tolerance to hallucinogens correlates with downregulation of 5-HT2A receptors. For example, daily administration of LSD selectively reduced 5-HT2 receptor density in the rat brain [Buckholtz et al., Eur. J. Pharmacol. 1990, 109:421-425. 1985; Buckholtz et al., Life Sci. 1985, 42:2439-2445].

[0007] Classical and dissociative hallucinogens are known to have rapid-onset antidepressant and anti-addictive effects unlike any currently available treatment. Randomized, controlled clinical trials have confirmed the antidepressant and anxiolytic effects of classical hallucinogens in humans.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0022] The compounds of the present application modulate the activity of serotonin receptor subtypes, particularly 5-HT2A, by directly binding to the receptor.

[0023] Thus, the present application provides compounds of formula I: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 H, halo, NH2, C 1~6 Alkyl, C 1~6 Alkoxyl, NH(C 1~6 alkyl) and N(C 1~6 alkyl)2; Q is Q1, Q2, Q3, Q4, Q5 and Q6: [ka] Selected from the structure: [ka] is a single or double bond, provided that the structure in Q1: [ka] is a double bond, R 8 and R 14 does not exist, and the structure in Q2: [ka] is a double bond, R 16 and R 24 does not exist, and the structure in Q6: [ka] is a double bond, R 53 and R 62 does not exist; R 2 and R 5 are independently H, halo, OH, C 1~6 Alkyl and C 1~6 selected from alkoxy; R 3 and R 4One or both of may independently be H, halo, or C 1~6 Alkyl and C 1~6 alkoxy; R 3 and R 4 together to form O-(CH2) 1~2 Form O, or R 3 and R 4 One of them is selected from XLA and R 3 and R 4 The other is H, halo, C 1~6 Alkyl and C 1~6 selected from alkoxy; X is a direct bond, O, C(O), or NR a , N.R. a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a Selected from; L is a direct bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 1~6 Alkylene O, C 2~6 Alkenylene O,C 1~6 Alkylene C(O), C 2~6 Alkenylene C(O), C 1~6 Alkylene NR b C(O), C 2~6 Alkenylene NR b C(O), C 1~6 AlkyleneC(O)NR b , C 2~6 AlkenyleneC(O)NR b , C 1~6 Alkylene OC(O), C 2~6 Alkenylene OC(O), C 1~6 Alkylene C(O)O, C 2~6 Alkenylene C(O)O, C 1~6 Alkylene OC(O)NR b , C 2~6 Alkenylene OC(O)NR b , C 1~6Alkylene NR b C(O)O, C 2~6 Alkenylene NR b C(O)O, C 1~6 Alkylene O-C(O)O, C 2~6 Alkenylene O-C(O)O, C 1~6 Alkylene NR b C(O)NR b and C 2~6 Alkenylene NR b C(O)NR b Selected from; R a H and C 1~6 alkyl; R b is H, C 1~6 alkyl and A; A is H, C 1~30 Alkyl, C 2~30 Alkenyl, phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 53 and 3-6 membered heterocycloalkyl containing 1-4 hetero moieties independently selected from O, S, S(O), SO, N, and NR 63 wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with halo, OH, C 1~4 Alkyl and OC 1~4 optionally substituted with one or more substituents independently selected from alkyl; R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25, R 26 , R 27 , R 28 , R 31 , R 32 , R 33 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 57 , R 58 , R 59 , R 60 , R 61 and R 62 are independently H, halo, and C 1~6 alkyl; R 11 , R 19 , R 34 , R 44 and R 56 are independently H, C 1~6 selected from alkyl and C(O)-A'; R 29 and R 30 are independently H and C 1~6 alkyl; or R 29 and R 30 One of them is C(O)-A' and the other is H and C 1~6 alkyl; where A' is Y, OY and OC 1~4 alkylene-OC(O)-Y; Y is C 7~30 Alkyl and C 7~30 alkenyl; or R 29 and R30 together with the nitrogen atom to which they are attached, form O, S, S(O), SO2, N, and NR 64 and optionally includes one or two additional hetero moieties independently selected from halo, OH, C 1~4 Alkyl and OC 1~4 forming a 3- to 6-membered heterocyclic ring, optionally substituted with one or more substituents independently selected from alkyl; R 63 and R 64 are independently H and C 1~6 alkyl; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; However, if Q is Q3;R 2 , R 3 , R 4 , R 5 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 At least one of is or contains D, or R 2 , R 3 , R 4 , R 5 at least one of R is alkyl substituted with one or more fluorine and / or chlorine atoms; or R 2 , R 3 , R 4 , R 5 at least three of which are not H; or If Q is Q3; R 3 and R 4 together to form O-(CH2) 1~2 Form O; or If Q is Q3; R 3 and R 4 One of them is selected from XLA and R 3 and R 4 The other is H, halo, C 1~6 Alkyl and C 1~6alkoxy; and A is selected from H, C 1~6 Alkyl or C 2~6 Not alkenyl; If Q is Q1 or Q4, then R 3 and R 4 One of them is a halo, and R 3 and R 4 If the other is H, then R 7 ~R 14 or R 31 ~R 40 are not all H].

[0024] In some embodiments, the compound of Formula I: [ka] is defined as follows, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof: [In formula: R 1 is H; Q is Q1, Q2, Q3, Q4, Q5 and Q6: [ka] Selected from the structure: [ka] is a single or double bond, provided that the structure in Q1: [ka] is a double bond, R 8 and R 14 does not exist, and the structure in Q2: [ka] is a double bond, R 16 and R 24 is not present, and the structure in Q6: [ka] is a double bond, R 53 and R 62 does not exist; R 2 and R 5 is independently selected from H, D, and F; R 3 and R 4 One or both of these are H, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy and C 1~4 deuteroalkoxy; or R 3 and R 4 together to form O-(CH2) 1~2 Forming O; R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 31 , R 32 , R 33 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55, R 57 , R 58 , R 59 , R 60 , R 61 and R 62 is independently selected from H and D; R 11 , R 19 , R 29 , R 30 , R 34 , R 44 and R 56 are independently H, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 selected from deuteroalkyl].

[0025] The present application discloses compounds 12 and 16: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

[0026] In a further embodiment, the compounds of the present application are used as pharmaceuticals. Thus, the present application also includes compounds of the present application for use as pharmaceuticals.

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

[0028] The present application also includes a method of treating a psychiatric disorder, the method comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need of treatment.

[0029] The present application also includes methods of treating central nervous system (CNS) and / or neurological diseases, disorders or conditions, comprising administering to a subject in need of treatment a therapeutically effective amount of one or more compounds of the present application.

[0030] The present application additionally provides processes for preparing the compounds of the present application. General and specific processes are discussed in more detail below and provided in the examples below.

[0031] Other features and advantages of the present application will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while showing embodiments of the present application, are given by way of example only, and the scope of the claims is not limited by these embodiments, but should be accorded the broadest interpretation consistent with the entire description. DETAILED DESCRIPTION OF THE INVENTION

[0032] I. Definition Unless otherwise stated, the definitions and embodiments set forth in this and other sections are intended to be applicable to all embodiments and aspects of this application and are appropriately described herein as understood by one of ordinary skill in the art.

[0033] The terms "compound(s) of the present application" or "compound(s) of the present application," etc., as used herein, refer to the compounds of Formula I, Compound 12, and Compound 16, including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, and all stereoisomers and positional isomers thereof.

[0034] The terms "composition(s) of the present application" or "composition(s) of the present application" and the like, as used herein, refer to a composition, e.g., a pharmaceutical composition, comprising one or more compounds of the present application.

[0035] The term "and / or," as used herein, refers to the presence or use of the listed items, either individually or in combination. In effect, the term means that "at least one" or "one or more" of the listed items are used or present. With respect to pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, the term "and / or" means that the compounds of the present application are present as individual salts, solvates, and prodrugs, as well as in combinations, e.g., solvate salts of the compounds of the present application.

[0036] As used in this application, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, an embodiment including "a compound" should be understood to represent one compound, or several embodiments with two or more additional compounds.

[0037] As used in this application and in the claims, the words "comprising" (and any form of comprising, e.g., "comprise" and "comprises"), "having" (and any form of having, e.g., "have" and "has"), "including" (and any form of including, e.g., "include" and "includes" or "containing" (and any form of containing, e.g., "contain" and "contains") are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0038] The term "consisting of" and its derivatives, as used herein, is intended to be a qualifying term specifying the presence of stated features, elements, components, groups, integers and / or steps, and excluding the presence of other unstated features, elements, components, groups, integers and / or steps.

[0039] The term "consisting essentially of," as used herein, is intended to identify the presence of the stated features, elements, components, groups, integers, and / or steps, and that which does not materially affect the basic property(ies) and novel property(ies) of those features, elements, components, groups, integers, and / or steps.

[0040] In embodiments that include an "additional" or "second" component, e.g., an additional or second compound, the second component, as used herein, is chemically distinct from the other or first component. A "third" component is different from the other, first, or second component, and further listed or "additional" components are similarly distinct.

[0041] The term "suitable," as used herein, means that the selection of a particular compound or conditions will depend on the specific synthetic operation being performed, the properties of the molecule(s) being altered, and / or the specific use of the compound, but such selection would be well within the skill of one of ordinary skill in the art. All process / method steps described herein are carried out under conditions sufficient to provide the indicated product. One of ordinary skill in the art will understand that all reaction conditions, such as reaction solvent, reaction time, reaction temperature, reaction pressure, ratio of reactants, and whether the reaction should be carried out under anhydrous conditions or an inert atmosphere, can be varied to optimize production of the desired product, and this is within the skill of one of ordinary skill in the art.

[0042] The terms "about," "substantially," and "approximately," as used herein, refer to a reasonable amount of deviation from the modified word that does not significantly change the end result. These terms of degree should be interpreted as including a deviation of at least ±5% of the modified word, unless the deviation would negate the meaning of the modified word or the context would suggest otherwise to one of ordinary skill in the art.

[0043] This description makes reference to numerous chemical terms and abbreviations used by those of ordinary skill in the art. Nonetheless, definitions of selected words are provided for clarity and consistency.

[0044] The term "solvate" as used herein means a compound or a salt and / or prodrug of a compound, wherein suitable solvent molecules are incorporated into the crystal lattice.

[0045] The term "prodrug," as used herein, means a compound or a salt and / or prodrug of a compound that is converted into an active drug after administration.

[0046] The term "alkyl," as used herein, whether used alone or as part of another group, refers to a straight or branched chain saturated alkyl group. The possible number of carbon atoms in the referenced alkyl group is indicated by the prefix "C n1-n2 ". Thus, for example, the term "C 1~6 "Alkyl" (or "C1-C6 alkyl") means an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0047] The term "alkenyl," as used herein, whether used alone or as part of another group, refers to a straight or branched chain saturated alkenyl group containing at least one double bond. The possible number of carbon atoms in the referenced alkenyl group is indicated by the prefix "C n1~n2 ". Thus, for example, the term "C 2~6"Alkyl" (or "C2-C6 alkyl") means an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms.

[0048] The term "alkenylene," as used herein, whether used alone or as part of another group, refers to a straight or branched chain, unsaturated alkylene group, i.e., an unsaturated carbon chain containing substituents at its two termini and containing at least one double bond. The possible number of carbon atoms in the referenced alkenylene group is indicated by the prefix "C n1~n2 For example, the term C 2~6 Alkenylene means an alkenylene group having 2, 3, 4, 5 or 6 carbon atoms.

[0049] The term "alkoxy" as used herein, alone or in combination, includes an alkyl group bound to an atom which is bound to an oxygen.

[0050] The term "cycloalkyl," as used herein, whether used alone or as part of another group, refers to a saturated carbocyclic group containing from 3 to 6 carbon atoms and one or more rings. The possible number of carbon atoms in a referenced cycloalkyl group is determined by the numerical prefix "C n1-n2 For example, the term C 3~6 Cycloalkyl means a cycloalkyl group having 3, 4, 5 or 6 carbon atoms.

[0051] The term "heterocycloalkyl," as used herein, whether used alone or as part of another group, refers to a heterocycloalkyl group containing 3 to 6 atoms, one or more of which may be O, S, S(O), SO, NH, NC, or a combination thereof. 1~6 Heterocycloalkyl groups refer to cyclic groups containing at least one non-aromatic ring containing a hetero group (hetero group selected from alkyl and N, with the remaining atoms being C). Heterocycloalkyl groups are either saturated or unsaturated (i.e., contain one or more double bonds). Heterocycloalkyl groups are defined by the prefix C. n1-n2or "n1-n2", this prefix refers to the number of carbon atoms in the corresponding carbocyclic group, where one or more, preferably 1 to 4, of the ring atoms are O, S, S(O), SO2, NH, NC 1~6 substituted with hetero moieties selected from alkyl and N, the remaining atoms being C;

[0052] The term "aryl," as used herein, whether used alone or as part of another group, refers to a carbocyclic group containing at least one aromatic ring and containing from 6 to 10 carbon atoms.

[0053] The term "heteroaryl," as used herein, whether used alone or as part of another group, refers to a cyclic group containing at least one heteroaromatic ring containing 5 to 6 atoms, of which one or more atoms are heteroatoms selected from O, S, and N, and the remaining atoms are C. A heteroaryl group is denoted by the prefix C. n1~n2 When included, this prefix refers to the number of carbon atoms in the corresponding carbocyclic group, where one or more, preferably 1 to 4, of the ring atoms are replaced by a heteroatom as defined above.

[0054] The term "halogen" (or "halo"), whether used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo, and iodo.

[0055] The term "haloalkyl," as used herein, refers to an alkyl group, as defined above, in which one or more available hydrogen atoms has been replaced with a halogen. Thus, for example, "C 1~6 "Haloalkyl" refers to a C1 to C6 straight or branched chain alkyl group as defined above having one or more halogen substituents.

[0056] The term "deuteroalkyl," as used herein, refers to an alkyl group, as defined above, in which one or more available hydrogen atoms have been replaced with deuterium. Thus, for example, "C 1~6 "Deuteroalkyl" refers to a C1-C6 straight or branched chain alkyl group as defined above having one or more deuterium substituents.

[0057] The term "available" as in "available hydrogen atom" or "available atom" refers to an atom known by those skilled in the art to be replaceable with a substituent.

[0058] As used herein, the term "one or more" includes a single item selected from the list and mixtures of two or more items selected from the list.

[0059] The term "alternate isotopes thereof," as used herein, refers to isotopes of an element other than the most common isotope occurring in nature.

[0060] In the compounds of general formula I, and their pharmaceutically acceptable salts, solvates and / or prodrugs, atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. The present application is intended to include all appropriate isotopic variations of the compounds of general formula I, and their pharmaceutically acceptable salts, solvates and / or prodrugs. For example, protium ( 1 H), deuterium ( 2 H) and tritium ( 3 Protium is the predominant hydrogen isotope found in nature.

[0061] The term "compound" refers to the compound, and in some embodiments, to any hydrates or solvates thereof, to the extent they are stable. A hydrate is a compound complexed with water, and a solvate is a compound complexed with a solvent, which may be an organic or inorganic solvent. A "stable" compound is one that can be prepared and isolated, and whose structure and properties remain essentially unchanged or essentially unchanged for a period of time sufficient to use the compound for the purposes described herein (e.g., administering a therapeutic agent to a subject). The compounds of the present application are limited to stable compounds encompassed by general formula (I), or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0062] The term "pharmaceutically acceptable" refers to compatible with the treatment of a subject.

[0063] The term "pharmaceutically acceptable carrier" refers to a non-toxic solvent, dispersant, excipient, adjuvant or other material that is mixed with an active ingredient to enable the formulation of a pharmaceutical composition, i.e., a dosage form that can be administered to a subject.

[0064] The term "pharmaceutically acceptable salt" means either an acid addition salt or a base addition salt which is appropriate or compatible with the treatment of a subject.

[0065] Acid addition salts suitable or compatible for the treatment of a subject are any non-toxic organic or inorganic acid addition salts of any basic compounds.

[0066] A base addition salt that is suitable or compatible for the treatment of a subject is any non-toxic organic or inorganic base addition salt of any acidic compound.

[0067] The term "protecting group" or "PG" as used herein refers to a chemical moiety that protects or masks a reactive site of a molecule, preventing side reactions at that reactive site while a different site of the molecule is manipulated or reacted. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remainder of the molecule. The selection of an appropriate protecting group can be made by one skilled in the art. Many conventional protecting groups are known in the art and are described, for example, in "Protective Groups in Organic Chemistry" McOmie, JFW Ed., Plenum Press, 1973, in Greene, TW and Wuts, PGM, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3rd Edition, 1999, and Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0068] The term "subject," as used herein, includes all members of the animal kingdom, including mammals, and suitably refers to humans. Thus, the methods of the present application are applicable to both human therapy and veterinary uses.

[0069] The terms "treating" or "treatment," as used herein and as well understood in the art, refer to an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in disease extent, stabilized (i.e., not worsening) disease, preventing disease spread, delay or slowing of disease progression, palliative care, reduction in disease recurrence, and remission (partial or complete remission), which may or may not be detectable. "Treating" and "treatment" can also mean prolonging survival compared to expected survival in the absence of treatment. "Treating" and "treatment," as used herein, also include prophylactic treatment. For example, a subject with an early stage neurological disease can be treated to prevent progression, or a subject in remission can be treated with a compound or composition of the present application to prevent recurrence. The method of treatment involves administering to the subject a therapeutically effective amount of one or more compounds of the present application, which may consist of a single dose or may include a series of multiple doses, as appropriate.

[0070] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of one or more compounds of the present application that is effective at dosages and for periods of time necessary to achieve a desired result. For example, in the context of treating a disease, disorder, or condition mediated or treated by agonism or activation of serotonergic receptors and downstream second messengers, an effective amount is, for example, an amount that improves activation compared to the activation when one or more compounds are not administered.

[0071] "Palliating" a disease, disorder, or condition means reducing the severity and / or undesirable clinical symptoms of the disease, disorder, or condition and / or slowing or prolonging the course of progression compared to not treating the disorder.

[0072] The term "administered," as used herein, means administering a therapeutically effective amount of one or more compounds or compositions of the present application to a cell, tissue, organ, or subject.

[0073] The terms "prevention" or "prophylaxis," or synonyms thereof, as used herein, refer to reducing the risk or likelihood that a patient will acquire a disease, disorder, or condition, or develop symptoms associated with a disease, disorder, or condition.

[0074] "Disease, disorder, or condition," as used herein, refers to a disease, disorder, or condition that is treated or treatable by activation of a serotonin receptor (e.g., 5-HT2A, particularly using a serotonin receptor agonist (e.g., one or more compounds of the present application described herein)).

[0075] The disease, disorder or condition may be due to another mechanism, e.g., 5-HT 2A and / or 5-HT 1A The present invention may be treated or treatable through modulation, inactivation, antagonism or inverse agonism of serotonin receptors, including

[0076] The term "treating a disease, disorder, or condition by activating serotonin receptors," as used herein, means that the disease, disorder, or condition to be treated is directly or indirectly affected, modulated, and / or has some biological basis that includes (particularly increases) serotonergic activity. These diseases preferably respond when the serotonergic activity associated with the disease, disorder, or condition is modulated, e.g., agonized, by one or more compounds or compositions of the present application.

[0077] The term "activation" as used herein includes agonism, partial agonism, and positive allosteric modulation of serotonin receptors.

[0078] The term "5-HT1A " and "5-HT 2A " as used herein refer to the 5-HT serotonin receptor, 5-HT 1A and 5-HT 2A It refers to the receptor subtype.

[0079] The term "therapeutic agent," as used herein, refers to any drug or active agent that has a pharmacological effect when administered to a subject.

[0080] II. Compounds The present application provides compounds of formula I: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 H, halo, NH2, C 1~6 Alkyl, C 1~6 Alkoxyl, NH(C 1~6 alkyl) and N(C 1~6 alkyl)2; Q is Q1, Q2, Q3, Q4, Q5 and Q6: [ka] Selected from the structure: [ka] is a single or double bond, provided that the structure in Q1: [ka] is a double bond, R 8 and R 14 does not exist, and the structure in Q2: [ka] is a double bond, R 16 and R 24does not exist, and the structure in Q6: [ka] is a double bond, R 53 and R 62 does not exist; R 2 and R 5 are independently H, OH, halo, and C 1~6 Alkyl and C 1~6 selected from alkoxy; R 3 and R 4 One or both of may independently be H, halo, or C 1~6 Alkyl and C 1~6 alkoxy; R 3 and R 4 together to form O-(CH2) 1~2 Form O, or R 3 and R 4 One of the two is selected from XLA and R 3 and R 4 The other is H, halo, C 1~6 Alkyl and C 1~6 selected from alkoxy; X is a direct bond, O, C(O), or NR a , N.R. a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a Selected from; L is a direct bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 1~6 Alkylene O, C 2~6 Alkenylene O,C 1~6 Alkylene C(O), C 2~6 Alkenylene C(O), C 1~6 Alkylene NR b C(O), C 2~6 Alkenylene NR bC(O), C 1~6 AlkyleneC(O)NR b , C 2~6 AlkenyleneC(O)NR b , C 1~6 Alkylene OC(O), C 2~6 Alkenylene OC(O), C 1~6 Alkylene C(O)O, C 2~6 Alkenylene C(O)O, C 1~6 Alkylene OC(O)NR b , C 2~6 Alkenylene OC(O)NR b , C 1~6 Alkylene NR b C(O)O, C 2~6 Alkenylene NR b C(O)O, C 1~6 Alkylene O-C(O)O, C 2~6 Alkenylene O-C(O)O, C 1~6 Alkylene NR b C(O)NR b and C 2~6 Alkenylene NR b C(O)NR b Selected from; R a is H and C 1~6 alkyl; R b is H, C 1~6 alkyl, and A; A is H, C 1~30 Alkyl, C 2~30 Alkenyl, phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 63 and 3-6 membered heterocycloalkyl containing 1-4 hetero moieties independently selected from O, S, S(O), SO, N, and NR 63 wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with halo, OH, C 1~4 Alkyl and OC 1~4optionally substituted with one or more substituents independently selected from alkyl; R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 31 , R 32 , R 33 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 57 , R 58 , R 59 , R 60 , R 61 and R 62 are independently H, halo, and C 1~6 alkyl; R 11 , R 19 , R 34 , R 44 and R 56 are independently H, C 1~6 selected from alkyl and C(O)-A'; R 29 and R 30are independently H and C 1~6 alkyl; or R 29 and R 30 One of the groups is C(O)-A' and the other is H and C 1~6 alkyl; where A' is Y, OY and OC 1~4 alkylene-OC(O)-Y; Y is C 7~30 Alkyl and C 7~30 alkenyl; or R 29 and R 30 together with the nitrogen atom to which they are attached, form O, S, S(O), SO2, N, and NR 64 and optionally includes one or two additional hetero moieties independently selected from halo, OH, C 1~4 Alkyl and OC 1~4 forming a 3- to 6-membered heterocyclic ring, optionally substituted with one or more substituents independently selected from alkyl; R 63 and R 64 are independently H and C 1~6 alkyl; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; However, if Q is Q3;R 2 , R 3 , R 4 , R 5 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 At least one of is or contains D, or R 2 , R 3 , R 4 , R 5 at least one of R is alkyl substituted with one or more fluorine and / or chlorine atoms; or R 2 , R3 , R 4 , R 5 at least three of which are not H; or If Q is Q3; R 3 and R 4 together to form O-(CH2) 1~2 forming O; or If Q is Q3; R 3 and R 4 One of them is selected from XLA and R 3 and R 4 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy; A is selected from H, C 1~6 Alkyl or C 2~6 Not alkenyl; If Q is Q1 or Q4, then R 3 and R 4 One of them is a halo, and R 3 and R 4 If the other is H, then R 7 ~R 14 or R 31 ~R 40 are not all H].

[0081] As used herein, "substituted" in the context of "substituted with a fluorine atom or a chlorine atom" or "substituted with an alternative isotope thereof" or "substituted with deuterium" means that any hydrogen can be replaced with a fluorine atom or a chlorine atom, or any atom can be replaced with an alternative isotope thereof (e.g., deuterium). Thus, in some embodiments, all available hydrogen atoms can be independently and optionally replaced with a fluorine atom or a chlorine atom, or all available atoms can be independently and optionally replaced with an alternative isotope thereof. In some embodiments, all available hydrogen atoms can be independently and optionally replaced with a fluorine atom or a deuterium atom.

[0082] In some embodiments, when Q is Q3; R 2 , R 3 , R 4 , R5 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 At least one of is or contains D.

[0083] In some embodiments, R 2 , R 3 , R 4 , R 5 At least one of is alkyl substituted with one or more fluorine and / or chlorine atoms.

[0084] In some embodiments, R 2 , R 3 , R 4 , R 5 At least three of these are not H.

[0085] In some embodiments, R 3 and R 4 together to form O-(CH2) 1~2 Form O.

[0086] In some embodiments, R 3 and R 4 One of them is selected from XLA and R 3 and R 4 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy; A is selected from H, C 1~6 Alkyl or C 2~6 It is not alkenyl.

[0087] In some embodiments, when Q is Q1 or Q4, R 3 and R 4 One of them is a halo, and R 3 and R 4 If the other is H, then R 7 ~R 14 or R 31 ~R 40 Not all of them are H.

[0088] In some embodiments, all available hydrogen atoms of a group may be replaced with deuterium, where appropriate, provided that all available atoms may be replaced with their alternative isotopes.

[0089] In some embodiments, Q is Q1: [ka] and the structure: [ka] is a single bond, and compounds of formula I have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 is as defined for formula I, any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; However, R 7 ~R 14 Not all of them are H, but R 3 and R 4 If one of the is a halo, R 3 and R 4 the other is H].

[0090] In some embodiments, Q is Q1: [ka] and the structure: [ka] is a double bond, and compounds of formula I have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 9 , R 10 , R 11 , R 12 and R 13 is as defined for formula I, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0091] In some embodiments, Q is Q2: [ka] and the structure: [ka] is a single bond, and compounds of formula I have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 15 , R16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 is as defined for formula I, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0092] In some embodiments, Q is Q2: [ka] and the structure: [ka] is a double bond, and compounds of formula I have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 15 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 is as defined for formula I, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0093] In some embodiments, Q is Q3: [ka] and the compound of formula I has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 is as defined for formula I, any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; However, R 2 , R 3 , R 4 , R 5 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 at least one of is or contains D, or R 2 , R 3 , R 4 , R 5 at least one of R is alkyl substituted with one or more fluorine and / or chlorine atoms; or R 2 , R 3 , R 4 , R 5 at least three of which are not H; or R 3 and R 4 together to form O-(CH2) 1~2 Form O; or R 3 and R 4 One of them is XLA, and the other is R3 and R 4 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy; A is selected from H, C 1~6 Alkyl or C 2~6 not alkenyl].

[0094] In some embodiments, Q is Q4: [ka] and the compound of formula I has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 and R 40 is as defined for formula I, any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; However, R 2 , R 5 , R 31 ~R 40 Not all of them are H, but R 3 and R 4 If one of the is a halo, R 3 and R 4 the other is H].

[0095] In some embodiments, Q is Q5: [ka] and the compound of formula I has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 and R 52 is as defined for formula I, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0096] In some embodiments, Q is Q6: [ka] and the structure: [ka] is a single bond, and compounds of formula I have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 2 , R 3 , R 4 , R5 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 and R 62 is as defined for formula I, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0097] In some embodiments, Q is Q6: [ka] and the structure: [ka] is a double bond, and compounds of formula I have the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 and R 61 is as defined for formula I, All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0098] In some embodiments, R 1, R 2 , R 4 and R 5 are all H, and the compound of formula I has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 3 and Q is as defined for formula I; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; However, if Q is Q3;R 2 , R 3 , R 4 , R 5 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 At least one of is or contains D, or R 3 is alkyl substituted with one or more fluorine and / or chlorine atoms; or If Q is Q3; R 3 is XLA, A is H, C 1~6 Alkyl or C 2~6 is not alkenyl, or If Q is Q1 or Q4, then R 3 If is a halo, then R 7 ~R 14 or R 31 ~R 40 are not all H].

[0099] In some embodiments, R 1 , R 2 , R 3 and R 5 are all H, and the compound of formula I has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 4 and Q is as defined for formula I; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; However, if Q is Q3;R 2 , R 3 , R 4 , R 5 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 at least one of is or contains D, or R 4 is alkyl substituted with one or more fluorine and / or chlorine atoms; or If Q is Q3; R 4 is XLA, A is H, C 1~6 Alkyl or C 2~6 Not alkenyl; If Q is Q1 or Q4, then R 4 If is a halo, then R 7 ~R 14 or R 31 ~R 40 are not all H].

[0100] In some embodiments, R 1 , R 2 and R 5 are all H, and the compound of formula I has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: R 3 , R 4and Q is as defined for formula I; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; However, if Q is Q3;R 2 , R 3 , R 4 , R 5 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 at least one of is or contains D, or R 3 and R 4 at least one of is alkyl substituted with one or more fluorine and / or chlorine atoms; or If Q is Q3; R 3 and R 4 together to form O-(CH2) 1~2 Form O; or If Q is Q3; R 3 and R 4 One of them is selected from XLA and R 3 and R 4 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy; A is selected from H, C 1~6 Alkyl or C 2~6 Not alkenyl; If Q is Q1 or Q4, then R 3 and R 4 One of them is a halo, and R 3 and R 4 If the other is H, then R 7 ~R 14 or R 31 ~R 40 are not all H].

[0101] In some embodiments, R 1 is H and R 2 , R 3 , R4 and R 5 are all D, and the compound of formula I has the structure: [ka] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. [In formula: Q is as defined for formula I; All available hydrogen atoms may be independently replaced with fluorine or chlorine atoms, and all available atoms may be replaced with alternative isotopes thereof.

[0102] In some embodiments, R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 31 , R 32 , R 33 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R57 , R 58 , R 59 , R 60 , R 61 and R 62 are independently H, D, F, Cl, C 1~6 Alkyl, C 1~6 Fluoroalkyl and C 1~6 In some embodiments, R is selected from deuteroalkyl. 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 31 , R 32 , R 33 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 57 , R 58 , R 59 , R 60 , R 61 and R 62is independently selected from H, F, D, CH, CDH, CDH, CD, CF, CHF, CHCH, CHCHD, CHCDH, and CDCD. 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 31 , R 32 , R 33 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 57 , R 58 , R 59 , R 60 , R 61 and R 62 is independently selected from H and D.

[0103] 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 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 and R 57 is independently selected from H and D.

[0104] In some embodiments, R 25 , R 26 , R 27 and R 28 is independently selected from H and D. In some embodiments, R 25 , R 26 , R 27 and R 28 is H. In some embodiments, R 25 , R 26 , R 27 and R 28 is D. In some embodiments, R 25 and R 26 is H and R 27 and R 28 is D. In some embodiments, R 25 and R 26 is D and R 27 and R 28 is H.

[0105] In some embodiments, Q is (Q4) or (Q5): [ka] If R 33 or R 43 The stereochemistry at the carbon to which is attached is either R or S. Thus, in some embodiments, Q4 has the structure: [ka] and Q5 has the structure: [ka] is.

[0106] In some embodiments, R 33 or R 43 The stereochemistry at the carbon to which is attached is R. In some embodiments, R 33 or R 43 The stereochemistry at the carbon to which is attached is S.

[0107] In some embodiments, Q is (Q1), (Q2), or (Q6): [ka] and the structure: [ka] is a single bond, R 14 , R 24 or R 53 The stereochemistry at the carbon to which is attached is either R or S. Thus, in some embodiments, Q1 has the structure: [ka] and Q2 has the structure: [ka] and Q6 is structure; [ka] is.

[0108] In some embodiments, R 14 , R 24 or R 53 The stereochemistry at the carbon to which is attached is R. In some embodiments, R 14 , R 24 or R 53 The stereochemistry at the carbon to which is attached is S.

[0109] In some embodiments, Q is selected from one of the following groups: [ka] [ka] [In the formula, R 11 , R 19 , R 29 , R 30 , R 34 , R 44 and R 56 are independently H, D, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 In some embodiments, R 11 , R 19 , R 29 , R 30 , R 34 , R 44 and R 56 are independently H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 In some embodiments, R is selected from deuteroalkyl and C(O)-A'. 11 , R 19 , R 29 , R 30 , R 34 , R44 and R 56 are independently H, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, R is selected from deuteroalkyl. 11 , R 19 , R 29 , R 30 , R 34 , R 44 and R 56 is independently selected from H, CH, CD, CDH, CFH, and CF. In some embodiments, R 11 , R 19 , R 29 , R 30 , R 34 , R 44 and R 56 is independently selected from H, CH3, and CD3. In some embodiments, R 11 , R 19 , R 29 , R 30 , R 34 , R 44 and R 56 is independently selected from CH3 and CD3.

[0110] In some embodiments, Q is selected from one of the following groups: [ka] [In the formula, R 34 H, D, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 In some embodiments, R 34 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, R is selected from deuteroalkyl, and C(O)-A'. 34 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4In some embodiments, R is selected from deuteroalkyl. 34 is selected from H, CH, CD, CDH, CFH, and CF. In some embodiments, R 34 is selected from H, CH3 and CD3. In some embodiments, R 34 is selected from CH3 and CD3.

[0111] In some embodiments, R 29 and R 30 together with the nitrogen atom to which they are attached, form O, N, and NR 64 and optionally includes one or two additional hetero moieties independently selected from halo, OH, C 1~4 Alkyl and OC 1~4 It forms a 3- to 6-membered heterocyclic ring which may be optionally substituted with one or more substituents independently selected from alkyl.

[0112] In some embodiments, R 11 , R 19 , R 29 , R 30 , R 34 , R 44 and R 56 are independently selected from C(O)-A'.

[0113] In some embodiments, R 29 and R 30 One of them is C(O)-A' and the other is H and C 1~6 In some embodiments, R 29 and R 30 One of them is C(O)-A' and the other is H and C 1~4 alkyl.

[0114] In some embodiments, A' is selected from the group consisting of Y, OY, and OC. 1~2alkylene-OC(O)-Y, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms, hi some embodiments, A' is selected from Y, OY, and O-C ... O-C alkylene-OC(O)-Y, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms, hi some embodiments, A' is selected from O-C alkylene-OC(O)-Y, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms, hi some embodiments, A' is selected from O-C alkylene-OC(O)-Y, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms, hi some embodiments, A' is selected from O-C alkylene-OC(O)-Y, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms, hi some embodiments, A' is selected from O-C alkylene

[0115] In some embodiments, Y is C 10~25 In some embodiments, Y is C alkyl, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms. 13~21 alkyl, where any available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0116] In some embodiments, Y is C 10~25 In some embodiments, Y' is C 13~21 In some embodiments, Y is C 10~25 is alkenyl and contains 1, 2, 3, 4, 5 or 6 double bonds;

[0117] In some embodiments, the alkyl or alkene group of Y is an alkyl or alkenyl group present in a fatty acid, where all available hydrogen atoms may be optionally replaced with deuterium. In some embodiments, Y is an alkenyl group present in a fatty acid, where all available hydrogen atoms may be optionally replaced with deuterium. In some embodiments, the fatty acid is an ω-6 fatty acid (i.e., an unsaturated or polyunsaturated fatty acid in which the double bond closest to the methyl end of the molecule is located at carbon number 6, counting from the terminal methyl group) or an ω-3 fatty acid (i.e., an unsaturated or polyunsaturated fatty acid in which the double bond closest to the methyl end of the molecule is located at carbon number 3, counting from the terminal methyl group), where all available hydrogen atoms may be optionally replaced with deuterium. In some embodiments, Y is an alkyl group present in a fatty acid, where all available hydrogen atoms may be optionally replaced with deuterium. In some embodiments, the alkyl or alkene group of Y is an alkyl or alkene group present in a fatty acid listed in Table 1: [Table 1] [Table 2] [Table 3] wherein all available hydrogen atoms may be optionally replaced with deuterium atoms.

[0118] In some embodiments, the alkene group of Y is an alkyl or alkenyl group present in linoleic acid, eicosadienoic acid, and docosahexanoic acid.

[0119] In some embodiments, Y is an alkyl or alkenyl group of a fatty acid in which 1 to 10, 2 to 8, 2 to 6, or 2 to 4 hydrogen atoms have been replaced with deuterium.

[0120] In some embodiments, Y is (CH2)7CH=CH(CH2)7CH3. In some embodiments, Y is (CH2)7CH=CHCH2CH=CH(CH2)4CH3. In some embodiments, Y is (CH2)8CH=CHCH2CH=CH(CH2)4CH3. In some embodiments, Y is (CH2)7CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3. In some embodiments, Y is (CH2)3CH=CHCH2CH=CH(CH2)1CH=CHCH2CH=CH(CH2)3CH3. In some embodiments, Y is (CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3. In some embodiments, Y is (CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3. Thus, in some embodiments, Y is (CH2)7CH=CH(CH2)7CH3, (CH2)7CH=CHCH2CH=CH(CH2)4CH3, (CH2)8CH=CHCH2CH=CH(CH2)4CH3, (CH2)7CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3, (CH2)3CH=CHCH2CH=CH(CH2)1CH=CHCH2CH=CH(CH2)3CH3, or (CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3.

[0121] In some embodiments, A' is Y.

[0122] In some embodiments, A' is -OY.

[0123] In some embodiments, A' is -O-C3 alkylene-OC(O)-Y.

[0124] In some embodiments, R 1 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 1 are H, D, Cl, F, NH2, C1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkyl, C 1~4 Deuteroalkyl, NH(C 1~4 alkyl), NH(C 1~4 Deuteroalkyl), NH(C 1~4 fluoroalkyl), N(C 1~4 alkyl)2, N(C 1~4 Fluoroalkyl)2, N(C 1~4 Deuteroalkyl)2, N(C 1~4 Fluoroalkyl)(C 1~4 alkyl), N(C 1~4 Fluoroalkyl)(C 1~4 Deuteroalkyl) and N(C 1~4 Deuteroalkyl)(C 1~4 In some embodiments, R 1 are H, D, Cl, F, NH2, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Fluoroalkyl, C 1~2 Deuteroalkyl, NH(C 1~2 alkyl), NH(C 1~2 Deuteroalkyl), NH(C 1~2 fluoroalkyl), N(C 1~2 alkyl)2, N(C 1~2 Fluoroalkyl)2, N(C 1~2 Deuteroalkyl)2, N(C 1~2 Fluoroalkyl)(C 1~2 alkyl), N(C 1~2 Fluoroalkyl)(C 1~2 Deuteroalkyl) and N(C 1~2 Deuteroalkyl)(C 1~2 In some embodiments, R 1 are H, D, Cl, F, OH, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Fluoroalkyl and C 1~2 In some embodiments, R is selected from deuteroalkyl. 1is 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 H, D, F, NH, CH, CF, CD, CH, O, CF, and CD. 1 is selected from H, D, F, CH, CFH, CDH, CHO, CF, and CD. 1 is selected from H and D. In some embodiments, R 1 is D. In some embodiments, R 1 is H.

[0125] In some embodiments, R 2 and R 5 are independently H, D, Cl, F, OH, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy, C 1~4 Deuteroalkoxy, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, R is selected from deuteroalkyl. 2 and R 5 are independently H, D, Cl, F, OH, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, R is selected from deuteroalkyl. 2 and R 5 are independently H, D, Cl, F, OH, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Fluoroalkoxy, C 1~2 Deuteroalkoxy, C 1~2 Fluoroalkyl and C 1~2 In some embodiments, R is selected from deuteroalkyl. 2 and R 5are independently H, D, Cl, F, OH, C 1~2 Alkyl, C 1~2 Alkoxy, C 1~2 Fluoroalkyl and C 1~2 In some embodiments, R is selected from deuteroalkyl. 2 and R 5 is independently selected from H, D, F, OH, CH, CHO, CFHO, CDHO, CFO, CDO, CFH, CDH, CF and CD. In some embodiments, R 2 and R 5 is independently selected from H, D, F, OH, CH, CFH, CDH, CHO, CF, and CD. 2 and R 5 is independently selected from H, D, F, OH, CH, CHO, CFHO, CFO, and CDO. In some embodiments, R 2 and R 5 is independently selected from H and D. In some embodiments, R 2 and R 5 At least one of R is D. In some embodiments, R 2 and R 5 Each R is D. In some embodiments, 2 and R 5 are H, respectively.

[0126] In some embodiments, R 3 and R 4 One or both of these may independently be H, D, F, Cl, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 Deuteroalkyl, C 1~6 Alkoxy, C 1~6 Fluoroalkoxy and C 1~6 In some embodiments, R is selected from deuteroalkoxy. 3 and R 4 Both independently H, D, F, Cl, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C1~4 Deuteroalkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy and C 1~4 In some embodiments, R is selected from deuteroalkoxy. 3 and R 4 are independently selected from H, D, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, CD3, CH(CH3)2O, CH3CH2CH2O, CH3CHO, CH3O, CF3O, CHF2O, CF2HCH2O, CF3CHO, (CF3)2CHO, and CD3O. 3 and R 4 are independently selected from H, D, F, Cl, CH3, CH(CH3)2, CF3, CF2H, CD3, CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O.

[0127] In some embodiments, R 3 and R 4 Both independently H, D, F, Cl, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 Deuteroalkyl, C 1~6 Alkoxy, C 1~6 Fluoroalkoxy and C 1~6 In some embodiments, R is selected from deuteroalkoxy. 3 and R 4 Both D, F, Cl, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 Deuteroalkyl, C 1~6 Alkoxy, C 1~6 Fluoroalkoxy and C 1~6 In some embodiments, R is selected from deuteroalkoxy. 3 and R 4 Both independently H, D, F, Cl, C 1~4 Alkyl, C 1~4Fluoroalkyl, C 1~4 Deuteroalkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy and C 1~4 In some embodiments, R is selected from deuteroalkoxy. 3 and R 4 are both independently selected from H, D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CFO, CHFO, and CDO. 3 and R 4 are both independently selected from D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CFO, CHFO, and CDO. 3 and R 4 are both independently selected from CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 3 and R 4 Both are CD3O or R 3 and R 4 Both are CHO.

[0128] In some embodiments, R 3 is H or D, and R 4 are H, D, F, Cl, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 Deuteroalkyl, C 1~6 Alkoxy, C 1~6 Fluoroalkoxy and C 1~6 In some embodiments, R is selected from deuteroalkoxy. 3 is H or D, and R 4 are H, D, F, Cl, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Deuteroalkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy and C 1~4In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 3 is H or D, and R 4 is selected from H, D, F, Cl, CH(CH3)2, CH3, CF3, CF2H, CD3, CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 3 is H or D, and R 4 is selected from D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CFO, CHFO, and CDO. 3 is H or D, and R 4 is selected from CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 3 is H and R 4 is selected from CH3O and CD3O.

[0129] In some embodiments, R 4 is H or D, and R 3 are H, D, F, Cl, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 1~6 Deuteroalkyl, C 1~6 Alkoxy, C 1~6 Fluoroalkoxy and C 1~6 In some embodiments, R is selected from the group consisting of deuteroalkoxy and deuteroalkoxy. 4 is H or D, and R 3 are H, D, F, Cl, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Deuteroalkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy and C 1~4 In some embodiments, R is selected from deuteroalkoxy. 4 is H or D, and R 3is selected from D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CFO, CHFO, and CDO. 4 is H or D, and R 3 is selected from CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 4 is H and R 3 is selected from CH3O and CD3O.

[0130] In some embodiments, R 2 , R 3 , R 4 and R 5 is selected from D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CFO, CHFO, and CDO. 2 , R 3 , R 4 and R 5 are all H, or in some embodiments, R 2 , R 3 , R 4 and R 5 are all D. In some embodiments, R 2 , R 3 , R 4 and R 5 is selected from CH(CH3)2O, CH3O, CF3O, CHF2O, and CD3O. In some embodiments, R 2 , R 3 , R 4 and R 5 Two of the groups are selected from H or D, and R 2 , R 3 , R 4 and R 5 and the remainder of R is selected from CH(CH)O, CHO, CFO, CHFO, and CDO. 2 , R 3 , R 4 and R 5 Two of the groups are selected from H or D, and R2 , R 3 , R 4 and R 5 and the remainder of R is selected from CHO and CDO. 2 , R 3 , R 4 and R 5 is selected from H or D, and R 2 , R 3 , R 4 and R 5 and the remainder of R is selected from CH(CH)O, CHO, CFO, CHFO, and CDO. 3 , R 4 , R 5 and R 6 is selected from H or D, and R 2 , R 3 , R 4 and R 5 the remainder being selected from CH3O and CD3O.

[0131] In some embodiments, R 3 and R 4 together to form O-CHO.

[0132] In some embodiments, R 3 and R 4 One of them is selected from XLA and R 3 and R 4 The other is H, halo, C 1~6 Alkyl and C 1~6 Alkoxy is selected from:

[0133] In some embodiments, X is a direct bond and R 3 and R 4 One of the two is selected from LA, and the other is R 3 and R 4 The other is H, halo, C 1~6 Alkyl and C 1~6 In some embodiments, X is selected from O, C(O), NR a , N.R. aC(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, X is selected from O, C(O), OC(O), C(O)O and OC(O)O. In some embodiments, X is selected from O, OC(O) and C(O)O. In some embodiments, X is O. In some embodiments, X is selected from OC(O) and C(O)O. In some embodiments, X is O, NR a , N.R. a C(O), C(O)NR a , N.R. a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, X is selected from NR a C(O), C(O)NR a , N.R. a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, X is selected from NR a C(O) and C(O)NR a In some embodiments, X is selected from NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, X is selected from O, OC(O), C(O)O, NR a C(O) and C(O)NR a is selected from.

[0134] In some embodiments, L is a direct bond, C 1~4 Alkylene, C 2~4 Alkenylene, C 1~4 Alkylene O, C 2~4 Alkenylene O,C 1~4 Alkylene C(O), C 2~4Alkenylene C(O), C 1~4 Alkylene NR b C(O), C 2~4 Alkenylene NR b C(O), C 1~4 AlkyleneC(O)NR b , C 2~4 AlkenyleneC(O)NR b , C 1~4 Alkylene OC(O), C 2~4 Alkenylene OC(O), C 1~4 Alkylene C(O)O, C 2~4 Alkenylene C(O)O, C 1~4 Alkylene OC(O)NR b , C 2~4 Alkenylene OC(O)NR b , C 1~4 Alkylene NR b C(O)O, C 2~4 Alkenylene NR b C(O)O, C 1~4 Alkylene O-C(O)O, C 2~4 Alkenylene O-C(O)O, C 1~4 Alkylene NR b C(O)NR b and C 2~4 Alkenylene NR b C(O)NR b In some embodiments, L is selected from a direct bond, C 1~2 Alkylene, C 2~4 Alkenylene, C 1~2 Alkylene O, C 2~4 Alkenylene O,C 1~2 Alkylene C(O), C 2~4 Alkenylene C(O), C 1~2 Alkylene NR b C(O), C 2~4 Alkenylene NR b C(O), C 1~2 AlkyleneC(O)NR b , C 2~4 AlkenyleneC(O)NR b , C 1~2 Alkylene OC(O), C 2~4 Alkenylene OC(O), C 1~2 Alkylene C(O)O, C2~4 Alkenylene C(O)O, C 1~2 Alkylene OC(O)NR b , C 2~4 Alkenylene OC(O)NR b , C 1~2 Alkylene NR b C(O)O, C 2~4 Alkenylene NR b C(O)O, C 1~2 Alkylene O-C(O)O, C 2~4 Alkenylene O-C(O)O, C 1~2 Alkylene NR b C(O)NR b and C 2~4 Alkenylene NR b C(O)NR b In some embodiments, L is selected from a direct bond, C 1~2 Alkylene, C 1~2 Alkylene O, C 1~2 Alkylene C(O), C 1~2 Alkylene NR b C(O), C 1~2 AlkyleneC(O)NR b , C 1~2 Alkylene OC(O), C 1~2 Alkylene C(O)O, C 1~2 Alkylene OC(O)NR b , C 1~2 Alkylene NR b C(O)O, C 1~2 Alkylenes OC(O)O, and C 1~2 Alkylene NR b C(O)NR b In some embodiments, L is selected from a direct bond, CH, CF, CD, CH—O, CF—O, CD—O, CH—C(O), CF—C(O), CD—C(O), CH—NR b C(O), CD2-NR b C(O), CF2-NR b C(O), CH2-C(O)NR b , CF2-C(O)NR b , CD2-C(O)NR b, CH2-OC(O), CD2-OC(O), CF2-OC(O), CH2-C(O)O, CF2-C(O)O, CD2-C(O)O, CH2-OC(O)NR b , CD2-OC(O)NR b , CF2-OC(O)NR b , CH2-NR b C(O)O, CF2-NR b C(O)O, CD2-NR b C(O)O, CH2-OC(O)O, CF2-OC(O)O, CD2-OC(O)O, CH2-NR b C(O)NR b , CF2-NR b C(O)NR b and CD2-NR b C(O)NR b is selected from.

[0135] In some embodiments, X is a direct bond, L is a direct bond, and R 3 and R 4 one of which is selected from A and R 3 and R 4 The other is H, halo, C 1~4 Alkyl and C 1~4 Alkoxy is selected from:

[0136] In some embodiments, X is O, OC(O), C(O)O, NR a C(O) and C(O)NR a Selected from R 3 and R 4 On the other hand, OC 1~2 Alkylene-A, OC 1~2 Alkylene OA, OC 1~2 Alkylene C(O)-A, OC 1~2 Alkylene NR b C(O)-A, OC 1~2 AlkyleneC(O)NR b -A, O.C. 1~2 Alkylene OC(O)-A, OC 1~2 Alkylene C(O)OA, OC 1~2 Alkylene OC(O)NR b -A, O.C.1~2 Alkylene NR b C(O)OA, OC 1~2 Alkylene OC(O)OA, OC 1~2 Alkylene NR b C(O)NR b -A, OC(O)-C 1~2 Alkylene-A, OC(O)-C 1~2 Alkylene OA, OC(O)-C 1~2 Alkylene C(O)-A, O-C(O)-C 1~2 Alkylene NR b C(O)-A, OC(O)-C 1~2 AlkyleneC(O)NR b -A, OC(O)-C 1~2 Alkylene OC(O)-A, OC(O)-C 1~2 Alkylene C(O)OA, OC(O)-C 1~2 Alkylene OC(O)NR b -A, OC(O)-C 1~2 Alkylene NR b C(O)OA, OC(O)-C 1~2 Alkylene OC(O)OA, OC(O)-C 1~2 Alkylene NR b C(O)NR b -A, C(O)OC 1~2 Alkylene-A, C(O)OC 1~2 Alkylene OA, C(O)OC 1~2 Alkylene C(O)-A, C(O)OC 1~2 Alkylene NR b C(O)-A, C(O)OC 1~2 AlkyleneC(O)NR b -A, C(O)OC 1~2 Alkylene OC(O)-A, C(O)OC 1~2 Alkylene C(O)OA, C(O)OC 1~2 Alkylene OC(O)NR b -A, C(O)OC 1~2 Alkylene NR b C(O)OA, C(O)OC 1~2 Alkylene OC(O)OA, C(O)OC 1~2 Alkylene NR b C(O)NRb -A, NR a C(O)-C 1~2 Alkylene-A, NR a C(O)-C 1~2 Alkylene OA, NR a C(O)-C 1~2 Alkylene C(O)-A, NR a C(O)-C 1~2 Alkylene NR b C(O)-A, NR a C(O)-C 1~2 AlkyleneC(O)NR b -A, NR a C(O)-C 1~2 Alkylene OC(O)-A, NR a C(O)-C 1~2 Alkylene C(O)OA, NR a C(O)-C 1~2 Alkylene OC(O)NR b -A, NR a C(O)-C 1~2 Alkylene NR b C(O)OA, NR a C(O)-C 1~2 Alkylene OC(O)OA, NR a C(O)-C 1~2 Alkylene NR b C(O)NR b -A, C(O)NR a -C 1~2 Alkylene-A, C(O)NR a -C 1~2 Alkylene OA, C(O)NR a -C 1~2 Alkylene C(O)-A, C(O)NR a -C 1~2 Alkylene NR b C(O)-A, C(O)NR a -C 1~2 AlkyleneC(O)NR b -A, C(O)NR a -C 1~2 Alkylene OC(O)-A, C(O)NR a -C 1~2 Alkylene C(O)OA, C(O)NR a -C 1~2Alkylene OC(O)NR b -A, C(O)NR a -C 1~2 Alkylene NR b C(O)OA, C(O)NR a -C 1~2 Alkylenes OC(O)OA, and C(O)NR a -C 1~2 Alkylene NR b C(O)NR b - selected from A and R 3 and R 4 The other is H, halo, C 1~4 Alkyl and C 1~4 In some embodiments, X is selected from O, OC(O), C(O)O, NR a C(O) and C(O)NR a Selected from R 3 and R 4 On the other hand, OC 1~2 Alkylene-A, OC 1~2 Alkylene OA, OC 1~2 Alkylene C(O)-A, OC 1~2 Alkylene NR b C(O)-A, OC 1~2 AlkyleneC(O)NR b -A, O.C. 1~2 Alkylene OC(O)-A, OC 1~2 Alkylene C(O)OA, OC 1~2 Alkylene OC(O)NR b -A, O.C. 1~2 Alkylene NR b C(O)OA, OC 1~2 Alkylene OC(O)OA, OC 1~2 Alkylene NR b C(O)NR b -A, OC(O)-C 1~2 Alkylene-A, OC(O)-C 1~2 Alkylene OA, OC(O)-C 1~2 Alkylene C(O)-A, O-C(O)-C 1~2 Alkylene NR bC(O)-A, OC(O)-C 1~2 AlkyleneC(O)NR b -A, OC(O)-C 1~2 Alkylene OC(O)-A, OC(O)-C 1~2 Alkylene C(O)OA, OC(O)-C 1~2 Alkylene OC(O)NR b -A, OC(O)-C 1~2 Alkylene NR b C(O)OA, OC(O)-C 1~2 Alkylene OC(O)OA, OC(O)-C 1~2 Alkylene NR b C(O)NR b -A, C(O)OC 1~2 Alkylene, C(O)OC 1~2 Alkylene OA, C(O)OC 1~2 Alkylene C(O)-A, C(O)OC 1~2 Alkylene NR b C(O)-A, C(O)OC 1~2 AlkyleneC(O)NR b -A, C(O)OC 1~2 Alkylene OC(O)-A, C(O)OC 1~2 Alkylene C(O)OA, C(O)OC 1~2 Alkylene OC(O)NR b -A, C(O)OC 1~2 Alkylene NR b C(O)OA, C(O)OC 1~2 Alkylene OC(O)OA, C(O)OC 1~2 Alkylene NR b C(O)NR b -A, NR a C(O)-C 1~2 Alkylene-A, NR a C(O)-C 1~2 Alkylene OA, NR a C(O)-C 1~2 Alkylene C(O)-A, NR a C(O)-C 1~2 Alkylene NR b C(O)-A, NR a C(O)-C 1~2 AlkyleneC(O)NR b-A, NR a C(O)-C 1~2 Alkylene OC(O)-A, NR a C(O)-C 1~2 Alkylene C(O)OA, NR a C(O)-C 1~2 Alkylene OC(O)NR b -A, NR a C(O)-C 1~2 Alkylene NR b C(O)OA, NR a C(O)-C 1~2 Alkylene OC(O)OA, NR a C(O)-C 1~2 Alkylene NR b C(O)NR b -A, C(O)NR a -C 1~2 Alkylene-A, C(O)NR a -C 1~2 Alkylene OA, C(O)NR a -C 1~2 Alkylene C(O)-A, C(O)NR a -C 1~2 Alkylene NR b C(O)-A, C(O)NR a -C 1~2 AlkyleneC(O)NR b -A, C(O)NR a -C 1~2 Alkylene OC(O)-A, C(O)NR a -C 1~2 Alkylene C(O)OA, C(O)NR a -C 1~2 Alkylene OC(O)N R b -A, C(O)NR a -C 1~2 Alkylene NR b C(O)OA, C(O)NR a -C 1~2 Alkylenes OC(O)OA, and C(O)NR a -C 1~2 Alkylene NR b C(O)NR b - selected from A and R 3 and R 4The other is H, halo, C 1~4 Alkyl and C 1~4 alkoxy, wherein all available hydrogen atoms may be independently optionally replaced with fluorine or deuterium atoms.

[0137] In some embodiments, R 3 and R 4 The other is H, F, Cl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Deuteroalkyl and C 1~4 alkoxy, wherein all available hydrogen atoms may be independently optionally replaced with fluorine or deuterium atoms. 3 and R 4 is selected from D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CF, CHF, and CD, where any available hydrogen atom may be independently replaced with a fluorine atom or a deuterium atom, as appropriate; 3 and R 4 The other is H or D.

[0138] In some embodiments, R 3 is XLA and R 4 H, halo, C 1~6 Alkyl and C 1~6 In some embodiments, R is selected from alkoxy. 4 is XLA and R 3 H, halo, C 1~6 Alkyl and C 1~6 Alkoxy is selected from:

[0139] In some embodiments, R a is H and C 1~4 alkyl.

[0140] In some embodiments, R b is H, C 1~4alkyl, and A'.

[0141] In some embodiments, A is H and R 3 and R 4 One of them is OH, C(O)H, NHR a , NHR a C(O), C(O)NHR a , OC(O)H, C(O)OH, OC(O)OH, NR a C(O)OH, OC(O)NHR a , NHR a C(O)NR a , XC 1~4 Alkylene, XC 2~4 Alkenylene, XC 1~4 Alkylene OH, XC 2~4 Alkenylene OH, XC 1~4 Alkylene C(O)H, XC 2~4 Alkenylene C(O)H, XC 1~4 Alkylene NR b C(O)H, XC 2~4 Alkenylene NR b C(O)H, XC 1~4 AlkyleneC(O)NHR b , XC 2~4 AlkenyleneC(O)NHR b , XC 1~4 Alkylene OC(O)H, XC 2~4 Alkenylene OC(O)H, XC 1~4 Alkylene C(O)OH, C 2~4 Alkenylene C(O)H, XC 1~4 Alkylene OC(O)NHR b , XC 2~4 AlkenyleneOC(O)NHR b , XC 1~4 Alkylene NR b C(O)OH, XC 2~4 Alkenylene NR b C(O)OH, XC 1~4 Alkylene OC(O)OH, XC 2~4 Alkenylene OC(O)OH, XC 1~4 Alkylene NR b C(O)NHR band XC 2~4 Alkenylene NR b C(O)NHR b Selected from R 3 and R 4 The other is H, halo, C 1~4 Alkyl and C 1~4 In some embodiments, A is H and R is selected from the group consisting of alkoxy, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 3 and R 4 One of them is OH, C(O)H, NHR a , NHR a C(O), C(O)NHR a , OC(O)H, C(O)OH, OC(O)OH, NR a C(O)OH, OC(O)NHR a , NHR a C(O)NR a , XC 1~2 Alkylene, XC 2~4 Alkenylene, XC 1~2 Alkylene OH, XC 2~4 Alkenylene OH, XC 1~2 Alkylene C(O)H, XC 2~4 Alkenylene C(O)H, XC 1~2 Alkylene NR b C(O)H, XC 2~4 Alkenylene NR b C(O)H, XC 1~2 AlkyleneC(O)NHR b , XC 2~4 AlkenyleneC(O)NHR b , XC 1~2 Alkylene OC(O)H, XC 2~4 Alkenylene OC(O)H, XC 1~2 Alkylene C(O)OH, C 2~4 Alkenylene C(O)H, XC 1~2 Alkylene OC(O)NHR b , XC 2~4 AlkenyleneOC(O)NHR b , XC 1~2 Alkylene NR b C(O)OH, XC2~4 Alkenylene NR b C(O)OH, XC 1~2 Alkylene OC(O)OH, XC 2~4 Alkenylene OC(O)OH, XC 1~2 Alkylene NR b C(O)NHR b and XC 2~4 Alkenylene NR b C(O)NHR b Selected from R 3 and R 4 The other is H, halo, C 1~4 Alkyl and C 1~4 alkoxy, wherein all available hydrogen atoms may be independently optionally replaced with fluorine or deuterium atoms.

[0142] In some embodiments, A is H and X is a direct bond. Thus, in some embodiments, R 3 and R 4 One of them is C 1~4 Alkyl, C 2~4 Alkenyl, C 1~4 Alkylene OH, C 2~6 Alkenylene OH, C 1~4 Alkylene C(O)H, C 2~4 Alkenylene C(O)H, C 1~4 Alkylene NR b C(O)H, C 2~4 Alkenylene NR b C(O)H, C 1~4 AlkyleneC(O)NHR b , C 2~4 AlkenyleneC(O)NHR b , C 1~4 Alkylene OC(O)H, C 2~4 Alkenylene O-C(O)H, C 1~4 Alkylene C(O)OH, C 2~4 Alkenylene C(O)H, C 1~4 Alkylene OC(O)NHR b , C 2~6 AlkenyleneOC(O)NHR b , C 1~4 Alkylene NR 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 Selected from R 3 and R 4 The other is H, halo, C 1~6 Alkyl and C 1~6 Alkoxy is selected from:

[0143] In some embodiments, A is H and X is O, C(O), NR a , N.R. a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, A is H and X is selected from O, C(O), OC(O), C(O)O and OC(O)O. In some embodiments, A is H and X is selected from O, OC(O) and C(O)O. In some embodiments, A is H and X is O. In some embodiments, A is H and X is selected from OC(O) and C(O)O. In some embodiments, A is H and X is NR a , N.R. a C(O), C(O)NR a , N.R. a C(O)O, OC(O)NR a and N.R. a C(O)NR a In some embodiments, A is H and X is selected from NR a C(O), C(O)NR a , N.R. a C(O)O, OC(O)NR a and N.R.a C(O)NR a In some embodiments, A is H and X is selected from NR a C(O) and C(O)NR a In some embodiments, A is H and X is selected from NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a is selected from.

[0144] In some embodiments, A is H, L is a direct bond, and R 3 and R 4 One of R is selected from XH. Thus, in some embodiments, R 3 and R 4 One of them is OH, C(O)H, NHR a , NHR a C(O), C(O)NHR a , OC(O)H, C(O)OH, OC(O)OH, NR a C(O)OH, OC(O)NHR a and NHR a C(O)NR a wherein all available hydrogen atoms may be independently optionally replaced with fluorine or deuterium atoms.

[0145] In some embodiments, when A is H, R b H and C 1~4 alkyl, where any available hydrogen atoms may be independently optionally replaced with fluorine or deuterium atoms.

[0146] In some embodiments, R 3 and R 4 One side is A, OA, C(O)-A, C(O)-A, C(O)OA, C 1~4 Alkylene-A, C 1~4 Alkylene-C(O)-A,C 1~4 Alkylene-C(O)OA, OC 1~4 Alkylene-A, OC1~4 Alkylene-C(O)-A, and O-C 1~4 alkylene-C(O)OA; R 3 and R 4 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy, wherein all available hydrogen atoms may be independently optionally replaced with fluorine or deuterium atoms.

[0147] In some embodiments, R 3 and R 4 is selected from A, OA, C(O)-A, C(O)-A, and C(O)OA; R 3 and R 4 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy, wherein all available hydrogen atoms may be independently optionally replaced with fluorine or deuterium atoms. 3 and R 4 One of R is A. In some embodiments, R 3 and R 4 One of R is OA. 3 and R 4 One of R is C(O)-A. In some embodiments, R 3 and R 4 One of them is C(O)OA.

[0148] In some embodiments, R 3 and R 4 One of them is C 1~4 Alkylene-A, C 1~4 Alkylene-C(O)-A,C 1~4 Alkylene-C(O)OA, OC 1~4 Alkylene-A, OC 1~4 Alkylene-C(O)-A, and O-C 1~4 alkylene-C(O)OA; R 3 and R 4 The other is H, halo, C 1~6Alkyl and C 1~6 alkoxy, wherein all available hydrogen atoms may be independently optionally replaced with fluorine or deuterium atoms. 3 and R 4 One of them is C 1~4 In some embodiments, R 3 and R 4 One of them is C 1~4 In some embodiments, R 3 and R 4 One of them is C 1~4 alkylene-C(O)OA. In some embodiments, R 3 and R 4 On the other hand, OC 1~4 In some embodiments, R 3 and R 4 On the other hand, OC 1~4 In some embodiments, R 3 and R 4 On the other hand, OC 1~4 It is alkylene-C(O)OA.

[0149] In some embodiments, R 3 and R 4 One side is A, OA, C(O)-A, C(O)OA, C 1~4 Alkylene-A, C 1~4 Alkylene-C(O)-A,C 1~4 Alkylene-C(O)OA, OC 1~4 Alkylene-A, OC 1~4 Alkylene-C(O)-A, and O-C 1~4 alkylene-C(O)OA; R 3 and R 4 The other is H, F, Cl, C 1~4 Alkyl and C 1~4 alkoxy, wherein all available hydrogen atoms may be independently optionally replaced with fluorine or deuterium atoms. 3 and R4 One side is A, OA, C(O)-A, C(O)OA, C 1~4 Alkylene-A, C 1~4 Alkylene-C(O)-A,C 1~4 Alkylene-C(O)OA, OC 1~4 Alkylene-A, OC 1~4 Alkylene-C(O)-A, and O-C 1~4 alkylene-C(O)OA; R 3 and R 4 The other is H, F, Cl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Deuteroalkyl and C 1~4 alkoxy, wherein all available hydrogen atoms may be independently optionally replaced with fluorine or deuterium atoms. 3 and R 4 One side is A, OA, C(O)-A, C(O)OA, C 1~2 Alkylene-A, C 1~2 Alkylene-C(O)-A,C 1~2 Alkylene-C(O)OA, OC 1~2 Alkylene-A, OC 1~2 Alkylene-C(O)-A, and O-C 1~2 alkylene-C(O)OA; R 3 and R 4 and the other is selected from D, F, Cl, CH, CH(CH), CF, CFH, CD, CH(CH)O, CHO, CF, CHF, and CD, where any available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 3 and R 4 One side is A, OA, C(O)-A, C(O)OA, C 1~2 Alkylene-A, C 1~2 Alkylene-C(O)-A,C 1~2 Alkylene-C(O)OA, OC 1~2 Alkylene-A, OC 1~2 Alkylene-C(O)-A, and O-C1~2 alkylene-C(O)OA; R 3 and R 4 and the other is H or D, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 3 and R 4 One side is A, OA, C(O)-A, C(O)OA, CH2-A, CD2-A, CF2-A, CH2-C(O)-A, CF2-C(O)-A, CD2-C(O)-A, CH2-C(O)OA, CD2-C(O)OA, CF2-C(O)OA, selected from 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 3 and R 4 The other is H or D.

[0150] In some embodiments, R 3 is A, OA, C(O)-A, C(O)OA, C 1~2 Alkylene-A, C 1~2 Alkylene-C(O)-A,C 1~2 Alkylene-C(O)OA, OC 1~2 Alkylene-A, OC 1~2 Alkylene-C(O)-A, and O-C 1~2 Alkylene-C(O)OA and OC 1~2 alkylene-A is selected from R 4 is H or D, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 3are A, OA, C(O)-A, C(O)OA, CH2-A, CD2-A, CF2-A, CH2-C(O)-A, CF2-C(O)-A, CD2-C(O)-A, CH2-C(O)OA, CD2-C(O)OA, CF2-C(O)OA, O- CH2A, O-CF2A, O-CD2A, O-CH2-C(O)-A, O-CD2-C(O)-A, O-CF2-C(O)-A, O-CH2-C(O)OA, O-CF2-C(O)OA, and O-CD2-C(O)OA, R 4 is H or D. In some embodiments, R 4 is A, OA, C(O)-A, C(O)OA, C 1~2 Alkylene-A, C 1~2 Alkylene-C(O)-A,C 1~2 Alkylene-C(O)OA, OC 1~2 Alkylene-A, OC 1~2 Alkylene-C(O)-A, and O-C 1~2 Alkylene-C(O)OA and OC 1~2 alkylene-A is selected from R 3 is H or D, where all available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate. 4 are A, OA, C(O)-A, C(O)OA, CH2-A, CD2-A, CF2-A, CH2-C(O)-A, CF2-C(O)-A, CD2-C(O)-A, CH2-C(O)OA, CD2-C(O)OA, CF2-C(O)OA, O- CH2A, O-CF2A, O-CD2A, O-CH2-C(O)-A, O-CD2-C(O)-A, O-CF2-C(O)-A, O-CH2-C(O)OA, O-CF2-C(O)OA, and O-CD2-C(O)OA, R 3 is H or D.

[0151] In some embodiments, A is C 1~30 Alkyl, C 2~30 Alkenyl, phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 64and 3-6 membered heterocycloalkyl containing 1-3 hetero moieties independently selected from O, S, S(O), SO, N, and NR 64 wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with F, Cl, OH, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 In some embodiments, A is optionally substituted with one or two substituents independently selected from fluoroalkyl, where all available hydrogen atoms are independently optionally replaced with fluorine atoms or deuterium atoms. 1~30 Alkyl, C 2~30 Alkenyl, phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 63 and 3-6 membered heterocycloalkyl containing 1-3 hetero moieties independently selected from O, S, S(O), SO, N, and NR 53 wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with F, Cl, OH, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 It may be optionally substituted with one or two substituents independently selected from fluoroalkyl.

[0152] In some embodiments, A is phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 53and 3-6 membered heterocycloalkyl containing 1-3 hetero moieties independently selected from O, S, S(O), SO, N, and NR 63 wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with F, Cl, OH, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 In some embodiments, A is optionally substituted with one or two substituents independently selected from phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 63 and 5-6 membered heterocycloalkyl containing 1-2 hetero moieties independently selected from O, S, S(O), SO, N, and NR 63 wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with F, Cl, OH, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 It may be optionally substituted with one or two substituents independently selected from fluoroalkyl.

[0153] In some embodiments, C in A 3~6 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. 3~6 Cycloalkyl is F, Cl, C 1~4 Alkyl, C 1~4Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 and cyclopropyl optionally substituted with one or two substituents independently selected from fluoroalkyl.

[0154] In some embodiments, O, S, S(O), SO, N, and NR in A 64 and 3-6 membered heterocycloalkyl containing 1 to 3 hetero moieties independently selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxathiolidinyl, thiazolidinyl, isothiazolidinyl, and selected from F, C, C, F, C, C- ... 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 In some embodiments, A is optionally substituted with one or two substituents independently selected from O, S, S(O), SO, N, and NR 64and 3-6 membered heterocycloalkyl containing 1-3 heteromoieties independently selected from tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, piperidinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl oxide, tetrahydrothiopyranyl dioxide, dihydropyranyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl, each of which is selected from F, C, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 It may be optionally substituted with one or two substituents independently selected from fluoroalkyl.

[0155] In some embodiments, the 5-6 membered heteroaryl in A is selected from furyl, imidazolyl, isothiazolyl, thiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyrrolyl, thienofuryl, triazolyl, and thienyl, each of which is selected from F, C, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 In some embodiments, the 5- to 6-membered heteroaryl in A is selected from furyl, isothiazolyl, thiazolyl, pyridyl, and pyrrolyl, which are each independently selected from F, C, and C. 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Fluoroalkyl, OC 1~4 Alkyl, OC 1~4 Deuteroalkyl and OC 1~4 It may be optionally substituted with one or two substituents independently selected from fluoroalkyl.

[0156] In some embodiments, the phenyl in A, C 3~10 The cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl may be optionally substituted with one or two substituents independently selected from F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, CD3, CH(CH3)2O, CH3CH2CHO, CH3CHO, CHO, CF3O, CHF2O, CF2HCHO, CF3CHO, (CF3)2CHO, and CD3O.

[0157] In some embodiments, A is C 1~30 Alkyl and C 2~30 alkenyl, where any available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0158] In some embodiments, A is C 10~25 In some embodiments, A is alkyl, where any available hydrogen atoms may be independently replaced with fluorine or deuterium atoms, as appropriate. 13~21 alkyl, where any available hydrogen atoms may be independently replaced with fluorine or deuterium atoms as appropriate.

[0159] In some embodiments, A is C 10~25 In some embodiments, A is an alkenyl group, where any available hydrogen atoms may be independently replaced with a fluorine atom or a deuterium atom. 13~21 In some embodiments, A is an alkenyl group, where any available hydrogen atoms may be independently replaced with a fluorine atom or a deuterium atom. 10~25 is alkenyl and contains 1, 2, 3, 4, 5 or 6 double bonds;

[0160] In some embodiments, the alkyl or alkene group in A is an alkyl or alkenyl group present in a fatty acid, where all available hydrogen atoms may be optionally replaced with deuterium. In some embodiments, A is an alkenyl group present in a fatty acid, where all available hydrogen atoms may be optionally replaced with deuterium. In some embodiments, the fatty acid is an ω-6 fatty acid (i.e., an unsaturated or polyunsaturated fatty acid in which the double bond closest to the methyl end of the molecule is located at carbon number 6, counting from the terminal methyl group) or an ω-3 fatty acid (i.e., an unsaturated or polyunsaturated fatty acid in which the double bond closest to the methyl end of the molecule is located at carbon number 3, counting from the terminal methyl group), where all available hydrogen atoms may be optionally replaced with deuterium. In some embodiments, A is an alkyl group present in a fatty acid, where all available hydrogen atoms may be optionally replaced with deuterium. In some embodiments, the alkyl or alkene group in A is an alkyl or alkene group present in a fatty acid selected from the list of fatty acids in Table 1, where all available hydrogen atoms are optionally replaced with deuterium.

[0161] In some embodiments, the alkene group in A is an alkyl or alkenyl group present in linoleic acid, eicosadienoic acid, or decosahexanoic acid.

[0162] In some embodiments, when A is an alkyl or alkenyl group of a fatty acid, 1 to 10, 2 to 8, 2 to 6, or 2 to 4 hydrogen atoms are replaced with deuterium.

[0163] In some embodiments, A is (CH2)7CH=CH(CH2)7CH3. In some embodiments, A is (CH2)7CH=CHCH2CH=CH(CH2)4CH3. In some embodiments, A is (CH2)8CH=CHCH2CH=CH(CH2)4CH3. In some embodiments, A is (CH2)7CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3. In some embodiments, A is (CH2)3CH=CHCH2CH=CH(CH2)1CH=CHCH2CH=CH(CH2)3CH3. In some embodiments, A is (CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3. In some embodiments, A is (CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)1CH3.

[0164] In some embodiments, R 63 and R 64 are independently H, D, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, R is selected from deuteroalkyl. 63 and R 64 is independently selected from H, D, CH, CF, and CD. In some embodiments, R 63 and R 64 is independently selected from H and D.

[0165] In some embodiments, the compound of Formula I: [ka] is defined as follows, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof: [In formula: R 1 is H; Q is Q1, Q2, Q3, Q4, Q5 and Q6: [ka] Selected from the structure: [ka] is a single or double bond, provided that the structure in Q1: [ka] is a double bond, R 8 and R 14 does not exist, and the structure in Q2: [ka] is a double bond, R 16 and R 24 does not exist, and the structure in Q6: [ka] is a double bond, R 53 and R 62 does not exist; R 2 and R 5 is independently selected from H, D, and F; R 3 and R 4 One or both of these are H, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy and C 1~4 deuteroalkoxy; or R 3 and R 4 together to form O-(CH2) 1~2 Forming O; R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R26 , R 27 , R 28 , R 31 , R 32 , R 33 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 and R 52 is independently selected from H and D; R 11 , R 19 , R 29 and R 30 , R 34 and R 44 are independently H, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 is selected from deuteroalkyl; However, if Q is Q3;R 2 , R 3 , R 4 , R 5 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 At least one of is or contains D, or R 2 , R 3 , R 4 , R 5 at least one of R is alkyl substituted with one or more fluorine and / or chlorine atoms; or R 2 , R 3 , R 4 , R 5 at least three of which are not H; or If Q is Q3; R 3 and R 4together to form O-(CH2) 1~2 Form O.

[0166] In some embodiments, the compound of Formula I: [ka] is defined as follows, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof: [In formula: R 1 H, halo, NH2, C 1~6 Alkyl, C 1~6 Alkoxyl, NH(C 1~6 alkyl) and N(C 1~6 alkyl)2; Q is Q1, Q2, Q3, Q4, Q5 and Q6: [ka] Selected from the structure: [ka] is a single or double bond, provided that the structure in Q1: [ka] is a double bond, R 8 and R 14 does not exist, and the structure in Q2: [ka] is a double bond, R 16 and R 24 does not exist, and the structure in Q6: [ka] is a double bond, R 53 and R 62 does not exist; R 2 and R 5 are independently H, halo, OH, C1~6 Alkyl and C 1~6 selected from alkoxy; R 3 and R 4 One or both of may independently be H, halo, or C 1~6 Alkyl and C 1~6 alkoxy; R 3 and R 4 together to form O-(CH2) 1~2 Form O, or R 3 and R 4 One of them is selected from XLA and R 3 and R 4 The other is H, halo, C 1~6 Alkyl and C 1~6 selected from alkoxy; X is a direct bond, O, C(O), or NR a , N.R. a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and N.R. a C(O)NR a Selected from; L is a direct bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 1~6 Alkylene O, C 2~6 Alkenylene O,C 1~6 Alkylene C(O), C 2~6 Alkenylene C(O), C 1~6 Alkylene NR b C(O), C 2~6 Alkenylene NR b C(O), C 1~6 AlkyleneC(O)NR b , C 2~6 AlkenyleneC(O)NR b , C 1~6 Alkylene OC(O), C 2~6 Alkenylene OC(O), C 1~6 Alkylene C(O)O, C 2~6 Alkenylene C(O)O, C1~6 Alkylene OC(O)NR b , C 2~6 Alkenylene OC(O)NR b , C 1~6 Alkylene NR b C(O)O, C 2~6 Alkenylene NR b C(O)O, C 1~6 Alkylene O-C(O)O, C 2~6 Alkenylene O-C(O)O, C 1~6 Alkylene NR b C(O)NR b and C 2~6 Alkenylene NR b C(O)NR b Selected from; R a is H and C 1~6 alkyl; R b is H, C 1~6 alkyl, and A; A is H, C 1~30 Alkyl, C 2~30 Alkenyl, phenyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 53 and 3-6 membered heterocycloalkyl containing 1-4 hetero moieties independently selected from O, S, S(O), SO, N, and NR 63 wherein the phenyl, C 3~10 Cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are substituted with halo, OH, C 1~4 Alkyl and OC 1~4 optionally substituted with one or more substituents independently selected from alkyl; R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R18 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 31 , R 32 , R 33 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 57 , R 58 , R 59 , R 60 , R 61 and R 62 are independently H, halo, and C 1~6 alkyl; R 11 , R 19 , R 34 , R 44 and R 56 are independently H, C 1~6 selected from alkyl and C(O)-A'; R 29 and R 30 are independently H and C 1~6 alkyl; or R 29 and R 30 One of them is C(O)-A' and the other is H and C 1~6 alkyl; where A' is Y, OY and OC 1~4 alkylene-OC(O)-Y; Y is C 7~30 Alkyl and C 7~30 alkenyl; or R 29 and R 30 together with the nitrogen atom to which they are attached, form O, S, S(O), SO2, N, and NR 64 and optionally includes one or two additional hetero moieties independently selected from halo, OH, C 1~4 Alkyl and OC 1~4 forming a 3- to 6-membered heterocyclic ring, optionally substituted with one or more substituents independently selected from alkyl; R 63 and R 64 are independently H and C 1~6 alkyl; any available hydrogen atom may be independently optionally replaced by a fluorine atom or a chlorine atom, and any available atom may be optionally replaced by its alternative isotope; However, R 11 , R 19 , R 29 , R 30 , R 34 , R 44 and R 56 is C(O)-A'; or R 3 and R 4 One of them is selected from XLA and R 3 and R 4 The other is H, halo, C 1~6 Alkyl and C 1~6 alkoxy, provided that when X and L are both direct bonds, A is selected from H, C 1~6 Alkyl or C 1~6 not alkenyl].

[0167] In some embodiments, R 11 , R 19 , R 29 , R 30 , R 34 , R 44 and R 56In some embodiments, one of R is C(O)-A'. 3 and R 4 One side is A, OA, C(O)-A, C(O)OA, C 1~4 Alkylene-A, C 1~4 Alkylene-C(O)-A,C 1~4 Alkylene-C(O)OA, OC 1~4 Alkylene-A, OC 1~4 Alkylene-C(O)-A and OC 1~4 alkylene-C(O)OA.

[0168] In some embodiments, the compound of Formula I is selected from the compounds listed in the table below, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof: [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

[0169] The present application discloses compounds 12 and 16: [Table 21] or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

[0170] In some embodiments, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt.The selection of an appropriate salt can be performed by those skilled in the art.Suitable salts include acid addition salts, for example, can be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid (e.g., hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid). Additionally, acids generally considered suitable for forming pharmaceutically useful salts from pharmaceutical basic compounds are discussed, for example, in P. Stahl et al., Camille G. (ed.) and Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley VCH; S. Berge et al., Journal of Pharmaceutical Sciences 1977 66(1)1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (website of the U.S. Food and Drug Administration, Washington, D.C.).

[0171] Acid addition salts suitable for or compatible with the treatment of subjects are any non-toxic organic or inorganic acid addition salts for any basic compound.Basic compounds that form acid addition salts include, for example, compounds containing amino groups.Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acid metal salts, such as sodium hydrogen phosphate and potassium hydrogen sulfate.Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids. Examples of such organic acids include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In some embodiments, exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate ("mesylate"), naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), and the like. In some embodiments, mono- or di-acid salts are formed, and such salts exist in either hydrate, solvate, or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base forms. The criteria for selecting an appropriate salt will be well known to those skilled in the art.Other pharmaceutically unacceptable salts, such as, but not limited to, oxalates, may be used, for example, in the isolation of compounds of the present application for experimental use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0172] The base addition salt suitable for or compatible with the treatment of the subject is any non-toxic organic or inorganic base addition salt of any acidic compound.A compound that forms a base addition salt includes, for example, a compound containing a carbonyl group.Exemplary inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide, and ammonia.Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.Selecting an appropriate salt may be useful, for example, to prevent the ester functional group of another part of the compound, if present, from being hydrolyzed.The criteria for selecting an appropriate salt will be well known to those skilled in the art.In some embodiments, representative basic salts also include ammonium salts, alkali metal salts (e.g., sodium, lithium, and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), salts containing organic bases (e.g., organic amines) (e.g., dicyclohexylamine, butylamine, choline), and salts containing amino acids (e.g., arginine, lysine). Groups containing a basic nitrogen may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfate), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl bromide and phenethyl bromide), and the like.Compounds having an acidic moiety can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands, such as quaternized ammonium salts. Also, when an acid (—COOH) or alcohol group is present, pharmaceutically acceptable esters can be used to modify the solubility or hydrolysis characteristics of the compound.

[0173] All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of this application, and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of this application. Furthermore, when a compound of this application contains both a basic moiety (e.g., but not limited to, an aliphatic primary, secondary, tertiary, or cyclic amine, an aromatic amine, or a heteroaryl amine, pyridine, or imidazole) and an acidic moiety (e.g., but not limited to, a tetrazole or a carboxylic acid), zwitterions ("internal salts") may be formed and are included within the scope of the term "salt(s)" as used herein. It is understood that some compounds of this application may exist in the form of zwitterions, having both an anionic and a cationic center in the same compound and having a net neutral charge. Such zwitterions are included within the scope of this application.

[0174] Solvates of the compounds of the present application include, for example, those formed using pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvates are called hydrates) and ethanol. Suitable solvents are physiologically acceptable at the dosage administered.

[0175] Prodrugs of the compounds of the present application include, for example, conventional esters formed with available hydroxy, thiol, amino, or carboxyl groups. Some common esters that have been utilized as prodrugs include phenyl esters, aliphatic (C1-C6) esters, and the like. 24) esters, acyloxymethyl esters, carbamates and amino acid esters.

[0176] It is understood and appreciated that in some embodiments, the compounds of the present application may have at least one chiral center and, therefore, may exist as enantiomers and / or diastereomers. All such isomers and mixtures thereof, in all proportions, are encompassed within the scope of the present application. While the stereochemistry of a compound may be as shown in a given compound listed herein, it should be further understood that such compounds may contain a certain amount (e.g., less than 20%, preferably less than 10%, more preferably less than 5%) of compounds of the present application having an alternative stereochemistry. All optical isomers, as separated, pure, or partially pure optical isomers, or racemic mixtures thereof, are intended to be encompassed within the scope of the present application.

[0177] In some embodiments, the compounds of the present application may also include tautomeric forms, such as keto-enol tautomers. The tautomeric forms may be in equilibrium or may be sterically locked into one form by appropriate substitution. Any tautomeric forms that the compounds form, as well as mixtures thereof, are intended to be included within the scope of the present application.

[0178] The compounds of the present application may further exist in various amorphous and polymorphic forms, and any amorphous form, polymorph, or mixture thereof is contemplated and is within the scope of the present application.

[0179] The compounds of the present application may further be radiolabeled, and therefore all radiolabeled forms of the compounds of the present application are included within the scope of the present application. The compounds of the present application also include compounds having one or more radioactive atoms incorporated into their structure.

[0180] III. Composition The compounds of the present application are suitably formulated into compositions using one or more carriers in a conventional manner. Accordingly, the present application also includes compositions comprising one or more compounds of the present application and a carrier. The compounds of the present application are suitably formulated into pharmaceutical compositions for administration to a subject in a biologically compatible form suitable for in vivo administration. Accordingly, the compounds of the present application further include pharmaceutical compositions comprising one or more compounds of the present application and a pharmaceutically acceptable carrier. In an embodiment of the present application, the pharmaceutical composition is used in the treatment of any disease, disorder, or condition described herein.

[0181] The compounds of the present application may be administered to a subject in various forms depending on the route of administration selected, as will be understood by those skilled in the art. For example, the compounds of the present application may be administered orally, by inhalation, parenterally, bucally, sublingually, by insufflation, epidurally, nasally, rectally, intravaginally, by patch, pump, minipump, topically, or transdermally, and the pharmaceutical composition may be formulated accordingly. In some embodiments, the compounds may be administered by pump for periodic or continuous delivery. Conventional procedures and ingredients for selecting and preparing suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000-20 edition) and the United States Pharmacopeia: National Formulary, 1999 (USP 24 NF19).

[0182] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, and includes, for example, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary (e.g., using an aerosol), intrathecal, rectal, and topical (including use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0183] In some embodiments, the compounds of the present application are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or enclosed in a hard or soft shell gelatin capsule, or compressed into tablets, or taken directly with food at mealtimes. In some embodiments, the compounds are incorporated with excipients and used in the form of orally ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, 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 phosphate salts. Pharmaceutically acceptable excipients include binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), or solvents (e.g., medium-chain triglycerides, ethanol, water). In embodiments, tablets are coated by methods well known in the art. For tablets, capsules, caplets, pellets, or granules for oral administration, pH-sensitive enteric coatings, such as Eudragits™, designed to control the release of active ingredients, may be used as appropriate. Oral dosage forms also include modified release, such as immediate-release and timed-release formulations. Examples of modified release formulations include, for example, sustained release (SR), extended release (ER, XR, or XL), time-release or timed release, controlled release (CR), or continuous release (CR or Contin), used in the form of, for example, coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, agglomerated particles (e.g., as molecular sieve-type particles), or fine hollow permeable fiber bundles, or chopped hollow permeable fibers collected or held together in a fibrous packet.The time-release composition is formulated, for example, as a liposome, or in which the active compound is protected with a differentially degradable coating, for example, by microencapsulation, multilayer coating, etc. Liposomal delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. In some embodiments, liposomes are formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. For oral administration in capsule form, useful carriers, solvents, or diluents include lactose, medium-chain triglycerides, ethanol, and dried corn starch.

[0184] In some embodiments, liquid preparations for oral administration may take the form of, for example, solutions, syrups, or suspensions, or may be suitably provided as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compounds of the present application are suitably suspended or dissolved in an oil phase combined with an emulsifying and / or suspending agent. If desired, several sweetening and / or flavoring and / or coloring agents may be added. Such liquid preparations for oral administration are prepared by conventional means using pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., medium-chain triglycerides, almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0185] For example, it is possible to lyophilize the compounds of the present application and use the resulting lyophilizates for the preparation of injectable products.

[0186] In some embodiments, the compounds of the present application are administered parenterally. For example, solutions of the compounds of the present application are prepared in water, appropriately mixed with a surfactant such as hydroxypropyl cellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof (with or without alcohol), and in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. Those skilled in the art will know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the present application are usually prepared, and the pH of the solution is appropriately adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to make the preparation isotonic. For ophthalmic administration, ointments or instillable liquids are delivered, for example, by ophthalmic delivery systems (e.g., applicators or eyedroppers) known in the art. In some embodiments, such compositions comprise a mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose, or polyvinyl alcohol, a preservative such as sorbic acid, EDTA, or benzyl chromium chloride, and a conventional amount of diluent or carrier. For pulmonary administration, the diluent or carrier will be selected to be appropriate to allow for the formation of an aerosol.

[0187] In some embodiments, the compounds of the present application are formulated for parenteral administration by injection, including the use of conventional catheterization techniques or infusion. Formulations for injection are provided, for example, in unit dosage forms (e.g., in ampoules or multi-dose containers, with an added preservative). In some embodiments, the compositions take the form of a sterile suspension, solution, or emulsion in an oily or aqueous vehicle, and contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. In all cases, they must be sterile and fluid to the extent that they are easily syringable. Alternatively, the compounds of the present application are preferably in sterile powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0188] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels, and powders. For intranasal or inhalation administration, the compounds of the present application are conveniently delivered in the form of a solution, dry powder formulation, or suspension from a pump spray container that is squeezed or pumped onto the patient, or as an aerosol spray from a pressurized container or nebulizer. Aerosol formulations generally comprise a solution or fine suspension of an active compound in a physiologically acceptable aqueous or non-aqueous solvent, and are typically provided in a single or multiple doses in a sterile sealed container (e.g., in the form of a cartridge or refill for use with a spray device). Alternatively, the sealed container may be a single-dose device, such as a single-dose nasal inhaler, or an aerosol dispenser equipped with a metered-dose valve that is intended to be discarded after use. When the dosage form includes an aerosol dispenser, it will contain a propellant, such as a compressed gas, e.g., compressed air, or an organic propellant, e.g., a fluorochlorohydrocarbon. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or other suitable gases. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator are formulated containing, for example, a powder mix of the compound of the present application and a suitable powder base, such as lactose or starch. The aerosol dosage form can also take the form of a pump-atomizer.

[0189] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, in which the compounds of the present application are 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.

[0190] Suppository formulations of the compounds of the present application are useful for vaginal, urethral and rectal administration.Such suppositories will generally be composed of a mixture of materials that are solid at room temperature but melt at body temperature.Materials commonly used to make such vehicles include, but are not limited to, cocoa oil (also known as cocoa butter), glycerin gelatin, other glycerides, hydrogenated vegetable oils, and mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.For further description of suppository dosage forms, see, for example, Remington's Pharmaceutical Sciences, 16th edition, Mack Publishing, Easton, PA, 1980, pp. 1530-1533.

[0191] In some embodiments, the compounds of the present application are conjugated to soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, the compounds of the present application are conjugated to crosslinked or amphiphilic block copolymers of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylic acids, and hydrogels.

[0192] The compounds of the present application are particularly suitable for administration with nanocarrier systems such as liposomes, micelles, nanoparticles, nanoemulsions, lipid nanosystems, etc. (See, e.g., Bhat, M. et al. Chem. And Phys. Of Lipids, 2021, 236, 105053.) Accordingly, the present application includes compositions comprising one or more compounds of the present application and one or more components of a nanocarrier system.

[0193] Although the compounds of the present application, including their pharmaceutically acceptable salts and / or solvates, are suitably used per se, they will generally be administered in the form of a pharmaceutical composition in which one or more compounds of the present application (active ingredients) are combined with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will contain from about 0.05% to about 99% by weight, or from about 0.10% to about 70% by weight, of the active ingredient(s) and from about 1% to about 99.95% by weight, or from about 30% to about 99.90% by weight of the pharmaceutically acceptable carrier (all weight percentages based on the total weight of the composition).

[0194] In some embodiments, the compounds of the present application, including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, are used in and administered in compositions containing additional therapeutic agents. Accordingly, the present application also includes pharmaceutical compositions comprising one or more compounds of the present application, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, and additional therapeutic agents, and may optionally include one or more pharmaceutically acceptable excipients. In some embodiments, the additional therapeutic agent is another known agent useful for treating diseases, disorders, or conditions by activating serotonin receptors, such as those listed in the methods and uses section below. In some embodiments, the additional therapeutic agent is a psychoactive agent.

[0195] For clarity, in the above, the term "a compound" also includes embodiments in which more than one compound is referenced.

[0196] IV. Methods and Uses of the Present Application The compounds of the present application are useful for treating diseases, disorders, or conditions by modulating (e.g., activating) serotonin receptors. Therefore, the compounds of the present application are useful as pharmaceuticals. Therefore, the present application also includes the compounds of the present application for use as pharmaceuticals.

[0197] The present application also includes a method for treating a disease, disorder, or condition through activation of a serotonin receptor, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application.

[0198] The present application also includes the use of one or more compounds of the present application for treating a disease, disorder, or condition through activation of a serotonin receptor, as well as the use of one or more compounds of the present application for preparing a medicament for treating a disease, disorder, or condition through activation of a serotonin receptor. The present application further includes one or more compounds of the present application for use in treating a disease, disorder, or condition through activation of a serotonin receptor.

[0199] In some embodiments, the serotonin receptor is 5-HT 2A Thus, the present application provides a method for detecting intracellular 5-HT2+ (in a biological sample or in a patient) 2A The present application also provides a method for activating 5-HT2 receptor agonists, comprising administering to a cell an effective amount of one or more compounds of the present application. 2A and using one or more compounds of the present application to activate 5-HT in cells. 2A The present application also includes the use of the compound of the present invention for preparing a medicament for activating intracellular 5-HT 2A Further included are one or more compounds of the present application for use in activating.

[0200] In some embodiments, the serotonin receptor is 5-HT 1A Thus, the present application provides a method for determining 5-HT in cells of either a biological sample or a patient. 1AThe present application also provides a method for activating a 5-HT receptor in a cell, the method comprising administering to the cell an effective amount of one or more compounds of the present application. 1A and using the compounds of the present application to activate intracellular 5-HT 1A The present application also includes the use of the compound in the preparation of a medicament for activating intracellular 5-HT receptors. 1A Further included are one or more compounds of the present application for use in activating a receptor.

[0201] This application relates to 5-HT 2A The present application also includes a method for treating a disease, disorder, or condition by activating 5-HT, which method comprises administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application. 2A and using one or more compounds of the present application to treat a disease, disorder, or condition by activating 5-HT 2A The present application also includes the use of one or more compounds of the present application to prepare a medicament for the treatment of a disease, disorder, or condition resulting from activation of 5-HT 2A The present invention further includes one or more compounds of the present application for use in treating a disease, disorder, or condition through activation of

[0202] This application relates to 5-HT 1A The present application also includes a method for treating a disease, disorder, or condition by activating 5-HT, which method comprises administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application. 1A and using one or more compounds of the present application to treat a disease, disorder, or condition by activating 5-HT 1A The present application also includes the use of one or more compounds of the present application to prepare a medicament for the treatment of a disease, disorder, or condition through activation of 5-HT 1A The present invention further includes one or more compounds of the present application for use in treating a disease, disorder, or condition through activation of

[0203] The disease, disorder, or condition may be treated or treatable through another mechanism, for example, modulation, inactivation, antagonism, or inverse agonism of serotonin receptors (including 5-HT2A and / or 5-HT1A).

[0204] In some embodiments, the compounds of the present application are useful for preventing, treating, and / or reducing the severity of psychiatric disorders and / or conditions in a subject. Accordingly, in some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a psychiatric disorder. Accordingly, the present application also includes a method for treating a psychiatric disorder, the method comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need of treatment. The present application also includes the use of one or more compounds of the present application for treating a psychiatric disorder, as well as the use of one or more compounds of the present application for preparing a medicament for treating a psychiatric disorder. The present application further includes one or more compounds of the present application for use in treating a psychiatric disorder.

[0205] In some embodiments, the psychiatric disorder is selected from: anxiety disorders, such as generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobias; depression, such as hopelessness, loss of pleasure, fatigue, and suicidal ideation; mood disorders, such as depression, bipolar disorder, cancer-related depression, anxiety, and cyclothymic disorder; psychotic disorders, such as hallucinations, delusions, schizophrenia; impulse control disorders and addictive disorders, such as pyromania (fire-setting), kleptomania (stealing), and compulsive gambling; alcoholism; drug dependence, such as opioid dependence; personality disorders, such as antisocial behavior. Personality disorders, obsessive-compulsive personality disorder and paranoid personality disorder; obsessive-compulsive disorder (OCD), e.g., thoughts or fears that cause the subject to perform some ritualistic or daily activity; post-traumatic stress disorder (PTSD); stress response syndromes (formerly called adjustment disorders); dissociative disorders (formerly called multiple personality disorder, or "split personality," and depersonalization disorder); functional disorders; sexual and gender disorders, e.g., sexual dysfunction, gender identity disorder and paraphilia; somatoform disorders (formerly known as psychosomatic or somatic symptom disorders); and combinations of these.

[0206] In some embodiments, diseases, disorders, or conditions treated by activation of serotonin receptors include: cognitive dysfunction; ischemic stroke; neurodegeneration; refractory substance use disorders; sleep disorders; pain, e.g., social pain, acute pain, cancer pain, chronic pain, breakthrough pain, bone pain, soft tissue pain, neuralgia, referred pain, phantom limb pain, neuropathic pain, cluster headaches, and migraines; obesity and eating disorders; epilepsy and seizure disorders; neuronal cell death; excitotoxic cell death; or combinations thereof.

[0207] In some embodiments, the psychiatric disorder is selected from hallucinations and delusions, and combinations thereof.

[0208] In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, and chronoceptive hallucinations, and combinations thereof.

[0209] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is psychosis or a psychotic condition. Accordingly, the present application also includes a method of treating psychosis or a psychotic condition, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application.

[0210] The present application also includes the use of one or more compounds of the present application for treating psychosis or psychotic symptoms, as well as the use of one or more compounds of the present application for preparing a medicament for treating psychosis or psychotic symptoms. The present application further includes one or more compounds of the present application for use in treating psychosis or psychotic symptoms.

[0211] In some embodiments, administering a therapeutically effective amount of a compound of the present application to the subject in need of treatment does not worsen psychosis or psychotic symptoms (such as, but not limited to, hallucinations and delusions). In some embodiments, administering a therapeutically effective amount of a compound of the present application to the subject in need of treatment ameliorates psychosis or psychotic symptoms (such as, but not limited to, hallucinations and delusions). In some embodiments, administering a therapeutically effective amount of a compound of the present application to the subject in need of treatment ameliorates psychosis or psychotic symptoms.

[0212] In some embodiments, the compounds of the present application are useful for treating a central nervous system (CNS) disorder in a subject in need of therapy, the therapy comprising administering to the subject a therapeutically effective amount of a compound of general formula I, or a pharmaceutically acceptable salt thereof.

[0213] Thus, in some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a disease, disorder, or condition of the central nervous system (CNS) and / or a neurological disease, disorder, or condition. Accordingly, the present application also includes a method for treating a disease, disorder, or condition of the CNS and / or a neurological disease, disorder, or condition, comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need of treatment. The present application also includes the use of one or more compounds of the present application for treating a disease, disorder, or condition of the CNS and / or a neurological disease, disorder, or condition, as well as the use of one or more compounds of the present application for preparing a medicament for treating a disease, disorder, or condition of the CNS and / or a neurological disease, disorder, or condition. The present application further includes one or more compounds of the present application for use in treating a disease, disorder, or condition of the CNS and / or a neurological disease, disorder, or condition. In some embodiments, the CNS disease, disorder or condition and / or neurological disease, disorder or condition is selected from neurological diseases, including neurodevelopmental and neurodegenerative diseases, such as Alzheimer's disease; presenile dementia; senile dementia; vascular dementia; dementia with Lewy bodies; cognitive impairment, Parkinson's disease and Parkinson's disease-related disorders, such as Parkinsonism, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disorders; Fragile X syndrome; Angelman syndrome; genetic disorders. These conditions include ataxia; neuro-otological and oculomotor disorders; retinal neurodegenerative diseases; amyotrophic lateral sclerosis; tardive dyskinesia; hyperkinetic disorder; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette's syndrome; schizophrenia; autism spectrum disorder; tuberous sclerosis; Rett's syndrome; cerebral palsy; eating disorders, such as reward system disorders including anorexia nervosa ("AN") and bulimia nervosa ("BN"); and binge eating disorder ("BED"), trichotillomania, excoriation disorder, nail biting; migraine; fibromyalgia; and peripheral neuropathies of any etiology, and combinations thereof.

[0214] In some embodiments, the subject is a mammal. In other embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. Thus, the compounds, methods, and uses of the present application are directed to diseases, disorders, and conditions in both human and veterinary medicine.

[0215] In some embodiments, the compounds of the present application are useful for treating behavioral problems in subjects that are cats or dogs.

[0216] Thus, in some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is problem behavior in a cat or dog subject. Thus, the present application also includes a method for treating problem behavior, comprising administering a therapeutically effective amount of one or more compounds of the present application to a non-human subject in need of treatment. The present application also includes the use of one or more compounds of the present application to treat problem behavior in a non-human subject, as well as the use of one or more compounds of the present application to prepare a medicament for treating problem behavior in a non-human subject. The present application further includes one or more compounds of the present application for use in treating problem behavior in a non-human subject.

[0217] In some embodiments, the problem behavior is selected from, but not limited to, anxiety, fear, stress, sleep disorders, cognitive impairment, aggression, excessive fussing, scratching, biting, and combinations thereof.

[0218] In some embodiments, the non-human subject is a dog. In some embodiments, the non-human subject is a cat.

[0219] The present application also includes a method for treating a disease, disorder, or condition by activating serotonin receptors, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application in combination with other known agents useful for treating the disease, disorder, or condition by activating serotonin receptors. The present application also includes the use of one or more compounds of the present application in combination with other known agents useful for treating the disease, disorder, or condition by activating serotonin receptors to treat the disease, disorder, or condition by activating serotonin receptors, as well as the use of one or more compounds of the present application in combination with other known agents useful for treating the disease, disorder, or condition by activating serotonin receptors to prepare a medicament for treating the disease, disorder, or condition by activating serotonin receptors. The present application further includes one or more compounds of the present application for use in combination with other known agents useful for treating the disease, disorder, or condition by activating serotonin receptors in the treatment of a disease, disorder, or condition by activating serotonin receptors.

[0220] In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a psychiatric disorder. In some embodiments, the psychiatric disorder is selected from hallucinations and delusions, and combinations thereof. In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a disorder of the central nervous system (CNS). In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is psychosis or a psychotic symptom. In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is problematic behavior in non-human subjects.

[0221] In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a psychiatric disorder, and one or more compounds of the present application are administered in combination with one or more additional treatments for the psychiatric disorder. In some embodiments, the additional treatment for the psychiatric disorder is selected from antipsychotic drugs, including typical and atypical antipsychotic drugs; antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and monoamine oxidase inhibitors (MAOIs) (e.g., bupropion); antianxiety drugs, including benzodiazepines such as alprazolam; mood stabilizers, such as lithium, and anticonvulsants, such as carbamazepine, dipalproex (valproic acid), lamotrigine, gabapentin, and topiramate.

[0222] In some embodiments, the disease, disorder or condition that is treated by activating serotonin receptor is selected from attention deficit hyperactivity disorder and attention deficit disorder, and combinations thereof.In some embodiments, the disease, disorder or condition that is treated by activating serotonin receptor is selected from attention deficit hyperactivity disorder and / or attention deficit disorder, and combinations thereof, and one or more compounds of the present application are administered in combination with one or more additional treatments for attention deficit hyperactivity disorder and / or attention deficit disorder, and combinations thereof.In some embodiments, the one or more additional treatments for attention deficit hyperactivity disorder and / or attention deficit disorder, and combinations thereof are selected from methylphenidate, atomoxetine and amphetamine, and combinations thereof.

[0223] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is dementia or Alzheimer's disease, and one or more compounds of the present application are administered in combination with one or more additional treatments for dementia or Alzheimer's disease. In some embodiments, the additional treatments for dementia and Alzheimer's disease are selected from an acetylcholinesterase inhibitor, an NMDA antagonist, a muscarinic agonist, a muscarinic antagonist, and a nicotinic agonist.

[0224] In some embodiments, the acetylcholinesterase inhibitor is selected from donepezil, galantamine, rivastigmine, and phenserine, and combinations thereof.

[0225] In some embodiments, the NMDA antagonist is selected from MK-801, ketamine, phencyclidine, and memantine, and combinations thereof.

[0226] 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.

[0227] In some embodiments, the muscarinic agonist is a muscarinic M1 agonist or a muscarinic M4 agonist, or a combination thereof.

[0228] In some embodiments, the muscarinic antagonist is a muscarinic M2 antagonist.

[0229] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is psychosis or a psychotic condition, and one or more compounds of the present application are administered in combination with one or more additional treatments for the psychosis or psychotic condition. In some embodiments, the additional treatment for the psychosis or psychotic condition is selected from a typical antipsychotic and an atypical antipsychotic.

[0230] In some embodiments, the typical antipsychotic is acepromazine, acetophenazine, benperidol, bromperidol, butaperazine, carphenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, dixyrazine, droperidol, fluanisone, flupenthixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, lenperone, loxapine, mesoridazine, methytepin, molindone, mope The active ingredient is selected from the group consisting of thiazol-3, thiazol-4, thiazol-5, thiazol-6, thiazol-7, thiazol-8, thiazol-9, thiazol-10, thiazol-11, thiazol-12, thiazol-13, thiazol-14, thiazol-15, thiazol-16, thiazol-17, thiazol-18, thiazol-19, thiazol-20, thiazol-21, thiazol-22, thiazol-23, thiazol-24, thiazol-25, thiazol-26, thiazol-27, thiazol-28, thiazol-29, thiazol-30, thiazol-31, thiazol-32, thiazol-33, thiazol-34, thiazol-35, thiazol-36, thiazol-37, thiazol-38, thiazol-40, thiazol-41, thiazol-42, thiazol-43, thiazol-44, thiazol-45, thiazol-46, thiazol-47, thiazol-48, thiazol-49, thiazol-50, thiazol-51, thiazol-52, thiazol-53, thiazol-54, thiazol-55, thiazol-56, thiazol-57, thiazol-58, thiazol-59, thiaz

[0231] In some embodiments, the atypical antipsychotic is selected from amoxapine, amisulpride, aripiprazole, asenapine, blonanserin, brexpiprazole, cariprazine, carpipramine, clocapramine, chlorothepine, clotiapine, clozapine, iloperidone, levosulpiride, lurasidone, melperone, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpiride, sultopride, tiapride, veralipride, ziprasidone, and zotepine, and combinations thereof.

[0232] In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a psychiatric disorder, and one or more compounds of the present application 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.

[0233] In some embodiments, an effective amount varies depending on factors such as the disease state, age, sex, and / or weight of the subject or species. In some embodiments, the amount of a given compound, or the amount of a compound that corresponds to an effective amount, will vary depending on factors such as the given agent(s) or compound(s), pharmaceutical formulation, route of administration, condition, type of disease or disorder, identity of the subject being treated, etc., but can nevertheless be routinely determined by one of ordinary skill in the art.

[0234] In some embodiments, the compound of the present application is administered once, twice, three times, or four times per year. In some embodiments, the compound of the present application is administered at least once per week. However, in other embodiments, the compound is administered to a subject from about once per two weeks, three weeks, or month. In other embodiments, the compound is administered from about once per week to about once per day. In other embodiments, the compound is administered 1, 2, 3, 4, 5, or 6 times per day. The length of treatment depends on various factors, such as the severity of the disease, disorder, or condition, the age of the subject, the concentration and / or activity of the compound of the present application, and / or a combination thereof. It will also be understood that the effective dosage of the compound used for treatment may increase or decrease during a particular treatment regimen. Dosage variations will occur and be evident using standard diagnostic assays known in the art. In some cases, long-term administration is necessary. For example, the compound is administered to a subject in an amount and for a duration sufficient to treat the subject.

[0235] In some embodiments, the compounds of the present application are administered at a hallucinogenic or psychotomimetic dose, taken in conjunction with psychotherapy or therapy, and may be administered once, twice, three times, or four times per year. However, in some embodiments, the compounds are administered to a subject at a dose that is not hallucinogenic or psychotomimetic, once per day, once every two days, once per three days, once per week, once every two weeks, once per month, once every two months, or once per three months.

[0236] The compounds of the present application may be used alone or in combination with other known agents (e.g., compounds of the present application) that are useful for treating diseases, disorders, or conditions by activating serotonin receptors. When used in combination with other known agents that are useful for treating diseases, disorders, or conditions by activating serotonin receptors, it is an embodiment for the compounds of the present application to be administered simultaneously with those agents. As used herein, "co-administration" of two substances to a subject means providing the two substances, respectively, so that both are active in the individual at the same time. The exact details of administration depend on the pharmacokinetics of the two substances in the presence of each other, but may include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of the other, if the pharmacokinetics are suitable. Designing an appropriate dosing regimen is a routine task for those skilled in the art. In certain embodiments, the two substances are administered substantially simultaneously, i.e., within a few minutes of each other, or in a single composition containing both substances. It is a further embodiment of the present application that the combination of drugs is administered to a subject non-simultaneously. In some embodiments, the compounds of the present application are administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or are administered together in a single unit dosage form. Thus, the present application provides a single unit dosage form comprising one or more compounds of the present application, an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0237] The dosage of the compounds of the present application varies depending on many factors, including the pharmacokinetic properties of the compound, the mode of administration, the age, health, and weight of the recipient, the nature and severity of symptoms, the frequency of treatment and type of concurrent treatment (if any), and the clearance rate of the compound in the treated subject. Those skilled in the art can determine appropriate dosages based on the above factors. In some embodiments, one or more compounds of the present application are initially administered at an appropriate dosage, and the dosage is adjusted as needed depending on the clinical response. Dosages are generally selected to maintain serum levels of one or more compounds of the present application between about 0.01 μg / cc and about 1000 μg / cc, or between about 0.1 μg / cc and about 100 μg / cc. Typically, oral dosages of one or more compounds of the present application range from about 10 μg / day to about 1000 mg / day, preferably about 10 μg / day to about 500 mg / day, and more preferably about 10 μg / day to about 200 mg / day for adults. For parenteral administration, a typical dose would be about 0.0001 mg / kg to about 10 mg / kg, about 0.0001 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, or about 0.0001 mg / kg to about 0.01 mg / kg. For oral administration, a typical dose would be about 0.001 μg / kg to about 10 mg / kg, about 0.1 μg / kg to about 10 mg / kg, about 0.01 μg / kg to about 1 mg / kg, or about 0.1 μg / kg to about 1 mg / kg. For administration in suppository form, a typical dose would be about 0.1 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. In some embodiments of the present application, the compositions are formulated for oral administration, and the one or more compounds are preferably in tablet form, with each tablet containing 0.1, 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the active ingredient (one or more compounds of the present application).In some embodiments of the present application, one or more compounds of the present application are administered in a dose once daily, once weekly, or once monthly, or the total daily dose is divided into two, three, or four doses per day.

[0238] In some embodiments, the compounds of the present application are used or administered in an effective amount, including administering a dose or dosage regimen that lacks clinically meaningful hallucinogenic / psychotometic effects. In some embodiments, the compounds of the present application are used or administered in an effective amount, including administering a dose or dosage regimen that provides a clinical effect manifested by a human plasma psilocin Cmax of 4 ng / mL or less and / or a human 5-HT2A human CNS receptor occupancy of 40% or less, or a clinical effect similar to a clinical effect manifested by a human plasma psilocin Cmax of 1 ng / mL or less and / or a human 5-HT2A human CNS receptor occupancy of 30% or less. In some embodiments, the compounds of the present application are used or administered in an effective amount, including administering a dose or dosage regimen that provides a clinical effect similar to a clinical effect manifested by a human plasma psilocin Tmax of greater than 60 minutes, greater than 120 minutes, or greater than 180 minutes.

[0239] For clarity, in the above, the term "a compound" includes embodiments in which more than one compound is referenced. Similarly, the term "compounds of the present application" includes embodiments in which only one compound is referenced.

[0240] V. Compound Preparation The compounds of the present application may be prepared by a variety of synthetic processes. The selection of certain structural features and / or substituents may influence the selection of one process over another. The selection of a particular process for preparing a given compound of the present application is within the skill of one of ordinary skill in the art. Some starting materials for preparing the compounds of the present application are available from commercial chemical sources or may be extracted from cells, plants, animals, or fungi. Other starting materials are readily prepared from available precursors using simple transformations well known in the art, for example, as described below. In the following schemes illustrating some embodiments of methods for preparing the compounds of the present application, all variables are as defined in Formula I unless otherwise specified.

[0241] In some embodiments, Q has the structure: [ka] When this is the case, compounds of formula I are prepared as shown in Scheme 1: [ka] Scheme 1

[0242] Thus, in some embodiments, a compound of formula A, wherein R 1 , R 2 , R 3 , R 4 and R 5 is as defined in formula I) can be prepared, for example, by reacting a compound of formula B, 25 28 is as defined in Formula I, and R 29 and / or R 30 is as defined in Formula I or is a suitable protecting group, such as an alkyloxycarbonyl or benzyloxycarbonyl protecting group, and LG is a suitable leaving group, such as chloro), to form a compound of Formula I. 29 and / or R 30 If is a protecting group, it is removed in a separate step.

[0243] In some embodiments, Q has the structure: [ka] and R 31 and R 32 When is either H or D, compounds of formula I are prepared as shown in Scheme 2: [ka] Scheme 2

[0244] Thus, in some embodiments, a compound of formula A, wherein R 1 , R 2 , R 3 , R 4 and R 5 is as defined in formula I), for example, by reacting a compound of formula C, 33 and R 35 ~R 40 is as defined in formula I, and R 34 is as defined in formula I or is a suitable protecting group, for example, an alkyloxycarbonyl or benzyloxycarbonyl protecting group, and LG′ is a suitable leaving group, for example, chloro), under basic conditions to provide a compound of formula D. For example, reduction of the keto group in a compound of formula C with an aluminum reducing agent (e.g., lithium borohydride, lithium aluminum hydride, or lithium aluminum deuteride) can be used to provide a compound of formula (I) (wherein R 31 and R 33 is either H or D). 34 When is a protecting group, it is removed in a separate step or, alternatively, it is removed during the reduction of the compound of formula D when the protecting group is removed in the presence of an aluminum reducing agent.

[0245] Q is the structure: [ka] Those skilled in the art will appreciate that similar reaction sequences can be used to prepare compounds of formula I, wherein:

[0246] In some embodiments, Q has the structure: [ka] and the structure: [ka] When is a single bond, compounds of formula I are prepared as shown in Scheme 3: [ka] Scheme 3

[0247] Thus, in some embodiments, a compound of formula A, wherein R 1 , R 2 , R 3 , R 4 and R 5 is as defined in formula I) and a compound of formula E, 15~18 and R 20~24 is as defined in formula I, and R 19 is as defined in Formula I or is a suitable protecting group, e.g., an alkyloxycarbonyl or benzyloxycarbonyl protecting group, and LG″ is a suitable leaving group, e.g., iodo, bromo, tosyl, or mesyl), under suitable conditions (e.g., in the presence of sodium hydride (NaH) or sodium tert-butoxide (t-BuONa)) to provide a compound of Formula I. 19 When Q is a protecting group, it is removed in a separate step. [ka] and the structure: [ka] Those skilled in the art will appreciate that an analogous reaction sequence can be used to prepare compounds of formula I in which is a single bond.

[0248] In some embodiments, Q has the structure: [ka] and the structure: [ka] Compounds of formula I, where is a single bond, are prepared using methods known in the art, for example, those described in JP2015096495A and WO2007102883A2.

[0249] In some embodiments, Q has the structure: [ka]

[0043] When this is the case, compounds of formula I are prepared as shown in Scheme 4: [ka] Scheme 4

[0250] Thus, in some embodiments, a compound of formula A, wherein R 1 , R 2 , R 3 , R 4 and R 5 is as defined in formula I) and a compound of formula F, 15~18 and R 20~24 is as defined in formula I, and R 19 is as defined in Formula I or is a suitable protecting group, such as an alkyloxycarbonyl or benzyloxycarbonyl protecting group), is coupled under appropriate conditions (e.g., Mitsunobu reaction conditions using triphenylphosphine (PPh3) in the presence of diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD)) to provide a compound of Formula I. 19When is a protecting group, it is removed under specific reaction conditions.

[0251] Q is the structure: [ka] Those skilled in the art will appreciate that similar reaction sequences can be used to prepare compounds of formula I, wherein:

[0252] In some embodiments, Q has the structure: [ka] Compounds of formula I, wherein:

[0253] In some embodiments, Q has the structure: [ka] and the structure: [ka] When is a double bond, compounds of formula I are prepared as shown in Scheme 5: [ka] Scheme 5

[0254] Thus, in some embodiments, a compound of formula A, wherein R 1 , R 2 , R 3 , R 4 and R 5 is as defined in formula I) and a compound of formula G, 15~18 and R 20~24 is as defined in formula I, and R 19is as defined in formula I or is a suitable protecting group, for example, an alkyloxycarbonyl or benzyloxycarbonyl protecting group, and R a and R b are independently selected from H or alkyl, or R a and R b together, -(CH2) 1~2 -) under suitable conditions, for example in the presence of a copper catalyst such as copper acetate, a suitable base such as pyridine, and a suitable inert solvent such as methylene chloride, to provide a compound of formula I. 19 If is a protecting group, it is removed in a separate step.

[0255] Q is the structure: [ka] and the structure: [ka] Those skilled in the art will appreciate that an analogous reaction sequence can be used to prepare compounds of formula I in which is a double bond.

[0256] In some embodiments, Q has the structure: [ka] and the structure: [ka] Compounds of formula I in which is a double bond are prepared using methods known in the art, for example, the methods described in WO2016112637A1 and JP2016141632A.

[0257] In some embodiments, Q has the structure: [ka] and the structure: [ka] is a single bond, and R 7 and R 8 is OH or protected OH and the other is H, and R 14 is H or has the structure: [ka] is a double bond and R 7 When is H, compounds of formula I are prepared as shown in Scheme 6: [ka] Scheme 6

[0258] Thus, in some embodiments, a compound of formula A, wherein R 1 , R 2 , R 3 , R 4 and R 5 is as defined in formula I) and a compound of formula H, 9~10 and R 12~13 is as defined in formula I, and R 11 is as defined in formula I or is a suitable protecting group, for example, an alkyloxycarbonyl or benzyloxycarbonyl protecting group) under suitable conditions, for example, in the presence of a base (e.g., sodium hydride) in a suitable inert solvent such as dimethylformamide (DMF), to produce a compound of formula I(a), wherein the structure: [ka] is a single bond, and R 7 and R 8 wherein one is OH and the other is H. The compound of formula I(a) is protected with a suitable protecting group, such as a mesylate group, to give a compound of formula I(b), where PG is a suitable protecting group, which is further reacted with a suitable base, such as sodium methoxide (NaOMe), to give a compound of formula I, where the structure: [ka] is a double bond and R 7 is H). R 11 If is a protecting group, it is removed in a separate step.

[0259] Q is the structure: [ka] Those skilled in the art will appreciate that similar reaction sequences can be used to prepare compounds of formula I, wherein:

[0260] In some embodiments, Q has the structure: [ka] and the structure: [ka] is a single bond, and R 7 and R 8 is OH or protected OH and the other is H, and R 14 is H or has the structure: [ka] is a double bond and R 7 When is H, compounds of formula I are prepared using methods known in the art, for example, the methods described in JP2014224104A.

[0261] Those skilled in the art will recognize that particular enantiomers or diastereomers of the compounds of the present application may be obtained using the corresponding single enantiomers or diastereomers of the corresponding starting materials.

[0262] In some embodiments, Q has the structure: [ka] and the structure: [ka] is a single bond, and R 53 Compounds of formula I, in which the stereochemistry at the carbon to which is attached is either R or S, are prepared using methods known in the art, for example, the methods described in WO2007102883A2.

[0263] In some embodiments, Q has the structure: [ka] and the structure: [ka] is a single bond, and R 14 , R 24 or R 53 Compounds of formula I, in which the stereochemistry at the carbon to which is attached is either R or S, are prepared using methods known in the art, for example, the methods described in JP2014224104 and WO2018092047A1.

[0264] It will be understood that throughout the processes described herein, appropriate and suitable protecting groups will be added and subsequently removed to the various reactants and intermediates in a manner readily apparent to those skilled in the art. Conventional procedures for using such protecting groups, as well as examples of suitable protecting groups, are described, for example, in "Protective Groups in Organic Synthesis," T.W. Green, P.G.M.Wuts, Wiley-Interscience, New York, (1999).

[0265] It should also be understood that chemical manipulations to transform groups or substituents into other groups or substituents can be performed on any intermediate or final product on the synthetic route toward the final product, with the types of transformations possible being limited only by the inherent incompatibility of other functional groups present on the molecule at that stage with the conditions or reagents used for the transformation. Such inherent incompatibilities and how to overcome them by performing the appropriate transformations and synthetic steps in the proper order will be readily apparent to those skilled in the art. While examples of transformations are provided herein, it should be understood that the transformations described are not limited to only the common groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are provided in "Comprehensive Organic Transformations—A Guide to Functional Group Preparations" by R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions can be found in organic chemistry textbooks, such as "Advanced Organic Chemistry," March, 4th Edition, McGraw Hill (1992) or "Organic Synthesis," Smith, McGraw Hill, (1994).

[0266] Techniques for purifying intermediates and final products include, for example, normal and reverse phase chromatography using columns or rotating plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, and are readily understood by those skilled in the art.

[0267] The products of the processes of the present application may be isolated according to known methods, for example the compounds may be isolated by evaporation of the solvent, filtration, centrifugation, chromatography or other suitable method.

[0268] Generally, the above reactions are carried out in a suitable inert organic solvent, at a suitable temperature, and for a suitable time that maximizes the formation of the desired compound. Examples of suitable inert organic solvents include, but are not limited to, 2-propanol, dimethylformamide (DMF), 1,4-dioxane, methylene chloride, chloroform, tetrahydrofuran (THF), toluene, and the like.

[0269] Formation of a desired compound salt is accomplished using standard techniques, for example, by treating a neutral compound with an acid or base in a suitable solvent and isolating the formed salt by filtration, extraction, or any other suitable method.

[0270] The formation of solvates of the compounds of the present application will vary depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in an appropriate solvent and isolating it by cooling or using an anti-solvent. Solvates are generally dried or lyophilized under amphiphilic conditions. The selection of appropriate conditions for forming a particular solvate can be performed by one skilled in the art.

[0271] Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino, or carboxyl groups. For example, an available hydroxy or amino group may be acylated with an activated acid (e.g., an acid chloride in pyridine) in the presence of a base, optionally in an inert solvent.

[0272] Those skilled in the art will recognize that when reaction steps of the present application are carried out in different solvents or solvent systems, said reaction steps may be carried out in a mixture of suitable solvents or solvent systems. [Example]

[0273] The following non-limiting examples are illustrative of the present application: Example 1: R-6-Methoxy-1-((1-methylpyrrolidin-2-yl)methyl)-1H-indazole ((R)I-111)- [ka]

[0274] (R)-2-(2-(6-methoxy-1H-indazole-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2λ 2 Synthesis of -ethan-1-one (2): A solution of ((benzyloxy)carbonyl)-D-proline (6.73 g, 26.99 mmol) in anhydrous THF (80 mL) was treated with thionyl chloride (3.93 mL, 53.99 mmol) at room temperature, and the resulting solution was refluxed for an additional 2 h. The reaction was allowed to warm to room temperature, and the solvent was evaporated to give the crude acid chloride as a pale yellow oil.

[0275] A solution of the crude acid chloride from above in CHCl (50 mL) was treated with a solution of 6-methoxy-1H-indazole (4.0 g, 26.99 mmol) in CHCl (30 mL) at 0 °C, followed by pyridine (4.32 mL, 53.99 mmol). The reaction was allowed to warm to room temperature and stirred overnight (16 h). The reaction was diluted with CHCl (100 mL) and washed with water (2 × 100 mL), 1 N HCl solution (100 mL), brine (50 mL), and dried (NaSO). The solvent was evaporated and the crude product was purified by silica gel flash column chromatography (EtOAc:CHCl, 1:9) to afford the title compound 2 (8.5 g, 83.4%) as a glassy solid, along with its regioisomer in a 9:1 ratio. ESI-MS (m / z, %): 402 (M+Na), 380 (MH + ,100).

[0276] Synthesis of (R)-6-methoxy-1-((1-methylpyrrolidin-2-yl)methyl)-1H-indazole ((R)I-111): A suspension of LiAlH (0.75 g, 19.76 mmol) in anhydrous THF (40 mL) was treated with AlCl (3.16 g, 23.71 mmol) at 0 °C. The reaction was stirred for 5 min to give I-2-(2-(6-methoxy-1H-indazole-1-carbonyl)pyrrolidin-1-yl)-1-phenyl ... 2 The reaction mixture was treated with a solution of 1.5 g (3.95 mmol) of 1-ethan-1-one in anhydrous THF (20 mL) and then stirred for 15 minutes. The reaction was allowed to warm to room temperature and stirred for an additional 4 hours. The reaction was cooled to 0° C. and quenched with water (1.0 mL), 2N NaOH solution (1 mL), and water (1 mL). The reaction was allowed to warm to room temperature and stirred for an additional 30 minutes. The reaction was diluted with THF (50 mL), passed through a pad of NaSO, and then filtered through a pad of silica gel. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (2 M NH in MeOH:CHCl, 5:95) to afford the title compound (R)I-111 (0.15 g, 15%) as a brown oil. 1 H NMR (DMSO-d6): δ 8.24 (s,1H),7.56 (d,1H,J = 6.0 Hz),6.92 (d,1H,J = 3.0 Hz),6.68 (dd,1H,J = 3.0,6.0 Hz),4.42-4.37 (m,1H),4.26-4.21 (m,1H),3.79 (s,3H),2.97-2.93 (m,1H),2.72-2.2.60 (m,1H),2.20-2.14 (m,4H),1.75-1.70 (m,1H),1.60-1.54 (m,3H); ESI-MS (m / z,%): 246 (MH + ,100).

[0277] Example 2: (S)-6-Methoxy-1-((1-methylpyrrolidin-2-yl)methyl)-1H-indazole ((S)-I-111) [ka] (S)-2-(2-(6-methoxy-1H-indazole-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2l 2 Synthesis of -ethan-1-one (4): A solution of ((benzyloxy)carbonyl)-L-proline (1.6 g, 6.74 mmol) in anhydrous THF (20 mL) was treated with thionyl chloride (1.0 mL, 13.49 mmol) at room temperature, and the resulting solution was refluxed for an additional 2 h. The reaction was allowed to warm to room temperature, and the solvent was evaporated to give the crude acid chloride as a pale yellow oil.

[0278] A solution of the crude acid chloride from above in CHCl (25 mL) was treated with a solution of 6-methoxy-1H-indazole (1.0 g, 6.74 mmol) in CHCl (10 mL) at 0 °C, followed by pyridine (1.09 mL, 13.49 mmol). The reaction was allowed to warm to room temperature and stirred overnight (16 h). The reaction was diluted with CHCl (50 mL), washed with water (2 × 50 mL), 1N HCl solution (50 mL), brine (25 mL), and dried (NaSO). The solvent was evaporated, and the crude product was purified by silica gel flash column chromatography (EtOAc:CHCl, 1:9) to afford the title compound 4 (2.3 g, 89.8%) as a sticky substance, along with its regioisomer in a 93:7 ratio. ESI-MS (m / z, %): 402 (M+Na), 380 (MH + ,100).

[0279] Synthesis of (S)-6-methoxy-1-((1-methylpyrrolidin-2-yl)methyl)-1H-indazole ((S)-I-111): A suspension of LiAlH (1.0 g, 26.35 mmol) in anhydrous THF (40 mL) was treated with AlCl (4.21 g, 31.62 mmol) at 0 °C. The reaction was concentrated to give (S)-2-(2-(6-methoxy-1H-indazole-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2H 2The reaction mixture was treated with a solution of 1-ethan-1-one (2.0 g, 5.27 mmol) in anhydrous THF (20 mL) over 5 minutes and then stirred for 15 minutes. The reaction was allowed to warm to room temperature and stirred for an additional 4 hours. The reaction was cooled to 0 °C and quenched with water (1.0 mL), 2 N NaOH solution (1 mL), and water (1 mL). The reaction was allowed to warm to room temperature and stirred for an additional 30 minutes. The reaction was diluted with THF (50 mL), passed through a pad of NaSO, and then filtered through a pad of silica gel. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (2 M NH in MeOH:CHCl, 5:95) to afford the title compound (S)I-111 (35 mg, 2.7%) as a pale yellow oil. 1 H NMR (DMSO-d6): δ 8.24 (s,1H),7.56 (d,1H,J = 6.0 Hz),6.92 (d,1H,J = 3.0 Hz),6.68 (dd,1H,J = 3.0,6.0 Hz),4.41-4.37 (m,1H),4.25-4.20 (m,1H),3.79 (s,3H),2.96-2.93 (m,1H),2.73-2.2.69 (m,1H),2.23-2.14 (m,4H),1.76-1.69 (m,1H),1.62-1.56 (m,3H); ESI-MS (m / z,%): 246 (MH + ,100).

[0280] Example 3: (R)-6-Fluoro-1-((1-methylpyrrolidin-2-yl)methyl)-1H-indazole ((R)-I-52) [ka] (R)-2-(2-(6-fluoro-1H-indazole-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2l 2 Synthesis of -ethan-1-one (7): A solution of ((benzyloxy)carbonyl)-D-proline (5.0 g, 20.06 mmol) in anhydrous THF (75 mL) was treated with thionyl chloride (2.93 mL, 40.19 mmol) at room temperature, and the resulting solution was refluxed for an additional 2 hours. The reaction was allowed to warm to room temperature, and the solvent was evaporated to give the crude acid chloride as a pale yellow oil. A solution of the crude acid chloride in CHCl (50 mL) was treated at 0 °C with a solution of 6-fluoro-1H-indazole (2.73 g, 20.06 mmol) in CHCl (25 mL), followed by pyridine (3.24 mL, 40.19 mmol). The reaction was allowed to warm to room temperature and stirred overnight (16 hours). The reaction mixture was diluted with CHCl (100 mL), washed with water (2×50 mL), 1N HCl solution (50 mL), brine (25 mL), and dried (NaSO). The solvent was evaporated, and the crude product was purified by silica gel flash column chromatography (EtOAc:CHCl, 1:9) to give the title compound 7 (6.5 g, 88.3%) as a pale yellow gum along with its regioisomer in a 7:3 ratio. ESI-MS (m / z, %): 406 (M+K, 100), 390 (M+Na), 368 (MH). + ).

[0281] Synthesis of (R)-6-fluoro-1-((1-methylpyrrolidin-2-yl)methyl)-1H-indazole ((R)-I-52): A suspension of LiAlH (0.775 g, 20.41 mmol) in anhydrous THF (30 mL) was treated with AlCl (3.26 g, 24.49 mmol) at 0 °C. The reaction was concentrated to give I-2-(2-(6-fluoro-1H-indazole-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2H 2The reaction mixture was treated with a solution of 1.5 g (4.08 mmol) of 1-ethan-1-one in anhydrous THF (20 mL) over 5 minutes and then stirred for 15 minutes. The reaction was allowed to warm to room temperature and stirred for an additional 4 hours. The reaction was cooled to 0 °C and quenched with water (1.0 mL), 2 N NaOH solution (1 mL), and water (1 mL). The reaction was allowed to warm to room temperature and stirred for an additional 30 minutes. The reaction was diluted with THF (50 mL), passed through a pad of NaSO, and then filtered through a pad of silica gel. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (2 M NH in MeOH:CHCl, 5:95) to give the title compound (R)-I-52 (0.12 g, 12.6%) as a light brown oil. 1 H NMR (DMSO-d6): δ 8.43 (s,1H),7.80-7.76 (m,1H),7.35-7.31 (m,1H),6.96-6.91 (m,1H),4.45 (dd,1H,J = 3.0,12.0 Hz),4.30 (dd,1H,J = ESI-MS (m / z,%): 234 (MH) + ,100).

[0282] Example 4: 2-(6-Methoxy-1H-indazol-1-yl)-N,N-dimethylethan-1-amine (12) [ka] Synthesis of ethyl 2-(6-methoxy-1H-indazol-1-yl)acetate (9): A solution of 6-methoxy-1H-indazole (4.0 g, 26.99 mmol) in anhydrous DMF (50 mL) was treated portionwise over 10 minutes at 0°C with sodium hydride (1.76 g, 44.00 mmol, 60% in mineral oil). The reaction was allowed to warm to room temperature and stirred for 30 minutes. Ethyl bromoacetate (5.39 mL, 48.60 mmol) was added dropwise over 30 minutes at 0°C and stirred at room temperature for an additional 24 hours. The reaction was quenched with water (300 mL) and the product extracted into diethyl ether (2 x 150 mL). The combined diethyl ether layers were washed with water (50 mL), brine (50 mL), and dried (Na2SO4). The solvent was evaporated and the crude product was purified by silica gel column chromatography (hexane: EtOAc, 1:4) to give the title compound 9 (2.05 g, 32.4%) as a pale yellow solid. 1 H NMR (CDCl3): δ 7.97 (s,1H),7.62 (d,1H,J = 6.0 Hz),6.86 (dd,1H,J =3.0,6.0 Hz),6.68 (s,1H),5.12 (s,2H),4.24 (q,2H),3.90 (s,3H),1.28 (t,3H,J = 6.0 Hz); ESI-MS (m / z,%): 235 (MH + ,100).

[0283] Synthesis of 2-(6-methoxy-1H-indazol-1-yl)ethan-1-ol (10): A solution of ethyl 2-(6-methoxy-1H-indazol-1-yl)acetate (2.0 g, 8.54 mmol) in anhydrous THF (20 mL) was treated with DIBAL-H (23 mL, 34.15 mmol, 25% in toluene) dropwise over 20 min at 0 °C. The reaction was allowed to warm to room temperature and stirred for an additional 2 h. The reaction was quenched by the dropwise addition of saturated NH4Cl solution (25 mL) at 0 °C and diluted with ethyl acetate (150 mL). The solid was filtered off through a Celite pad and washed with ethyl acetate (2 × 50 mL). The combined ethyl acetate layers were evaporated, and the crude product was purified by silica gel flash column chromatography (EtOAc) to give the title compound 10 (1.64 g, 82%) as a beige solid.1 H NMR (CDCl3): δ 7.91 (s,1H),7.60 (d,1H,J = 6.0 Hz),6.84 (dd,1H,J = 1.5,6.0 Hz),6.77 (d,1H,J = 3.0 Hz),4.43-4.41 (m,2H),4.14-4.12 (m,2H),3.91 (s,3H),3.18 (brs,1H); ESI-MS (m / z,%): 263 (100),215 (M+Na),193 (MH + ).

[0284] 2-(6-Methoxy-1H-indazol-1-yl)ethyl methanesulfonate (11): A solution of 2-(6-methoxy-1H-indazol-1-yl)ethan-1-ol (1.6 g, 8.32 mmol) and EtN (1.73 mL, 12.48 mmol) in anhydrous CHCl (15 mL) was treated with MsCl (0.71 mL, 9.16 mmol) dropwise over 5 min at 0 °C. The reaction was allowed to warm to room temperature and stirred for an additional 1.5 h. The reaction was quenched with brine (25 mL) and the product extracted into CHCl (2 × 50 mL). The combined CHCl layers were dried (NaSO) and the solvent evaporated to give the crude title compound 11 (2.2 g), which was used directly without further purification.

[0285] Synthesis of 2-(6-methoxy-1H-indazol-1-yl)-N,N-dimethylethan-1-amine (12): A solution of the crude product, 2-(6-methoxy-1H-indazol-1-yl)ethyl methanesulfonate (2.2 g, 8.14 mmol) in anhydrous THF (30 mL) was treated with dimethylamine (82 mL, 162.78 mmol) and stirred in a sealed tube at 100° C. for an additional 15 h. The reaction was cooled to room temperature, the solvent was evaporated, and the crude product was purified by silica gel column chromatography (2 M NH in MeOH:CHCl, 3:97) to give the title compound 12 (1.66 g, 93% over two steps) as a pale yellow gum. 1H NMR (DMSO-d6): δ 7.91 (d,1H,J = 1.5 Hz),7.59 (dd,1H,J = 1.5,6.0 Hz),7.12 (d,1H,J = 3.0 Hz),6.75 (dd,1H,J = 1.5,6.0 Hz),4.43 (t,2H,J = 6.0 Hz),3.85 (s,3H),2.70 (t,2H,J = 6.0 Hz),2.18 (s,6H).

[0286] Example 5: 2-(6-Fluoro-1H-indazol-1-yl)-N,N-dimethylethan-1-amine (16) [ka] Synthesis of ethyl 2-(6-fluoro-1H-indazol-1-yl)acetate (13): A solution of 6-fluoro-1H-indazole (4.0 g, 29.39 mmol) in anhydrous DMF (50 mL) was treated with sodium hydride (1.92 g, 47.91 mmol, 60% in mineral oil) in small portions over 10 minutes at 0° C. The reaction was allowed to warm to room temperature and stirred for 30 minutes. Ethyl bromoacetate (5.87 mL, 52.90 mmol) was added in small portions over 30 minutes at 0° C. and stirred at room temperature for an additional 24 hours. The reaction was worked up and purified as described for compound 9 to give the title compound 13 (2.05 g, 31.4%) as a pale yellow solid. 1 ESI-MS (m / z,%): 223 (MH + ,100).

[0287] Synthesis of 2-(6-fluoro-1H-indazol-1-yl)ethan-1-ol (14): A solution of ethyl 2-(6-fluoro-1H-indazol-1-yl)acetate (2.04 g, 9.24 mmol) in anhydrous THF (20 mL) was treated with DIBAL-H (24.8 mL, 36.88 mmol, 25% in toluene) dropwise over 20 minutes at 0° C. The reaction was allowed to warm to room temperature and stirred for an additional 2 hours. The reaction was worked up and purified as described for compound 10 to give the title compound 14 (1.46 g, 88.5%) as a pale yellow solid. 1 H NMR (CDCl3): δ 8.00 (d,1H,J = 1.5 Hz),7.69 (dd,1H,J = 3.0,6.0 Hz),7.11 (dd,1H,J = 3.0,6.0 Hz),6.99-6.94 (m,1H),4.44-4.41 (m,2H),4.13 (t,2H,J = 6.0 Hz),2.96 (brs,1H); ESI-MS (m / z,%): 203 (M+Na),181 (MH + ,100).

[0288] Synthesis of 2-(6-fluoro-1H-indazol-1-yl)ethyl methanesulfonate (15): A solution of 2-(6-fluoro-1H-indazol-1-yl)ethan-1-ol (1.43 g, 7.94 mmol) and EtN (1.65 mL, 11.91 mmol) in anhydrous CHCl (15 mL) was treated with MsCl (0.68 mL, 8.73 mmol) dropwise over 5 min at 0 °C. The reaction was allowed to warm to room temperature and stirred for an additional 1.5 h. The reaction was worked up as described for compound 11 to give the crude title compound 15 (2.0 g), which was used directly without further purification.

[0289] Synthesis of 2-(6-fluoro-1H-indazol-1-yl)-N,N-dimethylethan-1-amine (16): A solution of the crude 2-(6-fluoro-1H-indazol-1-yl)ethyl methanesulfonate (2.0 g, 7.74 mmol) in anhydrous THF (30 mL) was treated with dimethylamine (77 mL, 154.87 mmol) and stirred in a sealed tube at 100° C. for an additional 15 hours. The reaction was cooled to room temperature and worked up and purified as described for compound 12 to give the title compound 16 (1.4 g, 84.7% over two steps) as a pale yellow sticky material. 1 H NMR (DMSO-d6): δ 8.07 (d,1H,J = 1.5 Hz),7.78 (dd,1H,J = 3.0,6.0 Hz),7.60-7.56 (m,1H),7.03-6.98 (m,1H),4.45 (t,2H,J = 6.0 Hz),2.69 (t,2H,J = 6.0 Hz),2.16 (s,6H).

[0290] Example 6: 2-(6-Methoxy-1H-indazol-1-yl)-N,N-bis(methyl-d3)ethan-1-amine (I-6) [ka] Synthesis of 2-(6-methoxy-1H-indazol-1-yl)ethyl methanesulfonate (11): The title compound was prepared as described above starting from 2-(6-methoxy-1H-indazol-1-yl)ethan-1-ol (1.1 g, 5.72 mmol). The crude product was used in the next step without further purification.

[0291] 2-(6-Methoxy-1H-indazol-1-yl)-N,N-bis(methyl-d3)ethan-1-amine (I-6): A suspension of the crude 2-(6-methoxy-1H-indazol-1-yl)ethyl methanesulfonate, KCO (2.37 g, 17.17 mmol), bis(methyl-damine hydrochloride (1.0 g, 11.45 mmol), and DMF (0.3 mL) in anhydrous ACN (50 mL) was stirred overnight (16 h) in a sealed tube at 70° C. The reaction was cooled to room temperature and worked up and purified as described for compound 12 to afford the title compound I-6 (0.8 g, 62% over two steps) as a pale yellow gum. 1 H NMR (DMSO-d6): δ 7.91 (d,1H,J = 1.5 Hz),7.59 (d,1H,J = 6.0 Hz),7.12 (d,1H,J = 1.5 Hz),6.75 (dd,1H,J = 1.5,6.0 Hz),4.42 (t,2H,J = 6.0 Hz),3.85 (s,3H),2.69 (t,2H,J = 6.0 Hz); ESI-MS (m / z,%): 226 (MH + ,100).

[0292] Example 7: 2-(6-Fluoro-1H-indazol-1-yl)-N,N-bis(methyl-d3)ethan-1-amine (I-119) [ka] Synthesis of 2-(6-fluoro-1H-indazol-1-yl)ethyl methanesulfonate (17): The title compound was prepared as described above starting from 2-(6-fluoro-1H-indazol-1-yl)ethan-1-ol (0.92 g, 5.10 mmol). The crude product was used in the next step without further purification.

[0293] Synthesis of 2-(6-fluoro-1H-indazol-1-yl)-N,N-bis(methyl-d3)ethan-1-amine (I-119): A suspension of the crude 2-(6-fluoro-1H-indazol-1-yl)ethyl methanesulfonate, KCO (2.12 g, 15.32 mmol), bis(methyl-damine hydrochloride (0.89 g, 10.21 mmol), and DMF (0.3 mL) in anhydrous ACN (50 mL) was stirred overnight (16 h) in a sealed tube at 70° C. The reaction was cooled to room temperature and worked up and purified as described for compound 12 to afford the title compound I-119 (0.66 g, 60.5% over two steps) as a pale yellow oil. 1 H NMR (DMSO-d6): δ 8.07 (d,1H,J = 1.5 Hz),7.77 (dd,1H,J = 3.0,6.0 Hz),7.58 (dd,1H,J = 1.5,6.0 Hz),7.03-6.98 (m,1H),4.44 (t,2H,J = 6.0 Hz),2.69 (t,2H,J = 6.0 Hz); ESI-MS (m / z,%): 214 (MH+,100).

[0294] Example 8: (R)-6-Methoxy-1-(pyrrolidin-2-ylmethyl)-1H-indazole hydrochloride ((R)-I-121.HCl) [ka] Synthesis of tert-butyl (R)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (20): The title compound was prepared starting from tert-butyl (R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (5.43 g, 26.99 mmol) as described for compound 11. The crude product was used in the next step without further purification.

[0295] Synthesis of tert-butyl (R)-2-((6-methoxy-1H-indazol-1-yl)methyl)pyrrolidine-1-carboxylate (21): A solution of 6-methoxy-1H-indazole (2.0 g, 13.50 mmol) in anhydrous DMF (50 mL) was treated with sodium hydride (2.16 g, 53.99 mmol, 60% in mineral oil) in small portions over 10 minutes at 0° C. The reaction was allowed to warm to room temperature and stirred for 30 minutes. The crude product, tert-butyl (R)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate, in anhydrous DMF (25 mL) was added dropwise over 30 minutes at 0° C. and stirred at room temperature for an additional 24 hours. The reaction was worked up and purified as described for compound 9 to give the title compound 21 (1.5 g, 33.5% over two steps) as a pale yellow oil. ESI-MS (m / z, %): 354 (M+Na), 332 (MH + ,100).

[0296] Synthesis of (R)-6-methoxy-1-(pyrrolidin-2-ylmethyl)-1H-indazole hydrochloride ((R)-I-121.HCl): A solution of tert-butyl (R)-2-((6-methoxy-1H-indazol-1-yl)methyl)pyrrolidine-1-carboxylate (1.5 g, 4.53 mmol) in anhydrous diethyl ether (20 mL) was treated with 2 M HCl in diethyl ether (45.3 mL, 90.52 mmol) at room temperature. The reaction was stirred at 50° C. in a sealed tube for an additional 24 hours. The reaction was cooled to room temperature, and the solid was filtered off and washed with ether. The solid was dried under high vacuum to give the title compound (R)-I-121.HCl (1.11 g, 91.7%) as an off-white solid. 1 H NMR (DMSO-d6): δ 8.03 (d,1H,J = 1.5 Hz),7.64 (d,1H,J = 6.0 Hz),7.41 (d,1H,J = 3.0 Hz),6.80 (dd,1H,J = 3.0,6.0 Hz),5.81 (brs,2H),4.82-4.68 (m,2H),3.94-3.91 (m,1H),3.88 (s,3H),3.31-3.09 (m,2H),2.10-1.71 (m,4H); ESI-MS (m / z,%): 232 (MH +,100,free base).

[0297] Example 9: (R)-6-Fluoro-1-(pyrrolidin-2-ylmethyl)-1H-indazole hydrochloride ((R)-I-120.HCl) [ka] Synthesis of tert-butyl (R)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (20): The title compound was prepared starting from tert-butyl (R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (5.9 g, 29.39 mmol) as described for compound 11. The crude product was used in the next step without further purification.

[0298] Synthesis of tert-butyl (R)-2-((6-fluoro-1H-indazol-1-yl)methyl)pyrrolidine-1-carboxylate (23): A solution of 6-fluoro-1H-indazole (2.0 g, 14.69 mmol) in anhydrous DMF (50 mL) was treated with sodium hydride (2.35 g, 58.78 mmol, 60% in mineral oil) in small portions over 10 minutes at 0° C. The reaction was allowed to warm to room temperature and stirred for 30 minutes. A solution of the crude product, tert-butyl (R)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate, in anhydrous DMF (25 mL) was added dropwise over 30 minutes at 0° C. and stirred at room temperature for an additional 24 hours. The reaction was worked up and purified as described for compound 9 to give the title compound 23 (2.6 g, 55.4% over two steps) as a pale yellow oil. ESI-MS (m / z, %): 320 (MH + ,100).

[0299] Synthesis of (R)-6-fluoro-1-(pyrrolidin-2-ylmethyl)-1H-indazole hydrochloride ((R)-I-120.HCl): A solution of tert-butyl (R)-2-((6-fluoro-1H-indazol-1-yl)methyl)pyrrolidine-1-carboxylate (1.6 g, 5.01 mmol) in anhydrous diethyl ether (20 mL) was treated with 2 M HCl in diethyl ether (50.0 mL, 100.19 mmol) at room temperature. The reaction was stirred at 50° C. in a sealed tube for an additional 24 hours. The reaction was cooled to room temperature, and the solid was filtered off and washed with ether. The solid was dried under high vacuum to give the title compound (R)-I-120.HCl) (1.0 g, 78%) as an off-white solid. 1 H NMR (DMSO-d6): δ 8.20 (d,1H,J = 1.5 Hz),7.86-7.77 (m,2H),7.09-7.04 (m,1H),6.23 (brs,2H),4.85-4.70 (m,2H),3.96-3.92 (m,1H),3.31-3.25 (m,1H),3.16-3.11 (m,1H),2.08-1.69 (m,4H); ESI-MS (m / z,%): 220 (MH + ,100,free base).

[0300] B. Biological Testing Example 10: Human 5-HT2A: Functional FLIPR Assay the purpose: The potential excitatory effects of exemplary compounds of the present application targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A) in the agonist mode were evaluated. 1 Materials and equipment [Table 22] [Table 23] [Table 24]

[0301] 2.1 Cell culture HTR2A&Gα15-HEK293 cells were cultured in DMEM medium containing 10% dialyzed FBS, 1x penicillin-streptomycin, 100 μg / mL hygromycin B, and 300 μg / mL G418. Cells were subcultured approximately three times a week and maintained at approximately 30% to 90% confluence.

[0302] 2.2 Cell plating 1. Cell culture medium (DMEM medium containing 10% dialyzed FBS and 1× penicillin-streptomycin, 100 μg / mL hygromycin B, and 300 μg / mL G418), TrypLE™ Express, and DPBS were pre-warmed to room temperature.

[0303] 2. For expression induction, 1 μg / ml tetracycline (final concentration) was added to the cell culture medium and incubated at 37°C, 5% (v / v) CO2 for 48 hours before seeding the cells on plates. The cell culture medium was removed from the flasks. The cells were washed with DPBS.

[0304] 3. 2 mL of TrypLE™ Express was added to the flask, gently shaken to mix well, and the cells were incubated at 37° C. for a few minutes.

[0305] 4. The morphological changes of the cells were confirmed under a microscope, and when the majority of the cells had become round, 4 mL of cell culture medium was added to the flask to stop the digestion.

[0306] 5. The cell suspension was transferred to a 15 mL centrifuge tube and then centrifuged at 1,200 rpm for 5 minutes.

[0307] 6. The supernatant was removed and the cell pellet was resuspended in 2 mL of cell culture medium.

[0308] 7. Cell density was counted using a cell counter. Only cells with viability greater than 85% were used in the assay.

[0309] 8. The cells were diluted to 6.67 x 105 / mL using cell culture medium.

[0310] 9. 30 μL / well of the cell suspension was added to a 384-well cell plate (cell density was 20,000 cells / well).

[0311] 10. The cell plates were incubated overnight at 37°C under 5% (v / v) CO2.

[0312] 2.3 Cell handling 1. On the day of the experiment, the culture medium was removed from the cell plates.

[0313] 2. 10 μL of assay buffer (20 mM HEPES in 1×HBSS, pH 7.4) was added to each well of the cell plate.

[0314] 3. 2x dye solution was prepared according to the FLIPR® Calcium 6 Assay Kit manual:

[0315] i. The dye was diluted using assay buffer.

[0316] ii. Probenecid was added to a final concentration of 5 mM.

[0317] iii. Vortex vigorously for 1-2 minutes.

[0318] 4. 10 μL of 2× dye solution was added to each well of the cell plate.

[0319] 5. The cell plate was placed on a plate shaker and then shaken at 600 rpm for 2 minutes.

[0320] 6. The plate was incubated at 37°C for 2 hours, followed by an additional 15 minutes at 25°C.

[0321] 2.4 Preparation of 3x Compound 1. Serotonin HCl was prepared at a concentration of 10 mM using DMSO.

[0322] 2. Test compounds were prepared at a concentration of 10 mM using DMSO.

[0323] 3. Compounds were added to a 384-well compound source plate.

[0324] 4. 3-fold serial dilutions were performed using DMSO.

[0325] 5. Using the Echo, 90 nL / well of serially diluted compounds was transferred from the source plate to the 384-well compound plate.

[0326] 6. 30 μL / well of assay buffer (20 mM HEPES / 1×HBSS, pH 7.4) was added to the compound plate.

[0327] 7. The plate was mixed on a plate shaker for 2 minutes.

[0328] 2.5 FLIPR assay 1. After incubating the cells with the dye solution, the cell plate, the compound plate containing 3x compounds and the FLIPR chip were subjected to FLIPR.

[0329] 2. 10 μL of 3× compound was transferred from the compound plate to the cell plate by FLIPR.

[0330] 3. The plate was read at 1 second intervals for 160 seconds to obtain agonist mode data.

[0331] 3. Data analysis 1. Normalized fluorescence readings (RFU) were calculated as follows, where Fmax and Fmin represent the maximum and minimum values ​​of calcium signal within a given time period: RFU=Fmax-Fmin

[0332] 2. EC2 obtained by fitting the RFU to the logarithm of the compound concentration to the Hill equation 50 was calculated using XLfit.

[0333] Results and Discussion The results of the competitive binding ability of the exemplary compounds of the present application targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A) are summarized in Table 2. The results of the exemplary compounds of the present application are shown in the IC 50 is presented as. [Table 25]

[0334] Exemplary compounds of Formula I were evaluated using a radioligand binding assay for the human 5-HT2A receptor. The EC50 (nM) concentrations are shown in Table 2. This assay confirms that the exemplary compounds of the present application are effective ligands for the target human 5-HT2A receptor.

[0335] Example 11: Human 5-HT2A: Radioligand Binding Assay: the purpose The purpose of this study was to evaluate the binding of exemplary compounds of Formula I to the 5-hydroxytryptamine receptor 2A (5-HT2A). 1 Materials and equipment [Table 26] [Table 27]

[0336] 2. Experimental Method 1. Assay buffer was prepared according to the table below. [Table 28]

[0337] 2. Eight doses of reference and test compounds were prepared by 5-fold serial dilutions with 100% (v / v) DMSO, starting from the required stock solution of 10 mM.

[0338] 3. UniFilter-96 GF / B plates were pretreated:

[0339] 50 μl / well of 0.5% (v / v) PEI was added to a UniFilter-96 GF / C plate, which was sealed and incubated at 4° C. for 3 hours.

[0340] ii. After incubation, the plates were washed three times with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0341] 4. Assay plates were prepared:

[0342] i. Cell membranes were diluted in assay buffer and added to a 96-well round-bottom plate at 330 μl / well to reach a concentration of 20 μg / well.

[0343] ii. Eight concentrations of reference or test compounds were prepared and added at 110 μl / well to a 96 deep-well round-bottom plate.

[0344] iii. [3H]-Ketanserin was diluted in assay buffer to 5 nM (5x final concentration) and added at 110 μl / well to a 96 deep well round bottom plate.

[0345] 5. The plate was centrifuged at 1000 rpm for 30 seconds, then agitated at 600 rpm for 5 minutes at room temperature.

[0346] 6. The plate was sealed and incubated at 27°C for 90 minutes.

[0347] 7. The incubation was terminated by vacuum filtration onto GF / B filter plates, followed by four washes with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0348] 8. The plates were dried at 37°C for 45 minutes.

[0349] 9. The filter plate was sealed and 40 μl / well of scintillation cocktail was added.

[0350] 10. Microbeta 2 The plates were read using a microplate counter.

[0351] 3. Data analysis 1. For reference and test compounds, the results were expressed as % inhibition using the normalization formula: N = 100-100 × (U-C2) / (C1-C2), where U is the unknown value, C1 is the mean value of the high control, and C2 is the mean value of the low control.

[0352] 2. Use XLfit to fit the Hill equation with % inhibition as a function of compound concentration to obtain the IC 50 It was decided that:

[0353] Results and Discussion The results of the competitive binding ability of the exemplary compounds of the present application targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A) are summarized in Table 3. The results of the exemplary compounds of the present application are shown in the IC 50 is presented as. [Table 29]

[0354] II. Results and Discussion Exemplary compounds of Formula I were evaluated using a radioligand binding assay for the human 5-HT2A receptor. IC50 (nM) concentrations are shown in Table 3. This assay confirms that the compounds of the present application are effective ligands for the target human 5-HT2A receptor.

[0355] Example 12: Human 5-HT1A: Functional FLIPR Assay 1 purpose The potential excitatory effects of exemplary compounds of the present application, which target the 5-hydroxytryptamine receptor 1A (5-HT1A) in the agonist mode, were evaluated. 2 Materials and equipment [Table 30] [Table 31] [Table 32]

[0356] 3 Experimental Method 3.1 Cell culture HTR1A&Gα15-CHO cells were cultured in DMEM / F12 medium containing 10% dialyzed FBS, 1x penicillin-streptomycin, and 600 μg / mL hygromycin B. Cells were subcultured approximately three times a week and maintained at approximately 30% to 90% confluence.

[0357] 3.2 Cell plating 1. Cell culture medium (DMEM / F12 medium containing 10% dialyzed FBS, 1× penicillin-streptomycin, and 600 μg / mL hygromycin B), TrypLE™ Express, and DPBS were pre-warmed to room temperature.

[0358] 2. The cell culture medium was removed from the flask. The cells were washed with DPBS.

[0359] 3. 1 mL of TrypLE™ Express was added to the flask, gently shaken to mix well, and the cells were incubated at 37°C for a few minutes.

[0360] 4. The morphological changes of the cells were confirmed under a microscope, and when the majority of the cells had become round, the digestion was stopped by adding 2 mL of cell culture medium.

[0361] 5. The cell suspension was transferred to a 15 mL centrifuge tube and then centrifuged at 1,200 rpm for 5 minutes.

[0362] 6. The supernatant was removed and the cell pellet was resuspended in 2 mL of cell culture medium.

[0363] 7. Cell density was counted using a cell counter. Only cells with viability above 85% were used in the assay.

[0364] 8. The cells were diluted to 4 x 105 / mL using cell culture medium.

[0365] 9. 30 μL / well of the cell suspension was added to a 384-well cell plate (cell density was 12,000 cells / well).

[0366] 10. The cell plates were incubated overnight at 37°C under 5% (v / v) CO2.

[0367] 3.3 Cell handling 1. On the day of the experiment, the culture medium was removed from the cell plates.

[0368] 2. 10 μL of assay buffer (20 mM HEPES in 1×HBSS, pH 7.4) was added to each well of the cell plate.

[0369] 3. Prepare 2x dye solution according to the FLIPR® Calcium 6 Assay Kit product instructions:

[0370] i. The dye was diluted in assay buffer.

[0371] ii. Probenecid was added to a final concentration of 5 mM.

[0372] iii. Vortex vigorously for 1-2 minutes and adjust the pH to 7.4.

[0373] 4. 10 μL of 2× dye solution was added to each well of the cell plate.

[0374] 5. The cell plate was placed on a plate shaker and then shaken at 600 rpm for 2 minutes.

[0375] 6. The plate was incubated at 37°C for 2 hours, followed by an additional 15 minutes at 25°C.

[0376] 3.4 Preparation of 3x Compound 1. Serotonin was prepared at a concentration of 10 mM using DMSO, and serially diluted 3-fold using DMSO.

[0377] 2. A test compound was prepared at 10 mM using DMSO, and a 3-fold dilution series was prepared in advance using DMSO.

[0378] 3. Compounds were added to a 384-well compound source plate.

[0379] 4. Using the Echo, 90 nL / well of serially diluted compounds was transferred from the source plate to the 384-well compound plate.

[0380] 5. 30 μL / well of assay buffer was added to the compound plate.

[0381] 6. The plate was mixed on a plate shaker for 2 minutes.

[0382] 3.5 FLIPR assay 1. After incubating the cells with the dye solution, the cell plate, the compound plate containing 3x compound and the FLIPR chip were subjected to FLIPR.

[0383] 2. 10 μL of 3× compound was transferred from the compound plate to the cell plate by FLIPR.

[0384] 3. The plate was read at 1 second intervals for 160 seconds to obtain agonist mode data.

[0385] 4. Data analysis 1. Normalized fluorescence readings (RFU) were calculated as follows: where Fmax and Fmin represent the maximum and minimum values ​​of calcium signal within a given time period. RFU=Fmax-Fmin

[0386] 2. EC 50 was calculated by fitting the RFU to the logarithm of the compound concentration to the Hill equation using XLfit.

[0387] Results and Discussion The results of the competitive binding ability of the exemplary compounds of the present application targeting the human 5-hydroxytryptamine receptor 1A (5-HT1A) are summarized in Table 4. The results of the exemplary compounds of the present application are summarized in Table 4. 50 is presented as. [Table 33]

[0388] Exemplary compounds of Formula I were evaluated using a functional FLIPR assay against the human 5-HT1A receptor. EC 50 Concentrations (nM) are shown in Table 4. This assay confirms that the compounds of the present application have moderate functional activity at the target human 5-HT1A receptor.

[0389] Example 13: Human 5-HT1A: Radioligand Binding Assay: 1 purpose The purpose of this study was to evaluate the binding of test compounds to the 5-hydroxytryptamine receptor 1A (5-HT1A). 2 Materials and equipment [Table 34] [Table 35]

[0390] 3 Experimental Method 1. Assay buffer was prepared according to the table below. [Table 36]

[0391] 2. Eight doses of the reference and test compounds were prepared by 5-fold serial dilutions starting from a 10 mM stock solution with 100% (v / v) DMSO.

[0392] 3. UniFilter-96 GF / B plates were pretreated:

[0393] 50 μl / well of 0.5% (v / v) PEI was added to a UniFilter-96 GF / B plate, which was then sealed and incubated at 4° C. for 3 hours.

[0394] ii. After incubation, the plates were washed three times with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0395] 4. Assay plates were prepared:

[0396] i. Cell membranes were diluted in assay buffer and 100 μl / well was added to a 96-well round-bottom plate to give a concentration of 20 μg / well.

[0397] ii. Eight concentrations of reference or test compounds were prepared and 50 μl / well was added to a 96 deep-well round-bottom plate.

[0398] iii. [3H]-8-hydroxy-DPAT was diluted to 2 nM (4x final concentration) in assay buffer and 50 μl / well was added to a 96-well round-bottom plate.

[0399] 5. The plate was centrifuged at 1000 rpm for 30 seconds, then agitated at 600 rpm for 5 minutes at room temperature.

[0400] 6. The plate was sealed and incubated at 27°C for 90 minutes.

[0401] 7. The incubation was stopped by vacuum filtration onto GF / B filter plates, followed by four washes with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0402] 8. The plates were dried at 37°C for 45 minutes.

[0403] 9. The filter plate was sealed and 40 μl / well of scintillation cocktail was added.

[0404] 10. Microbeta 2 Plates were read using a microplate counter.

[0405] 4. Data analysis 1. For reference and test compounds, results were expressed as % inhibition using the normalization formula: N=100-100×(U-C2) / (C1-C2), where U is the unknown, C1 is the mean value of the high control, and C2 is the mean value of the low control.

[0406] 2. Using XLfit, calculate the IC by fitting the Hill equation as % inhibition versus bound compound concentration. 50 It was decided that:

[0407] Results and Discussion The competitive binding ability results of exemplary prodrug compounds of the present application targeting the human 5-hydroxytryptamine receptor (5-HT1A) are summarized in Table 5. The results of exemplary compounds of the present application are shown in the IC 50 is presented as. [Table 37]

[0408] Results and Discussion Exemplary compounds of Formula I were evaluated using a radioligand binding assay for the human 5-HT1A receptor. IC 50 Concentrations (nM) are shown in Table 5. This assay confirms that the compounds of the present application are effective ligands of the target human 5-HT1A receptor.

[0409] Example 14: Human, rat and mouse liver microsome stability the purpose The purpose of this study was to estimate the in vitro metabolic stability of exemplary compounds of the present application in pooled liver microsomes from humans, male rats, and male mice. To estimate stability in pooled liver microsomes from humans, male rats, and male mice, the concentration of the compound in the reaction system was assessed by LC-MS / MS. The in vitro intrinsic clearance of the test compound was also determined.

[0410] protocol A master solution containing phosphate buffer, ultrapure water, MgCl2 solution, and liver microsomes was made in an "incubation plate" according to Table 6. The mixture was pre-warmed in a 37°C water bath for 5 minutes. [Table 38]

[0411] To each well, 40 μL of 10 mM NADPH solution was added. The final concentration of NADPH was 1 mM. A negative control sample was prepared by replacing NADPH with 40 μL of ultrapure water. Samples were prepared in duplicate. One negative control was prepared.

[0412] Reactions were initiated by adding 4 μL of 200 μM of an exemplary test compound of the present application or a control compound to each master solution for a final concentration of 2 μM. The test was performed in duplicate.

[0413] At 0, 15, 30, 45, and 60 minutes, 50 μL aliquots were removed from the reaction mixture. The reaction mixture was stopped by adding four volumes of cold methanol containing IS (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol, and 2 μM ketoprofen). The samples were centrifuged at 3,220 g for 40 minutes. A 90 μL aliquot of the supernatant was mixed with 90 μL of ultrapure water and then used for LC-MS / MS analysis.

[0414] LC / MS analysis of all samples in this study was performed using a Shimadzu liquid chromatographic separation system equipped with a degasser DGU-20A5R, a solvent delivery unit LC-30AD, a system controller SIL-30AC, a column oven CTO-30A, and a CTC analytical HTC PAL system. Mass spectrometry was performed using a Triple Quad™ 5500 instrument.

[0415] All calculations were performed using Microsoft Excel. Peak area ratios of test compounds relative to internal standards (listed in the table below) were determined from extracted ion chromatograms.

[0416] All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The slope value k was determined by linear regression of the curve of the natural logarithm of the percentage of parent drug remaining versus incubation time.

[0417] The in vitro half-life (in vitro t) was determined from the slope value: In vitro 1 / 2 =-(0.693 / k)

[0418] Conversion of in vitro t (min) to in vitro intrinsic clearance (in vitro CLint, μL / min / mg protein) was performed using the following formula (mean of duplicate determinations):

number

[0419] For exemplified compounds or control compounds of the present application that showed an initial rapid elimination followed by a slower elimination, only time points within the initial rate were included in the calculations.

[0420] Results and Discussion Human, rat, and mouse liver microsomes contain various drug-metabolizing enzymes and are commonly used to support in vitro ADME (absorption, distribution, metabolism, and excretion) studies. These microsomes are used to examine potential first-pass metabolic byproducts of orally administered drugs. Exemplary compounds of the present application were evaluated for their stability in human, rat, and mouse liver microsomes.

[0421] In liver microsomes from two species, human and rat, the majority of exemplary compounds of the present application were recovered within 60 minutes, indicating that they were not rapidly cleared (see Table 7 for exemplary compounds of Formula I). [Table 39] [Table 40]

[0422] Consideration: The results show that the exemplary compounds exhibited a wide range of stability at the 30 and 60 minute time points.

[0423] Example 15: Human, rat, mouse and dog: plasma stability 1. Preparation of Stock Solutions

[0424] Stock solutions of test compounds are prepared in DMSO and diluted to a final concentration of 200 μM. 1 mM working solutions of lovastatin and propantheline are prepared in DMSO and acetonitrile, respectively. Lovastatin is used as a positive control for rat and dog plasma stability assays. Propantheline is used as a positive control in human, mouse, and monkey plasma stability assays.

[0425] 2. Plasma Stability Procedures

[0426] 2.5 μL of a 200 μM or 1 mM solution of test or control compound is mixed with 497.5 μL of plasma to give a final concentration of 1 μM or 5 μM. The final concentration of organic solvent is 0.5%. Assays are performed in duplicate.

[0427] b. Incubate the reaction samples in a water bath at 37°C at approximately 60 rpm.

[0428] c. 50 μL aliquots were removed from the reaction samples at 0, 30, 60, 120, 180, and 240 min. The reactions were stopped by adding 7 volumes of cold acetonitrile containing internal standards (IS: 100 nM alprazolam, 200 nM imipramine, 200 nM labetalol, and 2 μM ketoprofen).

[0429] 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 according to the LC-MS signal response and peak shape.

[0430] 3. Sample Analysis

[0431] Samples are analyzed by LC-MS / MS. LC system: Shimadzu MS analysis: Triple Quad™ 6500+ with ESI interface manufactured by AB Inc. (Canada) Column temperature: 40℃ Column: Xselect® Hss T3 2.5μ (2.1 x 30 mm) with pre-guard column Mobile phase: water containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B) [Table 41]

[0432] 4. Data Analysis

[0433] All calculations are performed using Microsoft Excel. The percentage of parent compound remaining at each time point is estimated by determining peak area ratios from extracted ion chromatograms.

[0434] Although the present application has been described with reference to examples, it should be understood that the scope of the claims is not limited to the embodiments set forth in the examples, but should be accorded the broadest interpretation consistent with the entire description.

[0435] All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entireties, and the disclosures of these publications are incorporated by reference in their entireties into this application in order to more fully describe the state of the art that is known to those skilled in the art as of the date of the application described and claimed herein.

Claims

1. Formula I: 【Chemistry 1】 Compounds thereof, or their pharmaceutically acceptable salts, solvates, and / or prodrugs [In the formula: R １ H, Halo, NH ２ , C １～６ Alkyl, C １～６ Alkoxyl, NH(C) １～６ Alkyl) and N(C) １～６ Alkyl) ２ Selected from; Q consists of Q1, Q3, Q4, Q5, and Q6: 【Chemistry 2】 Selected from, structure: 【Transformation 3】 This is a single bond or a double bond, provided that the structure in Q1 is: 【Chemistry 4】 is a double bond, R ８ and R １４ do not exist, and the structure in Q6 is: 【Transformation 5】 However, if it is a double bond, R ５３ and R ６２ It does not exist; R ２ H, OH, C １～６ Alkyl and C １～６ Selected from alkoxy; R ５ H, Halo, OH, C １～６ Alkyl and C １～６ Selected from alkoxy; R ３ and R ４ One or both of these independently constitute H, Halo, and C. １～６ Alkyl and C １～６ Selected from alkoxy, or R ３ and R ４ They come together as O-(CH ２ ) １～２ To form O, or R ３ and R ４ One of them is selected from X-L-A, R ３ and R ４ The other is H, Halo, C １～６ Alkyl and C １～６ Selected from alkoxy; X is 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 Selected from; L is directly bonded, 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 Alkilen NR ｂ C(O), C ２～６ Alkenirene 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 Alkilen NR ｂ C(O)O, C ２～６ Alkenirene NR ｂ C(O)O, C １～６ Alkylene OC(O)O, C ２～６ Alkenylene OC(O)O, C １～６ Alkilen NR ｂ C(O)NR ｂ and C ２～６ Alkenirene NR ｂ C(O)NR ｂ Selected from; R ａ H and C １～６ Selected from alkyl groups; R ｂ H, C １～６ Selected from alkyl and A; A is H, C １～３０ Alkyl, C ２～３０ Alkenyl, phenyl, C ３～６ Cycloalkyls, as well as O, S, S(O), SO ２ , N and NR ５３ 3-6 membered heterocycloalkyls containing 1-4 heteromolets independently selected from, as well as O, S, S(O), SO ２ , N and NR ６３ Selected from a 5-6 member heteroaryl compound containing 1-4 heteromoles independently selected from, where phenyl, C ３～６ Cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl compounds are halo, OH, C １～４ Alkyl and OC １～４ It may be appropriately substituted with one or more substituents independently selected from the alkyl group; R ７ 、 R ８ 、 R ９ 、 R １０ 、 R １２ 、 R １３ 、 R １４ 、 R ２５ 、 R ２６ 、 R ２７ 、 R ２８ 、 R ３１ 、 R ３２ 、 R ３３ 、 R ３５ 、 R ３６ 、 R ３７ 、 R ３８ 、 R ３９ 、 R ４０ 、 R ４１ 、 R ４２ 、 R ４３ 、 R ４５ 、 R ４６ 、 R ４７ 、 R ４８ 、 R ４９ 、 R ５０ 、 R ５１ 、 R ５２ 、 R ５３ 、 R ５４ 、 R ５５ 、 R ５７ 、 R ５８ 、 R[[ID=7I3]] ５９ 、 R ６０ 、 R ６１ 、および R ６２ は独立して、 H、ハロおよび C １～６ アルキルから選択され; R １１ , R ３４ , R ４４ and R ５６ H and C are independent of each other. １～６ Alkyl and C(O)C １～６ Selected from alkyl groups; R ２９ C １～６ It is alkyl, R ３０ H and C are independent of each other. １～６ Selected from alkyl groups; or R ２９ is C(O)-A', and R ３０ H and C １～６ Selected from alkyl groups; Here, A' is Y, O-Y, and O-C １～４ Selected from alkylene-O-C(O)-Y; Y is C ７～３０ Alkyl and C ７～３０ Selected from Alkenil; or R ２９ and R ３０ These, together with the nitrogen atoms to which they are bonded, form O, S, S(O), SO ２ , N, and NR ６４ It may optionally include one or two additional heteromotors selected independently of the above, such as halo, OH, and C. １～４ Alkyl and OC １～４ It forms a 3- to 6-membered heterocyclic ring which may be appropriately substituted with one or more substituents independently selected from the alkyl; R ６３ and R ６４ H and C are independent of each other. １～６ Selected from alkyl groups; All available hydrogen atoms may be independently substituted with fluorine or chlorine atoms as appropriate, and all available atoms may be substituted with their alternative isotopes as appropriate. However, if Q is Q3; R ２ , R ３ , R ４ , R ５ , R ２５ , R ２６ , R ２７ , R ２８ , R ２９ and R ３０ At least one of them is D, or includes D, or R ２ , R ３ , R ４ , R ５ At least one of them is an alkyl group substituted with one or more fluorine and / or chlorine atoms; or R ２ , R ３ , R ４ , R ５ At least three of them are not H; or If Q is Q3; R ３ and R ４ They come together as O-(CH ２ ) １～２ To form O; or If Q is Q3; R ３ and R ４ One of them is selected from X-L-A, R ３ and R ４ The other is H, Halo, C １～６ Alkyl and C １～６ Selected from alkoxy; and A is H, C １～６ Alkyl or C ２～６ Not Alkenil; If Q is Q1 or Q4, then R ３ and R ４ One of them is Halo, and R ３ and R ４ If the other is H, then R ７ ~R １４ or R ３１ ~R ４０ Each of these is not entirely H.

2. R ７ , R ８ , R ９ , R １０ , R １２ , R １３ , R １４ , R ２５ , R ２６ , R ２７ , R ２８ , R ３１ , R ３２ , R ３３ , R ３５ , R ３６ , R ３７ , R ３８ , R ３９ , R ４０ , R ４１ , R ４２ , R ４３ , R ４５ , R ４６ , R ４７ , R ４８ , R ４９ , R ５０ , R ５１ , R ５２ , R ５３ , R ５４ , R ５５ , R ５７ , R ５８ , R ５９ , R ６０ , R ６１ and R ６２ A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, wherein H and D are independently selected.

3. Q is based on the following: 【Transformation 6】 【Transformation 7】 A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, selected from one of the following: [In the formula, R １１ , R ３４ , R ４４ and R ５６ These are H, D, and C, independently. １～６ Alkyl, C １～６ Fluoroalkyl, C １～６ Deuteroalkyl and C(O)-C １ ~C ６ Selected from alkyl groups; R ２９ C １～６ Alkyl, C １～６ Fluoroalkyl and C １～６ Selected from deuteroalkyl groups, R ３０ H, D, C １～６ Alkyl, C １～６ Fluoroalkyl and C １～６ Selected from deuteroalkyl groups; or R ２９ is C(O)-A', and R ３０ H, D, C １～６ Alkyl, C １～６ Fluoroalkyl and C １～６ [Selected from deuteroalkyl groups].

4. R １１ , R ３０ , R ３４ , R ４４ and R ５６ H and C became independent. １～４ Alkyl, C １～４ Fluoroalkyl and C １～４ Selected from deuteroalkyl groups, R ２９ However, C １～４ Alkyl, C １～４ Fluoroalkyl and C １～４ A compound according to claim 3, selected from deuteroalkyls, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

5. Q is Q3, and R ２９ and R ３０ However, together with the nitrogen atom to which they are bonded, O, N and NR ６４ It includes one or two additional heteroparts independently selected from, halo, OH, C １～４ Alkyl and OC １～４ The compound according to claim 3, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, which forms a 3- to 6-membered heterocyclic ring that may be optionally substituted with one or more substituents independently selected from the alkyl group.

6. Q is based on the following: 【Transformation 8】 A compound according to claim 3, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, selected from one of the above. [In the formula, R ３４ H, D, C １～６ Alkyl, C １～６ Fluoroalkyl, C １～６ Selected from deuteroalkyl and C(O)-A'.

7. Q is Q3, and R ２９ However, C(O)-A' and R ３０ However, H and C １～６ A compound according to claim 1, selected from alkyl groups, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

8. R １ But, H, Halo, NH ２ , C １～４ Alkyl, C １～４ Alkoxy, NH(C) １～４ Alkyl) and N(C) １～４ Alkyl) ２ A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, selected from the above.

9. R ２ However, H, D, OH, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Fluoroalkyl, C １～４ Deuteroalkyl, C １～４ Deuteroalkoxy and C １～４ Selected from fluoroalkoxys, R ５ However, H, D, Cl, F, OH, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Fluoroalkyl, C １～４ Deuteroalkyl, C １～４ Deuteroalkoxy and C １～４ A compound according to claim 1, selected from fluoroalkoxys, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

10. R ３ and R ４ One or both of them independently constitute H, D, F, Cl, C １～６ Alkyl, C １～６ Fluoroalkyl, C １～６ Deuteroalkyl, C １～６ Alkoxy, C １～６ Fluoroalkoxy and C １～６ A compound according to claim 1, selected from deuteroalkoxys, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

11. R ３ and R ４ Together, O-CH ２ A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, which forms O.

12. R ３ and R ４ One of them is selected from X-L-A, R ３ and R ４ The other side is H, Halo, C １～６ Alkyl and C １～６ A compound according to claim 1, selected from alkoxys, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

13. R ３ However, H, Haro, C １～６ Alkyl and C １～６ Selected from alkoxy, R ４ The compound according to claim 12, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, wherein the compound is X-L-A.

14. R １ However, it is H; R ２ However, it is selected from H and D; R ５ However, it is selected from H, D, and F; R ３ and R ４ One or both of are H, C １～４ Alkoxy, C １～４ Fluoroalkoxy and C １～４ Selected from deuteroalkoxy, or R ３ and R ４ Together, O-(CH ２ ) １～２ Forming O; R ７ , R ８ , R ９ , R １０ , R １２ , R １３ , R １４ , R ２５ , R ２６ , R ２７ , R ２８ , R ３１ , R ３２ , R ３３ , R ３５ , R ３６ , R ３７ , R ３８ , R ３９ , R ４０ , R ４１ , R ４２ , R ４３ , R ４５ , R ４６ , R ４７ , R ４８ , R ４９ , R ５０ , R ５１ and R ５２ These are independently selected from H and D; and R １１ , R ３０ , R ３４ and R ４４ H and C became independent. １～４ Alkyl, C １～４ Fluoroalkyl and C １～４ Selected from deuteroalkyl groups, R ２９ However, C １～４ Alkyl, C １～４ Fluoroalkyl and C １～４ Selected from deuteroalkyl groups, The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

15. A compound according to claim 1, selected from the table below: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 or its pharmaceutically acceptable salts, solvates, and / or prodrugs.

16. A composition comprising one or more compounds according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, and a carrier.

17. An agent for treating a disease, disorder, or condition, comprising one or more compounds according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

18. Agents for treating CNS diseases, disorders or conditions and / or neurological diseases, disorders or conditions, comprising one or more compounds according to any one of claims 1 to 15, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof.

19. An agent for treating mental disorders or problematic behaviors, comprising one or more compounds according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, and an additional therapeutic agent.

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