Indole derivatives as serotonergic agents useful for the treatment of disorders related thereto

The present disclosure relates to indole derivatives of general Formula (I), to processes for their preparation, to compositions including indole derivatives of general Formula (I), and to their use in activation of a serotonin receptors in a cell, as well as to treating diseases, disorders, or conditions by activation of a serotonin receptors in a cell. The diseases, disorders, or conditions include, for example, psychosis, mental illnesses and CNS disorders.

1. 11. A compound of Formula (I) or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof, wherein: X is selected from S, S(O), and SO2; R1 is selected from H, C1-C6alkyl, C1-C6alkyleneP(O)(OR11)2, C1-C6alkyleneOP(O)(OR11)2, C(O)R11, CO2R11, C(O)N(R11)2, S(O)R11, and SO2R11; R2 is selected from H, halo, and C1-C6alkyl; R3 is selected from H, CN, halo, C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl; R4 is selected from H, CN, halo, C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl; R5 is selected from H, CN, halo, C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl; R6 is selected from H, C1-C10alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZR12, C2-C6alkenyleneZR12, C2-C6alkynyleneZR12, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, and C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13; R7 is selected from H, halo, and C1-C6alkyl; R8 is selected from H, halo, and C1-C6alkyl; each R9 is independently selected from halo, C1-C6alkyl, OH, OC1-C6alkyl, C1-C6alkyleneOH, and C1-C6alkyleneOC1-C6alkyl; R10 is selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6alkynyleneZ′R14, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, and C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR15, and C(O)R15; Z is selected from O, C(O), NR16C(O), NR16C(O)O, C(O)NR16, OC(O)NR16, and NR16; Z′ is selected from O, C(O), NR17C(O), NR17C(O)O, C(O)NR17, OC(O)NR17, and NR17; n is an integer selected from 0, 1, 2, 3, and 4; R11 is independently selected from H and C1-C6alkyl; R12 is selected from H, C1-C6alkyl, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, and C5-C10heteroaryl, the latter four groups being optionally substituted with one to four substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, and C(O) C1-C4alkyl; R13 is selected from H and C1-C6alkyl; R14 is selected from H, C1-C6alkyl, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, and C5-C10heteroaryl, the latter four groups being optionally substituted with one to four substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, and C(O) C1-C4alkyl; R15 is selected from H and C1-C6alkyl; R16 is selected from H and C1-C6alkyl; R17 is selected from H and C1-C6alkyl, and available hydrogen atoms are optionally replaced with a halogen atom and/or available hydrogen atoms are optionally replaced with deuterium.
2. 2

CROSS-REFERENCE TO RELATED APPLICATIONS AND CLAIMS OF PRIORITY
This application is a continuation application of International Application No. PCT/IB2024/000644 filed on Nov. 12, 2024, which claims the benefit of priority of U.S. Provisional Application No. 63/598,683 filed on Nov. 14, 2023, and U.S. Provisional Application No. 63/598,703 filed on Nov. 14, 2023, the complete disclosures of all of which are incorporated herein by reference and priority of each being claimed.


FIELD
The disclosure relates to indole derivatives of general Formula (I) for the treatment of different conditions that are treated by activation of serotonin receptors, for example, mental illnesses and neurological disease, in the fields of psychiatry, neurobiology, and pharmacotherapy. The present disclosure further comprises methods for making the compounds of Formula (I) and corresponding intermediates.
BACKGROUND
Mental health disorders, or mental illness, refer to a wide range of disorders that include, but are 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, as well as neurological disorders, are impacted by alterations, dysfunction, degeneration, and/or damage to the brain's serotonergic system, which may explain, in part, common endophenotypes and comorbidities among neuropsychiatric and neurological diseases.
The field of psychedelic neuroscience has witnessed a recent renaissance following a decade of restricted research due to the evolving legal status of psychedelics. Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. Today there is a consensus that psychedelics are agonists or partial agonists at serotonin 5-hydroxytryptamine 2A (5-HT2A) receptors.
Psychedelics have both rapid onset and persisting effects long after their acute effects, which includes changes in mood and brain function. Long lasting effects may result from their unique receptor affinities, which affect neurotransmission via neuromodulatory systems that serve to modulate brain activity, i.e., neuroplasticity, and promote cell survival, are neuroprotective, and modulate brain neuroimmune systems. The mechanisms which lead to these long-term neuromodulatory changes may be linked to epigenetic modifications, gene expression changes and modulation of pre- and post-synaptic receptor densities. These, previously under-researched, psychedelic drugs may potentially provide the next generation of neurotherapeutics, where treatment resistant psychiatric and neurological diseases, e.g., depression, post-traumatic stress disorder, dementia, and addiction, may become treatable with attenuated pharmacological risk profiles.
Although there is a general perception that psychedelic drugs are dangerous, from a physiologic safety standpoint, they are one of the safest known classes of central nervous system (CNS) drugs. Preliminary data show that psychedelic administration in humans results in a unique profile of effects and potential adverse reactions that need to be appropriately addressed to maximize safety. The primary safety concerns are largely psychologic, rather than physiologic, in nature. Somatic effects vary but are relatively insignificant, even at doses that elicit powerful psychologic effects. Psilocybin, when administered in a controlled setting, has frequently been reported to cause transient, delayed headache, with incidence, duration, and severity increased in a dose-related manner [Johnson et al., Drug Alcohol Depend (2012) 123(1-3):132-140]. It has been found that repeated administration of psychedelics leads to a very rapid development of tolerance known as tachyphylaxis, a phenomenon believed to be mediated, in part, by 5-HT2A receptors. In fact, several studies have shown that rapid tolerance to psychedelics correlates with downregulation of 5-HT2A receptors. For example, daily LSD administration selectively decreased 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].
Classic psychedelics and dissociative psychedelics are known to have rapid onset antidepressant and anti-addictive effects, unlike any currently available treatment. Randomized clinical control studies have confirmed antidepressant and anxiolytic effects of classic psychedelics in humans.
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) has the chemical formula C12H17N2O4P. It is a tryptamine-based prodrug and is one of the major psychoactive constituents in mushrooms of the psilocybe species. It was first isolated from psilocybe mushrooms by Hofmann in 1957, later synthesized by him in 1958 [Passie et al., Addict Biol., 2002, 7(4):357-364], and was used in psychiatric, psychological research and in psychotherapy during the early to mid-1960s up until its controlled drug scheduling in 1970 in the United States, and up until the 1980s in Germany [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 currently the preferred compound for use in studies of the effects of serotonergic hallucinogens [Carter et al., J. Cogn. Neurosci., 2005 17(10):1497-1508; Gouzoulis-Mayfrank et al., Neuropsychopharmacology 1999, 20(6):565-581; Hasler et al, Psychopharmacology (Berl) 2004, 172(2):145-156], likely because it has a shorter duration of action and suffers from less notoriety than LSD. Like other members of this class, psilocybin induces sometimes profound changes in perception, cognition, and emotion, including emotional lability.
In humans as well as other mammals, psilocybin is transformed into the active metabolite psilocin, or the 4-hydroxy-N,N-dimethyltryptamine parent compound. It is likely that psilocin partially or wholly produces most of the subjective and physiological effects of psilocybin in humans and non-human animals. Recently, human psilocybin research confirmed the 5-HT2A activity of psilocybin via the parent psilocin, and provides some support for indirect effects on dopamine through 5-HT2A activity and possible activity at other serotonin receptors. In fact, the most consistent finding for involvement of other receptors in the actions of psychedelics is the 5-HT1A receptor. That is particularly true for tryptamines and LSD, which generally have significant affinity and functional potency at this receptor. It is known that 5-HT1A receptors are colocalized with 5-HT2A receptors on cortical pyramidal cells [Martín-Ruiz et al., J Neurosci. 2001, 21(24):9856-986], where the two receptor types have opposing functional effects [Araneda et al., Neuroscience 1991, 40(2):399-412].
Although the exact role of the 5-HT2A receptor, and other 5-HT2 receptor family members, is not well understood with respect to the amygdala, it is evident that the 5-HT2A receptor plays an important role in emotional responses and is an important target to be considered in the actions of 5-HT2A agonist psychedelics. In fact, a majority of known 5-HT2A agonists produce hallucinogenic effects in humans, and rodents generalize from one 5-HT2A agonist to others, as between psilocybin and LSD [Aghajanian et al., Eur J Pharmacol., 1999, 367(2-3):197-206; Nichols at al., J Neurochem., 2004, 90(3):576-584]. Psilocybin has a stronger affinity for the human 5-HT2A receptor than for the rat receptor and it has a lower K(i) for both 5-HT2A and 5-HT2C receptors than LSD. Moreover, results from a series of drug-discrimination studies 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 reduce 5-HT2 receptor density in rat brain.
Today, psilocybin is one of the most widely used psychedelics in human studies due to its relative safety, moderately long active duration, and good absorption in subjects. There remains strong research and therapeutic potential for psilocybin as recent studies have shown varying degrees of success in neurotic disorders, alcoholism, depression associated with major depressive disorder, treatment resistant depression and in terminally ill cancer patients, obsessive compulsive disorder, addiction, anxiety, post-traumatic stress disorder, and even cluster headaches.
Recent developments include several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with treatment resistant depression, major depressive disorder, and cancer-related psychosocial distress that demonstrate unprecedented positive relief of anxiety and depression. Two recent small pilot studies of psilocybin-assisted psychotherapy also have shown positive benefit in treating both alcohol and nicotine addiction. Recently, blood oxygen level-dependent functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain's default mode network [Nichols D E. Pharmacol Rev., 2016, 68(2):264-355].
Preliminary studies using positron emission tomography (PET) showed that psilocybin ingestion (15 or 20 mg orally) increased absolute metabolic rate of glucose in frontal, and to a lesser extent in other, cortical regions as well as in striatal and limbic subcortical structures in healthy participants, suggesting that some of the key behavioral effects of psilocybin involve the frontal cortex [Gouzoulis-Mayfrank et al., Neuropsychopharmacology, 1999, 20(6):565-581; Vollenweider et al., Brain Res. Bull. 2001, 56(5):495-507]. Although 5-HT2A agonism is widely recognized as the primary action of classic psychedelic agents, psilocybin has less affinity for a wide range of other pre- and post-synaptic 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 antidepressant/anti-anxiety effects.
Depression and anxiety are two of the most common psychiatric disorders worldwide. Depression is a multifaceted condition characterized by episodes of mood disturbances alongside other symptoms such as anhedonia, psychomotor complaints, feelings of guilt, attentional deficits, and suicidal tendencies, all of which can range in severity. Similarly, anxiety disorders are a collective of etiologically complex disorders characterized by intense psychosocial distress and other symptoms depending on the subtype. Anxiety associated with life-threatening disease is the only anxiety subtype that has been studied in terms of psychedelic-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 satisfactory emotional relief. Recent interest into the use of psychedelic-assisted therapy may represent a promising alternative for patients with depression and anxiety that are ineffectively managed by conventional methods.
Generally, the psychedelic treatment model consists of administering the orally-active drug to induce a mystical experience lasting approximately 4-9 h depending on the psychedelic [Halberstadt, Behav Brain Res., 2015, 277:99-120; Nichols, Pharmacol. Rev., 2016, 68(2): 264-355]. This enables participants to work through and integrate difficult feelings and situations, leading to enduring anti-depressant and anxiolytic effects. Classical psychedelics like psilocybin and LSD are being studied as potential candidates. In one study with classical psychedelics for the treatment of depression and anxiety associated with life-threatening disease, it was found that, in a supportive setting, psilocybin and LSD consistently produced significant and sustained anti-depressant and anxiolytic effects.
Psychedelic treatment is generally well-tolerated with few if any persisting adverse effects. Regarding the mechanisms of action of psychedelics, they mediate their main therapeutic effects biochemically via serotonin receptor agonism, and psychologically by generating meaningful psycho-spiritual experiences that contribute to mental flexibility. Given the limited success rates of current treatments for anxiety and mood disorders, and considering the high morbidity associated with these conditions, there is potential for psychedelics to provide symptom relief in patients inadequately managed by conventional methods.
Further emerging clinical research and evidence suggest psychedelic-assisted therapy also shows potential as an alternative treatment for refractory substance use disorders and mental health conditions, and thus may be an important tool in a crisis where existing approaches have yielded limited success [dos Santos et al., Ther Adv Psychopharmacol., 2016, 6(3):193-213]. Similarly encouraging are findings from a recent pilot study of psilocybin-assisted therapy for tobacco use disorder, demonstrating abstinence rates of 80% at six months follow-up and 67% at 12 months follow-up [Johnson et al., https://www.ncbi.nlm.nih.gov/pubmed/27441452, J Drug Alcohol Abuse, 2017, 43(1):55-60; Johnson et al., Psychopharmacol. 2014, 28(11):983-992]; such rates are considerably higher than any documented in the tobacco cessation literature. Notably, mystical-type experiences generated from the psilocybin sessions were significantly correlated with positive treatment outcomes. These results coincide with bourgeoning evidence from recent clinical trials lending support to the effectiveness of psilocybin-assisted therapy for treatment-resistant depression and end-of-life anxiety [Carhart-Harris et al., Neuropsychopharmacology, 2017, 42(11):2105-2113]. Research on the potential benefits of psychedelic-assisted therapy for opioid use disorder (OUD) is beginning to emerge, and accumulating evidence supports a need to advance this line of investigation. Available evidence from earlier randomized clinical trials suggests a promising role for treating OUD: higher rates of abstinence were observed among participants receiving high dose LSD and ketamine-assisted therapies for heroin addiction compared to controls at long-term follow-up. Recently, a large United States population study among 44,000 individuals found that psychedelic use was associated with 40% reduced risk of opioid abuse and 27% reduced risk of opioid dependence in the following year, as defined by DSM-IV criteria [Pisano et al., J Psychopharmacol., 2017, 31(5):606-613]. Similarly, a protective moderating effect of psychedelic use was found on the relationship between prescription opioid use and suicide risk among marginalized women [Argento et al., J Psychopharmacol., 2018, 32(12):1385-1391]. Despite the promise of these preliminary findings with classical psychedelic agents, further research is warranted to determine how psychedelics may ameliorate the opioid crisis response. Meanwhile, growing evidence on the safety and efficacy of psilocybin for the treatment of mental and substance use disorders should help to motivate further clinical investigation into its use as a novel intervention for OUD.
Regular doses of psychedelics also ameliorate sleep disturbances, which are highly prevalent in depressed patients with more than 80% of depressed patients having complaints of poor sleep quality. The sleep symptoms are often unresolved by first-line treatment and are associated with a greater risk of relapse and recurrence. Interestingly, sleep problems often appear before other depression symptoms, and subjective sleep quality worsens before the onset of an episode in recurrent depression. Two other studies assessing electroencephalographic (EEG) brain activity during sleep showed that psychedelics, such as LSD, positively affect sleep patterns. It further was suggested that a single dose of a psychedelic causes a reset of the biological clock underlying sleep/wake cycles and thereby enhances cognitive-emotional processes in depressed people but also improves feelings of well-being and enhances mood in healthy individuals [Kuypers, Medical Hypotheses, 2019, 125:21-24].
In a systematic meta-analysis of clinical trials from 1960-2018 researching the therapeutic use of psychedelic treatment in patients with serious or terminal illnesses and related psychiatric illness, it was found that psychedelic therapy (mostly with LSD) may improve cancer-related depression, anxiety, and fear of death. Four randomized controlled clinical trials were published between 2011 and 2016, mostly with psilocybin treatment, that demonstrated psychedelic-assisted treatment can produce rapid, robust, and sustained improvements in cancer-related psychological and existential distress. [Ross S, Int Rev Psychiatry, 2018, 30(4):317-330]. Many patients facing cancer or other life-threatening illnesses experience significant existential distress related to loss of meaning or purpose in life, which can be associated with hopelessness, demoralization, powerlessness, perceived burdensomeness, and a desire for hastened death. Those features are also often at the core of clinically significant anxiety and depression, and they can substantially diminish quality of life in this patient population. The alleviation of these core features of existential distress should be among the central aims of palliative care. Accordingly, several manualized psychotherapies for cancer-related existential distress have been developed in recent years, with an emphasis on dignity and meaning-making. However, there are currently no pharmacologic interventions for existential distress per se, and available pharmacologic treatments for depressive symptoms in patients with cancer have not demonstrated superiority over placebo. There remains a need for additional effective treatments for those conditions [Rosenbaum et al., Curr. Oncol., 2019, 26(4): 225-226].
Recently, there has been growing interest in a new dosing paradigm for psychedelics, such as psilocybin and LSD, referred to colloquially as microdosing. Under this paradigm, sub-perceptive doses of the serotonergic hallucinogens, approximately 10% or less of the full dose, are taken on a more consistent basis of once each day, every other day, or every three days, or a permutation of the same. Not only is this dosing paradigm more consistent with current standards in pharmacological care, but it may be particularly beneficial for certain conditions, such as Alzheimer's disease, other neurodegenerative diseases, attention deficit disorder, attention deficit hyperactivity disorder, and for certain patient populations such as elderly, juvenile, and patients that are fearful of or opposed to psychedelic assisted therapy. Moreover, this approach may be particularly well suited for managing cognitive deficits and preventing neurodegeneration. For example, subpopulations of low attentive and low motivated rats demonstrate improved performance on the 5-choice serial reaction time and progressive ratio tasks, respectively, following doses of psilocybin below the threshold for eliciting the classical wet dog shake behavioral response associated with hallucinogenic doses (Blumstock et al., WO 2020/157569 A1). Similarly, treatment of patients with hallucinogenic doses of 5-HT2A agonists is associated with increased BDNF and activation of the mTOR pathway, which are thought to promote neuroplasticity and are hypothesized to serve as molecular targets for the treatment of dementias 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-psychomimetic, doses of 5-HT2A agonists also show similar neuroprotective and increased neuroplasticity effects (neuroplastogens) and reduced neuroinflammation, which could be beneficial in treatment of both neurodegenerative and neurodevelopmental diseases and chronic disorders (Manfredi et al., WO 2020/181194, Flanagan et al., Int. Rev. Psychiatry, 2018, 13:1-13; Nichols et al., 2016, Psychedelics as medicines; an emerging new paradigm). This repeated, lower dose paradigm may extend the utility of these compounds to additional indications and may prove useful for wellness applications.
Psychosis is often referred to as an abnormal state of mind that is characterized by hallucinatory experiences, delusional thinking, and disordered thoughts. Moreover, this state is accompanied by impairments in social cognition, inappropriate emotional expressions, and bizarre behavior. Most often, psychosis develops as part of a psychiatric disorder, of which it represents an integral part of schizophrenia. It corresponds to the most florid phase of the illness. The very first manifestation of psychosis in a patient (i.e., in vivo) is referred to as first-episode psychosis. It reflects a critical transitional stage toward the chronic establishment of the disease, that is presumably mediated by progressive structural and functional abnormalities seen in diagnosed patients. [ACS Chem. Neurosci., 2018, 9, 2241-2251]. Anecdotal evidence suggests that low, non-hallucinogenic doses (microdosing) of psychedelics that are administered regularly can reduce symptoms of schizophrenia and psychosis.
SUMMARY
This Summary is provided to introduce a selection of representative concepts in a simplified form, which representative concepts are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.
The present disclosure includes a compound of Formula (I):




    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof,
        wherein
        X is absent or selected from O, S, S(O), and SO2;
        R1 is selected from H, C1-C6alkyl, C1-C6alkyleneP(O)(OR11)2, C1-C6alkyleneOP(O)(OR11)2, C(O)R11, CO2R11, C(O)N(R11)2, S(O)R11, and SO2R11;
        R2 is selected from H, halo, and C1-C6alkyl;
        R3, R4, and R5 are independently selected from H, CN, halo, C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl;
        R6 is selected from H, C1-C10alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZR12, C2-C6alkenyleneZR12, C2-C6alkynyleneZR12, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, and C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13;
        R7 and R8 are independently selected from H, halo, and C1-C6alkyl;
        each R9 is independently selected from halo, C1-C6alkyl, OH, OC1-C6alkyl, C1-C6alkyleneOH, and C1-C6alkyleneOC1-C6alkyl;
        R10 is selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6alkynyleneZ′R14, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, and C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR15, and C(O)R15;
        Z is selected from O, C(O), NR16C(O), NR16C(O)O, C(O)NR16, OC(O)NR16, and NR16;
        Z′ is selected from O, C(O), NR17C(O), NR17C(O)O, C(O)NR17, OC(O)NR17, and NR17;
        n is an integer selected from 0, 1, 2, 3, and 4;
        R11, R13, R15, R16, and R17 are independently selected from H and C1-C6alkyl;
        R12 and R14 are independently selected from H, C1-C6alkyl, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, and C5-C10heteroaryl, the latter four groups being optionally substituted with one to four substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, and C(O)C1-C4alkyl, and
        available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof,
        provided when X is O, R1, R2, R3, R4, R5, R7, and R8 are H or D, n is 0, and R6 is H, CH3, or CD3, then R10 is not H, CH3, or CD3,
        provided when X is O, R1, R2, R3, R4, R5, R7, and R8 are H or D and n is 0, and R6 is CH3 or CHF2, then R10 is not H, CH3, or CD3, and
        provided when X is absent and R6 is H, then either n is not 0 or R10 is not H or C1-C6alkyl.
    
    


In some embodiments, provided (1) when X is absent, then R6 is not H, D, or halogen, and (2) when X is O, S, S(O), or SO2, then each R9 is not independently selected from H, D, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, and C1-C6deuterohaloalkyl and/or R10 is not selected from H, D, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, and C1-C6deuterohaloalkyl.
In some embodiments, provided when X is absent, then R6 is not H, D, or halogen.
In some embodiments, including when X is O, S, S(O), or SO2, each R9 is not independently selected from H, D, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, and C1-C6deuterohaloalkyl.
In some embodiments, including when X is O, S, S(O), or SO2, R10 is not selected from H, D, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, and C1-C6deuterohaloalkyl.
In some embodiments, provided (1) when X is absent, then R6 is not H, D, or halogen, and (2) when X is O, S, S(O), or SO2, then each R9 is not independently selected from H, D, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, and C1-C6deuterohaloalkyl.
In some embodiments, provided (1) when X is absent, then R6 is not H, D, or halogen, and (2) when X is O, S, S(O), or SO2, then R10 is not selected from H, D, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, and C1-C6deuterohaloalkyl.
In a further embodiment, the compounds of the disclosure are used as medicaments. Accordingly, the disclosure also includes a compound of the disclosure for use as a medicament.
The present disclosure includes a method for activating a serotonin receptor in a cell, either in a biological sample or in a patient, comprising administering an effective amount of one or more compounds of the disclosure to the cell.
The present disclosure also includes a method of treating psychosis or psychotic symptoms comprising administering a therapeutically effective amount of one or more compounds of the disclosure to a subject in need thereof.
The present disclosure also includes a method of treating a mental illness comprising administering a therapeutically effective amount of one or more compounds of the disclosure to a subject in need thereof.
The disclosure additionally provides a process for the preparation of compounds of the disclosure. General and specific processes are discussed in more detail below and set forth in the examples below.
This disclosure further provides intermediates for the compounds disclosed herein, methods of making the intermediates, and methods for making the compounds from the intermediates.
Other features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the disclosure, are given by way of illustration only and the scope of the claims should not be limited by these embodiments but should be given the broadest interpretation consistent with the description as a whole.



BRIEF DESCRIPTION OF THE DRAWINGS
The embodiments of the disclosure will be described in greater detail with reference to the attached drawings, which are incorporated herein by reference and in which:
FIG. 1 is a bar graph showing the effect of various doses of exemplary compound of Formula I-1, (R) I-1, on head-twitch response (HTR) in male C57BL6 mice. The mice were treated with exemplary compound (R) I-1 (3 mg/kg, 30 mg/kg, SC) by SC route, and the total number of head twitches were recorded over a 20 min period. Induction of head twitches elicited by 5-HT2A receptor agonists is believed to represent a behavioural proxy of their psychedelic effects. Data presented as mean±S.E.M. Analysed using one-way ANOVA with Fishers post-hoc LSD. *p<0.05, **p<0.01, *p<0.0001, #Acute effects of test compounds (20-minute post SC. dosing); and
FIGS. 2 to 5 are bar graphs showing the effect of various doses of exemplary compounds of Formula (I), specifically (R) I-98, (R) I-244, (R) I-245, and cis (R) I-248, respectively, on head-twitch response (HTR) in male C57BL6 mice. The mice were treated with exemplary compound (R) I-98, (R) I-244, (R) I-245, or cis (R) I-248 (3 mg/kg, 30 mg/kg, SC) by SC route (N=6 mice/dose), and the total number of head twitches were recorded over a 1 h period. Induction of head twitches elicited by 5-HT2A receptor agonists is believed to represent a behavioral proxy of their psychedelic effects. Data presented as mean±S.E.M. Analysed using one-way ANOVA with Fishers post-hoc LSD. *p<0.05, **p<0.01, *p<0.0001. #Acute effects of test compounds (20-minute post SC. dosing).



DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
I. Definitions
Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present disclosure herein described for which they are suitable as would be understood by a person skilled in the art.
The term “compound(s) of the disclosure” or “compound(s) of the present disclosure” and the like, as used herein, refers to a compound Formula (I) (including Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (I-K), (I-L), and (I-M) that fall within the scope of Formula (I)) and includes pharmaceutically acceptable salts, solvates, and/or prodrugs thereof.
The term “composition(s) of the disclosure” or “composition(s) of the present disclosure” and the like, as used herein, refers to a composition, such a pharmaceutical composition, comprising one or more compounds of the disclosure.
The term “and/or,” as used herein, means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of” or “one or more” of the listed items is used or present. The term “and/or” with respect to pharmaceutically acceptable salts and/or solvates thereof means that the compounds of the disclosure exist as individual salts and solvates, as well as a combination of, for example, a salt of a solvate of a compound of the disclosure. As used herein, the term “and/or” means either or both (or any combination or all of the terms or expressed referred to), e.g., “A, B, and/or C” encompasses A alone, B alone, C alone, A and B, A and C, B and C, and A, B, and C.
As used in the present disclosure, the singular forms “a,” “an,” and “the” include plural references unless the content clearly dictates otherwise. For example, an embodiment including “a compound” should be understood to present certain aspects with one compound, or two or more additional compounds. It will be understood by those with skill in the art that if a specific number of an introduced claim element is intended, such intent will be explicitly recited in the claim, and in the absence of such recitation no such limitation is present. For a non-limiting example, as an aid to understanding, the appended claims contain usage of the introductory phrases “at least one” and “one or more” to introduce claim elements. However, the use of such phrases should not be construed to imply that the introduction of a claim element by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim element to embodiments containing only one such element, even when the same claim includes the introductory phrase “one or more” or “at least one” and indefinite articles such as “a” or “an”; the same holds true for the use in the claims of definite articles.
As used in this disclosure and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
The term “consisting” and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers and/or steps and also exclude the presence of other unstated features, elements, components, groups, integers, and/or steps.
The term “consisting essentially of,” as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers and/or steps as well as those that do not materially affect the basic and novel characteristic(s) of these features, elements, components, groups, integers and/or steps.
In embodiments comprising an “additional” or “second” component, such as an additional or second compound, the second component, as used herein, is chemically different from the other components or first component. A “third” component is different from the other, first and second components and further enumerated or “additional” components are similarly different. “First,” “second,” “third,” etc. in this context is not meant to imply an order or sequence, other than the order in which the terms appear in the claims, unless the claims clearly indicate otherwise.
The term “suitable,” as used herein, means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, the identity of the molecule(s) to be transformed and/or the specific use for the compound, but the selection would be well within the skill of a person trained in the art. All process/method steps described herein are to be conducted under conditions sufficient to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.
The terms “about,” “substantially,” and “approximately,” as used herein, mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies or unless the context suggests otherwise to a person skilled in the art.
The present description refers to a number of chemical terms and abbreviations used by those skilled in the art. Nevertheless, definitions of selected terms are provided for clarity and consistency.
The term “alkyl,” as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cn1-Cn2.” Thus, for example, the term “C1-C6alkyl” (or “C1-6alkyl”) means an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms and includes, for example, any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and tert-butyl, n- and iso-propyl, ethyl, and methyl. As another example, “C1-C4alkyl” refers to n-, iso-, sec- and tert-butyl, n- and isopropyl, ethyl, and methyl.
The term “alkenyl,” as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkyl groups containing at least one double bond. The number of carbon atoms that are possible in the referenced alkenyl group are indicated by the prefix “Cn1-Cn2.” For example, the term C2-C6alkenyl (or C2-6alkenyl) means an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms.
The term “alkynyl,” as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkyl groups containing at least one triple bond. The number of carbon atoms that are possible in the referenced alkynyl group are indicated by the prefix “Cn1-Cn2.” For example, the term C2-C6alkynyl (or C2-6alkynyl) means an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms.
The term “cycloalkyl,” as used herein, whether it is used alone or as part of another group, means a saturated carbocyclic group containing one or more rings. The number of carbon atoms that are possible in the referenced cycloalkyl group are indicated by the numerical prefix “Cn1-Cn2.” For example, the term C3-7cycloalkyl (or C3-7cycloalkyl) means a cycloalkyl group having 3, 4, 5, 6, or 7 carbon atoms.
The term “heterocycloalkyl,” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one non-aromatic ring in which one or more of the atoms are a heteromoiety selected from O, S, and N, including oxidized or substituted versions thereof (e.g., S(O) and SO2), and the remaining atoms are C. Heterocycloalkyl groups are either saturated or unsaturated (i.e., contain one or more double bonds) and/or optionally comprise one or more C═O groups (i.e., one or more carbon atoms in the ring is oxidized to C═O). When a heterocycloalkyl group contains the prefix Cn1-Cn2 this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteromoiety as selected from O, S, and N including oxidized or substituted versions thereof, and the remaining atoms are C. Heterocycloalkyl groups may also be preceded by “n1- to n2-membered” which refers to the total number of atoms in the group. Heterocycloalkyl groups are optionally benzofused.
The term “aryl,” as used herein, whether it is used alone or as part of another group, refers to carbocyclic groups containing at least one aromatic ring.
The term “heteroaryl,” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one heteroaromatic ring in which one or more of the atoms are a heteromoiety selected from O, S, and N, including oxidized or substituted versions thereof (e.g., S(O) and SO2), and the remaining atoms are C. When a heteroaryl group contains the prefix Cn1-n2 this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteroatom as defined above. Heteroaryl groups may also be preceded by “n1- to n2-membered” which refers to the total number of atoms in the group. Heteroaryl groups are optionally benzofused.
All cyclic groups, including aryl, heteroaryl, heterocycloalkyl, and cycloalkyl groups, contain one or more than one ring (i.e., are polycyclic). When a cyclic group contains more than one ring, the rings may be fused, bridged, spirofused, or linked by a bond.
The term “benzofused,” as used herein, refers to a polycyclic group in which a benzene ring is fused with another ring.
A first ring being “fused” with a second ring means the first ring and the second ring share two adjacent atoms there between.
A first ring being “bridged” with a second ring means the first ring and the second ring share two non-adjacent atoms there between.
A first ring being “spirofused” with a second ring means the first ring and the second ring share one atom there between.
The term “halogen” (or “halo”) whether it is used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo, and iodo.
The term “haloalkyl,” as used herein, refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a halogen. Thus, for example, “C1-6haloalkyl” (or “C1-C6haloalkyl”) refers to a C1 to C6 linear or branched alkyl group as defined above with one or more halogen substituents.
As used herein, the term “haloalkenyl” refers to an alkenyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a halogen. Thus, for example, “C2-6haloalkenyl” (or “C2-C6haloalkenyl”) refers to a C2 to C6 linear or branched alkenyl group as defined above with one or more halogen substituents.
As used herein, the term “haloalkynyl” refers to an alkynyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a halogen. Thus, for example, “C2-6haloalkynyl” (or “C2-C6haloalkynyl”) refers to a C2 to C6 linear or branched alkynyl group as defined above with one or more halogen substituents.
The term “deuteroalkyl,” as used herein, refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a deuterium. Thus, for example, “C1-6deuteroalkyl” (or “C1-C6deuteroalkyl”) refers to a C1 to C6 linear or branched alkyl group as defined above with one or more deuterium substituents.
The term “deuteroalkenyl,” as used herein, refers to an alkenyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a deuterium. Thus, for example, “C2-6deuteroalkenyl” (or “C2-C6deuteroalkenyl”) refers to a C2 to C6 linear or branched alkenyl group as defined above with one or more deuterium substituents.
The term “deuteroalkynyl,” as used herein, refers to an alkynyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a deuterium. Thus, for example, “C2-6deuteroalkynyl” (or “C2-C6deuteroalkynyl”) refers to a C2 to C6 linear or branched alkynyl group as defined above with one or more deuterium substituents.
The term “fluoroalkyl,” as used herein, refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a fluorine. Thus, for example, “C1-6fluoroalkyl” (or “C1-C6fluoroalkyl”) refers to a C1 to C6 linear or branched alkyl group as defined above with one or more fluorine substituents.
The term “fluoroalkenyl,” as used herein, refers to an alkenyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a fluorine. Thus, for example, “C2-6fluoroalkenyl” (or “C2-C6fluoroalkenyl”) refers to a C2 to C6 linear or branched alkenyl group as defined above with one or more fluorine substituents.
The term “fluoroalkynyl,” as used herein, refers to an alkynyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a fluorine. Thus, for example, “C2-6fluoroalkynyl” (or “C2-C6fluoroalkynyl”) refers to a C2 to C6 linear or branched alkynyl group as defined above with one or more fluorine substituents.
The term “deuterohaloalkyl,” as used herein, refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a deuterium and one or more of the available hydrogen atoms have been independently replaced with a halogen. Thus, for example, “C1-6deuterohaloalkyl” (or “C1-C6deuterohaloalkyl”) refers to a C1 to C6 linear or branched alkyl group as defined above with one or more deuterium substituents and one or more halogen substituents.
The term “deuterohaloalkenyl,” as used herein, refers to an alkenyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a deuterium and one or more of the available hydrogen atoms have been independently replaced with a halogen. Thus, for example, “C2-6deuterohaloalkenyl” (or “C2-C6deuterohaloalkenyl”) refers to a C2 to C6 linear or branched alkenyl group as defined above with one or more deuterium substituents and one or more halogen substituents.
The term “deuterohaloalkynyl,” as used herein, refers to an alkynyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a deuterium and one or more of the available hydrogen atoms have been independently replaced with a halogen. Thus, for example, “C2-6deuterohaloalkynyl” (or “C2-C6deuterohaloalkynyl”) refers to a C2 to C6 linear or branched alkynyl group as defined above with one or more deuterium substituents and one or more halogen substituents.
The term “deuterofluoroalkyl,” as used herein, refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a deuterium and one or more of the available hydrogen atoms have been independently replaced with a fluorine. Thus, for example, “C1-6deuterofluoroalkyl” (or “C1-C6deuterofluoroalkyl”) refers to a C1 to C6 linear or branched alkyl group as defined above with one or more deuterium substituents and one or more fluorine substituents.
The term “deuterofluoroalkenyl,” as used herein, refers to an alkenyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a deuterium and one or more of the available hydrogen atoms have been independently replaced with a fluorine. Thus, for example, “C2-6deuterofluoroalkenyl” (or “C2-C6deuterofluoroalkenyl”) refers to a C2 to C6 linear or branched alkenyl group as defined above with one or more deuterium substituents and one or more fluorine substituents.
The term “deuterofluoroalkynyl,” as used herein, refers to an alkynyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a deuterium and one or more of the available hydrogen atoms have been independently replaced with a fluorine. Thus, for example, “C2-6deuterofluoroalkynyl” (or “C2-C6deuterofluoroalkynyl”) refers to a C2 to C6 linear or branched alkynyl group as defined above with one or more deuterium substituents and one or more fluorine substituents.
The suffix “ene” at the end of a group (for example “alkylene” or “alkenylene”) means that the group is bivalent, that is that it is bonded to two variables each on a different end of or location on the group.
The term “optionally substituted,” as used herein, means that the subject group is unsubstituted or substituted and the terms “optionally substituted” and “unsubstituted or substituted” are used interchangeably herein. As used herein, when referring to more than one item or “each” item, “optionally substituted” and “unsubstituted or substituted” means that the items are independently unsubstituted or substituted with respect to one another, e.g., for item A and item B, both may be substituted, both may be unsubstituted, or one may be substituted and the other unsubstituted. Additionally, as used herein, the term “optionally substituted” when referring to more than one item means that if more than one of the items is substituted, the substitutions may be independent from one another, e.g., for item A and item B that are both substituted, item A may have a first substitution and item B may have a second substitution that is the same or different from the first substitution of item A.
As used herein, the term “one or more” item includes a single item selected from the list as well as two or more items (e.g., mixtures) selected from the list.
The term “substituted,” as used herein, means, unless otherwise indicated, that the referenced group is substituted with one or more substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, C1-C4haloalkyl, OC1-C4haloalkyl, CN, OH, NH2, NH(C1-C4alkyl), N(C1-C4alkyl)(C1-C4alkyl), SC1-C4alkyl, S(O)C1-C4alkyl, SO2C1-C4alkyl, CO2H, CO2C1-C4alkyl, C(O)NH2, C(O)NHC1-C4alkyl, C(O)N(C1-C4alkyl)(C1-C4alkyl), C3-C6cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO2, N, NH, and NC1-C4alkyl.
When a group is substituted with more than one substituent selected from a list of substituents, each of the substituents is independently selected from the listed group of substituents.
The term “available,” as in “available hydrogen atoms” or “available atoms” refers to atoms that would be known to a person skilled in the art to be capable of replacement by a substituent.
The term “alternate isotope thereof,” as used herein, refers to an isotope of an element that is other than the isotope that is most abundant in nature.
The term “all available atoms are optionally replaced with alternate isotope thereof” or “available atoms are optionally replaced with alternative isotope thereof,” as used herein, means that available atoms, optionally each and every available atom, are optionally and independently replaced with an isotope of that atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. When a compound comprises an atom that has been replaced with an alternate isotope thereof, the compound comprises that alternate isotope in greater amounts than would otherwise be present in the compound if said replacement had not taken place.
The term “all available hydrogen atoms are optionally replaced with a halogen atom” or “available hydrogen atoms are optionally replaced with a halogen atom,” as used herein, means that available hydrogen atoms, optionally each and every available hydrogen atom, are optionally and independently replaced with a halogen atom.
The term “all available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom” or “available hydrogen atoms are optionally replaced with a fluorine atoms and/or a chlorine atom,” as used herein, means that available hydrogen atoms, optionally each and every available hydrogen atom, are optionally and independently replaced with a fluorine atom or a chlorine atom.
The term “pharmaceutically acceptable” means compatible with the treatment of subjects.
The term “pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant, or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject.
The term “pharmaceutically acceptable salt” means either an acid addition salt or a base addition salt which is suitable for, or compatible with, the treatment of subjects.
An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound.
A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound.
The term “solvate,” as used herein, means a compound, or a salt or prodrug of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered.
The term “prodrug,” as used herein, means a compound, or salt of a compound, that, after administration, is converted into an active drug.
The term “protecting group” or “PG” and the like, as used herein, refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule. The selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in “Protective Groups in Organic Chemistry,” McOmie, J. F. W. Ed., Plenum Press, 1973, in Greene, T. W. and Wuts, P. G. M., “Protective Groups in Organic Synthesis,” John Wiley & Sons, 3rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).
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 disclosure are applicable to both human therapy and veterinary applications.
The term “treating” or “treatment,” as used herein, and as is well understood in the art, means an approach for obtaining 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, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay, or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease and remission (whether partial or total), whether detectable or undetectable. “Treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. “Treating” and “treatment,” as used herein, also include prophylactic treatment. Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the disclosure and optionally consist of a single administration, or alternatively comprise a series of administrations.
As used herein, the term “effective amount” or “therapeutically effective amount” means an amount of one or more compounds of the disclosure that is effective, at dosages and for periods of time necessary to achieve the 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 an amount that, for example, increases said activation compared to the activation without administration of the one or more compounds.
“Palliating” a disease, disorder, or condition means that the extent and/or undesirable clinical manifestations of a disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to not treating the disorder.
The term “administered,” as used herein, means administration of a therapeutically effective amount of one or more compounds or compositions of the disclosure to a cell, tissue, organ, or subject.
The term “prevention” or “prophylaxis,” or synonym thereto, as used herein, refers to a reduction in the risk or probability of a patient becoming afflicted with a disease, disorder, or condition or manifesting a symptom associated with a disease, disorder, or condition.
The term “disease, disorder, or condition,” as used herein, refers to a disease, disorder, or condition treated or treatable by activation and/or binding of any serotonin receptor (5HT1 to 5HT7) and their sub-receptors and subtypes (e.g., 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C) and particularly using one or more compounds of the disclosure herein described.
The term “treating a disease, disorder, or condition by activation of a serotonin receptor,” as used herein, means that the disease, disorder, or condition to be treated is affected by, modulated by and/or has some biological basis, either direct or indirect, that includes serotonergic activity, in particular increases in serotonergic activity. These diseases respond favorably when serotonergic activity associated with the disease, disorder, or condition is agonized by one or more of the compounds or compositions of the disclosure.
The term “activation,” as used herein, includes agonism, partial agonist, and positive allosteric modulation of a serotonin receptor.
The term “5-HT2A,” as used herein, means the 5-HT2A receptor subtype of the 5-HT2 serotonin receptor.
The terms “5-HT1A,” as used herein, means the 5-HT1A receptor subtypes of the 5-HT1 serotonin receptor.
The term “5-HT2B,” as used herein, means the 5-HT2B receptor subtype of the 5-HT2 serotonin receptor.
The term “5-HT2C,” as used herein, means the 5-HT2C receptor subtype of the 5-HT2 serotonin receptor.
The term “therapeutic agent,” as used herein, refers to any drug or active agent that has a pharmacological effect when administered to a subject.
II. Compounds
The present disclosure includes a compound of Formula (I):




    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof,
        wherein:
        X is absent or selected from O, S, S(O), and SO2;
        R1 is selected from H, C1-C6alkyl, C1-C6alkyleneP(O)(OR11)2, C1-C6alkyleneOP(O)(OR11)2, C(O)R11, CO2R11, C(O)N(R11)2, S(O)R11, and SO2R11;
        R2 is selected from H, halo, and C1-C6alkyl;
        R3, R4, and R5 are independently selected from H, CN, halo, C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl;
        R6 is selected from H, C1-C10alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZR12, C2-C6alkenyleneZR12, C2-C6alkynyleneZR12, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, and C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13;
        R7 and R8 are independently selected from H, halo, and C1-C6alkyl;
        each R9 is independently selected from halo, C1-C6alkyl, OH, OC1-C6alkyl, C1-C6alkyleneOH, and C1-C6alkyleneOC1-C6alkyl;
        R10 is selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6alkynyleneZ′R14, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, and C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR15, and C(O)R15;
        Z is selected from O, C(O), NR16C(O), NR16C(O)O, C(O)NR16, OC(O)NR16, and NR16;
        Z′ is selected from O, C(O), NR17C(O), NR17C(O)O, C(O)NR17, OC(O)NR17, and NR17;
        n is an integer selected from 0, 1, 2, 3, and 4;
        R11, R13, R15, R16, and R17 are independently selected from H and C1-C6alkyl;
        R12 and R14 are independently selected from H, C1-C6alkyl, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, and C5-C10heteroaryl, the latter four groups being optionally substituted with one to four substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, and C(O)C1-C4alkyl, and
        available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof,
        provided when X is O, R1, R2, R3, R4, R5, R7, and R8 are H or D, n is 0, and R6 is H, CH3, or CD3, then R10 is not H, CH3, or CD3;
        provided when X is O, R1, R2, R3, R4, R5, R7, and R8 are H or D and n is 0, and R6 is CH3 or CHF2, then R10 is not H, CH3, or CD3; and
        provided when X is absent and R6 is H, then either n is not 0 or R10 is not H or C1-C6alkyl.
    
    


According to one or more embodiments, the present disclosure includes a compound of Formula (I) as defined above or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof, wherein:

    
    
        X is selected from S, S(O), and SO2;
        R1 is selected from H, C1-C6alkyl, C1-C6alkyleneP(O)(OR11)2, C1-C6alkyleneOP(O)(OR11)2, C(O)R11, CO2R11, C(O)N(R11)2, S(O)R11, and SO2R11;
        R2 is selected from H, halo, and C1-C6alkyl;
        R3, R4, and R5 are independently selected from H, CN, halo, C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl;
        R6 is selected from H, C1-C10alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZR12, C2-C6alkenyleneZR12, C2-C6alkynyleneZR12, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, and C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13;
        R7 and R8 are independently selected from H, halo, and C1-C6alkyl;
        each R9 is independently selected from halo, C1-C6alkyl, OH, OC1-C6alkyl, C1-C6alkyleneOH, and C1-C6alkyleneOC1-C6alkyl;
        R10 is selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6alkynyleneZ′R14, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, and C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR15, and C(O)R15;
        Z is selected from O, C(O), NR16C(O), NR16C(O)O, C(O)NR16, OC(O)NR16, and NR16;
        Z′ is selected from O, C(O), NR17C(O), NR17C(O)O, C(O)NR17, OC(O)NR17, and NR17;
        n is an integer selected from 0, 1, 2, 3, and 4;
        R11, R13, R15, R16, and R17 are independently selected from H and C1-C6alkyl;
        R12 and R14 are independently selected from H, C1-C6alkyl, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, and C5-C10heteroaryl, the latter four groups being optionally substituted with one to four substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, and C(O)C1-C4alkyl, and
        available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof.
    
    


According to one or more embodiments, the present disclosure includes a compound of Formula (I) as defined above or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof, wherein:

    
    
        X is absent or O;
        R1 is selected from H, C1-C6alkyl, C1-C6alkyleneP(O)(OR11)2, C1-C6alkyleneOP(O)(OR11)2, C(O)R11, CO2R11, C(O)N(R11)2, S(O)R11, and SO2R11;
        R2 is selected from H, halo, and C1-C6alkyl;
        R3, R4, and R5 are independently selected from H, CN, halo, C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl;
        R6 is selected from H, C1-C10alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZR12, C2-C6alkenyleneZR12, C2-C6alkynyleneZR12, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, and C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13;
        R7 and R8 are independently selected from H, halo, and C1-C6alkyl;
        each R9 is independently selected from halo, C1-C6alkyl, OH, OC1-C6alkyl, C1-C6alkyleneOH, and C1-C6alkyleneOC1-C6alkyl;
        R10 is selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6alkynyleneZ′R14, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, and C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR15, and C(O)R15;
        Z is selected from O, C(O), NR16C(O), NR16C(O)O, C(O)NR16, OC(O)NR16, and NR16;
        Z′ is selected from O, C(O), NR17C(O), NR17C(O)O, C(O)NR17, OC(O)NR17, and NR17;
        n is an integer selected from 0, 1, 2, 3, and 4;
        R11, R13, R15, R16, and R17 are independently selected from H and C1-C6alkyl;
        R12 and R14 are independently selected from H, C1-C6alkyl, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, and C5-C10heteroaryl, the latter four groups being optionally substituted with one to four substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, and C(O)C1-C4alkyl, and
        available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof,
        provided when X is O, R1, R2, R3, R4, R5, R7, and R8 are H or D, n is 0, and R6 is H, CH3, or CD3, then R10 is not H, CH3, or CD3;
        provided when X is O, R1, R2, R3, R4, R5, R7, and R8 are H or D and n is 0, and R6 is CH3 or CHF2, then R10 is not H, CH3, or CD3; and
        provided when X is absent and R6 is H, then either n is not 0 or R10 is not H or C1-C6alkyl.
    
    


In some embodiments, especially but not necessarily when X is O, n is 0, 1, 2, 3, or 4, R9 is selected from halo or C1-C6alkyl, R10 is H or C1-C6alkyl, and R6 is H, or substituted or unsubstituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7-cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl or C5-C10heteroaryl, available hydrogen atoms are optionally replaced with a halogen atom (i.e., all available hydrogen atoms in H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl and C5-C10heteroaryl are not optionally replaced with deuterium). In some embodiments, when X is 0, n is 0, 1, 2, 3, or 4, R9 is halo or C1-C6alkyl, R10 is H or C1-C6alkyl, and R6 is H or substituted or unsubstituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, or C5-C10heteroaryl, the compound of Formula (I) does not comprise deuterium.
In some embodiments, when available hydrogen atoms in a group are optionally replaced with a halogen atom, the halogen atom is selected from F, Cl, and Br. In some embodiments, when available hydrogen atoms in a group are optionally replaced with a halogen atom, the halogen atom is selected from F and Br. In some embodiments, when available hydrogen atoms are replaced with a halogen atom, the halogen atom is selected from F and Cl. In some embodiments, when available hydrogen atoms in a group are optionally replaced with a halogen atom, the halogen atom is F.
In some embodiments, available hydrogen atoms are optionally independently replaced with an alternate isotope thereof. In some embodiments, the alternate isotope of hydrogen is deuterium.
Therefore, in some embodiments, available hydrogen atoms are optionally replaced with a halogen atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, especially when X is S, S(O), or SO2, and for other embodiments in which X is O or absent, when available hydrogen atoms in a group are optionally replaced with a halogen atom, the halogen atom is selected from F, Cl, and I. In some embodiments, especially when X is S, S(O), or SO2, and for other embodiments of X as well, when available hydrogen atoms in a group are optionally replaced with a halogen atom, the halogen atom is selected from F and I. In some embodiments, available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, available hydrogen atoms are optionally replaced with a fluorine atom and/or available hydrogen atoms are replaced with deuterium. In some embodiments, available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom.
In some embodiments, the compounds of the disclosure are isotopically enriched with deuterium. In some embodiments, one or more of R1, R2, R3, R4, R5, R6, R7 R8, R9, R10, R11, R12, R13, R14, R15, R16, and R17 independently comprises one or more deuterium or one or more of R1, R2, R3, R4, R5, R6, R7 R8, R9, R10, R11, R12, R13 R14, R15, R16, and R17 independently is deuterium.
In some embodiments, particularly when X is selected from S, S(O), and SO2, but also when X is O or absent, when R9 is halo or C1-C6alkyl, R10 is H or C1-C6alkyl, n is 0, 1, 2, 3, or 4 and R6 is H, or substituted or unsubstituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, or C5-C10heteroaryl, available hydrogen atoms are optionally replaced with a halogen atom (e.g., available hydrogen atoms in H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, and C5-C10heteroaryl are not optionally replaced with deuterium). In some embodiments, when R9 is halo or C1-C6alkyl, R10 is H or C1-C6alkyl, n is 0, 1, 2, 3, or 4 and R6 is H or substituted or unsubstituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, or C5-C10heteroaryl, the compound of Formula (I) does not comprise deuterium.
In some embodiments, particularly when X is absent or O, as well as when X is S, S(O), or SO2, when R10 is selected from H and C1-C6alkyl, available hydrogen atoms in H and C1-C6alkyl of R10 are optionally replaced with a halogen atom (e.g., available hydrogen atoms in H and C1-C6alkyl of R10 are not optionally replaced with deuterium). In some embodiments, when R10 is selected from H and C1-C6alkyl, the compound of Formula (I) does not comprise deuterium.
In some embodiments, X is S(O), as shown in the structure below:




In some embodiments, X is SO2, as shown in the structure below:




In some embodiments, X is S, as shown in the structure below:




In some embodiments, X is absent (e.g., a direct bond), as shown in the structure below.




In some embodiments, X is O, as shown in the structure below.




In some embodiments, R1 is selected from S(O)R11 and SO2R11.
In some embodiments, R1 is selected from H, C1-C4alkyl, C1-C3alkyleneP(O)(OR11)2, C1-C4alkyleneOP(O)(OR11)2, C(O)R11, CO2R11, and C(O)N(R11)2, wherein available hydrogen atoms are optionally replaced with an iodine atom, a fluorine atom, and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R1 is selected from H, C1-C4alkyl, C1-C4alkyleneP(O)(OR11)2, C1-C4alkyleneOP(O)(OR11)2, C(O)R11, CO2R11, and C(O)N(R11)2, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R1 is selected from H, C1-C3alkyl, CH2P(O)(OR11)2, CH2CH2P(O)(OR11)2, CH2CH(CH3)P(O)(OR11)2, CH(CH3)CH2P(O)(OR11)2, CH(CH3)P(O)(OR11)2, CH(CH2CH3)P(O)(OR11)2, (CH2)OP(O)(OR11)2, C(O)R11, and CO2R11, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R1 is selected from H, CH3, CH2CH3, CH2P(O)(OR11)2, CH(CH3)P(O)(OR11)2, and (CH2)OP(O)(OR11)2, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R1 is selected from H, CH3, CH2CH3, CH2P(O)(OR11)2, CH(CH3)P(O)(OR11)2, and (CH2)OP(O)(OR11)2, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R1 is selected from H, CH3, CH2CH3, CH2P(O)(OR11)2, and (CH2)OP(O)(OR11)2, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R1 is selected from H, CH3, CH2CH3, CH2P(O)(OR11)2, (CH2)OP(O)(OR11)2, C(O)R11, and CO2R11, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R1 is selected from H, CH3, and CH2CH3, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R1 is selected from H and D. In some embodiments, R1 is H. In some embodiments, R1 is D. In some embodiments, R1 is CD3. In some embodiments, R1 is CH3.
In some embodiments, R2 is selected from H, halo, and C1-C4alkyl wherein available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof. In some embodiments, R2 is selected from H, halo, and C1-C4alkyl wherein available hydrogen atoms are optionally replaced with an iodine atom, a fluorine atom, and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R2 is selected from H, halo, and C1-C4alkyl wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R2 is selected from H, D, F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, and C1-C4deuterofluoroalkyl. In some embodiments, R2 is selected from H, D, F, Br, Cl, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2F, CH2CH3, CH2CH2F, CF2CF3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R2 is selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2F, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R2 is selected from H, D, CH3, CF3, CHF2, CH2F, CD2H, CDH2, and CD3. In some embodiments, R2 is selected from H, D, CH3, CF3, and CD3. In some embodiments, R2 is H. In some embodiments, R2 is D. In some embodiments, R2 is CD3. In some embodiments, R2 is CH3.
In some embodiments, R3 is selected from H, halo, CN, C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl, wherein available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof. In some embodiments, R3 is selected from H, halo, CN, C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl, wherein available hydrogen atoms are optionally replaced with an iodine atom, a fluorine atom, and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R3 is selected from H, halo, CN, C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R3 is selected from H, D, CN, halo, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, C2-C4alkenyl, C2-C4fluoroalkenyl, C2-C4deuteroalkenyl, C2-C4deuterofluoroalkenyl, C2-C4alkynyl, C2-C4deuteroalkynyl, C2-C4fluoroalkynyl, and C2-C4deuterofluoroalkynyl. In some embodiments, R3 is selected from H, D, CN, halo, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, C2-C4alkenyl, and C2-C4fluoroalkenyl. In some embodiments, R3 is selected from H, D, CN, F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, and C1-C4deuterofluoroalkyl. In some embodiments, R3 is selected from H, D, CN, F, Br, Cl, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3, and CD2CD3. In some embodiments, R3 is selected from H, D, CN, F, Cl, CH3, CD2H, CDH2, CD3, CF2H, CFH2, and CF3. In some embodiments, R3 is selected from H, F, and D. In some embodiments, R3 is selected from H, F, and Cl. In some embodiments, R3 is selected from H and D. In some embodiments, R3 is H.
In some embodiments, R3 is selected from H, CN, C1-C4alkyl, C1-C4haloalkyl, C2-C4alkenyl, C2-C4haloalkenyl, C2-C4alkynyl, and C2-C4haloalkynyl, wherein available atoms are optionally replaced with an alternate isotope thereof. In some embodiments, R3 is selected from H, CN, C1-C4alkyl, C1-C4fluoroalkyl, C2-C4alkenyl, C2-C4fluoroalkenyl, C2-C4alkynyl, and C2-C4fluoroalkynyl, wherein available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R3 is selected from H, D, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, C2-C4alkenyl, C2-C4fluoroalkenyl, C2-C4deuteroalkenyl, C2-C4deuterofluoroalkenyl, C2-C4alkynyl, C2-C4deuteroalkynyl, C2-C4fluoroalkynyl, and C2-C4deuterofluoroalkynyl. In some embodiments, R3 is selected from H, D, CN, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, C2-C4alkenyl, C2-C4fluoroalkenyl, C2-C4deuteroalkenyl, and C2-C4deuterofluoroalkenyl. In some embodiments, R3 is selected from H, D, CN, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, and C1-C4deuterofluoroalkyl. In some embodiments, R3 is selected from H, D, CN, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3, and CD2CD3. In some embodiments, R3 is H.
In some embodiments, R4 and R5 are independently selected from H, halo, CN, C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl, wherein available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof. In some embodiments, R4 and R5 are independently selected from H, halo, CN, C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl, wherein available hydrogen atoms are optionally replaced with an iodine atom, a fluorine atom, and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R4 and R5 are independently selected from H, halo, CN, C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R4 and R5 are independently selected from H, D, CN, halo, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, C2-C4alkenyl, C2-C4fluoroalkenyl, C2-C4deuteroalkenyl, C2-C4deuterofluoroalkenyl, C2-C4alkynyl, C2-C4deuteroalkynyl, C2-C4fluoroalkynyl, and C2-C4deuterofluoroalkynyl. In some embodiments, R4 and R5 are independently selected from H, D, CN, halo, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, C2-C4alkenyl, C2-C4fluoroalkenyl, C2-C4alkynyl, and C2-C4fluoroalkynyl. In some embodiments, R4 and R5 are independently selected from H, D, CN, F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, and C1-C4deuterofluoroalkyl. In some embodiments, R4 and R5 are independently selected from H, D, CN, F, Cl, Br, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3, and CD2CD3. In some embodiments, R4 and R5 are independently selected from H, D, CN, F, Cl, Br, CH3, CD2H, CDH2, CD3, CF2H, CFH2, and CF3. In some embodiments, R4 and R5 are independently selected from H, F, and D. In some embodiments, R4 and R5 are independently selected from H and D. In some embodiments, R4 and R5 are both H.
In some embodiments, each of R3, R4, and R5 is H. In some embodiments, each of R2, R3, R4, and R5 is H. In some embodiments, at least one of R3, R4, and R5 is D. In some embodiments, each of R2, R3, R4, and R5 is D.
In some embodiments, R6 is selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZR12, C2-C6alkenyleneZR12, C2-C6alkynyleneZR12, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof. In some embodiments, R6 is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZR12, C2-C6alkenyleneZR12, C2-C6alkynyleneZR12, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally replaced with an iodine atom, a fluorine atom, and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R6 is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZR12, C2-C6alkenyleneZR12, C2-C6alkynyleneZR12, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, R6 is C1-C6alkyl, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, particularly when X is S, S(O), or SO2, as well as when X is O or absent, R6 is selected from C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, and C1-C6deuterofluoroalkyl. In some embodiments, R6 is selected from C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, and C1-C6deuterofluoroalkyl. In some embodiments, R6 is selected from CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3, CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2, CH(CHD2)2, CH(CDH2)2, C(CH3)3, C(CF3)3, C(CHF2)3, C(CFH2)3, C(CD3)3, C(CHD2)3, C(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2CH(CH3)CH3, CH2CH(CH3) CF3, CH2CH(CH3) CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3, and CH2CH2C(CD3)3. In some embodiments, R6 is selected from CH3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH(CH3)2, CH(CF3)2, C(CH3)3, C(CF3)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CHF2, CH2CH(CH3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH2C(CH3)3, CH2C(CF3)3, CH2CH2C(CH3)3, and CH2CH2C(CF3)3. In some embodiments R6 is selected from CH3, CH2CH3, CH2CF3, CH2CH2CH3, CH(CH3)2, CH2C(CH3)3, CH2CH2C(CH3)3, CD3, CF3, CHF2, CHEF, CH2CF2H, CH2CH2F, CH2CH2CHF2, CH2CH2CF3, and CH2CH2CH2CF3. In some embodiments, especially for when X is S, S(O), or SO2, and for other embodiments in which X is O or absent, R6 is selected from CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CF2H, CH2CH2CF3, CH2CH2CH2CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2CH(CH3)2, CH(CH3)CH2CH3, and CH2C(CH3)3. In some embodiments, especially for when X is absent or oxygen, and for other embodiments of X, R6 is selected from H, D, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CF2H, CH2CH3, CH2CH2CH3, CH2CH2CF3, CH2CH2CH2CF3, CH(CH3)2, C(CH3)3, CH2CH(CH3)2, CH(CH3)CH2CH3, and CH2C(CH3)3. In some embodiments, R6 is selected from CH3, CD3, CD2H, CDH2, CF2H, CH2CF2H, CFH2, and CF3. In some embodiments, R6 is selected from CH3 and CD3. In some embodiments, R6 is CH3.
In some embodiments, R6 is selected from C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZR12, C2-C6alkenyleneZR12, C2-C6alkynyleneZR12, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, R6 is selected from C4-C6alkenyl and C2-C6alkynyl wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R6 is selected from C2-C6alkenyl, C2-C6fluoroalkenyl, C2-C6deuteroalkenyl, C2-C6deuterofluoroalkenyl, C2-C6alkynyl, C2-C6fluoroalkynyl, C2-C6deuteroalkynyl, and C2-C6deuterofluoroalkynyl. In some embodiments, R6 is selected from C2-C4alkenyl, C2-C4fluoroalkenyl, C2-C6deuteroalkenyl, C2-C6deuterofluoroalkenyl, C2-C4alkynyl, C2-C4fluoroalkynyl, C2-C4deuteroalkynyl, and C2-C4deuterofluoroalkynyl. In some embodiments, R6 is selected from CH═CH2, CH2CH═CH2, CF2CH═CH2, CD2CH═CH2, CH═CH2CH3, CH═CH2CF3, CH═CH2CHF2, CH═CH2CH2F, CH═CH2CD3, CH═CH2CHD2, CH═CH2CH2D, C≡CH, C≡CCH3, C≡CCF3, C≡CCHF2, C≡CCFH2, C≡CCD3, C≡CCHD2, C≡CCDH2, CH2C≡CH, CF2C≡CH, CD2C≡CH, CH2C≡CCH3, CF2C≡CCH3, CD2C≡CCH3, CH2C≡CCD3, CF2C≡CCD3, CD2C≡CCD3, CH2C≡CCF3, CF2C≡CCF3, CD2C≡CCF3, CH2C≡CCHD2, CF2C≡CHD2, CD2C≡CHD2, CH2C≡CHF2, CF2C≡CHF2, and CD2C≡CHF2. In some embodiments, R6 is selected from CH═CH2, CH2CH═CH2, C≡CH C≡CCH3, CH2C≡CH, and CH2C≡CCH3.
In some from C1-C6alkyleneZR12, C2-C6alkenyleneZR12, and C2-C6alkynyleneZR12, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, R6 is selected d from C1-C6alkyleneZR12, C1-C6fluoroalkyleneZR12, C1-C6deuteroalkyleneZR12, C1-C6deuterofluoroalkyleneZR12, C2-C6alkenyleneZR12, C2-C6fluoroalkenyleneZR12, C2-C6deuteroalkenyleneZR12, C2-C6deuterofluoroalkenyleneZR12, C6alkynyleneZR12, C2-C6fluoroalkynyleneZR12, C2-C6deuteroalkynyleneZR12, and C2-C6deuterofluoroalkynyleneZR12. In some embodiments, R6 is selected from C1-C6alkyleneZR12, C1-C6fluoroalkyleneZR12, C1-C6deuteroalkyleneZR12, C1-C6deuterofluoroalkyleneZR12, C2-C6alkenyleneZR12, and C2-C6alkynyleneZR12. In some embodiments, R6 is selected from C1-C4alkyleneZR12, C1-C4fluoroalkyleneZR12, C1-C4deuteroalkyleneZR12, C1-C4deuterofluoroalkyleneZR12, C2-C4alkenyleneZR12, C2-C4fluoroalkenyleneZR12, C2-C4deuteroalkenyleneZR12, C2-C4deuterofluoroalkenyleneZR12, C2-C4alkynyleneZR12, C2-C4fluoroalkynyleneZR12, C2-C4deuteroalkynyleneZR12, and C2-C4deuterofluoroalkynyleneZR12. In some embodiments, R6 is selected from C1-C4alkyleneZR12, C1-C4fluoroalkyleneZR12, C1-C4deuteroalkyleneZR12, C1-C4deuterofluoroalkyleneZR12, C2-C4alkenyleneZR12, and C2-C4alkynyleneZR12.
In some embodiments, R6 is selected from CH2ZR12. CH2CH2ZR12, CH2CH2CH2ZR12, CH2CH2CH2CH2ZR12, CH(CH3)CH2ZR12, CH(CH3)CH2CH2ZR12, CH2CH(CH3) ZR12, CF2ZR12, CFHZR12, CH2CHFZR12, CH2CF2ZR12, CF2CF2ZR12, CH2CH2CF2ZR12, CH2CH2CFHZR12, CH2CH2CF2ZR12, CH(CH3)CF2ZR12, CH(CH3)CHFZR12, CH2CH2CH2CF2ZR12, CH2CH2CH2CHFZR12, CH(CH3)CH2CF2ZR12, CH(CH3)CH2CHFZR12, CD2ZR12, CDHZR12, CH2CHDZR12, CH2CD2ZR12, CD2CD2ZR12, CH2CH2CD2ZR12, CH2CH2CDHZR12, CH2CH2CD2ZR12, CH(CH3) CD2ZR12, CH(CH3)CHDZR12, CH2CH2CH2CD2ZR12, CH2CH2CH2CHDZR12, CH(CH3)CH2CD2ZR12, CH(CH3)CH2CHDZR12, CH═CHZR12, CH2CH═CHZR12, C≡CZR12, C≡CCH2ZR12, CH2C≡CZR12, and CH2C≡CH2ZR12. In some embodiments, R6 is selected from CH2ZR12, CH2CH2ZR12, CH2CH2CH2ZR12, CH2CH2CH2CH2ZR12, CH(CH3)CH2ZR12, CH(CH3)CH2CH2ZR12, CH2CH(CH3) ZR12, CH═CHZR12, CH2CH═CHZR12, CH═CH2CHZR12, C≡CCH2ZR12, CH2C≡CZR12, and CH2C≡CH2ZR12.
In some embodiments, R6 is selected from C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, each of which is optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R6 is selected from C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, C1-C4alkyleneC5-C10heteroaryl, C1-C4fluoroalkyleneC3-C7cycloalkyl, C1-C4fluoroalkyleneC3-C10heterocycloalkyl, C1-C4fluoroalkyleneC6-C10aryl, C1-C4fluoroalkyleneC5-C10heteroaryl, C1-C4deuteroalkyleneC3-C7cycloalkyl, C1-C4deuteroalkyleneC3-C10heterocycloalkyl, C1-C4deuteroalkyleneC6-C10aryl, C1-C4deuteroalkyleneC5-C10heteroaryl, C1-C4deuterofluoroalkyleneC3-C7cycloalkyl, C1-C4deuterofluoroalkyleneC3-C10heterocycloalkyl, C1-C4deuterofluoroalkyleneC6-C10aryl, and C1-C4deuterofluoroalkyleneC5-C10heteroaryl, in which each of the cyclic groups is optionally substituted with one to four substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R6 is selected from C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C2alkyleneC3-C7cycloalkyl, C1-C2alkyleneC3-C10heterocycloalkyl, C1-C2alkyleneC6-C10aryl, C1-C2alkyleneC5-C10heteroaryl, C1-C2fluoroalkyleneC3-C7cycloalkyl, C1-C2fluoroalkyleneC3-C10heterocycloalkyl, C1-C2fluoroalkyleneC6-C10aryl, C1-C2fluoroalkyleneC5-C10heteroaryl, C1-C2deuteroalkyleneC3-C7cycloalkyl, C1-C2deuteroalkyleneC3-C10heterocycloalkyl, C1-C2deuteroalkyleneC6-C10aryl, C1-C2deuteroalkyleneC5-C10heteroaryl, C1-C2deuterofluoroalkyleneC3-C7cycloalkyl, C1-C2deuterofluoroalkyleneC3-C10heterocycloalkyl, C1-C2deuterofluoroalkyleneC6-C10aryl, and C1-C2deuterofluoroalkyleneC5-C10heteroaryl, in which each of the cyclic groups is optionally substituted with one to four substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are atoms are optionally replaced with deuterium.
In some embodiments, the C3-C7cycloalkyl in R6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which is optionally substituted with one to four substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, the C3-C7cycloalkyl in R6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is optionally substituted with one to three substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR13, and C(O)R13 and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, the C3-C7cycloalkyl in R6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is optionally substituted with one or two substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the C3-C10heterocycloalkyl in R6 is a monocyclic C3-C7heterocycloalkyl or a bicyclic C7-C10heterocycloalkyl, each of which is optionally substituted with one to four substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR13, and C(O)R13.
In some embodiments, the monocyclic C3-C7heterocycloalkyl in R6 is selected from aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, 1,3-dioxolanyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2H-1λ3-thiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxothiolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, imidazolinyl, dioxolanyl, dithiolanyl, triazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, dihydropyranyl, isothiazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl dioxide, dioxanyl, thiazolinyl, thianyl, thianyl oxide, thianyl dioxide, dithianyl, azepanyl, pyrazolidinyl, oxepanyl, thiepanyl, diazepanyl, and 2,5-pyrrolidinedionyl (e.g., succinimidyl), each of which is optionally substituted with one to four substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, the monocyclic C3-C7heterocycloalkyl in R6 is selected from oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2H-1λ3-thiophenyl, pyrrolidinyl, imidazolidinyl, tetrahydropyranyl, dihydropyranyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, thianyl, thianyl oxide, thianyl dioxide, dithianyl, and 2,5-pyrrolidinedionyl, each of which is optionally substituted with one to three, or one or two, substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the bicyclic C7-C10heterocycloalkyl in R6 is selected from benzoisoxazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzopyranyl, benzothiopyranyl, chromanyl, isochromanyl, dihydroindenyl, isoindolinyl, 1-oxoisoindolinyl, 3-oxoisoindolinyl, 1,3-dioxoisoindolinyl (e.g., phthalimido), octahydroisoindolinyl, octahydro-isoindolin-1-onyl (e.g., tetrahydroisoquinoline), and hexahydroisoindoline-1,3-dionyl (e.g., cis-hexahydrophthalimidyl), each of which is optionally substituted with one to four substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, the bicyclic C7-C10heterocycloalkyl in R6 is selected from isoindolinyl, 1-oxoisoindolinyl, 3-oxoisoindolinyl, 1,3-dioxoisoindolinyl, octahydro-1H-isoindolinyl, octahydro-1H-isoindolin-1-onyl, and hexahydro-1H-isoindoline-1,3-dionyl, each of which is optionally substituted with one to three, or one or two, substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the C6-C10aryl in R6 is phenyl, optionally substituted with one to four, one to three, or one or two, substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the C5-C10heteroaryl in R6 is selected from azepinyl, benzofuranyl, benzofurazanyl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, thiazolyl, thienofuranyl, triazolyl, and thienyl (e.g., thiophenyl), each of which is optionally substituted with one to four, one to three, or one or two, substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the substituents on R6 are independently selected from one to four of F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CD2H, CDH2, CD3, CF3, CHF2, CH2F, CH2CH2F, CF2CF3, CH2CH2D, CH2CD2H, CD2CD3, OR14, and C(O)R14. In some embodiments, the substituents on R6 are independently selected from one to three of F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)2, CD2H, CDH2, CD3, CF3, CHF2, CH2F, OR14, and C(O)R14. In some embodiments one, more, or all the substituents on R6 are independently selected from one or two of F, Cl, CH3, CH(CH3)2, CH(CH3)2, CF3, CHF2, CH2F, OR14, and C(O)R14.
In some embodiments, Z is selected from NR16C(O), NR16C(O)O, C(O)NR16, OC(O)NR16, and NR16. In some embodiments, Z is selected from O, C(O), NR16C(O), and NR16C(O)O. In some embodiments, Z is O. In some embodiments, Z is C(O). In some embodiments, Z is NR16C(O). In some embodiments, Z is NR16C(O)O.
In some embodiments, R7 and R8 are independently selected from H, halo, and C1-C4alkyl, wherein available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof. In some embodiments, R7 and R8 are independently selected from H, halo, and C1-C4alkyl, wherein available hydrogen atoms are optionally replaced with an iodine atom, a fluorine atom, and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In embodiments for when X is S, S(O), or SO2, as well as embodiments in which X is O or absent, R7 and R8 are independently selected from H, D, F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, and C1-C4deuterofluoroalkyl. In some embodiments, R7 and R8 are independently selected from H, halo and C1-C4alkyl, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R7 and R8 are independently selected from H, D, F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, and C1-C4deuterofluoroalkyl.
In some embodiments, R7 and R8 are independently selected from H, F, Br, Cl, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3CF2CF3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R7 and R8 are independently selected from H, D, F, Br, Cl, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R7 and R8 are independently selected from H, D, F, Br, CH3, CF2H, CFH2, CF3, CD2H, CDH2, and CD3. In some embodiments R7 and R8 are independently selected from H, D, F, CH3, CF3, and CD3. In some embodiments, R7 and R8 are independently selected from H, D, CH3, and CD3. In some embodiments, R7 and R8 are independently selected from H, F, and D. In some embodiments, R7 and R8 are independently selected from H and D. In some embodiments, R7 and R8 are both H. In some embodiments, R7 and R8 are both D. In some embodiments, R7 is H. In some embodiments, R7 is D. In some embodiments, R8 is H. In some embodiments, R8 is D.
In some embodiments, each R9 is independently selected from D, halo, C1-C4alkyl, OH, OC1-C4alkyl, C1-C4alkyleneOH, and C1-C4alkyleneOC1-C6alkyl, wherein available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof. In some embodiments, each R9 is independently selected from D, halo, C1-C4alkyl, OH, OC1-C4alkyl, C1-C4alkyleneOH, and C1-C4alkyleneOC1-C6alkyl, wherein available hydrogen atoms are optionally replaced with an iodine atom, a fluorine atom, and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, each R9 is independently selected from D, halo, C1-C4alkyl, OH, OC1-C4alkyl, C1-C4alkyleneOH, and C1-C4alkyleneOC1-C6alkyl, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, at least one R9 is selected from halo and C1-C4alkyl, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, at least one R9 is selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, and C1-C4deuterofluoroalkyl. In some embodiments, at least one R9 is selected from F, Cl, Br, OH, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2, CH(CHD2)2, CH(CDH2)2, C(CH3)3, C(CF3)3, C(CHF2)3, C(CFH2)3, C(CD3)3, C(CHD2)3, C(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3, and CH2CH2C(CD3)3. In some embodiments, at least one R9 is selected from F, Cl, CH3, CF2H, CFH2, CF3, and CD3.
In some embodiments, at least one R9 is selected from OH, OC1-C4alkyl, C1-C4alkyleneOH, and C1-C4alkyleneOC1-C6alkyl, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, at least one R9 is selected from OH, OC1-C4alkyl, OC1-C4deuteroalkyl, OC1-C4fluoroalkyl, OC1-C4deuterofluoroalkyl, C1-C4alkyleneOH, C1-C4fluoroalkyleneOH, C1-C4deuteroalkyleneOH, C1-C4deuterofluoroalkyleneOH, C1-C4alkyleneOC1-C4alkyl, C1-C4alkyleneOC1-C4fluoroalkyl, C1-C4alkyleneOC1-C4deuteroalkyl, C1-C4alkyleneOC1-C4deuterofluoroalkyl, C1-C4fluoroalkyleneOC1-C4alkyl, C1-C4deuteroalkyleneOC1-C4alkyl, C1-C4deuterofluoroalkyleneOC1-C4alkyl, C1-C4fluoroalkyleneOC1-C4fluoroalkyl, C1-C4fluoroalkyleneOC1-C4deuteroalkyl, C1-C4deuteroalkyleneOC1-C4fluoroalkyl, C1-C4deuteroalkyleneOC1-C4deuteroalkyl, C1-C4deuterofluoroalkyleneOC1-C4fluoroalkyl, C1-C4fluoroalkyleneOC1-C4deuterofluoroalkyl, and C1-C4deuterofluoroalkyleneOC1-C4deuterofluoroalkyl. In some embodiments, at least one R9 is selected from OH, OC1-C4alkyl, OC1-C4deuteroalkyl, OC1-C4fluoroalkyl, OC1-C4deuterofluoroalkyl, C1-C4alkyleneOH, C1-C4fluoroalkyleneOH, C1-C4alkyleneOC1-C4alkyl, C1-C4alkyleneOC1-C4fluoroalkyl, C1-C4alkyleneOC1-C4deuteroalkyl, and C1-C4alkyleneOC1-C4deuterofluoroalkyl. In some embodiments, at least one R9 is selected from OH, OC1-C4alkyl, OC1-C4deuteroalkyl, OC1-C4fluoroalkyl, OC1-C4deuterofluoroalkyl, C1-C4alkyleneOH, C1-C4fluoroalkyleneOH, C1-C4deuteroalkyleneOH, C1-C4deuterofluoroalkyleneOH, C1-C4alkyleneOC1-C3alkyl, and C1-C4alkyleneOC1-C3fluoroalkyl.
In some embodiments, at least one R9 is selected from OH, OCH3, OCD2H, OCDH2, OCD3, OCF2H, OCFH2, OCF3, OCH2CH3, OCH2CH2F, OCH2CF2H, OCH2CF3, OCF2CF3, OCH2CH2D, OCH2CD2H, OCH2CD3OCD2CD3, OCH2CH2CH3, OCH2CH2CHF2, OCH2CH2CFH2, OCH2CH2CF3, OCH2CH2CHD2, OCH2CH2CDH2, OCH2CH2CD3, OCH(CH3)2, OCH(CF3)2, OCH(CHF2)2, OCH(CFH2), OCH(CD3)2, OCH(CHD2)2, OCH(CDH2)2, OC(CH3)3, OC(CF3)3, OC(CHF2)3, OC(CFH2)3, OC(CD3)3, OC(CHD2)3, OC(CDH2)3, OCH2CH2CH2CH3, OCH2CH2CH2CF3, OCH2CH2CH2CD3, OCH2CH(CH3)2, OCH2CH(CD3)2, OCH2CH(CF3)2, OCH(CH3)CH2CH3, OCH(CH3)CH2CF3, OCH(CH3)CH2CD3, OCH2C(CH3)3, OCH2C(CF3)3, OCH2C(CD3)3, OCH2CH2C(CH3)3, OCH2CH2C(CF3)3, OCH2CH2C(CD3)3, CH2OH, CF2OH, CD2OH, CH2CH2OH, CF2CF2OH, CH2CF2OH, CH2CD2OH, CD2CD2OH, CH2OCH3, CH2OCD2H, CH2OCDH2, CH2OCD3, CH2OCF3, CH2OCHF2, CH2OCH2F, CH2CH2OCH3, CH2CH2OCD2H, CH2CH2OCDH2, CH2CH2OCD3, CH2CH2OCF3, CH2CH2OCHF2, and CH2CH2OCH2F. In some embodiments, at least one R9 is selected from OH, OCH3, OCF2H, OCFH2, OCF3, and OCD3.
In some embodiments, n is an integer selected from 0, 1, and 2. In some embodiments, n is 2. In some embodiments, n is an integer selected from 0 and 1. In some embodiments, n is 1. In some embodiments, n is 0.
In some embodiments, R10 is selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6alkynyleneZ′R14, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof. In some embodiments, R10 is selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6alkynyleneZ′R14, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with an iodine atom, a fluorine atom, and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R10 is selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6alkynyleneZ′R14, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, one of R6 and R10 is not H, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, or C1-C6deuterofluoroalkyl. In some embodiments, one of R6 and R10 is not H, C1-C6fluoroalkyl, C1-C6deuteroalkyl, or C1-C6deuterofluoroalkyl. In some embodiments, R6 is selected from C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZR12, C2-C6alkenyleneZR12, C2-C6alkynyleneZR12, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13, and R10 is selected from H and C1-C6alkyl, wherein available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof.
In some embodiments, R6 is selected from H and C1-C6alkyl, and R10 is selected from C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6alkynyleneZ′R14, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted one to four substituents independently selected from halo, C1-C6alkyl, OR15, and C(O)R15, wherein available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof.
In some embodiments, R10 is selected from H and C1-C6alkyl, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R10 is selected from H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, and C1-C6deuteroalkyl. In some embodiments, R10 is selected from H, D, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2, CH(CHD2)2, CH(CDH2)2, C(CH3)3, C(CF3)3, C(CHF2)3, C(CFH2)3, C(CD3)3, C(CHD2)3, C(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2CH(CH3)CH3, CH2CH(CH3) CF3, CH2CH(CH3) CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3, and CH2CH2C(CD3)3. In some embodiments, R10 is selected from H, CH3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH(CH3)2, CH(CF3)2, C(CH3)3, C(CF3)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CHF2, CH2CH(CH3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH2C(CH3)3, CH2C(CF3)3, CH2CH2C(CH3)3, and CH2CH2C(CF3)3. In some embodiments R10 is selected from H, CH3, CH2CH3, CH2CF3, CH2CH2CH3, CH(CH3)2, CH2C(CH3)3, CH2CH2C(CH3)3, CD3, CF3, CHF2, CH2F, CH2CF2H, CH2CH2F, CH2CH2CHF2, and CH2CH2CF3.
In some embodiments, R10 is selected from C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6alkynyleneZ′R14, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted one to four substituents independently selected from halo, C1-C6alkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, R10 is selected from C4-C6alkenyl and C2-C6alkynyl wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R10 is selected from C2-C6alkenyl, C2-C6fluoroalkenyl, C2-C6deuteroalkenyl, C2-C6deuterofluoroalkenyl, C2-C6alkynyl, C2-C6fluoroalkynyl, C2-C6deuteroalkynyl, and C2-C6deuterofluoroalkynyl. In some embodiments, R10 is selected from C2-C4alkenyl, C2-C4fluoroalkenyl, C2-C6deuteroalkenyl, C2-C6deuterofluoroalkenyl, C2-C4alkynyl, C2-C4fluoroalkynyl, C2-C4deuteroalkynyl, and C2-C4deuterofluoroalkynyl. In some embodiments, R10 is selected from CH═CH2, CH2CH═CH2, CF2CH═CH2, CD2CH═CH2, CH═CH2CH3, CH═CH2CF3, CH═CH2CHF2, CH═CH2CH2F, CH═CH2CD3, CH═CH2CHD2, CH═CH2CH2D, C≡CH, C≡CCH3, C≡CCF3, C≡CCHF2, C≡CCFH2, C≡CCD3, C≡CCHD2, C≡CCDH2, CH2C≡CH, CF2C≡CH, CD2C≡CH, CH2C≡CCH3, CF2C≡CCH3, CD2C≡CCH3, CH2C≡CCD3, CF2C≡CCD3, CD2C≡CCD3, CH2C≡CCF3, CF2C≡CCF3, CD2C≡CCF3, CH2C≡CCHD2, CF2C≡CHD2, CD2C≡CHD2, CH2C≡CHF2, CF2C≡CHF2, and CD2C≡CHF2. In some embodiments, R10 is selected from CH═CH2, CH2CH═CH2, C≡CH C≡CCH3, CH2C≡CH, and CH2C≡CCH3.
In some embodiments, R10 is selected from C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, and C2-C6alkynyleneZ′R14, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R10 is selected from C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, and C2-C6alkynyleneZ′R14, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, R10 is selected from C1-C6alkyleneZ′R14, C1-C6fluoroalkyleneZ′R14, C1-C6deuteroalkyleneZ′R14, C1-C6deuterofluoroalkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6fluoroalkenyleneZ′R14, C2-C6deuteroalkenyleneZ′R14, C2-C6deuterofluoroalkenyleneZ′R14, C2-C6alkynyleneZ′R14, C2-C6fluoroalkynyleneZ′R14, C2-C6deuteroalkynyleneZ′R14, and C2-C6deuterofluoroalkynyleneZ′R14. In some embodiments, R10 is selected from C1-C6alkyleneZ′R14, C1-C6fluoroalkyleneZ′R14, C1-C6deuteroalkyleneZ′R14, C1-C6deuterofluoroalkyleneZ′R14, C2-C6alkenyleneZ′R14, and C2-C6alkynyleneZ′R14. In some embodiments, R10 is selected from C1-C4alkyleneZ′R14, C1-C4fluoroalkyleneZR14, C1-C4deuteroalkyleneZ′R14, C1-C4deuterofluoroalkyleneZ′R14, C2-C4alkenyleneZ′R14, C2-C4fluoroalkenyleneZ′R14, C2-C4deuteroalkenyleneZ′R14, C2-C4deuterofluoroalkenyleneZ′R14, C2-C4alkynyleneZ′R14, C2-C4fluoroalkynyleneZ′R14, C2-C4deuteroalkynyleneZ′R14, and C2-C4deuterofluoroalkynyleneZ′R14. In some embodiments, R10 is selected from C1-C4alkyleneZ′R14, C1-C4fluoroalkyleneZ′R14, C1-C4deuteroalkyleneZ′R14, C1-C4deuterofluoroalkyleneZ′R14, C2-C4alkenyleneZ′R14, and C2-C4alkynyleneZ′R14.
In some embodiments, R10 is selected from CH2Z′R14, CH2CH2Z′R14, CH2CH2CH2Z′R14, CH2CH2CH2CH2Z′R14, CH(CH3)CH2Z′R14, CH(CH3)CH2CH2Z′R14, CH2CH(CH3)Z′R14. CF2Z′R14, CFHZ′R14, CH2CHFZ′R14, CH2CF2Z′R14, CF2CF2Z′R14, CH2CH2CF2Z′R14, CH2CH2CFHZ′R14, CH2CH2CF2Z′R14, CH(CH3)CF2Z′R14, CH(CH3)CHFZ′R14, CH2CH2CH2CF2Z′R14, CH2CH2CH2CHFZ′R14, CH(CH3)CH2CF2Z′R14, CH(CH3)CH2CHFZ′R14, CD2Z′R14, CDHZ′R14, CH2CHDZ′R14, CH2CD2Z′R14, CD2CD2Z′R14, CH2CH2CD2Z′R14, CH2CH2CDHZ′R14, CH2CH2CD2Z′R14, CH(CH3)CD2Z′R14, CH(CH3)CHDZ′R14, CH2CH2CH2CD2Z′R14, CH2CH2CH2CHDZ′R14, CH(CH3)CH2CD2Z′R14, CH(CH3)CH2CHDZ′R14, CH═CHZ′R14, CH2CH═CHZ′R14, C≡CZ′R14, C≡CCH2Z′R14, CH2C≡CZ′R14, and CH2C≡CH2Z′R14. In some embodiments, R10 is selected from CH2Z′R14, CH2CH2Z′R14, CH2CH2CH2Z′R14, CH2CH2CH2CH2Z′R14, CH(CH3)CH2Z′R14, CH(CH3)CH2CH2Z′R14, CH2CH(CH3)Z′R14, CH═CHZ′R14, CH2CH═CHZ′R14, CH═CH2CHZ′R14, C≡CCH2Z′R14, CH2C≡CZ′R14, and CH2C≡CH2Z′R14.
In some embodiments, R10 is selected from C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, each of which is optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R10 is selected from C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, C1-C4alkyleneC5-C10heteroaryl, C1-C4fluoroalkyleneC3-C7cycloalkyl, C1-C4fluoroalkyleneC3-C10heterocycloalkyl, C1-C4fluoroalkyleneC6-C10aryl, C1-C4fluoroalkyleneC5-C10heteroaryl, C1-C4deuteroalkyleneC3-C7cycloalkyl, C1-C4deuteroalkyleneC3-C10heterocycloalkyl, C1-C4deuteroalkyleneC6-C10aryl, C1-C4deuteroalkyleneC5-C10heteroaryl, and C1-C4deuterofluoroalkyleneC3-C7cycloalkyl, C1-C4deuterofluoroalkyleneC3-C10heterocycloalkyl, C1-C4deuterofluoroalkyleneC6-C10aryl, and C1-C4deuterofluoroalkyleneC5-C10heteroaryl, in which each of the cyclic groups is optionally substituted with one to four substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R10 is selected from C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C2alkyleneC3-C7cycloalkyl, C1-C2alkyleneC3-C10heterocycloalkyl, C1-C2alkyleneC6-C10aryl, C1-C2alkyleneC5-C10heteroaryl, C1-C2fluoroalkyleneC3-C7cycloalkyl, C1-C2fluoroalkyleneC3-C10heterocycloalkyl, C1-C2fluoroalkyleneC6-C10aryl, C1-C2fluoroalkyleneC5-C10heteroaryl, C1-C2deuteroalkyleneC3-C7cycloalkyl, C1-C2deuteroalkyleneC3-C10heterocycloalkyl, C1-C2deuteroalkyleneC6-C10aryl, C1-C2deuteroalkyleneC5-C10heteroaryl, C1-C2deuterofluoroalkyleneC3-C7cycloalkyl, C1-C2deuterofluoroalkyleneC3-C10heterocycloalkyl, C1-C2deuterofluoroalkyleneC6-C10aryl, and C1-C2deuterofluoroalkyleneC5-C10heteroaryl, in which each of the cyclic groups is optionally substituted with one to four substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the C3-C7cycloalkyl in R10 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each or which is optionally substituted with one to four substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, the C3-C7cycloalkyl in R10 is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is optionally substituted with one to three substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, the C3-C7cycloalkyl in R10 is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is optionally substituted with one or two substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the C3-C10heterocycloalkyl in R10 is a monocyclic C3-C7heterocycloalkyl or a bicyclic C7-C10heterocycloalkyl, each of which is optionally substituted with one to four, one to three, or one or two, substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the monocyclic C3-C7heterocycloalkyl in R10 is selected from aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, 1,3-dioxolanyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2H-1λ3-thiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxothiolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, imidazolinyl, dioxolanyl, dithiolanyl, triazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, dihydropyranyl, isothiazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl dioxide, dioxanyl, thiazolinyl, thianyl, thianyl oxide, thianyl dioxide, dithianyl, azepanyl, pyrazolidinyl, oxepanyl, thiepanyl, diazepanyl, and 2,5-pyrrolidinedionyl (e.g., succinimidyl), each of which is optionally substituted with one to four substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, the monocyclic C3-C7heterocycloalkyl in R10 is selected from oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2H-1λ3-thiophenyl, pyrrolidinyl, imidazolidinyl, tetrahydropyranyl, dihydropyranyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, thianyl, thianyl oxide, thianyl dioxide, dithianyl, and 2,5-pyrrolidinedionyl, each of which is optionally substituted with one to three, or one or two, substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the bicyclic C7-C10heterocycloalkyl in R10 is selected from benzoisoxazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzopyranyl, benzothiopyranyl, chromanyl, isochromanyl, dihydroindenyl, isoindolinyl, 1-oxoisoindolinyl, 3-oxoisoindolinyl, 1,3-dioxoisoindolinyl (e.g., phthalimido), octahydroisoindolinyl, octahydro-isoindolin-1-onyl (e.g., tetrahydroisoquinoline), and hexahydroisoindoline-1,3-dionyl (e.g., cis-hexahydrophthalimidyl), each of which is optionally substituted with one to four substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, the bicyclic C7-C10heterocycloalkyl in R10 is selected from isoindolinyl, 1-oxoisoindolinyl, 3-oxoisoindolinyl, 1,3-dioxoisoindolinyl, octahydro-1H-isoindolinyl, octahydro-1H-isoindolin-1-onyl, and hexahydro-1H-isoindoline-1,3-dionyl, each of which is optionally substituted with one to three, or one or two, substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the C6-C10aryl in R10 is phenyl, optionally substituted with one to four, one to three, or one or two, substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the C5-C10heteroaryl in R10 is selected from azepinyl, benzofuranyl, benzofurazanyl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, thiazolyl, thienofuranyl, triazolyl, and thienyl (e.g., thiophenyl), each of which is optionally substituted with one to four, one to three, or one or two, substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the substituents on R10 are independently selected from one to four of F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CD2H, CDH2, CD3, CF3, CHF2, CH2F, CH2CH2F, CF2CF3, CH2CH2D, CH2CD2H, CD2CD3, OR15, and C(O)R15. In some embodiments, the substituents on R10 are independently selected from one to three of F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)2, CD2H, CDH2, CD3, CF3, CHF2, CH2F, OR15, and C(O)R15. In some embodiments, the substituents on R10 are independently selected from one or two of F, Cl, CH3, CH(CH3)2, CH(CH3)2, CF3, CHF2, CH2F, OR15, and C(O)R15.
In some embodiments, particularly when X is absent or O, as well as for X is S, S(O), or SO2, R6 is selected from C1-C4fluoroalkyl, C1-C4alkyleneZR12, and C1-C4fluoroalkyleneZR12 or R10 is selected from C1-C4fluoroalkyl, C1-C4alkyleneZ′R14, and C1-C4fluoroalkyleneZ′R14. In some embodiments, particularly when X is absent or O, as well as other embodiments, R6 is selected from C1-C4alkyleneZR12 and C1-C4fluoroalkyleneZR12 or R10 is selected from C1-C4alkyleneZ′R14 and C1-C4fluoroalkyleneZ′R14.
In some embodiments, particularly when X is absent or O, or when X is S, S(O), or SO2, Z′ is selected from NR17C(O), NR17C(O)O, C(O)NR17, OC(O)NR17, and NR17. In some embodiments, Z is selected from O, C(O), NR17C(O), and NR17C(O)O. In some embodiments, Z′ is O. In some embodiments, Z′ is C(O). In some embodiments, Z′ is NR17C(O). In some embodiments, Z′ is NR17C(O)O.
In some embodiments, R12 and R14 are independently selected from H, C1-C4alkyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, and C5-C10heteroaryl, the latter four groups being optionally substituted with one to four substituents independently selected from F, Cl, Br, C1-C4alkyl, OC1-C4alkyl, and C(O)C1-C4alkyl, and wherein available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof. In some embodiments, R12 and R14 are independently selected from H, C1-C4alkyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, and C5-C10heteroaryl, the latter four groups being optionally substituted with one to three substituents independently selected from F, Cl, C1-C4alkyl, and OC1-C4alkyl, and wherein available hydrogen atoms are optionally replaced with an iodine atom, a fluorine atom, and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R12 and R14 are independently selected from H, C1-C4alkyl, C3-C7-cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, and C5-C10heteroaryl, the latter four groups being optionally substituted with one to three substituents independently selected from F, Cl, C1-C4alkyl, and OC1-C4alkyl, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, R12 and R14 are independently selected from H and C1-C6alkyl, wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R12 and R14 are independently selected from H, D, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, and C1-C6deuterofluoroalkyl.
In some embodiments, R12 and R14 are independently selected from H, D, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, CF2H, CFH2, CF3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, C(CF3)3, C(CHF2)3, C(CFH2)3, CH2CH2CH2CF3, CH2CH(CF3)2, CH(CH3)CH2CF3, CD2H, CDH2, CD3, CH2CH2D, CH2CD2H, CH2CD3, CD2CD3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3, CH(CD3)2, CH(CHD2)2, CH(CDH2)2, C(CD3)3, C(CHD2)3, C(CDH2)3, CH2CH2CH2CD3, CH2CH(CD3)2, and CH(CH3)CH2CD3. In some embodiments, R12 and R14 are independently selected from H, D, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF2H, CFH2, CF3, CH2CH2F, CH2CF2H, CH2CF3, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, C(CF3)3, C(CHF2)3, C(CFH2)3, CD2H, CDH2, CD3, CH2CH2D, CH2CD2H, CH2CD3, CH(CD3)2, CH(CHD2)2, CH(CDH2)2, C(CD3)3, C(CHD2)3, and C(CDH2)3. In some embodiments, R12 and R14 are independently selected from H, D, CH3, CH(CH3)2, C(CH3)3, CF2H, CDF2, CF3, CD2H, CDH2, and CD3.
In some embodiments, R12 and R14 are independently selected from C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, and C5-C10heteroaryl, each of which is optionally substituted with one to four substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, and C(O)C1-C4alkyl, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the C3-C7cycloalkyl in R12 and/or R14 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which is optionally substituted with one to four substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, and C(O)C1-C4alkyl, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the C3-C10heterocycloalkyl in R12 and/or R14 is independently a monocyclic C3-C7heterocycloalkyl or a bicyclic C7-C10heterocycloalkyl, each of which is optionally substituted with one to four substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, and C(O)C1-C4alkyl, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the monocyclic C3-C7heterocycloalkyl in R12 and/or R14 is independently selected from aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, 1,3-dioxolanyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2H-1λ3-thiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxothiolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, imidazolinyl, dioxolanyl, dithiolanyl, triazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, dihydropyranyl, isothiazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl dioxide, dioxanyl, thiazolinyl, thianyl, thianyl oxide, thianyl dioxide, dithianyl, azepanyl, pyrazolidinyl, oxepanyl, thiepanyl, diazepanyl, and 2,5-pyrrolidinedionyl (e.g., succinimidyl), each of which is optionally substituted with one to four substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, and C(O)C1-C4alkyl, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, the monocyclic C3-C7heterocycloalkyl in R12 and/or R14 is independently selected from oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2H-1λ3-thiophenyl, pyrrolidinyl, imidazolidinyl, tetrahydropyranyl, dihydropyranyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, thianyl, thianyl oxide, thianyl dioxide, dithianyl, and 2,5-pyrrolidinedionyl, each of which is optionally substituted with one to four substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, and C(O)C1-C4alkyl, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the bicyclic C7-C10heterocycloalkyl in R12 and/or R14 is independently selected from benzoisoxazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzopyranyl, benzothiopyranyl, chromanyl, isochromanyl, dihydroindenyl, isoindolinyl, 1-oxoisoindolinyl, 3-oxoisoindolinyl, 1,3-dioxoisoindolinyl (e.g., phthalimido), octahydroisoindolinyl, octahydro-isoindolin-1-onyl (e.g., tetrahydroisoquinoline), and hexahydroisoindoline-1,3-dionyl (e.g., cis-hexahydrophthalimidyl), each of which is optionally substituted with one to four substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, and C(O)C1-C4alkyl, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, the bicyclic C7-C10heterocycloalkyl in R12 and/or R14 is independently selected from isoindolinyl, 1-oxoisoindolinyl, 3-oxoisoindolinyl, 1,3-dioxoisoindolinyl, octahydro-1H-isoindolinyl, octahydro-1H-isoindolin-1-onyl, and hexahydro-1H-isoindoline-1,3-dionyl, each of which is optionally substituted with one to four substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, and C(O)C1-C4alkyl, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the C6-C10aryl in R12 and/or R14 is independently phenyl, which is optionally substituted with one to four substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, and C(O)C1-C4alkyl, and wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, the C5-C10heteroaryl in R12 and/or R14 is independently selected from azepinyl, benzofuranyl, benzofurazanyl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, thiazolyl, thienofuranyl, triazolyl, and thienyl (e.g., thiophenyl), each of which is optionally substituted with one to four substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, and C(O)C1-C4alkyl, and wherein available hydrogen atoms are atoms are optionally replaced with deuterium.
In some embodiments, the substituents on R12 and/or R14 are independently selected from one to four, one to three, or one or two, of F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CD2H, CDH2, CD3, CF3, CHF2, CH2F, CH2CH2F, CF2CF3, CH2CH2D, CH2CD2H, CD2CD3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OC(CH3)3, OCD2H, OCDH2, OCD3, OCF3, OCHF2, OCH2F, OCH2CH2F, OCF2CF3, OCH2CH2D, OCH2CD2H, OCD2CD3, C(O)CH3, C(O)CH2CH3, C(O)CH2CH2CH3, C(O)CH(CH3)2, C(O)C(CH3)3, C(O)CD2H, C(O)CDH2, C(O)CD3, C(O)CF3, C(O)CHF2, C(O)CH2F, C(O)CH2CH2F, C(O)CF2CF3, C(O)CH2CH2D, C(O)CH2CD2H, and C(O)CD2CD3.
In some embodiments, R11, R13, R15, R16, and R17 are independently selected from H and C1-C4alkyl wherein available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof. In some embodiments, R11, R13, R15, R16, and R17 are independently selected from H and C1-C4alkyl wherein available hydrogen atoms are optionally replaced with an iodine atom, a fluorine atom, and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium. In some embodiments, R11, R13, R15, R16, and R17 are independently selected from H and C1-C4alkyl wherein available hydrogen atoms are optionally replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
In some embodiments, R11, R13, R15, R16, and R17 are independently selected from H, D, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, and C1-C4deuterofluoroalkyl. In some embodiments, R11, R13, R15, R16, and R17 are independently selected from H, D, F, Br, Cl, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2F, CH2CH3, CH2CH2F, CF2CF3, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R11, R13, R15, R16, and R17 are independently selected from H, CH3, CF3, CHF2, CD2H, CDH2, and CD3. In some embodiments, R11, R13, R15, R16, and R17 are independently selected from H, D, CH3, CF3, CHF2, CH2F, CD2H, CDH2, and CD3. In some embodiments, R11, R13, R15, R16, and R17 are independently selected from H, D, CH3, CF3, and CD3.
In some embodiments, particularly when X is selected from S, S(O), and SO2, as well for X being O or absent, R6 is selected from

    
    
        CH3, CD3, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2,
        CH2C(CH3)3, CH2CH2C(CH3)3,
        CH2F, CHF2, CH2CHF2, CH2CF3, CH2CH2CF3,
    
    






In some embodiments, R10 is selected from (particularly for when X is S, S(O), or SO2, as well as other embodiments in which X is O or is absent) or R6 and R10 are independently selected from (particularly for when X is absent or oxygen, as well as for other embodiments of X):

    
    
        H, CH3, CD3, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2,
        CH2C(CH3)3, CH2CH2C(CH3)3,
        CH2F, CHF2, CH2CHF2, CH2CF3, CH2CH2CF3,
        C1-C4alkyleneOCH3, C1-C4alkyleneOCHF2, C1-C4alkyleneOCH2F,
    
    






    
    
        C1-C4alkyleneC(O)CHF2, C1-C4alkyleneC(O)CF3,
    
    


















In the above embodiments and in other embodiments using the term herein, C1-C4alkylene includes, for example, —CH2, —CH2CH2—, —CH2CH2CH2, —CH2CH2CH2CH2—, —CH(CH3)CH2—, —CH2CH(CH3)—, —C(CH3)2—, —CH(CH3)CH2CH2—, —CH2CH(CH3)CH2—, —CH2CH2CH(CH3)—, —C(CH3)2CH2—, —CH2C(CH3)2—, and —CH(CH3)CH(CH3)—. Available hydrogen(s) on the C1-C4alkylene is/are optionally substituted with deuterium and/or one or more halogen atoms, for example but not limited to, —CF2—, —CBr2—, —CCl2—, —CHD-, —CD2-, —CDF—, —CF2CF2—, —CH2CD2-, —CD2CH2—, —CH2CHD-, —CHDCH2—, —CH2CHY—, —CHYCH2—, —CH2CY2—, —CY2CH2—, —CHYCHY—, —CHDCHY—, —CHYCHD-, —CD2CHY—, CHYCD2, —CHDCY2—, —CY2CHD-, —CY2CD2-, —CD2CY2—, —CD2CHD-, —CHDCD2-, —CD2CD2-, —CD2CD2CD2-, —CH2CD2CD2-, —CD2CH2CH2—, —CH2CH2CD2-, —CD2CD2CH2—, —CH2CD2CH2—, —CH2CH2CHD-, —CHDCHDCH2—, —CH2CHDCHD-, —CD2CD (CH3)—, —CD2CHDCH2—, —CH2CD (CH3)—, —CH2CHDCH2—, —CD2CH(CH3)—, —CHDCH2CH2—, —CHDCH(CH3)—, etc. (wherein each Y is independently selected from F, Cl, Br, and I).
In some embodiments, particularly when X is absent or oxygen, as well as for other embodiments in which X is S, S(O), or SO2, R10 in addition to the list above, is further independently H.
In some embodiments, the compound of Formula (I) is a compound of Formula (I-A):




    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof,
        wherein:
        X, n, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are as defined in Formula (I) including embodiments thereof, wherein X is selected from S, S(O), and SO2;
        available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof,
        provided when R9 is selected from halo and C1-C6alkyl, R10 is selected from H and C1-C6alkyl, n is 0, 1, 2, 3, or 4, and R6 is selected from H, substituted or unsubstituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, and C5-C10heteroaryl, then the compound does not comprise deuterium.
    
    


In some embodiments, the compound of Formula (I) is a compound of Formula (I-B):




    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof,
        wherein
        X, n, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are as defined in Formula (I) including embodiments thereof, wherein X is selected from S, S(O), and SO2; and
        available hydrogen atoms are optionally replaced with a halogen atom.
    
    


In some embodiments, the compound of Formula (I) is a compound of Formula (I-C):




    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof,
        wherein:
        each R9 is independently selected from OH, OC1-C6alkyl, C1-C6alkyleneOH, and C1-C6alkyleneOC1-C6alkyl;
        X, R1, R2, R3, R4, R5 R6, R7, R8, and R10, and n are as defined in Formula (I) including embodiments thereof, wherein X is selected from S, S(O), and SO2; and
        available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof.
    
    


In some embodiments, the compound of Formula (I) is a compound of Formula (I-D):




    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof,
        wherein:
        R10 is selected from C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6alkynyleneZ′R14, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR15, and C(O)R15;
        X, Z′, R1, R2, R3, R4, R5 R6, R7, R8, R9, R14, R15, and n are as defined in Formula (I) including embodiments thereof, wherein X is selected from S, S(O), and SO2; and available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof.
    
    


In some embodiments, the compound of Formula (I) is a compound of Formula (I-E):




    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof,
        wherein:
        R6 is selected from C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZR12, C2-C6alkenyleneZR12, C2-C6alkynyleneZR12, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, and C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13;
        X, Z, R1, R2, R3, R4, R5, R7, R8, R9, R10. R12, and R13, and n are as defined in Formula (I) including embodiments thereof, wherein X is selected from S, S(O), and SO2; and
        available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof.
    
    


In some embodiments, X is S and R2, R3, R4, and R5 are all H and the compound of Formula (I) is a compound of Formula (I-F). Accordingly, in some embodiments, the present disclosure includes a compound of Formula (I-F):




    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof,
        wherein:
        R6, R7, R8, R9, R10, and n are as defined in Formula (I) including embodiments thereof;
        wherein available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof.
    
    


In some embodiments, in the compound of Formula (I-F), R10 is selected from C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6alkynyleneZ′R14, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, I, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR15, and C(O)R15, wherein Z′, R14, and R15 are as defined in Formula (I) including embodiments thereof.
In some embodiments, the compound of Formula (I) is selected from one or more of the compounds listed in Table 1 below:








TABLE 1





Com-



pound
Structure







(R) I-1






 


(S) I-1






 


(R) I-2






 


(S) I-2






 


(R) I-3






 


(R) I-4






 


(R) I-5






 


(R) I-6






 


(R) I-7






 


(R, R) I-8






 


(R, S) I-8






 


(R, S) I-9






 


(R, R) I-9






 


(R) I-10






 


(R) I-11






 


(R) I-12






 


(R, S) I-13






 


(R, R) I-13






 


(R) I-14






 


trans (R) I-15






 


trans (R) I-16






 


(R, R) I-17






 


(R) I-18






 


(R) I-19






 


(R) I-20






 


(R) I-21






 


(R) I-22






 


(R) I-23






 


(R, S) I-24






 


(R, R) I-24






 


(R, S) I-25






 


(R, R) I-25






 


(R) I-26






 


(R) I-27






 


(R) I-28






 


(R) I-29






 


(R) I-30






 


(R) I-31






 


(R) I-32






 


(R) I-33






 


(R) I-34






 


(R) I-35






 


(R) I-36






 


(R) I-37






 


(R) I-38






 


(R) I-39






 


(R) I-40






 


(R, S) I-41






 


(R, R) I-41






 


(R, S) I-42






 


(R, R) I-42






 


(R) I-43






 


(R) I-44






 


(R) I-45






 


(R) I-46






 


(R) I-47






 


(R) I-48






 


(R) I-49






 


(R) I-50






 


(R) I-51






 


(R) I-52






 


(R) I-53






 


(R) I-54






 


(R) I-55






 


(R) I-56






 


(R) I-57






 


(R) I-58






 


(R) I-59






 


(R) I-60






 


(R) I-61






 


(R) I-62






 


(R) I-63






 


(R) I-64






 


(R) I-65






 


(R) I-66






 


(R) I-67






 


(R) I-68






 


(R) I-69






 


(R) I-70






 


(R) I-71






 


(R) I-72






 


(R) I-73






 


(R) I-74






 


(R) I-75






 


(R) I-76






 


(R) I-77






 


(R) I-78






 


(R) I-79






 


(R) I-80






 


(R) I-81






 


cis- (R) I-82






 


trans- (R) I-82






 


(R) I-83






 


(R) I-84






 


cis- (R) I-85






 


cis- (R) I-86






 


trans- (R) I-86






 


(R) I-87






 


(R) I-88






 


(R) I-89






 


(R) I-90






 


(R) I-91






 


(R) I-92






 


(R, S) I-93






 


(R, S) I-94






 


(R) I-95






 


(R) I-96






 



and


 


(R) I-97













    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof.
    
    


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









TABLE 2






Compound
Structure








II-1






 



(R) II-2






 



II-3






 



II-4






 



II-5






 



(R) II-6






 



(R) II-7






 



(R) II-8






 



(R) II-9






 



(R) II-10






 



(R) II-11






 



(R) II-12






 



(R) II-13






 



(R) II-14






 



(R) II-15






 



(R) II-16






 



(R) II-17






 



(R) II-18






 



(R) II-19






 



(R) II-20






 



(R) II-21






 



(R) II-22






 



(R) II-23






 



(R) II-24






 



(R) II-25






 



(R) II-26






 



(R) II-27






 



(R) II-28






 



(R) II-29






 



(R) II-30






 



(R) II-31






 



(R) II-32






 



(R) II-33






 



(R) II-34






 



(R) II-35






 



(R) II-36






 



(R) II-37






 



(R) II-38






 



(R) II-39






 



(R) II-40






 



(R) II-41






 



(R) II-42






 



(R) II-43






 



(R) II-44






 



(R) II-45






 



(R) II-46






 



(R) II-47






 



(R) II-48






 



(R) II-49






 



(R) II-50






 



(R) II-51






 



(R) II-52






 



(R) II-53






 



(R) II-54






 



(R) II-55






 




and


 



(R) II-56













    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof.
    
    


In some embodiments, the compound of Formula (I) is a compound of Formula (I-G):




    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof,
        wherein:
        X, n, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are as defined in Formula (I) including embodiments thereof, wherein X is absent or oxygen;
        available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof;
        provided when X is O, R9 is selected from halo and C1-C6alkyl, R10 is selected from H and C1-C6alkyl, n is 0, 1, 2, 3, or 4 and R6 is selected from H, substituted or unsubstituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, and C5-C10heteroaryl, then the compound does not comprise deuterium;
        provided when X is O, R1, R2, R3, R4, R5, R7, and R8 are H or D, n is 0, and R6 is H, CH3, or CD3, then R10 is not H, CH3, or CD3;
        provided when X is O, R1, R2, R3, R4, R5, R7, and R8 are H or D and n is 0, and R6 is CH3 or CHF2, then R10 is not H, CH3, or CD3; and
        provided when X is absent and R6 is H, then either n is not 0 or R10 is not H or C1-C6alkyl.
    
    


In some embodiments, the compound of Formula (I) is a compound of Formula (I-H):




    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof,
        wherein:
        X, n, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are as defined in Formula (I) including embodiments thereof, wherein X is absent or oxygen; and
        available hydrogen atoms are optionally replaced with a halogen,
        provided when X is O, R9 is halo, C1-C6alkyl or C1-C6haloalkyl, n is 0, 1, 2, 3, or 4, and R10 is H, C1-C6alkyl, or C1-C6haloalkyl, then R6 is not H, C1-C6alkyl, or C1-C6haloalkyl;
        provided when X is O, R1, R2, R3, R4, R5, R7, and R8 are H or D, n is 0 and R6 is H, CH3, or CD3, then R10 is not H, CH3, or CD3;
        provided when X is O, R1, R2, R3, R4, R5, R7, and R8 are H or D and n is 0, and R6 is CH3 or CHF2, then R10 is not H, CH3, or CD3; and
        provided when X is absent and R6 is H, then either n is not 0 or R10 is not H or C1-C6alkyl.
    
    


In some embodiments, the compound of Formula (I) is a compound of Formula (I-I):




    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof,
        wherein:
        n is an integer selected from 1, 2, 3, and 4;
        each R9 is independently selected from OH, OC1-C6alkyl, C1-C6alkyleneOH, and C1-C6alkyleneOC1-C6alkyl;
        X, R1, R2, R3, R4, R5, R6, R7, R8, and R10 are as defined in Formula (I) including embodiments thereof, wherein X is absent or oxygen; and
        available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof.
    
    


In some embodiments, the compound of Formula (I) is a compound of Formula (I-J):




    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof,
        wherein:
        R10 is selected from C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6alkynyleneZ′R14, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, and C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR15, and C(O)R15;
        X, Z′, R1, R2, R3, R4, R5, R6, R7, R8, R9, R14, R15, and n are as defined in Formula (I) including embodiments thereof, wherein X is absent or oxygen; and
        available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof.
    
    


In some embodiments, the compound of Formula (I) is a compound of Formula (I-K):




    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof,
        wherein:
        R6 is selected from C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZR12, C2-C6alkenyleneZR12, C2-C6alkynyleneZR12, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, and C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13;
        X, Z, R1, R2, R3, R4, R5, R7, R8, R9, R10, R12, R13, and n are as defined in Formula (I) including embodiments thereof, wherein X is absent or oxygen; and
        available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof.
    
    


In some embodiments, R2, R3, R4, and R5 are all H and the compound of Formula (I) is a compound of Formula (I-L). Accordingly, in some embodiments, the present disclosure includes a compound of Formula (I-L):




    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof,
        wherein:
        X, n, R6, R7, R8, R9, and R10 are as defined in Formula (I) including embodiments thereof, wherein X is absent or oxygen;
        available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof,
        provided when X is O, R7 and R8 are H or D, n is 0 and R6 is H, CH3, or CD3, then R10 is not H, CH3, or CD3;
        provided when X is O, R7 and R8 are H or D, n is 0, and R6 is CH3 or CHF2, then R10 is not H, CH3, or CD3; and
        provided when X is absent and R6 is H, then either n is not 0 or R10 is not H or C1-C6alkyl.
    
    


In some embodiments, X is absent and the compound of Formula (I) is a compound of Formula (I-M). Accordingly, in some embodiments, the present disclosure includes a compound of Formula (I-M):




    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof,
        wherein:
        X is absent;
        n, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are as defined in Formula (I) including embodiments thereof; and
        available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof,
        provided when R6 is H, then either n is not 0 or R10 is not H or C1-C6alkyl.
    
    


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








TABLE 3





Compound
Structure







(R) I-98






 


(R) I-99






 


(R) I-100






 


(R) I-101






 


(R,R) I-102






 


(R,S) I-102






 


(R,S) I-103






 


(R,R) I-103






 


(S) I-104






 


(R) I-105






 


(R) I-106






 


(R,S) I-107






 


(R,R) I-107






 


(R) I-108






 


Trans-(R) I-109






 


Trans (R) I-110






 


(R,R) I-111






 


(R) I-112






 


(R) I-113






 


(R) I-114






 


(R) I-115






 


(R) I-116






 


(R) I-117






 


(R,S) I-118






 


(R,R) I-118






 


(R,R) I-119






 


(R,S) I-119






 


(R) I-120






 


(R) I-121






 


(R) I-122






 


(R) I-123






 


(R) I-124






 


(R) I-125






 


(R) I-126






 


(R) I-127






 


(R) I-128






 


(R) I-129






 


(R) I-130






 


(R) I-131






 


(R) I-132






 


(R) I-133






 


(R) I-134






 


(R,S) I-135






 


(R,R) I-135






 


(R,S) I-136






 


(R,R) I-136






 


(R) I-137






 


(R) I-138






 


(R) I-139






 


(R) I-140






 


(R) I-141






 


(R) I-142






 


(R) I-143






 


(R) I-144






 


(R) I-145






 


(R) I-146






 


(R) I-147






 


(R) I-148






 


(R) I-149






 


(R) I-150






 


(R) I-151






 


(R) I-152






 


(R) I-153






 


(R) I-154






 


(R) I-155






 


(R) I-156






 


(R) I-157






 


(R) I-158






 


(R) I-159






 


(R) I-160






 


(R) I-161






 


(R) I-162






 


(R) I-163






 


(R) I-164






 


(R) I-165






 


Cis (R) I-166






 


Trans (R) I-167






 


(R) I-168






 


(R) I-169






 


Cis (R) I-170






 


Cis (R) I-171






 


Trans (R) I-172






 


(R) I-173






 


(R) I-174






 


(R) I-175






 


(R) I-176






 


(R) I-177






 


(R,S) I-178






 


(R,S) I-179






 


(R,R) I-180






 


(R) I-181






 


(R) I-182






 


(R) I-183






 


(R) I-184






 


(R) I-185






 


(R) I-186






 


(R) I-187






 


(R) I-188






 


(R) I-189






 


(R) I-190






 


(R) I-191






 


(R) I-192






 


(R) I-193






 


(R) I-194






 


(R) I-195






 


(R) I-196






 


(R) I-197






 


(R) I-198






 


(R) I-198-A






 


(R) I-199






 


(R) I-200






 


(R) I-201






 


(R) I-202






 


(R) I-203






 


(R) I-204






 


(R) I-205






 


(R) I-206






 


(R) I-207






 


(R) I-208






 


(R) I-209






 


(R) I-210






 


(R) I-211






 


(R) I-212






 


(R) I-213






 


(R) I-214






 


(R) I-215






 


(R) I-216






 


(R) I-217






 


(R) I-218






 


(R) I-219






 


(R) I-220






 


(R) I-221






 


(R) I-222






 


(R) I-223






 


(R) I-224






 


(R) I-225






 


(R) I-226






 


(R) I-227






 


(R) I-228






 


(R) I-229






 


(R) I-230






 


(R) I-231






 


(R) I-232






 


(R) I-233






 


(R) I-234






 


Cis (R) I-235






 


Cis (R) I-236






 


(R) I-237






 


(R) I-238






 


(R) I-239






 


Cis (R) I-240






 


Trans (R) I-241






 


(R) I-242






 


(R) I-243






 


(R) I-244






 


(R) I-245






 


Cis (R) I-246






 


Cis (R) I-247






 


Cis (R) I-248






 


Rac (R) I-248






 


(R) I-249













    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof.
    
    


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









TABLE 4





Compound
Structure
IUPAC Name







(R) I-250




(R)-4-fluoro-5-methoxy-3- ((1-methylpyrrolidin-2- yl)methyl)-1H-indole


 


(R) I-251




(R)-4-fluoro-5-methoxy-3- ((1-(methyl-d3)pyrrolidin-2- yl)methyl)-1H-indole


 


(R) I-252




(R)-7-fluoro-5-methoxy-3- ((1-methylpyrrolidin-2- yl)methyl)-1H-indole


 


(R) I-253




(R)-7-fluoro-5-methoxy-3- ((1-(methyl-d3)pyrrolidin-2- yl)methyl)-1H-indole


 


(R) I-254




(R)-5-methoxy-6-methyl-3- ((1-methylpyrrolidin-2- yl)methyl)-1H-indole


 


(R) I-255




(R)-5-methoxy-6-methyl-3- ((1-(methyl-d3)pyrrolidin-2- yl)methyl)-1H-indole


 


(R) I-256




(R)-6-fluoro-5-methoxy-3- ((1-methylpyrrolidin-2- yl)methyl)-1H-indole


 










(R) I-257





(R)-6-fluoro-5-methoxy-3- ((1-(methyl-d3)pyrrolidin-2- yl)methyl)-1H-indole and 


 


(R) I-258





(R)-5-methoxy-1-methyl-3- ((1-methylpyrrolidin-2- yl)methyl)-1H-indole









    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof.
    
    










TABLE 5





Compound
Structure







(R) I-259






 


(R) I-260






 


(R) I-261






 


(R) I-262






 


(R) I-263






 


(R) I-264






 


(R) I-265






 


(R) I-266






 


(R) I-267






 


(R) I-268






 


(R) I-269






 


(R) I-270






 


(R) 1-271






 


(R) I-272






 


(R) I-273






 


(R) I-274






 


(R) I-275






 


(R) I-276






 


(R) I-277






 


(R) I-278






 


(R) I-279






 


(R) I-280






 


(R) I-281






 


(R) I-282






 


(R) I-283






 


(R) I-284






 


(R) I-285






 


(R) I-286






 


(R) I-287






 


(R) I-288






 


(R) I-289






 


(R) I-290






 


(R) I-291






 


(R) I-292






 


(R) I-293






 


(R) I-294






 


(R) I-295






 


(R) I-296






 


(R) I-297






 


(R) I-298






 


(R) I-299






 


(R) I-300






 


(R) I-301






 


(R) I-302






 


(R) I-303






 


(R) I-304






 


(R) I-305






 


(R) I-306






 


(R) I-307






 


(R) I-308






 


(R) I-309






 


(R) I-310






 


(R) I-311






 


(R) I-312






 


(R) I-313



 and


 


(R) I-314













    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof.
    
    


In some embodiments, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. The selection of a suitable salt may be made by a person skilled in the art. Suitable salts include acid addition salts that may, for example, be formed by mixing a solution of a compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Additionally, acids that are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) and Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley VCH; S. Berge et al, Journal of Pharmaceutical Sciences 1977 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food and Drug Administration, Washington, D.C. on their website).
An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound. Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di-, and tricarboxylic acids. Illustrative of such organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In some embodiments, exemplary acid addition salts also include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates (“mesylates”), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates), and the like. In some embodiments, the mono- or di-acid salts are formed and such salts exist in either a hydrated, solvated, or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the disclosure for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound. Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide as well as ammonia. Illustrative organic bases which 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, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The selection of the appropriate salt may be useful, for example, so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art. In some embodiments, exemplary basic salts also include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, butyl amine, choline, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen containing groups may be quarternized 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 sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. Compounds carrying 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 quaternary ammonium salts. Also, in the case of an acid (—COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the disclosure and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the disclosure. In addition, when a compound of the disclosure contains both a basic moiety, such as, but not limited to an aliphatic primary, secondary, tertiary, or cyclic amine, an aromatic or heteroaryl amine, pyridine, or imidazole and an acidic moiety, such as, but not limited to tetrazole or carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the terms “salt(s),” as used herein. It is understood that certain compounds of the disclosure may exist in zwitterionic form, having both anionic and cationic centers within the same compound and a net neutral charge. Such zwitterions are included within the disclosure.
Solvates of compounds of the disclosure include, for example, those made with solvents that are pharmaceutically acceptable. Examples of such solvents include water (resulting solvate is called a hydrate) and ethanol and the like. Suitable solvents are physiologically tolerable at the dosage administered.
Prodrugs of the compounds of the present disclosure include, for example, conventional esters formed with available hydroxy, thiol, amino, or carboxyl groups. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates, and amino acid esters.
It is understood and appreciated that in some embodiments, compounds of the present disclosure may have at least one chiral center and therefore can exist as enantiomers and/or diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present disclosure. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the present disclosure having an alternate stereochemistry. It is intended that any optical isomers, as separated, pure, or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present disclosure.
In some embodiments, the compounds of the present disclosure can also include tautomeric forms, such as keto-enol tautomers and the like. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. It is intended that any tautomeric forms which the compounds form, as well as mixtures thereof, are included within the scope of the present disclosure.
The compounds of the present disclosure may further exist in varying amorphous and polymorphic forms and it is contemplated that any amorphous forms, polymorphs, or mixtures thereof, which form are included within the scope of the present disclosure.
In the compounds of general Formula (I) and pharmaceutically acceptable salts, solvates, and/or prodrug thereof, the atoms may exhibit their natural isotopic abundances, or one or more of the 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 predominantly found in nature. The present disclosure is meant to include all suitable isotopic variations of the compounds of the disclosure and pharmaceutically acceptable salts, solvates, and/or prodrug thereof. For example, different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H), and tritium (3H). Protium is the predominant hydrogen isotope found in nature.
The compounds of the present disclosure may further be radiolabeled and accordingly all radiolabeled versions of the compounds of the disclosure are included within the scope of the present disclosure. Therefore, the compounds of the disclosure also include those in which one or more radioactive atoms are incorporated within their structure.
III. Compositions
The compounds of the present disclosure are suitably formulated in a conventional manner into compositions using one or more carriers. Accordingly, the present disclosure also includes a composition comprising one or more compounds of the disclosure and a carrier. The compounds of the disclosure are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present disclosure further includes a pharmaceutical composition comprising one or more compounds of the disclosure and a pharmaceutically acceptable carrier. In embodiments of the disclosure the pharmaceutical compositions are used in the treatment of any of the diseases, disorders, or conditions described herein.
The compounds of the disclosure are administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, a compound of the disclosure is administered by oral, inhalation, parenteral, buccal, sublingual, insufflation, epidurally, nasal, rectal, vaginal, patch, pump, minipump, topical, or transdermal administration and the pharmaceutical compositions formulated accordingly. In some embodiments, administration is by means of a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000—20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF 19) published in 1999.
Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract and includes, for example intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal, and topical (including the 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.
In some embodiments, a compound of the disclosure is orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it is enclosed in hard- or soft-shell gelatin capsules, or it is compressed into tablets, or it is incorporated directly with the food of the diet. In some embodiments, the compound is incorporated with excipient(s) and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions, suspensions, and the like. In the case of tablets, carriers that are used include lactose, corn starch, sodium citrate, and salts of phosphoric acid. Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); wetting agents (e.g., sodium lauryl sulphate); and/or solvents (e.g., medium chain triglycerides, ethanol, or water). In embodiments, the tablets are coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets, or granules for oral administration, pH sensitive enteric coatings, such as Eudragits™, designed to control the release of active ingredients are optionally used. Oral dosage forms also include modified release, for example 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), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. Timed-release compositions are formulated, for example, as liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. In some embodiments, liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. For oral administration in a capsule form, useful carriers, solvents, or diluents include lactose, medium chain triglycerides, ethanol, and dried corn starch.
In some embodiments, liquid preparations for oral administration take the form of, for example, solutions, syrups, or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and/or emulsions are administered orally, the compound of the disclosure is suitably suspended or dissolved in an oily phase that is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents are added. Such liquid preparations for oral administration are prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., medium chain triglycerides, almond oil, oily esters, or ethyl alcohol); and/or preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.
It is also possible to freeze-dry the compounds of the disclosure and use the lyophilizates obtained, for example, for the preparation of products for injection.
In some embodiments, a compound of the disclosure is administered parenterally. For example, solutions of a compound of the disclosure are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the disclosure are usually prepared and the pH's of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments, or droppable liquids are delivered, for example, by ocular delivery systems known to the art such as applicators or eye droppers. In some embodiments, such compositions include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose, or polyvinyl alcohol, preservatives such as sorbic acid, EDTA, or benzyl chromium chloride, and the usual quantities of diluents or carriers. For pulmonary administration, diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.
In some embodiments, a compound of the disclosure is formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection are, for example, presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In some embodiments, the compositions take such forms as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles and contain formulating agents such as suspending, stabilizing, and/or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. Alternatively, the compounds of the disclosure are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels, and powders. For intranasal administration or administration by inhalation, the compounds of the disclosure are conveniently delivered in the form of a solution, dry powder formulation, or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which, for example, take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which is, for example, a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide, or another suitable gas. 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, for example, formulated containing a powder mix of a compound of the disclosure and a suitable powder base such as lactose or starch. The aerosol dosage forms can also take the form of a pump-atomizer.
Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein a compound of the disclosure is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin, and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
Suppository forms of the compounds of the disclosure are useful for vaginal, urethral, and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include but are not limited to theobroma oil (also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. See, for example: Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms.
In some embodiments a compound of the disclosure is coupled with soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, a compound of the disclosure is coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.
A compound of the disclosure including pharmaceutically acceptable salts, solvates, and/or prodrugs thereof is suitably used on their own but will generally be administered in the form of a pharmaceutical composition in which the one or more compounds of the disclosure (the active ingredient) is in association with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05 wt % to about 99 wt %, or about 0.10 wt % to about 70 wt %, of the active ingredient and from about 1 wt % to about 99.95 wt %, or about 30 wt % to about 99.90 wt % of a pharmaceutically acceptable carrier, all percentages by weight being based on the total composition.
In some embodiments, the compounds of the disclosure including pharmaceutically acceptable salts, solvates, and/or prodrugs thereof are used are administered in a composition comprising an additional therapeutic agent. Therefore, the present disclosure also includes a pharmaceutical composition comprising one or more compounds of the disclosure, or pharmaceutically acceptable salts, solvates, and/or prodrugs thereof and an additional therapeutic agent, and optionally one or more pharmaceutically acceptable excipients. In some embodiments, the additional therapeutic agent is another known agent useful for treatment of a disease, disorder, or condition by activation of a serotonin receptor, for example those listed in the Methods and Uses section below. In some embodiments, the additional therapeutic agent is a psychoactive drug.
In the above, the term “a compound” also includes embodiments wherein one or more compounds are referenced.
IV. Methods and Uses of the Disclosure
The compounds of the disclosure are serotonergic binding agents that act as agonists or partial agonists at a serotonin receptor.
Accordingly, the present disclosure includes a method for activating a serotonin receptor in a cell, either in a biological sample or in a patient, comprising administering an effective amount of one or more compounds of the disclosure to the cell. The disclosure also includes or of one or more compounds of the disclosure for activating a serotonin receptor in a cell as well as use of one or more compounds of the disclosure for the preparation of a medicament for activating a serotonin receptor in a cell. The disclosure further includes one or more compounds of the disclosure for use in activating a serotonin receptor in a cell. In some embodiments, the method for activating a serotonin receptor is in or on a cell.
As the compounds of the disclosure are capable of activating a serotonin receptor, the compounds of the disclosure are useful for treating diseases, disorders, or conditions by activating a serotonin receptor. Therefore, the compounds of the present disclosure are useful as medicaments. Accordingly, the disclosure also includes a compound of the disclosure for use as a medicament.
The present disclosure also includes a method of treating a disease, disorder, or condition by activation of a serotonin receptor comprising administering a therapeutically effective amount of one or more compounds of the disclosure to a subject in need thereof.
The present disclosure also includes use of one or more compounds of the disclosure for treatment of a disease, disorder, or condition by activation of a serotonin receptor as well as use of one or more compounds of the disclosure for the preparation of a medicament for treatment of a disease, disorder, or condition by activation of a serotonin receptor. The disclosure further includes one or more compounds of the disclosure for use in treating a disease, disorder, or condition by activation of a serotonin receptor.
In some embodiments, the serotonin receptor is 5-HT2A. Accordingly, the present disclosure includes a method for activating 5-HT2A in a cell, either in a biological sample or in a patient, comprising administering an effective amount of one or more compounds of the disclosure to the cell. The disclosure also includes use of one or more compounds of the disclosure for activating 5-HT2A in a cell as well as use of one or more compounds of the disclosure for the preparation of a medicament for activating 5-HT2A in a cell. The disclosure further includes one or more compounds of the disclosure for use in activating 5-HT2A in a cell. In some embodiments, the method for activating 5-HT2A is in or on a cell.
The present disclosure also includes a method of treating a disease, disorder, or condition by activation of 5-HT2A comprising administering a therapeutically effective amount of one or more compounds of the disclosure to a subject in need thereof. The present disclosure also includes use of one or more compounds of the disclosure for treatment of a disease, disorder, or condition by activation of 5-HT2A as well as use of one or more compounds of the disclosure for the preparation of a medicament for treatment of a disease, disorder, or condition by activation of 5-HT2A. The disclosure further includes one or more compounds of the disclosure for use in treating a disease, disorder, or condition by activation of 5-HT2A.
In some embodiments, the compounds of the disclosure are useful for preventing, treating, and/or reducing the severity of a mental illness disorder and/or condition in a subject. Therefore, in some embodiments, the disease, disorder, or condition that is treated by activation of a serotonin receptor is a mental illness. Accordingly, the present disclosure also includes a method of treating a mental illness comprising administering a therapeutically effective amount of one or more compounds of the disclosure to a subject in need thereof. The present disclosure also includes use of one or more compounds of the disclosure for treatment a mental illness, as well as use of one or more compounds of the disclosure for the preparation of a medicament for treatment of a mental illness. The disclosure further includes one or more compounds of the disclosure for use in treating a mental illness.
In some embodiments, the mental illness 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 thoughts; mood disorders, such as depression, bipolar disorder, cancer-related depression, major depressive disorder (MDD), treatment-resistant depression (TRD), postpartum depression (PPD), anxiety, and cyclothymic disorder; psychotic disorders, such as hallucinations, delusions, and schizophrenia; impulse control, and addiction disorders, such as pyromania (starting fires), kleptomania (stealing), and compulsive gambling; alcohol addiction (e.g., reduction in alcohol consumption); drug addiction, such as opioid addiction; personality disorders, such as antisocial personality disorder, obsessive-compulsive personality disorder, and paranoid personality disorder; obsessive-compulsive disorder (OCD), such as thoughts or fears that cause a subject to perform certain rituals or routines; 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; factitious disorders; sexual and gender disorders, such as sexual dysfunction, gender identity disorder and the paraphilia's; somatic symptom disorders, formerly known as a psychosomatic disorder or somatoform disorder; body dysmorphic disorder; influencing goal-directed behavior; emotional state disorders (e.g., diminishment of negative emotions and promoting positive emotions); enhancements in creativity; and combinations thereof.
In some embodiments, the disease, disorder, or condition that is treated by activation of a serotonin receptor comprises cognitive impairment (e.g., amplifies cognitive capabilities, enhance and/or improve cognitive flexibility); ischemia including stroke; neurodegeneration; refractory substance use disorders; sleep disorders; pain, such as social pain, acute pain, cancer pain, chronic pain, breakthrough pain, bone pain, soft tissue pain, nerve pain, referred pain, phantom pain, neuropathic pain, cluster headaches, and migraine; obesity and eating disorders; epilepsies and seizure disorders; neuronal cell death; excitotoxic cell death; inflammation (e.g., autoimmune neuroinflammation); or a combination thereof.
In some embodiments, the mental illness is selected from hallucinations and delusions and a combination thereof.
In some embodiments, the hallucinations are selected from visual hallucinations, visual disorders (e.g., Prosopometamorphopsia (PMO), influencing facial recognition, and improving the processing of emotional faces in treatment-resistant depression (TRD)), auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, and chronoceptive hallucinations, and a combination thereof.
In some embodiments, the disease, disorder, or condition that is treated by activation of a serotonin receptor is psychosis or psychotic symptoms. Accordingly, the present disclosure also includes a method of treating psychosis or psychotic symptoms comprising administering a therapeutically effective amount of one or more compounds of the disclosure to a subject in need thereof.
The present disclosure also includes use of one or more compounds of the disclosure for treatment of psychosis or psychotic symptoms, as well as use of one or more compounds of the disclosure for the preparation of a medicament for treatment of psychosis or psychotic symptoms. The disclosure further includes one or more compounds of the disclosure for use in treating psychosis or psychotic symptoms.
In some embodiments, administering to said subject in need thereof a therapeutically effective amount of the compounds of the disclosure does not result in a worsening of psychosis or psychotic symptoms such as, but not limited to, hallucinations and delusions. In some embodiments, administering to said subject in need thereof a therapeutically effective amount of the compounds of the disclosure results in an improvement of psychosis or psychotic symptoms such as, but not limited to, hallucinations and delusions. In some embodiments, administering to said subject in need thereof a therapeutically effective amount of the compounds of the disclosure results in an improvement of psychosis or psychotic symptoms.
In some embodiments, the disease, disorder, or condition that is treated by activation of a serotonin receptor is a central nervous system (CNS) disease, disorder, or condition and/or a neurological disease, disorder, or condition. Accordingly, the present disclosure also includes a method of treating a CNS disease, disorder, or condition and/or a neurological disease, disorder, or condition that is treated by activation of a serotonin receptor comprising administering a therapeutically effective amount of one or more compounds of the disclosure to a subject in need thereof, that is a subject having the central nervous system (CNS) disease, disorder, or condition and/or a neurological disease, disorder, or condition. The present disclosure also includes use of one or more compounds of the disclosure for treatment a CNS disease, disorder, or condition and/or a neurological disease, disorder, or condition that is treated by activation of a serotonin receptor, as well as use of one or more compounds of the disclosure for the preparation of a medicament for treatment of a CNS disease, disorder, or condition and/or a neurological disease, disorder, or condition that is treated by activation of a serotonin receptor. The disclosure further includes one or more compounds of the disclosure for use in treating a CNS disease, disorder, or condition and/or a neurological disease, disorder, or condition that is treated by activation of a serotonin receptor.
In some embodiments the CNS disease, disorder, or condition, and/or neurological disease, disorder, or condition is selected from neurological diseases including neurodevelopmental diseases and neurodegenerative diseases such as Alzheimer's disease (e.g., restoring mGluR2 expression); presenile dementia; senile dementia; vascular dementia; Lewy body dementia; cognitive impairment; Parkinson's disease and Parkinsonian related disorders such as Parkinson's dementia, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infections; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disorders; Fragile X syndrome; Angelman syndrome; hereditary ataxias; neuro-otological and eye movement disorders; neurodegenerative diseases of the retina amyotrophic lateral sclerosis; tardive dyskinesias; hyperkinetic disorders; attention deficit hyperactivity disorder, and attention deficit disorders; restless leg syndrome; Tourette's syndrome; schizophrenia; autism spectrum disorders; tuberous sclerosis; Rett syndrome; cerebral palsy; disorders of the reward system including eating disorders such as anorexia nervosa (“AN”), and bulimia nervosa (“BN”); and binge eating disorder (“BED”); pica; rumination disorder; avoidant/restrictive food intake disorder; trichotillomania; dermotillomania; nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology; reduction in convergent thinking; increase in spontaneous divergent thinking and goal-oriented divergent thinking; and combinations thereof.
The present disclosure also includes a method of treating nonpsychiatric conditions, such as: fibromyalgia, irritable bowel syndrome (IBS), Fragile X, short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUHNA), chronic cluster, persistent post-concussive syndrome (PPCS), Alzheimer's disease, Lyme disease, neuropathic pain, migraines, Parkinson's disease, cluster headache, stroke, traumatic brain injury (TBI), pain, obesity, and smoking cessation.
In some embodiments, the subject is a mammal. In another embodiment, the subject is human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is canine. In some embodiments, the subject is feline. Accordingly, the compounds, methods, and uses of the present disclosure are directed to both human and veterinary diseases, disorders, and conditions.
In some embodiments, the “subject in need thereof” is a subject having the disease, disorder, or condition to be treated.
In some embodiments, the compounds of the disclosure are useful for treating behavioral problems in subjects that are felines or canines.
Therefore, in some embodiments, the disease, disorder, or condition that is treated by activation of a serotonin receptor is behavioral problems in subjects that are felines or canines. Accordingly, the present disclosure also includes a method of treating a behavioral problem comprising administering a therapeutically effective amount of one or more compounds of the disclosure to a non-human subject in need thereof. The present disclosure also includes use of one or more compounds of the disclosure for treatment of a behavioral problem in a non-human subject, as well as use of one or more compounds of the disclosure for the preparation of a medicament for treatment of a behavioral problem in a non-human subject. The disclosure further includes one or more compounds of the disclosure for use in treating a behavioral problem in a non-human subject.
In some embodiments, the behavioral problems are selected from, but are not limited to, anxiety, fear, stress, sleep disturbances, cognitive dysfunction, aggression, excessive noise making, scratching, biting, and a combination thereof.
In some embodiments, the non-human subject is canine. In some embodiments, the non-human subject is feline.
The present disclosure also includes a method of treating a disease, disorder, or condition by activation of a serotonin receptor comprising administering a therapeutically effective amount of one or more compounds of the disclosure in combination with another known agent useful for treatment of a disease, disorder, or condition by activation of a serotonin receptor to a subject in need thereof. The present disclosure also includes use of one or more compounds of the disclosure in combination with another known agent useful for treatment of a disease, disorder, or condition by activation of a serotonin receptor for treatment of a disease, disorder, or condition by activation of a serotonin receptor, as well as use of one or more compounds of the disclosure in combination with another known agent useful for treatment of a disease, disorder, or condition by activation of a serotonin receptor for the preparation of a medicament for treatment of a disease, disorder, or condition by activation of a serotonin receptor. The disclosure further includes one or more compounds of the disclosure in combination with another known agent useful for treatment of a disease, disorder, or condition by activation of a serotonin receptor for use in treating a disease, disorder, or condition by activation of a serotonin receptor.
In some embodiments, the disease, disorder, or condition that is treated by activation of a serotonin receptor is a mental illness. In some embodiments, the mental illness is selected from hallucinations and delusions and a combination thereof. In some embodiments, the disease, disorder, or condition that is treated by activation of a serotonin receptor is a central nervous system (CNS) disorder. In some embodiments, the disease, disorder, or condition that is treated by activation of a serotonin receptor is psychosis or psychotic symptoms. In some embodiments, the disease, disorder, or condition that is treated by activation of a serotonin receptor is behavioral problems in a non-human subject.
In some embodiments, the disease, disorder, or condition that is treated by activation of a serotonin receptor is a mental illness and the one or more compounds of the disclosure are administered in combination with one or more additional treatments for a mental illness. In some embodiments, the additional treatments for a mental illness is selected from antipsychotics, including typical antipsychotics and atypical antipsychotics; antidepressants including selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and monoamine oxidase inhibitors (MAOIs) (e.g., bupropion); anti-anxiety medication including benzodiazepines such as alprazolam; mood stabilizers such as lithium; and anticonvulsants such as carbamazepine, divalproex (valproic acid), lamotrigine, gabapentin, and topiramate.
In some embodiments, the disease, disorder, or condition that is treated by activation of a serotonin receptor is selected from attention deficit hyperactivity disorder and attention deficit disorder and a combination thereof. In some embodiments, the disease, disorder, or condition that is treated by activation of a serotonin receptor is attention deficit hyperactivity disorder and/or attention deficit disorder and a combination thereof and the one or more compounds of the disclosure are administered in combination with one or more additional treatments for attention deficit hyperactivity disorder and/or attention deficit disorder and a combination thereof. In some embodiments, the additional treatments for attention deficit hyperactivity disorder and/or attention deficit disorder are selected from methylphenidate, atomoxetine, amphetamine, and a combination thereof.
In some embodiments, the disease, disorder, or condition that is treated by activation of a serotonin receptor is dementia or Alzheimer's disease and the one or more compounds of the disclosure are administered in combination with one or more additional treatments for dementia or Alzheimer's disease. In some embodiments, the additional treatments for dementia and Alzheimer's disease are selected from acetylcholinesterase inhibitors, NMDA antagonists, and muscarinic agonists and antagonists, and nicotinic agonists.
In some embodiments, the acetylcholinesterase inhibitors are selected from donepezil, galantamine, rivastigmine, phenserine, and combinations thereof.
In some embodiments, the NMDA antagonists are selected from MK-801, ketamine, phencyclidine, memantine, and combinations thereof.
In some embodiments, the nicotinic agonist is nicotine, nicotinic acid, nicotinic alpha7 agonist, alpha2 beta4 agonist, or combinations thereof.
In some embodiments, the muscarinic agonist is a muscarinic M1 agonist, a muscarinic M4 agonist, or combinations thereof.
In some embodiments, the muscarinic antagonist is a muscarinic M2 antagonist.
In some embodiments, the disease, disorder, or condition that is treated by activation of a serotonin receptor is psychosis or psychotic symptoms and the one or more compounds of the disclosure are administered in combination with one or more additional treatments for psychosis or psychotic symptoms. In some embodiments, the additional treatments for psychosis or psychotic symptoms are selected from typical antipsychotics and atypical antipsychotics.
In some embodiments, the typical antipsychotics are selected from acepromazine, acetophenazine, benperidol, bromperidol, butaperazine, carfenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, dixyrazine, droperidol, fluanisone, flupentixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, lenperone, loxapine, mesoridazine, metitepine, molindone, moperone, oxypertine, oxyprotepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, piperacetazine, pipotiazine, prochlorperazine, promazine, prothipendyl, spiperone, sulforidazine, thiopropazate, thioproperazine, thioridazine, thiothixene, timiperone, trifluoperazine, trifluperidol, triflupromazine, zuclopenthixol, and combinations thereof.
In some embodiments, the atypical antipsychotics are selected from amoxapine, amisulpride, aripiprazole, asenapine, blonanserin, brexpiprazole, cariprazine, carpipramine, clocapramine, clorotepine, clotiapine, clozapine, iloperidone, levosulpiride, lurasidone, melperone, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpiride, sultopride, tiapride, veralipride, ziprasidone, zotepine, and combinations thereof.
In some embodiments, the disease, disorder, or condition that is treated by activation of a serotonin receptor is a mental illness and the one or more compounds of the disclosure are administered in combination with one or more additional treatments for a mental illness. In some embodiments, the additional treatment for a mental illness is selected from typical antipsychotics and atypical antipsychotics.
In some embodiments, effective amounts vary according to 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 compounds that will correspond to an effective amount will vary depending upon factors, such as the given drug(s) or compound(s), the pharmaceutical formulation, the route of administration, the type of condition, disease, or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.
In some embodiments, the compounds of the disclosure are administered one, two, three, or four times a year. In some embodiments, the compounds of the disclosure are administered at least once a week. However, in another embodiment, the compounds are administered to the subject from about one time per one week, two weeks, three weeks, or one month. In another embodiment, the compounds are administered about one time per week to about once daily. In another embodiment, the compounds are administered 1, 2, 3, 4, 5, or 6 times daily. The length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder, or condition, the age of the subject, the concentration and/or the activity of the compounds of the disclosure and/or a combination thereof. It will also be appreciated that the effective dosage of the compound used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration is required. For example, the compounds are administered to the subject in an amount and for duration sufficient to treat the subject.
In some embodiments, the compounds of the disclosure are administered at doses that are hallucinogenic or psychotomimetic and taken in conjunction with psychotherapy or therapy and may occur once, twice, three, or four times a year. However, in some embodiments, the compounds are administered to the subject once daily, once every two days, once every 3 days, once a week, once every two weeks, once a month, once every two months, or once every three months at doses that are not hallucinogenic or psychotomimetic.
A compound of the disclosure is either used alone or in combination with other known agent(s) useful for treating diseases, disorders, or conditions by activation of a serotonin receptor, such as the compounds of the disclosure. When used in combination with other known agents useful in treating diseases, disorders, or conditions by activation of a serotonin receptor, it is an embodiment that a compound of the disclosure is administered contemporaneously with those agents. As used herein, “contemporaneous administration” of two substances to a subject means providing each of the two substances so that they are both active in the individual at the same time. The exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other and can include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of administration of the other, if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art. In particular embodiments, two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances. It is a further embodiment of the present disclosure that a combination of agents is administered to a subject in a non-contemporaneous fashion. In some embodiments, a compound of the present disclosure is administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising one or more compounds of the disclosure, an additional therapeutic agent and/or a pharmaceutically acceptable carrier.
The dosage of a compound of the disclosure varies depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration, the age, health, and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment, and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. In some embodiments, one or more compounds of the disclosure are administered initially in a suitable dosage that is adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of the one or more compounds of the disclosure from about 0.01 μg/cc to about 1000 μg/cc, or about 0.1 μg/cc to about 100 μg/cc. As a representative example, oral dosages of one or more compounds of the disclosure will range between about 10 μg per day to about 1000 mg per day for an adult, suitably about 10 μg per day to about 500 mg per day, more suitably about 10 μg per day to about 200 mg per day. For parenteral administration, a representative amount is from 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 will be administered. For oral administration, a representative amount is from 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 representative amount is from 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 disclosure, compositions are formulated for oral administration and the one or more compounds are suitably in the form of tablets 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 active ingredient (one or more compounds of the disclosure) per tablet. In some embodiments of the disclosure the one or more compounds of the disclosure are administered in a single daily, weekly, or monthly dose or the total daily dose is divided into two, three, or four daily doses.
In some embodiments, the compounds of the disclosure are used or administered in an effective amount which comprises administration of doses or dosage regimens that are devoid of clinically meaningful psychedelic/psychotomimetic actions. In some embodiments, the compounds of the disclosure are used or administered in an effective amount which comprises administration of doses or dosage regimens that provide clinical effects similar to those exhibited by a human plasma psilocin Cmax of 4 ng/ml or less and/or human 5-HT2A human CNS receptor occupancy of 40% or less or those exhibited by a human plasma psilocin Cmax of 1 ng/ml or less and/or human 5-HT2A human CNS receptor occupancy of 30% or less. In some embodiments, the compounds of the disclosure are used or administered in an effective amount which comprises administration of doses or dosage regimens that provide clinical effects similar to those exhibited by a human plasma psilocin Tmax in excess of 60 minutes, in excess of 120 minutes or in excess of 180 minutes.
To be clear, in the above, the term “a compound” also includes embodiments wherein one or more compounds are referenced. Likewise, the term “compounds of the disclosure” also includes embodiments wherein only one compound is referenced.
V. Preparation of Compounds
Compounds of the present disclosure can be prepared by various synthetic processes. The choice of particular structural features and/or substituents may influence the selection of one process over another. The selection of a particular process to prepare a given compound of the disclosure is within the purview of the person of skill in the art. Some starting materials for preparing compounds of the present disclosure are available from commercial chemical sources or may be extracted from cells, plants, animals, or fungi. Other starting materials, for example as described below, are readily prepared from available precursors using straightforward transformations that are well known in the art. In the Schemes below showing some embodiments of methods of preparation of compounds of the disclosure, all variables are as defined in Formula (I), unless otherwise stated.
In some embodiments, the compounds of Formula (I) are prepared as shown in Scheme I.




Therefore, ortho-iodoanilin compounds of Formula (A) are coupled with suitable unsaturated precursors such as disubstituted alkyne compound of Formula (B) in the presence of a catalyst, such as a Pd catalyst, to provide a compound of Formula (I) through known methods, for example, using the Pd catalysis procedure found in Chem. Eur. J. 2019, 25, 897-903.
In some embodiments, the compounds of Formula (I) are synthesized according to Scheme II.




Therefore, a substituted indole compound of Formula (C) is coupled with a suitable pyrrolidine carboxylic acid compound of Formula (E) in the present of suitable coupling reagents such as oxalyl chloride to provide compounds of Formula (D). The compounds of Formula (D) are reduced with suitable reducing agents such as Al-based reducing agents to provide the compounds of general Formula (I).
In some embodiments, the compounds of Formula (I) are synthesized according to Scheme III




In some embodiments, as shown in Scheme III, the compounds of Formula (I) are prepared using known methods, for example using the synthetic procedures found in Gerasimov et al., J. Med. Chem. 1999, 42, 4257-4263 and/or Macor et al., J. Med. Chem. 1992, 35, 4503-4505. Therefore, a substituted indole compound of Formula (C) is brominated with a suitable brominated reagent such as N-bromosuccinimide (NBS) to provide brominated indole compounds of Formula (F). The compounds of Formula (F) are coupled with a suitable pyrrolidine carboxylic acid compound of Formula (E) in the present of suitable coupling reagents such as oxalyl chloride to provide compounds of Formula (D). The compounds of Formula (D) are reduced with suitable reducing agents such as Al-based reducing agents to provide the compounds of general Formula (I).
In some embodiments, compounds of Formula (C) wherein X is S are prepared as shown in Scheme IV.




Therefore, in some embodiments, as shown in Scheme IV, compounds of Formula (C) wherein X is S are synthesized by coupling the indole of compound (G) wherein Hal is halide, such as I or Br with a thiol compound of Formula R6SH under suitable coupling conditions such as in the presence of a suitable catalyst such as a palladium catalyst (e.g., bis(dibenzylideneacetone)palladium(0) (Pd(dba)2)), ligand (e.g., 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthen (Xantphos)), and base such as ethyldiisopropylamine in a suitable inert solvent such as dioxane.
In some embodiments, compounds of Formula (C) wherein X is S are synthesized using methods known in the art as shown in Scheme IV, for example, the methods described in Shmatova, O. I., Eur. J. Org. Chem. 2015, 6479-6488.
In some embodiments, compounds of Formula (C) wherein X is S are prepared as shown in Scheme V.




Therefore, in some embodiments, as shown in Scheme V, compounds of Formula (C) wherein X is S are synthesized by the desulfenylation of a compound of Formula (H) wherein Y is a suitable alkyl or aryl group in the presence of trifluoroacetic acid and a thiol as trapping agent, such as methyl thiosalicylate.
In some embodiments, compounds of Formula (C) wherein X is S are prepared as shown in Scheme V using methods known in the art, for example, the methods described in Hamel, P., J. Org. Chem. 1994, 59, 6372-6377.
In some embodiments, compounds of Formula (C) wherein X is S are prepared as shown in Scheme VI.




Therefore, in some embodiments, as shown in Scheme VI, compounds of Formula (C) wherein X is S are synthesized using the Fischer indole synthesis method. For example, in some embodiments, hydrazine compounds of compound J are reacted with pyruvic acid under suitable conditions such as in the presence of zinc chloride and phosphorus pentachloride to provide the compounds of Formula (C).
In some embodiments, compounds of Formula (C) wherein X is S are prepared as shown in Scheme VI using methods known in the art, for example, the methods described in Bratulescu, G., Letters 49 (2008) 984-986.
In some embodiments, compounds of Formula (I) wherein X is S(O) (compounds of Formula I(b)) and X is SO2 (compounds of Formula I(c)) are prepared from compounds of Formula (I) wherein X is S (compounds of Formula I(a)) according to Scheme VII.




In some embodiments, as shown in Scheme VII, compounds of Formula (I) wherein X is S (compounds of Formula I(a)) are oxidized to compounds of Formula (I) wherein X is S(O) compounds of Formula I(b)) under suitable oxidizing conditions such about one equivalent of meta-chloroperoxybenzoic acid (m-CPBA). Compounds of Formula (I) wherein X is S(O) (compounds of Formula I(b)) are then oxidized under suitable oxidizing conditions such as meta-chloroperoxybenzoic acid (m-CP BA) to compounds of Formula (I) wherein X is SO2 (compounds of Formula I(c)).
In some embodiments, compounds of Formula (I) wherein X is S(O) (compounds of Formula I(b)) and X is SO2 (compounds of Formula I(c)) are prepared from compounds of Formula (I) wherein X is S (compounds of Formula I(a)) as shown in Scheme VII using methods known in the art, for example, the methods described in United States patent application 2004/0043965.
In some embodiments, compounds of Formula (C) wherein X is S and R6 is CD3 (compounds of Formula C′) are prepared as shown in Scheme VIII.




Therefore, in some embodiments, as shown in Scheme VII, compounds of Formula (C) wherein X is S and R6 is CD3 (compounds of Formula (C′)) are synthesized by coupling the indole of compound (G) wherein Hal is I (compound of Formula G′) in the presence of a suitable catalyst such as a nickel based catalyst (e.g., nickel acetate) with a suitable electrophilic SCD3 reagent such as S-(methyl-D3) 4-methylbenzenesulfonothioate




    
    
         in the presence of a suitable reductant such as zinc powder and a base such as 2,2-bipyridyl to provide compounds of Formula (C) wherein X is S and R6 is CD3 (compounds of Formula C′).
    
    


In some embodiments, compounds of Formula (C) wherein X is S and R6 is CD3 (compounds of Formula C′) as shown ins Scheme VII are synthesized using methods known in the art, for example, the methods described in Zhang, Y., Org. Lett. 2022, 24, 6794-6799.
Compounds of Formula (I), wherein one or more of R1-R5 are deuterium are available, for example, using a hydrogen-deuterium exchange reaction on a suitable starting substrate, wherein this exchange reaction is catalyzed by Pd/C in D2O as described in Esaki, H. et al., Tetrahedron, 2006, 62:10954-10961, and modifications thereof known to a person skilled in the art.
Especially for embodiments in which X is absent or oxygen, as well as for other embodiments of X, compounds of Formula (I) wherein X—R6 is OCD3 are available, for example, using methods as described in Xu, Y-Z and Chen, C. J. Label Compd. Radiopharm. (2006) 49:897-902, and modifications thereof and modifications thereof known to a person skilled in the art.
A person skilled in the art would appreciate that further manipulation of the substituent groups using known chemistry can be performed on the intermediates and final compounds in the Schemes above to provide alternative compounds of the disclosure.
For example, especially for embodiments in which X is S, S(O), or SO2, as well as for other embodiments of X, a person skilled in the art would appreciate that R1 is H in a compound of Formula (I), then the compound of Formula (I) wherein R1 is H can be further reacted to prepare further compounds of Formula (I). For example, the compound of Formula (I) wherein R1 is H can be alkylated with an alkyl halide in the presence of suitable based such as NaH, NaOtBu, or LiHMDS.
For example, especially for embodiments in which X is absent or oxygen, as well as for other embodiments of X, a person skilled in the art would appreciate that R1 is H in compounds C and D above (see, e.g., Schemes II and III) resulting in a compound of Formula (I) wherein R1 is H, then the compound of Formula (I) wherein R1 is H can be further reacted to prepare further compounds of Formula (I). For example, the compound of Formula (I) wherein R1 is H can be alkylated with an alkyl halide in the presence of suitable based such as NaH, NaOtBu, or LiHMDS.
Salts of compounds of the disclosure may be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the disclosure with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in aqueous medium followed by lyophilization.
The formation of solvates will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art. Examples of suitable solvents are ethanol, water, and the like. When water is the solvent, the molecule is referred to as a “hydrate.” The formation of solvates of the compounds of the disclosure will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.
Isotopically-enriched compounds of the disclosure and pharmaceutically acceptable salts, solvates, and/or prodrug thereof, can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using suitable isotopically-enriched reagents and/or intermediates.
Throughout the processes described herein it is to be understood that, where appropriate, suitable protecting groups will be added to and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in “Protective Groups in Organic Synthesis,” T. W. Green, P. G. M. Wuts, Wiley-Interscience, New York, (1999). It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examples of transformations are given herein and itis to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations—A Guide to Functional Group Preparations,” R. C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry,” March, 4th ed. McGraw Hill (1992) or, “Organic Synthesis,” Smith, McGraw Hill, (1994). Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.
It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examples of transformations are given herein, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations-A Guide to Functional Group Preparations,” R. C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry,” March, 4th ed. McGraw Hill (1992) or, “Organic Synthesis,” Smith, McGraw Hill, (1994).
Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation, and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.
The products of processes disclosed in the disclosure may be isolated according to known methods, for example, the compounds may be isolated by evaporation of the solvent, by filtration, centrifugation, chromatography, or other suitable method.
Prodrugs of the compounds of the present disclosure may be, for example, conventional esters formed with available hydroxy, thiol, amino, or carboxyl groups. For example, available hydroxy or amino groups may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g., an acid chloride in pyridine).
One skilled in the art will recognize that where a reaction step of the present disclosure is carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
EXAMPLES
The following non-limiting examples are illustrative of the present disclosure.
General Methods
All starting materials used herein were commercially available or earlier described in the literature. The 1H and 13C NMR spectra were measured using a Bruker 300, Bruker DPX400, or Varian +400 spectrometer operating at 300, 400, and 400 MHz for 1H NMR respectively. TMS or the residual solvent signal was used as an internal reference; deuterated chloroform was used as the solvent unless otherwise indicated. All reported chemical shifts are in ppm on the delta-scale, and the fine splitting of the signals as appearing in the recordings is generally indicated, for example as s: singlet, br s: broad singlet, d: doublet, t: triplet, q: quartet, m: multiplet. Unless otherwise indicated, in the tables below, 1H NMR data was obtained at 400 MHZ, using CDCl3 as the solvent.
Purification of products was carried out using Chem Elut Extraction Columns (Varian, cat #1219-8002), Mega BE-SI (Bond Elut Silica) SPE Columns (Varian, cat #12256018; 12256026; 12256034) or by flash chromatography in silica-filled glass columns.
IUPAC names were generated with CHEMDRAW Professional 22.2.0 64-bit.
The following compounds were prepared using one or more of the synthetic methods outlined in Schemes I and II.
Part I
A. Synthesis of Exemplary Compounds of the Disclosure
Example 1: (R)-3-((1-Methylpyrrolidin-2-yl)methyl)-5-(methylthio)-1H-indole ((R) I-1)




Synthesis of (R)-2-(2-(5-(methylthio)-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenylethan-1-one (2)
A solution of 1-(2-oxo-2-phenylethyl)-D-proline (3.0 g, 12.03 mmol) in dry THF (50 mL) was treated with thionyl chloride (1.75 mL, 24.07 mmol) at 0° C. The reaction was brought to room temperature, then refluxed for 2 h. The reaction was brought to room temperature, solvent was evaporated and crude was dried under vacuum to obtain the corresponding acid chloride.
A solution of 5-(methylthio)-1H-indole (1.96 g, 12.03 mmol) in dry CH2Cl2 (50 mL) at 5-10° C. was treated with above crude acid chloride in dry CH2Cl2 (30 mL) and ethyl magnesium bromide (8.0 mL, 24.07 mmol, 3 M in THF (tetrahydrofuran)) simultaneously over a period of 15 min. and stirred at same temperature for further 15 min. The reaction was quenched with con. HCl (5 mL) followed by water (50 mL) and product was extracted into CH2Cl2 (2×50 mL). CH2Cl2 layer was washed with sat. NaHCO3 solution (50 mL), brine (25 mL), and dried (Na2SO4). Solvent was evaporated and crude was purified by flash column chromatography (CH2Cl2 to EtOAc: CH2Cl2, 1:4) on silica gel to obtain the title compound 2 (6.67 g, 75.3%) as a light brown foam. 1H NMR (DMSO-d6): δ 12.07, 12.05 (2s, 1H), 8.47, 8.44 (2d, 1H, J=6.0 Hz), 8.16, 8.12 (2s, 1H), 7.47-7.33 (m, 3H), 7.23-7.01 (m, 3H), 5.25-4.90 (m, 3H), 3.55-3.50 (m, 2H), 3.34 (s, 3H), 2.45-2.29 (m, 1H), 1.91-1.84 (m, 3H); ESI-MS (m/z, %): 453 (100), 417 (M+Na).
Synthesis of (R)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(methylthio)-1H-indole ((R) I-1)
A solution of (R)-2-(2-(5-(methylthio)-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenylethan-1-one (2.5 g, 6.33 mmol) in dry THF (50 mL) was treated with LiAlH4 (1.2 g, 31.68 mmol) at 0° C. over a period of 10 min. The reaction was brought to room temperature and then refluxed for overnight (16 h). The reaction was cooled to 0° C., quenched with water (1.2 mL), 4 N NaOH solution (1.2 mL) and water (1.2 mL). The reaction was brought to room temperature and stirred for additional 30 min. The reaction was filtered through a pad of sodium sulfate and washed with THF (3×25 mL). Combined THF layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) on silica gel to obtain the title compound (R) I-1 (1.53 g, 88.4%) as a pale-yellow solid. 1H NMR (DMSO-d6): δ 10.84 (s, 1H), 7.47 (s, 1H), 7.30 (d, 1H, J=6.0 Hz), 7.15 (s, 1H), 7.07 (dd, 1H, J=3.0, 6.0 Hz), 3.04-2.95 (m, 2H), 2.50-2.31 (m, 8H), 2.14-2.07 (m, 1H), 1.74-1.40 (m, 4H); ESI-MS (m/z, %): 261 (MH+, 100).
B. Biological Testing
Example 2: Human 5-HT2A: Functional Fluorometric Imaging Plate Reader (FLIPR) Assay
Objective
The potential excitatory effects of compounds targeting human 5-hydroxytryptamine receptor 2A (5-HT2A) under agonist mode was assessed.
1 Materials and Instrumentation
1.1 Cell Line (Table 6)















Cell line Name
Target
Host cell









HTR2A&Gα15-HEK293
5-HT2A
FIp-In-293










1.2 Materials (Table 7)
















Regents
Vendor
Cat#









DMEM
Gibco
10569-010



Dialyzed FBS
BIOSUN
BS-0005-500



Penicillin-Streptomycin
Invitrogen
15140



Hygromycin B
Invivogen
Ant-hg-5



Tetracycline
Abcam
ab141223



hydrochloride



TrypLE ™Express
Gibco
12604-013



DPBS
Gibco
14190250



DMSO
Millipore
1029312500



Probenecid
Sigma
P8761



FLIPR Calcium 6 Assay
Molecular Device
R8191



Kit



HEPES
Invitrogen
15630



Hank's Buffered Saline
Invitrogen
14025



Solution



Serotonin HCl
Selleck
S4244










1.3 Instrumentation and Consumables (Table 8)













Item
Supplier
Cat#







Fluorometric Imaging Plate Reader
Molecular Device
Tetra


(FLIPR)


Countess Automated Cell Counter
Invitrogen
Countess


Cell Counting Chamber Slides
Invitrogen
C10312


STERI-CYCLE CO2 Incubator
Thermo
371


1300 Series Class II Biological
Thermo
1389


Safety Cabinet


Table-type Large Capacity Low
Cence
L550


Speed Centrifuge


Centrifuge
Eppendorf
5702


Echo
Labcyte
550


Echo
Labcyte
655


Electro-thermal incubator
Shanghai Yiheng
DHP-9031


plate shaker
IKA
MS3 digital


Water Purification System
ULUPURE
UPH-III-20T


Versatile and Universal pH and
Mettler Toledo
S220


Conductivity Meters


384-Well plate
Corning
3764


384-Well LDV Clear microplate
LABCYTE
LP-0200


384-Well Polypropylene microplate
LABCYTE
PP-0200


384-well compound plate
Corning
3657


T25 cell culture flask
Corning
430639


50 mL Polypropylene Centrifuge Tube
JET
CFT011500


15 mL Polypropylene Centrifuge Tube
JET
CFT011150









2 Experimental Methods
2.1 Cell Culture
HTR2A&Gα15-HEK293 cells were cultured in DMEM medium containing 10% dialyzed FBS and 1× penicillin-streptomycin, 100 μg/mL Hygromycin B and 300 μg/mL G418. The cells were passaged about three times a week, maintained between ˜30% to ˜90% confluence.
2.2 Cell Plating
1. The 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 to room temperature was warmed in advance.
2. For induction, 1 μg/ml tetracycline (final concentration) was added to cell culture medium and incubated for 48 hours prior to seeding cells into plate at 37° C., 5% (v/v) CO2. The cell culture medium was removed from flask. Cells were washed with DP BS.
3. 2 mL TrypLE™ Express was added to the flask, mixed well by gentle shaking and cells were incubated at 37° C. for a few minutes.
4. The cells were checked for morphological change under microscope, the digestion was stopped by adding 4 mL cell culture medium to the flask when most of cells turned to round.
5. The cell suspension was transferred into a 15 mL centrifuge tube, and then centrifuged at 1,200 rpm for 5 minutes.
6. The supernatant was removed. The cell pellet was resuspended with 2 ml cell culture medium.
7. The cell density was counted using cell counter. Only cells with >85% viability were used for the assay.
8. Cells were diluted to 6.67×105/mL with cell culture medium.
9. 30 μL/well cell suspensions added into a 384-well cell plate (The cell density was 20,000 cells/well).
10. The cell plate was incubated overnight at 37° C., 5% (v/v) CO2.
2.3 Cell Handling
On the day of experiments, culture medium was removed from the cell plate.
10 μL of assay buffer (20 mM HEPES, in 1×HBSS, pH 7.4) was added to each well of the cell plate.
2× dye solution was prepared following the manual of the FLIPR® Calcium 6 Assay Kit:

    
    
        i. The dye was diluted with assay buffer.
        ii. Probenecid was added to the final concentration of 5 mM.
        iii. Vortexed vigorously for 1-2 minutes.
    
    


4. 10 μL of 2× dye solution was added to each well of the cell plate
5. The cell plate was placed on plate shaker, followed by shaking at 600 rpm for 2 minutes.
6. The plate was incubated at 37° C. for 2 hours followed by an additional 15-minute incubation at 25° C.
2.4 Prepare 3× Compound.
1. Serotonin HCl was prepared to the concentration of 10 mM with DMSO.
2. The test compounds were prepared to the concentration of 10 mM with DMSO.
3. The compounds were added to a 384-well compound source plate.
4. 3-folds serial dilutions were performed with DMSO.
5. 90 nL/well of serial diluted compounds was transferred from source plate to a 384-well compound plate by using an Echo.
6. 30 μL/well of assay buffer (20 mM HEPES in 1×HBSS, pH 7.4) was added to the compound plate.
7. The plate was mixed on-plate shaker for 2 minutes.
2.5 FLIPR Assay
1. After the cells were incubated with dye solution, the cell plate, compound plate containing 3× compounds and FLIPR tips were placed into FLIPR.
2. 10 μL of 3× compounds transferred from the compound plate to the cell plate by FLIPR.
3. The plate was read for 160 sec with 1 sec interval and the data of agonist mode was obtained.
3 Data Analysis
1. The normalized fluorescence reading (RFU) was calculated as shown below, wherein Fmax and Fmin stand for maximum and minimum of calcium signal during defined time window:



 
  RFU
  =
  
   
    F
    max
   
   -
   
    F
    min
   
  
 



2. EC50 by fitting RFU against log of compound concentrations with Hill equation was calculated using XLfit.
Results and Discussion
The results of potential competition binding properties of the exemplary compounds of the disclosure targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A) are summarized in Table 9. The results of exemplary compounds of the disclosure are presented as EC50 is provided in Table 9.
Table 9: Effect of Exemplary Compounds of Formula (I) Using FLIPR Functional Assay on Human 5-HT2A Receptor















Example
h5-HT2A, EC50 [nM]
RFU@10 μM (1)




















5-MeO-DMT
63
5,667



DMT
163
3,493



(R) I-1
47
5,663







(1) Curve fitting with activation (%) @ 10 mM with RFU






Exemplary compounds of Formula (I) were evaluated using FLIPR functional assay on human 5-HT2A receptor. EC50 (nM) concentrations are illustrated in Table 9. This assay confirms that compounds of the disclosure are effective agonists of the target human 5-HT2A receptors.
Example 2A: Human-5-HT2A-β-Arrestin Assay
Protocol
Compound potency (EC50) and efficacy (Max response) against the human 5-HT2A receptor in stably transfected U2OS cells were determined in a G protein-coupled receptors (GPCR) cell based β-arrestin reporter assay.
Cells were seeded in a total volume of 20 μL into white walled, 384-well microplates and incubated at 37° C. overnight before analysis. For agonist determination, cells were incubated with samples to induce response. Intermediate dilution of sample stocks was performed to generate 5× samples in assay buffer. 5 μL of 5× samples were added to cells and incubated at 37° C. for 120 minutes. The final assay vehicle concentration was 1%. The results are expressed as percent efficacy relative to the maximum response of the control ligand (serotonin) in Table 10.







TABLE 10







Effect of exemplary compounds of Formula (I) using


a β-arrestin reporter assay on human 5-HT2A receptor











Compound ID
EC50 (μM)
Emax (% of serotonin)















DMT
0.1136
38.86



5MeO-DMT
0.02945
72.41



(R) I-1
0.025396
79.27










Example 2B: Human-5HT1A-CAMP Assay
Protocol
Compound potency (EC50) and efficacy (Max response) against the human 5-HT1A receptor in stably transfected CHO-K1 cells were determined in a GPCR cell-based CAMP assay.
Cells were seeded in a total volume of 20 μL into white walled, 384-well microplates and incubated at 37° C. overnight before analysis. Prior to testing, cell plating media was exchanged with 10 μL of Assay buffer (HBSS+10 mM HEPES). Briefly, intermediate dilution of sample stocks were performed to generate 4× sample in assay buffer. 5 μL of 4× samples+5 μL of 4× forskolin were added to cells and incubated at 37° C. for 30 minutes (mins). The final assay vehicle concentration was 1%. The results are expressed as percent efficacy relative to the maximum response of the control ligand (serotonin) in Table 11.







TABLE 11







Effect of exemplary compounds of Formula (I) using


cAMP functional assay on human 5-HT1A receptor











Compound ID
EC50 (μM)
Emax (% of serotonin)















DMT
0.97437
87.1



5MeO-DMT
0.012699
99.98



(R) I-1
0.011138
99.41










Example 2C: Human-5HT2B FLIPR Assay
Protocol
Compound potency (EC50) and efficacy (Max response) against the human 5-HT2B receptor in stably transfected HEK293 cells were determined in a calcium mobilization-based assay.
Cells were seeded in a total volume of 20 μL into white walled, 384-well microplates and incubated at 37° C. overnight. Prior to testing, cell plating media was exchanged with 20 μL of Dye Loading buffer (HBSS+20 mM HEPES containing 1× Dye, 1× Additive A, and 2.5 mM Probenecid). Plates were incubated at 37° C. for 45 mins followed by 15 mins at room temperature.
10 μL of assay buffer (HBSS+20 mM HEPES) were added to cells. Intermediate dilution of sample stocks was performed to generate 4× samples in assay buffer. Assay plates and compound plates were loaded into the FLIPR instrument. 10 μL of sample was added using the FLIPR onboard robotics after 5 seconds of starting calcium measurement. A final assay vehicle concentration was 1%. The results are expressed as percent efficacy relative to the maximum response of the control ligand (serotonin) in Table 12.







TABLE 12







Effect of exemplary compounds of Formula (I) using


FLIPR functional assay on human 5-HT2B receptor











Compound ID
EC50 (μM)
Emax (% of serotonin)















DMT
>10
13.4



5MeO-DMT
0.015452
28.88



(R) I-1
0.0027402
62.94










Example 2D: Human-5HT2C FLIPR Assay
Protocol
Compound potency (EC50) and efficacy (Max response) against the human 5-HT2C receptor in stably transfected U2OS cells was determined in a calcium mobilization-based assay.
Cells were seeded in a total volume of 20 μL into white walled, 384-well microplates and incubated at 37° C. overnight. Prior to testing, cell plating media was exchanged with 20 μL of Dye Loading buffer (HBSS+20 mM HEPES containing 1× Dye, 1× Additive A, and 2.5 mM Probenecid). Plates were incubated at 37° C. for 45 mins followed by 15 mins at room temperature.
10 μL of assay buffer (HBSS+20 mM HEPES) was added to cells. Intermediate dilution of sample stocks were performed to generate 4× samples in assay buffer. Assay plates and compound plates were loaded into the FLIPR instrument. 10 μL of sample was added using the FLIPR onboard robotics after 5 seconds of starting calcium measurement. The final assay vehicle concentration was 1%. The results are expressed as percent efficacy relative to the maximum response of the control ligand (serotonin) in Table 13.







TABLE 13







Effect of exemplary compounds of Formula (I) using


FLIPR functional assay on human 5-HT2C receptor











Compound ID
EC50 (μM)
Emax (% of serotonin)















DMT
0.01112
94.56



5MeO-DMT
0.0027312
95.42



(R) I-1
0.00060025
95.27










Example 2E: Human-5HT2B Positive Allosteric Modulator (PAM) Assay
Protocol
Compound potency (EC50) and efficacy (Max response) against the human 5-HT2B receptor in stably transfected HEK293 cells were determined in a GPCR cell-based assay.
For Positive Allosteric Modulator determination, cells were pre-incubated with sample followed by EC20 addition. Intermediate dilution of sample stocks were performed to generate 5× samples in assay buffer. 5 μL of 5× samples were added to cells and incubated at 37° C. for 10 mins. 5 μL of agonist at 6×EC20 concentration was added and cells were incubated at 37° C. for 120 mins. Final assay vehicle concentration was 1%. The results are expressed as percent efficacy relative to the maximum response of the control ligand (serotonin) in Table 14.







TABLE 14







Effect of exemplary compounds of Formula (−I)


using PAM functional assay on human 5-HT2B receptor











Compound ID
EC50 (μM)
Emax (% of serotonin)















DMT
>10
0



5MeO-DMT
>10
0



(R) I-1
>10
0










Example 3: Human 5-HT2A: Radioligand Binding Assay
Objective
The objective of this study was to evaluate the binding properties of exemplary compounds of Formula (I) on 5-hydroxytryptamine receptor 2A (5-HT2A).
1 Materials and Instrumentation
1.1 Regents (Table 15)












Items
Vendor
Cat#







Ketanserin Hydrochloride,
PerkinElmer
NET791250UC


[Ethylene-3H]−


Ketanserin
MedChemExpress
HY-10562


Bovine Serum Albumin (BSA)
Sigma
A1933


Calcium chloride (CaCl2)
Sigma
C5670


Tris(hydroxymethyl)aminomethane
Alfa Aesar
A18494


(Tris)


Polyethylenimine, branched (PEI)
Sigma
408727









1.2 Instrumentation and Consumables (Table 16)













Item
Supplier
Cat#







Microbeta2 Microplate Counter
PerkinElmer
2450-0060


UniFilter-96 GF/B
PerkinElmer
6005177


TopSeal
Biotss
SF-800


MicroBeta Filtermate-96
PerkinElmer
D961962


Seven Compact pH meter
Mettler Toledo
S220


Ultrapure Water Meter
Sichuan Ulupure
UPH-III-20T


Benchtop Centrifuge
Hunan Xiangyi
L550


Microplate Shaker
Allsheng
MX100-4A


384-Well Polypropylene
Labcyte
PP-0200


Microplate


96 Round Well Plate
Corning
3799


96 Round Deep Well Plate
Axygen
P-DW-11-C


Echo
LABCYTE
550









2 Experimental Methods
1. The assay buffer was prepared following Table 17 below.














Reagent
Concentration









Tris
50 mM



CaCl2
 4 mM



BSA
0.1% (w/v)







Adjust pH to 7.4 followed by 0.2 μM sterile filtration






2. 8 doses of reference and test compounds starting from 10 mM stock solution as required were prepared by 5-fold serial dilutions with 100% (v/v) DMSO.
3. UniFilter-96 GF/B plate was pretreated:

    
    
        i. 50 μl/well of 0.5% (v/v) PEI was added to UniFilter-96 GF/C plates. The plates were sealed and incubated at 4° C. for 3 hours (hrs).
        ii. After incubation, the plates were washed 3 times with ice-cold wash buffer (50 mM Tris, pH7.4).
    
    


4. The assay plate was prepared:

    
    
        i. Cell membrane was diluted with assay buffer and 330 μl/well was added to 96 round deep well plates to reach a concentration of 20 μg/well.
        ii. 8 concentrations of reference or test compounds were prepared and 110 μl/well was added to 96 round deep well plates.
        iii. [3H]-ketanserin was diluted with assay buffer to 5 nM (5× final concentration) and 110 μl/well was added to 96 round deep well plates.
    
    


5. The plate was centrifuged at 1000 rpm for 30 seconds (secs) and then agitated at 600 rpm at room temperature for 5 min.
6. The plates were sealed and the plate incubated at 27° C. for 90 min.
7. The incubation was stopped by vacuum filtration onto GF/B filter plates followed by 4 times washing with ice-cold wash buffer (50 mM Tris, pH7.4).
8. The plates were dried at 37° C. for 45 min.
8. The filter plates were sealed and 40 μl/well of scintillation cocktail was added.
10. The plate was read by using a Microbeta2 microplate counter.
3 Data Analysis
1. For reference and test compounds, the results were expressed as % Inhibition, using the normalization equation: N=100−100×(U−C2)/(C1−C2), where U is the unknown value, C1 is the average of high controls, and C2 is the average of low controls.
2. The IC50 was determined by fitting percentage of inhibition as a function of compound concentrations with Hill equation using XLfit.
Results and Discussion
The results of potential competition binding properties of the exemplary compound of the disclosure targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A) are summarized in Table 18. The results of exemplary compounds of the disclosure are presented as IC50 provided in Table 18.







TABLE 18







Effect of exemplary compounds of Formula (I) using


Radioligand binding assay on human 5-HT2A receptor










Compound ID
h5-HT2A, IC50 [nM]














5-MeO-DMT
603



DMT
954



(R) I-1
154










II. Results and Discussion
Exemplary compounds of Formula (I) were evaluated using radioligand binding assay on human 5-HT2A receptor. IC50 (nM) concentrations are illustrated in Table 18. This assay confirms that compounds of the disclosure are effective ligands of the target human 5-HT2A receptors.
Example 4: Human 5-HT1A: Functional FLIPR Assay
1 Objective
The potential excitatory effects of compounds targeting on 5-hydroxytryptamine receptor 1A (5-HT1A) under agonist mode was assessed.
2 Materials and Instrumentation
2.1 Cell Line (Table 19)















Cell line Name
Target
Host cell









HTR1A&Gα15-CHO
5-HT1A
Flp-in CHO










2.2 Materials (Table 20)













Regents
Vendor
Cat#

















DMEM/F12
Gibco
11330057


Dialyzed FBS
BIOSUN
BS-0005-500


Penicillin-Streptomycin
Invitrogen
15140


Hygromycin B
Invivogen
Ant-hg-5


TrypLE ™ Express
Gibco
12604-013


DPBS
Gibco
14190250


DMSO
Millipore
1029312500


Probenecid
Sigma
P8761


FLIPR Calcium 6 Assay Kit
Molecular Device
R8191


HEPES
Invitrogen
15630


Hank's Buffered Saline
Invitrogen
14025


Solution


Serotonin HCl
Selleck
S4244









2.3 Instrumentation and Consumables (Table 21)













Item
Supplier
Cat#







Fluorometric Imaging Plate Reader
Molecular Device
Tetra


(FLIPR)


Countess Automated Cell Counter
Invitrogen
Countess


Cell Counting Chamber Slides
Invitrogen
C10312


STERI-CYCLE CO2 Incubator
Thermo
371


1300 Series Class II Biological
Thermo
1389


Safety Cabinet


Table-type Large Capacity Low
Cence
L550


Speed Centrifuge


Centrifuge
Eppendorf
5702


Echo
Labcyte
550


Echo
Labcyte
655


Electro-thermal incubator
Shanghai Yiheng
DHP-9031


plate shaker
IKA
MS3 digital


Water Purification System
ULUPURE
UPH-III-20T


Versatile and Universal pH and
Mettler Toledo
S220


Conductivity Meters


384-Well plate
Corning
3764


384-Well LDV Clear microplate
LABCYTE
LP-0200


384-Well Polypropylene microplate
LABCYTE
PP-0200


384-well compound plate
Corning
3657


T25 cell culture flask
Corning
430639


50 mL Polypropylene Centrifuge Tube
JET
CFT011500


15 mL Polypropylene Centrifuge Tube
JET
CFT011150









3 Experimental Methods
3.1 Cell Culture
HTR1A&Gα15-CHO cells were cultured in DMEM/F12 medium containing 10% dialyzed FBS, 1× penicillin-streptomycin and 600 μg/mL Hygromycin B. The cells were passaged about three times a week, maintained between ˜30% to ˜90% confluence.
3.2 Cell Plating
1. The cell culture medium (DME M/F12 medium containing 10% dialyzed FBS, 1× penicillin-streptomycin and 600 μg/mL Hygromycin B), TrypLE™ Express and DPBS was warmed to room temperature in advance.
2. The cell culture medium was removed from flask. Washed cells with DP BS.
3. 1 mL TrypLE™ Express was added to the flask, mixed well by gentle shaking and cells were incubated at 37° C. for a few minutes.
4. The cells were checked for morphological change under microscope, the digestion was stopped by adding 2 mL cell culture medium to the flask when most of cells turned to round.
5. The cell suspension was transferred into a 15 mL centrifuge tube, and then centrifuged at 1,200 rpm for 5 minutes.
6. The supernatant was removed. The cell pellet were resuspended with 2 mL cell culture medium.
7. The cell density were counted using cell counter. Only cells with >85% viability were used for the assay.
8. Cells were diluted to 4×105/mL with cell culture medium.
9. 30 μL/well cell suspensions were added into a 384-well cell plate (The cell density was 12,000 cells/well).
10. The cell plate was incubated overnight at 37° C., 5% (v/v) CO2.
3.3 Cell Handling
1. On the day of experiments, culture medium was removed from the cell plate.
2. 10 μL of assay buffer (20 mM HEPES, in 1×HBSS, pH 7.4) was added to each well of the cell plate.
3. 2× dye solution was prepared following the manufacture's instruction of the FLIPR® Calcium 6 assay kit:

    
    
        i. The dye was diluted with assay buffer.
        ii. probenecid was added to the final concentration of 5 mM.
        iii. Vortexed vigorously for 1-2 minutes, adjust pH to 7.4.
    
    


4. 10 μL of 2× dye solution was added to each well of the cell plate.
5. The cell plate was placed on plate shaker, followed by shaking at 600 rpm for 2 minutes.
6. The plate was incubated at 37° C. for 2 hours followed by an additional 15-minute incubation at 25° C.
3.4 Prepare 3× Compounds.
1. Serotonin was prepared to the concentration of 10 mM with DMSO, 3-folds serial dilutions were performed with DMSO.
2. Prepare the test compound to the concentration of 10 mM with DMSO, preform 3-folds serial dilutions with DMSO.
3. The compounds were added to a 384-well compound source plate.
4. 90 nL/well of serial diluted compounds were transferred from source plate to a 384-well compound plate by using an Echo.
5. 30 μL/well of assay buffer was added to the compound plate.
6. The plate was mixed on-plate shaker for 2 minutes.
3.5 FLIPR Assay
1. After the cells incubate with dye solution, the cell plate, compound plate containing 3× compounds and FLIPR tips were placed into FLIPR.
2. 10 μL of 3× compounds were transferred from the compound plate to the cell plate by FLIPR.
3. The plate was read for 160 sec with 1 sec interval to obtain the data of agonist mode.
4 Data Analysis
1. The normalized fluorescence reading (RFU) was calculated as shown below, wherein Fmax and Fmin stand for maximum and minimum of calcium signal during defined time window:



 
  RFU
  =
  
   
    F
    max
   
   -
   
    F
    min
   
  
 



2. EC50 was calculated by fitting RFU against log of compound concentrations with Hill equation using XLfit.
Results and Discussion
The results of potential competition binding properties of the exemplary compounds of the disclosure targeting the human 5-hydroxytryptamine receptor 1A (5-HT1A) are summarized in Table 22. The results of exemplary compounds of the disclosure are presented as EC50 provided in Table 22.
Table 22: Effect of Exemplary Compounds of Formula (I) Using FLIPR Functional Assay on Human 5-HT1A Receptor















Compound ID
h5-HT1A, EC50 [nM]
RFU@10 μM (1)




















5-MeO-DMT
1,066
3,891



DMT
ND (2)
204



(R) I-1
581
3,355







(1) Curve fitting with activation (%) @ 10 mM with RFU



(2) Not detected






Exemplary compounds of Formula (I) were evaluated using functional FLIPR assay on human 5-HT1A receptor. EC50 (nM) concentrations are illustrated in Table 22. This assay confirms that compounds of the disclosure are functionally active at the target human 5-HT1A receptors.
Example 5: Human 5-HT1A: Radioligand Binding Assay
1 Objective
The objective of this study was to evaluate the binding properties of test compounds on 5-hydroxytryptamine receptor 1A (5-HT1A).
2 Materials and Instrumentation







TABLE 23







2.1 Regents









Items
Vendor
Cat#





[3H]-8-Hydroxy-DPAT
PE
NET929250UC


Serotonin HCl
Selleck
S4244


Bovine Serum Albumin (BSA)
Sigma
A1933


Calcium chloride (CaCl2)
Sigma
C5670


MgCl2
Sigma
M1028


Tris(hydroxymethyl)aminomethane
Alfa Aesar
A18494


(Tris)


Polyethylenimine, branched (PEI)
Sigma
408727
















TABLE 24







2.2 Instrumentation and Consumables









Item
Supplier
Cat#





Microbeta2 Microplate Counter
PerkinElmer
2450-0060


UniFilter-96 GF/B
PerkinElmer
6005177


TopSeal
Biotss
SF-800


MicroBeta Filtermate-96
PerkinElmer
D961962


Seven Compact pH meter
Mettler Toledo
S220


Ultrapure Water Meter
Sichuan Ulupure
UPH-III-20T


Benchtop Centrifuge
Hunan Xiangyi
L550


Microplate Shaker
Allsheng
MX100-4A


384-Well Polypropylene
Labcyte
PP-0200


Microplate


96 Round Well Plate
Corning
3799


96 Round Deep Well Plate
Axygen
P-DW-11-C


Echo
LABCYTE
550









3 Experimental Methods
1. The assay buffer was prepared following Table 25 below.










TABLE 25







Reagent
Concentration




















Tris
25
mM



MgCl2
10
mM



CaCl2
1
mM



BSA
0.5%
(w/v)







Adjust pH to 7.4 followed by 0.2 μM sterile filtration






2. 8 doses of reference and test compounds were prepared starting from 10 mM stock solution as required by 5-fold serial dilutions with 100% (v/v) DMSO.
3. UniFilter-96 GF/B plate was pretreated:

    
    
        i. 50 μl/well of 0.5% (v/v) PEI was added to UniFilter-96 GF/B plates. The plates were sealed and incubated at 4° C. for 3 hrs.
        ii. After incubation, the plates were washed 3 times with ice-cold wash buffer (50 mM Tris, pH7.4).
    
    


4. Assay plate was prepared:

    
    
        i. Cell membrane was diluted with assay buffer and 100 μl/well was added to 96 round well plates to reach a concentration of 20 μg/well.
        ii. 8 concentrations of reference or test compounds were prepared and 50 μl/well was added to 96 round deep well plates.
        iii. [3H]-8-Hydroxy-DPAT was diluted with assay buffer to 2 nM (4× final concentration) and 50 μl/well was added to 96 round well plates.
    
    


5. The plate was centrifuged at 1000 rpm for 30 secs and then agitated at 600 rpm at room temperature for 5 min.
6. The plates were sealed and the plate was incubated at 27° C. for 90 min.
7. The incubation was stopped by vacuum filtration onto GF/B filter plates followed by 4 times washing with ice-cold wash buffer (50 mM Tris, pH7.4).
8. The plates were dried at 37° C. for 45 min.
9. The filter plates were sealed and 40 μl/well of scintillation cocktail was added.
10. The plate was read by using a Microbeta2 microplate counter.
4 Data Analysis
1. For reference and test compounds, the results were expressed as % Inhibition, using the normalization equation: N=100−100×(U−C2)/(C1−C2), where U is the unknown value, C1 is the average of high controls, and C2 is the average of low controls.
2. The IC50 was determined by fitting percentage of inhibition as a binding of compound concentrations with Hill equation using XLfit.
Results and Discussion
The results of potential competition binding properties of the exemplary compounds presented as IC50 of the disclosure targeting the human 5-hydroxytryptamine receptor (5-HT1A) are summarized in Table 26.







TABLE 26







Effect of exemplary compounds of Formula (I) using


Radioligand binding assay on human 5-HT1A receptor










Compound ID
h5-HT1A, IC50 [nM]














5-MeO-DMT
6



DMT
689



(R) I-1
3










Results and Discussion
Exemplary compounds of Formula (I), thereof were evaluated using radioligand binding assay on human 5-HT1A receptor. IC50 (nM) concentrations are illustrated in Table 26. This assay confirms that compounds of Formula (I) of the disclosure are effective ligands of the target human 5-HT1A receptors.
Example 5A: Human 5-HT2B: Radioligand Binding Assay
The objective of this study was to evaluate the binding properties of test compounds on 5-HT2B.







TABLE 27







Materials and Instruments









Materials
Vendor
Cat#





[3H]-LSD
PerkinElmer
NET638250UC


Yohimbine
MedChemExpress
HY-N0127


Bovine Serum Albumin (BSA)
Sigma
A1933


Calcium chloride (CaCl2)
Sigma
C5670


Tris(hydroxymethyl)amino-
Alfa Aesar
A18494


methane (Tris)


Polyethylenimine, branched (PEI)
Sigma
408727
















TABLE 28







Instrumentation and Consumables









Item
Supplier
Cat#





Microbeta2 Microplate Counter
PerkinElmer
2450-0060


UniFilter-96 GF/B
PerkinElmer
6005177


TopSeal
Biotss
SF-800


MicroBeta Filtermate-96
PerkinElmer
D961962


Seven Compact pH meter
Mettler Toledo
S220


Ultrapure Water Meter
Sichuan Ulupure
UPH-III-20T


Benchtop Centrifuge
Hunan Xiangyi
L550


Microplate Shaker
Allsheng
MX100-4A


384-Well Polypropylene Microplate
Labcyte
PP-0200


96 Round Well Plate
Corning
3799


96 Round Deep Well Plate
Axygen
P-DW-11-C


Echo
LABCYTE
550









Experimental Methods
1) The assay buffer was prepared following Table 29 below.










TABLE 29







Reagent
Concentration




















Tris
50
mM



CaCl2
4
mM



BSA
0.1%
(w/v)







Adjust to 7.4 followed by 0.2 μM sterile filtration






2) Eight doses of reference and test compounds starting from 10 mM stock solution as requested by 5-fold serial dilutions with 100% (v/v) DMSO.
3) UniFilter-96 GF/B plate was pretreated:

    
    
        a. 50 μL/well of 0.5% (v/v) PEI to UniFilter-96 GF/B plates. The plates were sealed and incubated at 4° C. for 3 hrs.
        b. After incubation, the plates were washed 3 times with ice-cold wash buffer (50 mM Tris, pH 7.4).
    
    


4) Assay plate preparation:

    
    
        a. Cell membrane was diluted with assay buffer and 330 μL/well added to 96 round deep well plates to reach a concentration of 1 unit/well.
        b. Eight concentrations of reference or test compounds were prepared and 110 μL/well added to 96 round deep well plates.
        c. [3H]-LSD was diluted with assay buffer to 5 nM (5× final concentration) and 110 μL/well was added to 96 round deep well plates.
    
    


5) The plate was centrifuged at 1000 rpm for 30 secs and then agitated at 600 rpm at room temperature for 5 mins.
6) The plates were sealed and incubated at 37° C. for 90 mins.
7) The incubation was stopped by vacuum filtration onto GF/B filter plates followed by washing four times with ice-cold wash buffer (50 mM Tris, pH7.4).
8) The plates were dried at 37° C. for 45 min.
9) The filter plates were sealed and 40 μL/well of scintillation cocktail was added.
10) The plate was read using a Microbeta2 microplate counter.
Data Analysis
For reference and test compounds, the results are expressed as % Inhibition, using the normalization equation: N=100−100×(U−C2)/(C1−C2), where U is the unknown value, C1 is the average of high controls, and C2 is the average of low controls. The IC50 is determined by fitting percentage of inhibition as a function of compound concentrations with Hill equation.







TABLE 30







Effect of exemplary compounds of Formula (I) using


Radioligand binding assay on human-5-HT2B receptor











Compound ID
5-HT2B, IC50 [nM]
5-HT2B, Ki [nM]















5-MeO-DMT
248.92
128.79



DMT
423.14
218.92



(R) I-1
18.99
9.82










Example 6: Psychedelic-Like Effect of Exemplary Compounds of Formula (I)
The effect of different doses of exemplary compounds of Formula (I) were evaluated on head-twitch response (HTR) as a behavior-based model of psychedelic activity.
Head Twitch Response (HTR) Assay Protocol:
Adult C57BL/6J mice (body weight range 20-30 g) were each placed into an open-top test cage made of transparent plastic for 20-30 min of habituation prior to testing. Habituation and testing were both conducted under low light conditions (˜100 lux). Mice received a subcutaneous (SC) injection of either vehicle, positive control substance (e.g., 2,5-dimethoxy-4-iodoamphetamine (DOI)), or test compound at appropriate doses and volumes (10 ml/kg). Immediately post-treatment each mouse was placed back in its respective test cage. The cages were placed at approximately 50 cm from each other on a white, adjustable height table/flat surface so that the experimenter could easily monitor fine behaviors of both mice within the testing environment. An opaque divider was placed between the cages to prevent animals from observing each other. Immediately after placing the mice back into the test cages, the experimenter sat directly in front of the two containers, and recorded in real time the number of head twitch responses (HTR, defined as rapid side-to-side rotational shaking of the head) performed by each mouse for 20 min, subdivided in 5 min intervals with the use of a silent timer. To ensure scoring accuracy and consistency, one experienced experimenter performed HTR recording for all mice included in a study. While mice were subjected to HTR testing, another mouse pair underwent habituation in a separate set of test cages, so that at the end of the HTR scoring period new animals were ready to undergo substance administration and testing. Between individual HTR tests, cages were cleaned with water, disinfected with a 70% ethanol aqueous solution, and dried using paper towels.
Results and Discussion
FIG. 1 is a graph showing the effect of various doses of exemplary compound of Formula (I), (R) I-1, on head-twitch response (HTR) in male C57BL6 mice. The mice were treated with exemplary compounds (R) I-1 by SC route, and the total number of head twitches were recorded over a 20 min period. Data is expressed as mean±SEM. The induction of head twitches elicited by 5-HT2A receptor agonists is believed to represent a behavioral proxy of their psychedelic effects.
Example 7: Pharmacokinetic Studies in Rat
Protocol
Study Details:
Animals: Male Sprague-Dawley rats (˜225-350 g) from Charles River Labs were acclimatized for a minimum of 5 days prior to start of study procedures. Body weights were recorded on the day of dosing.
Food restriction: None.
Clinical observations: Animals were observed at the time of dosing and each sample collection. Any abnormalities were documented including presence/absence of wet dog shakes/back muscle contractions (WDS/BMC).
Dosing: Formulations were administered intravenously (i.v.) via the tail vein using a 25 G needle connected to a 1 cc syringe.
Formulation:
The exemplary compounds of Formula (I) were freshly prepared at the appropriate concentrations in 5% Tween-80 in saline.
Sample Collection:
Blood collection time (h): 0, 25, 1 and 4
Volume/time-point: ˜0.25 mL (saphenous vein)
Bioanalytical Method Development and Sample Analysis:
Analytes: Compounds of Formula (I)
Matrix: Rat plasma.
Instrumentation: AB Sciex QTRAP 4000 or 6500 MS/MS system equipped with an LC system with a binary pump, a solvent degasser, a thermostated column compartment, and a multiplate autosampler.
Bioanalytical Method(s) Development Included:
1. The ion transition for the test compounds and potential internal standards was selected (i.e., identification of the parent and product ions).
2. The mass spectrometric operating parameters were optimized.
3. The chromatographic condition for the analytes was established.
4. An appropriate internal standard (IS) was selected.
5. S sample clean-up method using protein precipitation was developed.
Method(s) Qualification:
1. The quantification dynamic range using non-zero calibration standards (STDs) in singlet was determined. The STDs consisted of a blank matrix sample (without IS), a zero sample (with IS), and at least 6 non-zero STDs covering the expected range and including the lower level of quantitation (LLOQ).
2. Triplicate injections of a system suitability sample (neat solution containing the analyte and IS) bracketing the batch were done.
Method(s) Acceptance Criteria:
1. At least 75% of non-zero STDs was included in the calibration curve with all back-calculated concentrations within ±20% deviation from nominal concentrations (±25% for the lower level of quantification, LLOQ).
2. The correlation coefficient (r) of the calibration curve was greater than or equal to 0.99 using quadratic regression analysis (1/x2 weighting).
3. The area ratio variation between the pre- and post-run injections of the system suitability samples was within ±25%.
Sample Analysis Batch:
1. Triplicate injections of a system suitability sample bracketing the batch were done.
2. The STDs were placed in ascending order.
3. The study samples and the dosing solutions were diluted as 3 independent dilutions into blank matrix (plasma).
4. For more than 40 study samples in a batch, two sets of STDs bracketing the samples were utilized.
Samples which were 25% greater than the highest calibration standard, were diluted and re-assayed along with a corresponding dilution quality control standard. Dilution standards were acceptable if they were within 25% accuracy of the target concentration.
PK Analysis
Analysis software: Phoenix® WinNonlin® 8.3 (Pharsight, Certara, Mountainview, CA).
Analysis methods: non-compartmental analysis, linear up/log down trapezoidal rule.
PK parameters: t1/2 and AUC0-tlast was estimated.
Results
Table 31 shows the plasma concentration of exemplary compound (R) I-1 following a dose of 1.19 i.v. administration.







TABLE 31







Plasma concentrations of (R) I-1 following


1.10 mg/kg i.v. administration (Group 2).











Dose




Example
(mg/
Experimental
Plasma concentration (ng/mL)













ID
kg)
time (h)/Rat#
R01
R02
R03
Mean ± SD
















(R) I-1
1.19
0.25
120
112
94.7
 109 ± 12.9




1
42.3
30.3
65.8
46.1 ± 18.1




4
7.04
1.56
3.27
3.96 ± 2.80





*Values in italics are below the lower limit of quantitation (BLQ, 0.5 ng/mL) but were included in calculations.


*BLQ denotes below the lower limit of quantitation (0.5 ng/mL).






Table 32 is a summary of the plasma apparent t1/2 and AUC0-tlast for exemplary compound I-1 following 1.10 mg/kg i.v. administration (Group 2).







TABLE 32







Summary of plasma apparent t1/2 and AUC0-tlast for I-1


following 1.19 mg/kg i.v. administration (Group 2).











Dose




Exam-
(mg/

Parameter estimate for each animal













ple ID
kg)
Parameter
R01
R02
R03
Mean ± SD
















(R) I-1
1.19
Apparent
0.975
0.632
0.748
0.785 ± 0.174




t1/2 (h)a




AUC0-tlast
151
111
147
 136 ± 22.0




(h*ng/mL)





aApparent t1/2 was estimated from 2 points only






Example 8: Human, Rat and Mouse Liver Microsomes Stability
Objective
The objective of this study was to estimate in vitro metabolic stability of exemplary compounds of Formula (I) or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof in pooled human, male rat, and male mouse liver microsomes. The concentrations of compounds in reaction systems were evaluated by LC-MS/MS for estimating the stability in pooled human, male rat, and male mouse liver microsomes. The in vitro intrinsic clearances of test compounds were determined as well.
Protocol
A master solution in the “Incubation Plate” containing phosphate buffer, ultra-pure H2O, MgCl2 solution and liver microsomes was made according to Table 33. The mixture was pre-warmed at 37° C. water bath for 5 minutes.







TABLE 33







Preparation of master solution










Reagent
Stock Concentration
Volume
Final Concentration
















Phosphate buffer
200
mM
200
μL
100
mM











Ultra-pure H2O
—
106
μL
—













MgCl2 solution
50
mM
40
μL
5
mM


Microsomes
20
mg/mL
10
μL
0.5
mg/mL









40 μL of 10 mM nicotinamide adenine dinucleotide phosphate (NADPH) solution was added to each well. The final concentration of NADPH was 1 mM. The negative control samples were prepared by replacing NADPH with 40 μL of ultra-pure H2O. Samples were prepared in duplicate. Negative controls were prepared in singlet.
The reaction was started with the addition of 4 μL of 200 μM exemplary test compounds of the disclosure or control compounds to each master solution to get the final concentration of 2 μM. This study was performed in duplicate.
Aliquots of 50 μL were taken from the reaction solution at 0, 15, 30, 45, and 60 minutes. The reaction solutions were stopped by the addition of 4 volumes of cold methanol with IS (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol, and 2 μM ketoprofen). Samples were centrifuged at 3,220 g for 40 minutes. Aliquot of 90 μL of the supernatant was mixed with 90 μL of ultra-pure H2O and then was used for LC-MS/MS analysis.
LC/MS analysis was performed for all samples from this study using a Shimadzu liquid chromatograph separation system equipped with degasser DGU-20A5R; solvent delivery unit LC-30AD; system controller SIL-30AC; column oven CTO-30A; CTC Analytics HTC PAL System. Mass spectrometric analysis was performed using a Triple Quad™ 5500 instrument.
All calculations were carried out using Microsoft Excel. Peak area ratios of test compound to internal standard (listed in the below table) were determined from extracted ion chromatograms.
All calculations were carried out using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The slope value, k, was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve.
The in vitro half-life (in vitro t1/2) was determined from the slope value:



 
  
   in
   ⁢
      
   vitro
   ⁢
      
   
    t
    
     1
     /
     2
    
   
  
  =
  
   -
   
    (
    
     0.693
     /
     k
    
    )
   
  
 



Conversion of the in vitro t1/2 (min) into the in vitro intrinsic clearance (in vitro CLint, in μL/min/mg proteins) was done using the following equation (mean of duplicate determinations):



 
  
   in
   ⁢
      
   vitro
   ⁢
      
   
    CL
    int
   
  
  =
  
   
    (
    
     0.693
     
      (
      
       t
       
        1
        /
        2
       
      
      )
     
    
    )
   
   *
   
    (
    
     
      volume
      ⁢
         
      of
      ⁢
         
      incubation
      ⁢
         
      
       (
       
        μ
        ⁢
        L
       
       )
      
     
     
      amount
      ⁢
         
      of
      ⁢
         
      proteins
      ⁢
         
      
       (
       mg
       )
      
     
    
    )
   
  
 



For the exemplary compounds of the disclosure or control compound that showed an initial fast disappearance followed by a slow disappearance, only the time points that were within the initial rate were included in the calculation.
Results and Discussion
Human, rat, and mouse liver microsomes contain a wide variety of drug metabolizing enzymes and are commonly used to support in vitro ADME (absorption, distribution, metabolism, and excretion) studies. These microsomes are used to examine the potential first-pass metabolism by-products of orally administered drugs. Representative compounds of the disclosure were evaluated for their stability in human, rat, and mouse liver microsomes.
Most of the exemplary compounds of the disclosure in three species, human, rat, and mouse liver microsomes were recovered within a 60-minute time period indicating that the compounds were not rapidly cleared (see Tables 34 and 35 for Exemplary compounds of Formula (I)).







TABLE 34







Metabolic Stability of Test Compounds in


Liver Microsomes of Different Species (a)















C Lint
Scaled-up
Predicted


Compound

T1/2
(μL/min/mg
CLint
hepatic CL


ID
Species
(min)
protein)
(mL/min/Kg)
(mL/min/kg)















Diclofenac
Human
10.73
129.12
161.94
18.35



Rat
15.22
91.05
163.16
41.25



Mouse
43.31
32.00
140.00
54.78


5-MeO-
Human
12.14
114.19
143.22
18.09


DMT
Rat
5.68
244.17
437.56
49.02



Mouse
44.52
31.13
136.21
54.19


Diclofenac
Human
10.73
129.12
161.94
18.35



Rat
15.22
91.05
163.16
41.25



Mouse
43.31
32.00
140.00
54.78


(R) I-1
Human
24.03
57.68
72.34
16.09



Rat
10.45
132.67
237.74
44.80



Mouse
<4.51
>307.01
>1343.17
>84.35





Notes:


1. For the compounds that showed an initial fast disappearance followed by a slow disappearance, only the time points that were within the initial rate were included in the calculation.


2. If % remaining at 30 minutes was lower than 1%, then CLint and t1/2 will be reported as “>307.01” and “<4.51,” respectively.













TABLE 35







Metabolic Stability of Test Compounds in


Liver Microsomes of Different Species (b)













Remaining


Compound
Spe-

Percentage (%)












ID
cies
Assay Format
0 min
30 min
60 min















Diclofenac
Human
With Cofactors
100.00
5.01
1.77




Without Cofactors
100.00
112.67
96.67



Rat
With Cofactors
100.00
11.86
6.35




Without Cofactors
100.00
102.19
100.63



Mouse
With Cofactors
100.00
45.55
33.71




Without Cofactors
100.00
89.49
96.59


5-MeO-
Human
With Cofactors
100.00
19.24
3.25


DMT

Without Cofactors
100.00
18.58
3.00



Rat
With Cofactors
100.00
2.57
0.36




Without Cofactors
100.00
49.55
23.82



Mouse
With Cofactors
100.00
61.84
39.30




Without Cofactors
100.00
104.76
95.24


(R) I-1
Human
With Cofactors
100.00
50.51
17.72




Without Cofactors
100.00
101.47
97.56



Rat
With Cofactors
100.00
13.67
0.44




Without Cofactors
100.00
93.44
95.17



Mouse
With Cofactors
100.00
0.15
0.23




Without Cofactors
100.00
98.55
103.02









Discussion
Exemplary compounds of the disclosure, represented by (R) I-1, were evaluated for their stability in human, rat, and mouse liver microsomes. Table 34 and Table 35 show the results of the stability studies. These results show that the compounds of the disclosure show a spectrum of stability across different species, including human, rat, and mouse.
Example 9: Protein Binding Measurements in Different Species, (Human, Rat, Mouse, and Dog) Plasma Using Equilibrium Dialysis Method
Protocol
1. The Frozen Plasma (Stored at −80° C.) was Thawed Immediately in a 37° C. Water Bath.
2. Preparation of Working Solution
The working solution of test compounds and control compound was prepared in DMSO at the concentration of 200 μM, and then the working solution was spiked into plasma. The final concentration of compound was 1 μM. The final concentration of DMSO was 0.5%. Ketoconazole was used as positive control in the assay.
3. Preparation of Dialysis Membranes
The dialysis membranes were soaked in ultrapure water for 60 minutes to separate strips, then in 20% ethanol for 20 minutes, finally in dialysis buffer for 20 minutes.
4. Procedure for Equilibrium Dialysis
The dialysis set up was assembled according to the manufacturer's instruction. Each Cell was with 150 μL of plasma sample and dialyzed against equal volume of dialysis buffer (PBS). The assay was performed in duplicate. The dialysis plate was sealed and incubated in an incubator at 37° C. with 5% CO2 at 100 rpm for 6 hours. At the end of incubation, 50 μL of samples from both buffer and plasma chambers were transferred to wells of a 96-well plate.
5. Procedure for Sample Analysis
50 μL of plasma was added to each buffer samples and an equal volume of PBS was supplemented to the collected plasma sample. 400 μL of precipitation buffer acetonitrile containing internal standards (IS, 200 nM labetalol, 100 nM tolbutamide and 100 nM ketoprofen) was added to precipitate protein and release compounds. Samples were vortexed for 2 minutes and centrifuged for 30 minutes at 3,220 g. Aliquot of 50 μL of the supernatant was diluted by 150 μL acetonitrile containing internal standards: ultra-pure H2O=1:1, and the mixture was used for LC-MS/MS analysis.
6. Data Analysis
All calculations were carried out using Microsoft Excel. The concentrations of test compounds in the buffer and plasma chambers were determined from peak area ratios. The percentages of bound compound were calculated as follows:



 
  
   %
   ⁢
      
   Free
  
  =
  
   
    (
    
     Peak
     ⁢
        
     Area
     ⁢
        
     Ratio
     ⁢
        
     buffer
     ⁢
        
     chamber
     /
     

     Peak
     ⁢
        
     Area
     ⁢
        
     Ratio
     ⁢
        
     plasma
     ⁢
        
     chamber
    
    )
   
   *
   100
   ⁢
   %
  
 




 
  
   %
   ⁢
      
   Bound
  
  =
  
   
    100
    ⁢
    %
   
   -
   
    %
    ⁢
       
    Free
   
  
 




 
  
   %
   ⁢
      
   Recovery
  
  =
  
   
    (
    
     
      Peak
      ⁢
         
      Area
      ⁢
         
      Ratio
      ⁢
         
      buffer
      ⁢
         
      chamber
     
     +
     

     
      Peak
      ⁢
         
      Area
      ⁢
         
      Ratio
      ⁢
         
      plasma
      ⁢
         
      chamber
     
    
    )
   
   /
   Peak
   ⁢
      
   Area
   ⁢
      
   Ratio
   ⁢
      
   total
   ⁢
      
   sample
   *
   100
   ⁢
   %
  
 



Materials







TABLE 36







Plasma information










Species
Strain/Gender
Batch No.
Source





Human
Pooled; Male & Female
HUMANPLK2PNNV20230717
Healthy Asian volunteers from local





vendor (collected in domestic





hospital with Ethical approval)


Dog
Beagle; Pooled; Male & Female
PH-Dog-20230612
Local Supplier


Rat
SD; Pooled; Male & Female
RAT542174
BioIVT


Mouse
CD-1; Pooled; Male & Female
MSE441125
BioIVT



















Bioanalytical Method (Table 37)






















A
Time (min)
0
0.2
0.6
1.1
1.2
1.4



% B
5
5
100
100
5
5


B
Time (min)
0
2.4
2.5
2.6
3



% B
5
100
100
5
5
















TABLE 38





Injection Volume



















A
3
μL



B
20
μL







Flow rate: 0.65 mL/min






    
    
        Column temperature: 40° C.
        MS parameters:
        Ion source: Turbo spray
        Ionization model: ESI
        Scan type: MRM
        Collision gas: 6 L/min
        Curtain gas: 30 L/min
        Nebulize gas: 50 L/min
        Auxiliary gas: 50 L/min
        Temperature: 500 Degree Celsius
        Ion spray voltage: +5500 v (positive MRM)
    
    


Results and Discussion
Table 39 shows the results of protein binding measurements in different species using exemplary compounds of the disclosure.











TABLE 39





Compound



% Remaining


ID
Species
% Bound
% Recovery
@ 6 hours



















Ketoconazole
Human
99.12
111.51
114.03



Dog
99.01
87.17
92.22



Rat
99.55
105.06
101.20



Mouse
99.32
108.90
103.60


(R) I-1
Human
84.03
101.61
103.38



Dog
82.60
92.92
95.50



Rat
46.57
103.10
105.76



Mouse
47.88
113.26
112.85









Part II

The following compounds were prepared using one or more of the synthetic methods outlined in Schemes I and II.
A. Synthesis of Exemplary Compounds of the Disclosure
Example 10: (R)-5-Methoxy-3-((1-(2-methoxyethyl)pyrrolidin-2-yl)methyl)-1H-indole ((R) I-98,)




Synthesis of (R)-5-methoxy-3-(pyrrolidin-2-ylmethyl)-1H-indole (1): Prepared according to literature procedure (WO2022183288A1). 1H NMR (DMSO-d6): δ 10.68 (s, 1H), 7.23 (d, 1H, J=6.0 Hz), 7.14 (s, 1H), 7.02 (d, 1H, J=3.0 Hz), 6.72 (dd, 1H, J=3.0, 6.0 Hz), 3.38 (s, 3H), 3.36-3.31 (m, 1H), 3.01-2.95 (m, 1H), 2.87-2.72 (m, 3H), 1.82-1.62 (m, 3H), 1.44-1.37 (m, 1H); ESI-MS (m/z, %): 231 (MH+, 100).
Synthesis of (R)-5-methoxy-3-((1-(2-methoxyethyl)pyrrolidin-2-yl)methyl)-1H-indole (2): A solution of (R)-5-methoxy-3-(pyrrolidin-2-ylmethyl)-1H-indole (1.1 g, 4.77 mmol) in dry DMF (20 mL) was treated with 2-methoxyethyl 4-methylbenzenesulfonate (1.32 g, 5.73 mmol) and triethyl amine (1.65 mL, 11.94 mmol) at room temperature and stirred for overnight (16 h). The reaction was quenched with water (50 mL) and product was extracted into ethyl acetate (2×50 mL). Combined ethyl acetate layer was washed with water (25 mL), brine (25 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) on silica gel to obtain the title compound (R) I-98 (1.0 g, 73%) as a light brown glue. 1H NMR (DMSO-d6): δ 10.60 (s, 1H), 7.21 (d, 1H, J=6.0 Hz), 7.09 (s, 1H), 6.98 (s, 1H), 6.70 (dd, 1H, J=3.0, 6.0 Hz), 3.76 (s, 3H), 3.47 (t, 2H, J=6.0 Hz), 3.13 (s, 3H), 3.09-3.06 (m, 2H), 2.97-2.93 (m, 1H), 2.65-2.60 (m, 1H), 2.48-2.37 (m, 2H), 2.22-2.15 (m, 1H), 1.71-1.57 (m, 3H), 1.48-1.42 (m, 1H); ESI-MS (m/z, %): 289 (MH+, 100).
Example 11: (R)-2-(4-((3-((1-(Methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-5-yl)oxy)butyl)isoindoline-1,3-dione ((R) I-244)




Synthesis of (R)-2-(2-(5-(benzyloxy)-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenylethan-1-one (4)
A solution of 1-(2-oxo-2-phenylethyl)-D-proline (4.0 g, 16.04 mmol) in dry THF (50 mL) was treated with thionyl chloride (2.34 mL, 32.09 mmol) at 0° C. The reaction was brought to room temperature, then refluxed for 2 h. The reaction was brought to room temperature, solvent was evaporated, and crude was dried under vacuum to obtain the corresponding acid chloride.
A solution of 5-(benzyloxy)-1H-indole (3.58 g, 16.04 mmol) in dry CH2Cl2 (50 mL) at 5-10° C. was treated with above crude acid chloride in dry CH2Cl2 (30 mL) and ethyl magnesium bromide (10.7 mL, 32.09 mmol, 3 M in THF) simultaneously over a period of 15 min. and stirred at same temperature for further 15 min. The reaction was quenched with con. HCl (10 mL), followed by water (100 mL), and product was extracted into CH2Cl2 (2×100 mL). Combined CH2Cl2 layer was washed with water (50 mL), brine (50 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (EtOAc: CH2Cl2, 1:4) on silica gel to obtain the title compound 4 (5.6 g, 76.7%) as a light brown solid. 1H NMR (DMSO-d6): δ 11.94, 11.92 (2s, 1H), 8.40, 8.38 (2d, 1H, J=3.0 Hz), 7.85, 7.81 (2d, 1H, J=3.0 Hz), 7.51-7.34 (m, 9H), 7.15-6.94 (m, 3H), 5.24-4.92 (m, 5H), 3.55-3.50 (m, 2H), 2.44-2.29 (m, 1H), 2.29-1.83 (m, 3H); ESI-MS (m/z, %): 514 (100), 477 (M+Na), 455 (MH+).
Synthesis of (R)-5-(benzyloxy)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole (5)
A solution of (R)-2-(2-(5-(benzyloxy)-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenylethan-1-one (5.5 g, 12.10 mmol) in dry THF (100 mL) was treated with LiAlD4 (2.54 g, 60.50 mmol) at 0° C. over a period of 15 min. The reaction was brought to room temperature and then refluxed for overnight (16 h). The reaction was cooled to 0° C., quenched with water (2.54 mL), 4 N NaOH solution (2.54 mL) and water (2.54 mL). The reaction was brought to room temperature and stirred for additional 30 min. The reaction was filtered through a pad of sodium sulfate and washed with THF (3×50 mL). Combined THF layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) on silica gel to obtain the title compound 5 (3.6 g, 91.4%) as a pale-yellow glue. 1H NMR (DMSO-d6): δ 10.62 (s, 1H), 7.49-7.30 (m, 5H), 7.23 (d, 1H, J=6.0 Hz), 7.09-7.05 (m, 1H), 6.80 (dd, 1H, J=3.0, 6.0 Hz), 5.11 (s, 2H), 2.99-2.95 (m, 1H), 2.32-2.28 (m, 1H), 2.11-2.07 (m, 1H), 1.66-1.41 (m, 4H); ESI-MS (m/z, %): 326 (MH+, 100).
Synthesis of (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-5-ol (6)
A solution of (R)-5-(benzyloxy)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole (3.55 g, 10.90 mmol) in methanol (60 mL) was treated with palladium on carbon (0.35 g, 10% dry basis) and stirred under hydrogen atm (balloon pressure) for additional 16 h (overnight). The reaction was filtered through a pad of celite and washed with methanol (3×15 mL). Combined methanol layer was evaporated, and crude was purified through flash column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) on silica gel to obtain the title compound 6 (2.35 g, 91.4%) as an off-white foam. 1H NMR (DMSO-d6): δ 10.44 (s, 1H), 8.55 (s, 1H), 7.11 (d, 1H, J=6.0 Hz), 7.02 (d, 1H, J=3.0 Hz), 6.81 (d, 1H, J=3.0 Hz), 6.58 (dd, 1H, J=3.0, 6.0 Hz), 3.00-2.96 (m, 1H), 2.34-2.30 (m, 1H), 2.15-2.10 (m, 1H), 1.69-1.42 (m, 4H); ESI-MS (m/z, %): 236 (MH+, 100).
Synthesis of (R)-2-(4-((3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-5-yl)oxy)butyl)isoindoline-1,3-dione ((R) I-244)
A solution of (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-5-ol (1.0 g, 4.24 mmol) in dry DMF (30 mL) was treated with Cs2CO3 (2.07 g, 6.37 mmol) followed by 2-(4-bromobutyl)isoindoline-1,3-dione (1.32 g, 5.73 mmol) at room temperature and stirred for additional 48 h. The reaction was quenched with water (100 mL) and product was extracted into ethyl acetate (2×50 mL). Combined ethyl acetate layer was washed with water (50 mL), brine (50 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) on silica gel to obtain the title compound (R) I-244 (0.81 g, 44%) as a pale-yellow glue. 1H NMR (DMSO-d6): δ 10.59 (s, 1H), 7.89-7.83 (m, 4H), 7.18 (d, 1H, J=6.0 Hz), 7.07 (s, 1H), 6.95 (s, 1H), 6.69 (d, 1H, J=6.0 Hz), 3.98 (t, 2H, J=3.0, 6.0 Hz), 3.66 (t, 2H, J=3.0, 6.0 Hz), 2.97 (t, 1H, J=6.0 Hz), 2.35-2.30 (m, 1H), 2.15-2.10 (m, 1H), 1.79-1.42 (m, 8H), ESI-MS (m/z, %): 437 (MH+, 100).
Example 12: (R)-2-(5-((3-((1-(Methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-5-yl)oxy)pentyl)isoindoline-1,3-dione ((R) I-245)




Synthesis of (R)-2-(5-((3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-5-yl)oxy)pentyl)isoindoline-1,3-dione ((R) I-245)
A solution of (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-5-ol (1.0 g, 4.24 mmol) in dry DMF (30 mL) was treated with Cs2CO3 (2.07 g, 6.37 mmol) followed by 2-(5-bromopentyl)isoindoline-1,3-dione (2.51 g, 8.49 mmol) at room temperature and stirred for additional 48 h. The reaction was worked-up and purified as described for compound (R) I-244 to obtain title compound (R) I-245 (0.8 g, 42%) as a pale-yellow glue. 1H NMR (DMSO-d6): δ 10.58 (s, 1H), 7.89-7.83 (m, 4H), 7.18 (d, 1H, J=6.0 Hz), 7.07 (s, 1H), 6.95 (s, 1H), 6.67 (dd, 1H, J=1.5, 6.0 Hz), 3.94 (t, 2H, J=3.0, 6.0 Hz), 3.62 (t, 2H, J=3.0, 6.0 Hz), 2.96 (t, 1H, J=3.0, 6.0 Hz), 2.32 (t, 1H, J=6.0 Hz), 2.10-2.06 (m, 1H), 1.78-1.43 (m, 10H); ESI-MS (m/z, %): 451 (MH+, 100).
Example 13:2-(5-((3-(((R)-1-(Methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-5-yl)oxy)pentyl)hexahydro-1H-isoindole-1,3(2H)-dione ((R) I-248) (Mixture of Cis-Diastereomers)




Synthesis of 2-(5-((3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-5-yl)oxy)pentyl)hexahydro-1H-isoindole-1,3(2H)-dione (9) (Mixture of Cis-Diastereomers)
A solution of (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indol-5-ol (0.78 g, 3.31 mmol) in dry DMF (20 mL) was treated with Cs2CO3 (1.62 g, 4.97 mmol) followed by cis-2-(4-bromobutyl)hexahydro-1H-isoindole-1,3(2H)-dione (2.0 g, 6.62 mmol) at room temperature and stirred for additional 48 h. The reaction was worked-up and purified as described for compound (R) I-248 to obtain title compound (R) I-248 (0.88 g, 58%) as a light brown glue. 1H NMR (DMSO-d6): δ 10.59 (s, 1H), 7.20 (d, 1H, J=6.0 Hz), 7.08 (d, 1H, J=1.5 Hz), 6.95 (d, 1H, J=1.5 Hz), 6.69 (dd, 1H, J=3.0, 6.0 Hz), 3.93 (t, 2H, J=6.0 Hz), 3.40 (t, 2H, J=6.0 Hz), 3.00-2.89 (m, 3H), 2.35 (t, 1H, J=3.0, 6.0 Hz), 2.15-2.09 (m, 1H), 1.74-1.25 (m, 18H); ESI-MS (m/z, %): 457 (MH+, 100).
Example 13A: Synthesis of (R)-4-Fluoro-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (R) I-250




Synthesis of (R)-2-(2-(4-fluoro-5-methoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenylethan-1-one 2A: A solution of 1-(2-oxo-2-phenylethyl)-D-proline (2.2 g, 8.83 mmol) in dry THF (40 mL) was treated with thionyl chloride (1.28 mL, 17.65 mmol) at 0° C. The reaction was brought to room temperature, then refluxed for 2 hrs. The reaction was brought to room temperature, the solvent was evaporated, and the crude acid chloride was dried under vacuum to obtain the corresponding acid chloride.
A solution of 4-fluoro-5-methoxy-1H-indole (1.45 g, 8.83 mmol) in dry CH2Cl2 (50 mL) at 5-10° C. was treated with above crude acid chloride in dry CH2Cl2 (20 mL) and ethyl magnesium bromide (6.2 mL, 18.53 mmol, 3 M in diethyl ether) simultaneously over a period of 5 mins. and stirred at the same temperature for a further 15 mins. The reaction was quenched with concentrated HCl (10 mL) followed by water (50 mL) and product was extracted into CH2Cl2 (2×100 mL). CH2Cl2 layer was washed with saturated NaHCO3 solution (50 mL), brine (25 mL) and dried (Na2SO4). Solvent was evaporated and the crude product was purified by crystallization from a mixture of CH2Cl2, Hexanes 1:5 to obtain the title compound 2A (2.25 g, 64.3%) as a beige solid. 1H NMR (DMSO-d6): δ 12.15, 12.13 (2s, 1H), 8.44 (d, 1H, J=12.0 Hz), 7.39-7.05 (m, 7H), 5.30-5.22 (m, 1H), 5.11-4.91 (m, 2H), 3.86 (s, 3H), 3.54-3.48 (m, 2H), 2.42-2.30 (m, 1H), 1.90-1.75 (m, 3H); ESI-MS (m/z, %): 397 (MH+), 419 (M+Na).
Synthesis of (R)-4-fluoro-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (R) I-250
A solution of (R)-2-(2-(4-fluoro-5-methoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenylethan-1-one (2.0 g, 5.04 mmol) in dry THF (30 mL) was treated with lithium aluminum hydride (26 mL, 25.22 mmol, 1M solution in THF) at 0° C. over a period of 10 mins. The reaction was brought to room temperature, then refluxed for additional 16 hrs. The reaction was brought to room temperature, then cooled to 0° C. and quenched with the sequential addition of water (1.0 mL), 4N NaOH solution (1.0 mL) and water (1.0 mL). The reaction was brought to room temperature and stirred for additional 30 mins. The reaction was filtered, and washed with THF (2×50 mL). Combined THF layer was evaporated and the crude product was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) on silica gel to obtain the title compound (R) I-250 (1.0 g, 75.7%) as a pale-yellow glue. 1H NMR (DMSO-d6): δ 10.87 (s, 1H), 7.12 (s, 1H), 7.06 (d, 1H, J=6.0 Hz), 6.93 (t, 1H, J=6.0 Hz), 3.81 (s, 3H), 3.15-3.10 (m, 1H), 2.99-2.95 (m, 1H), 2.48-2.45 (m, 1H), 2.36-2.30 (m, 4H), 2.14-2.00 (m, 1H), 1.66-1.46 (m, 4H); ESI-MS (m/z, %): 263 (MH+, 100).
Example 13B: Synthesis of (R)-4-Fluoro-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole (R) I-251




Synthesis of (R)-2-(2-((4-fluoro-5-methoxy-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenylethan-1-one 4A
A solution of (R)-2-(2-(4-fluoro-5-methoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenylethan-1-one (2.5 g, 6.31 mmol) in dry THF (30 mL) was treated with a solution of lithium borohydride (12.61 mL, 25.23 mmol, 2 M solution in THF) at room temperature over a period of 5 mins. and the reaction was refluxed for additional 4 hrs. The reaction was cooled to 0° C., quenched with the careful addition of methanol (25 mL) over a period of 15 mins. The reaction was brought to room temperature and was stirred for an additional 1 hr. The reaction was treated with saturated NaHCO3 solution (30 mL) and product was extracted into ethyl acetate (3×50 mL). The combined ethyl acetate layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by flash column chromatography (MeOH; CH2Cl2, 2:98) on silica gel to obtain the title compound 4A (1.2 g, 49.8%) as a pale yellow semi-solid. The compound was used in the subsequent step without any characterization.
Synthesis of (R)-4-fluoro-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole (R) I-251
A suspension of (R)-2-(2-((4-fluoro-5-methoxy-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenylethan-1-one (1.2 g, 3.14 mmol) in dry THF (25 mL) was treated with lithium aluminum deuteride (0.32 g, 7.57 mmol) at 0° C. The reaction was brought to room temperature, then refluxed for additional 16 hrs. The reaction was brought to room temperature, and then cooled to 0° C. and quenched with the sequential addition of water (1.0 mL), 4N NaOH solution (1.0 mL) and water (1.0 mL). The reaction was brought to room temperature and stirred for additional 30 mins. The reaction was filtered and washed with THF (2×50 mL). The combined THF layer was evaporated and the crude product was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) on silica gel to obtain the title compound (R) I-251 (0.73 g, 87.7%) as an off-white solid. 1H NMR (DMSO-d6): δ 10.86 (s, 1H), 7.12 (s, 1H), 7.06 (d, 1H, J=6.0 Hz), 6.93 (t, 1H, J=6.0 Hz), 3.81 (s, 3H), 3.14-3.10 (m, 1H), 2.99-2.95 (m, 1H), 2.51-2.45 (m, 1H), 2.38-2.32 (m, 1H), 2.14-2.06 (m, 1H), 1.64-1.45 (m, 4H); ESI-MS (m/z, %): 266 (MH+, 100).
Example 13C: Synthesis of (R)-5-Methoxy-6-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (R) I-254




Synthesis of (R)-2-(2-(5-methoxy-6-methyl-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenylethan-1-one 7A
A solution of 1-(2-oxo-2-phenylethyl)-D-proline (3.0 g, 12.03 mmol) in dry THF (30 mL) was treated with thionyl chloride (1.75 mL, 24.07 mmol) at 0° C. The reaction was brought to room temperature, then refluxed for 2 hrs. The reaction was brought back to room temperature, the solvent was evaporated, and the crude product was dried under vacuum to obtain the corresponding acid chloride.
A solution of 5-methoxy-6-methyl-1H-indole (1.94 g, 12.03 mmol) in dry CH2Cl2 (50 mL) at 5-10° C. was treated with above crude acid chloride in dry CH2Cl2 (20 mL) and ethyl magnesium bromide (8.4 mL, 25.27 mmol, 3 M in diethyl ether) simultaneously over a period of 5 mins. and stirred at the same temperature for further a 15 mins. The reaction was quenched with concentrated HCl (10 mL) followed by water (50 mL) and then the product was extracted into CH2Cl2 (2×100 mL). CH2Cl2 layer was washed with saturated NaHCO3 solution (50 mL), brine (25 mL) and dried (Na2SO4). Solvent was evaporated and the crude product was purified by crystallization from a mixture of CH2Cl2, Hexanes 1:5 to obtain the title compound 7A (3.3 g, 70.2%) as a light brown solid. 1H NMR (DMSO-d6): δ 11.81 (s, 1H), 8.31 (dd, 1H, J=3.0 Hz), 7.68 (d, 1H, J=12.0 Hz), 7.40-7.32 (m, 2H), 7.15 (d, 1H, J=3.0 Hz), 7.11-7.03 (m, 3H), 5.24-4.91 (m, 3H), 3.83 (s, 3H), 3.56-3.49 (m, 2H), 2.43-2.25 (m, 4H), 1.90-1.80 (m, 3H); ESI-MS (m/z, %): 393 (MH+), 415 (M+Na).
Synthesis of (R)-5-methoxy-6-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (R) I-254: A solution of (R)-2-(2-(5-methoxy-6-methyl-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenylethan-1-one (1.2 g, 3.05 mmol) in dry THF (20 mL) was treated with lithium aluminum hydride (15.3 mL, 15.29 mmol, 1M solution in THF) at 0° C. over a period of 10 mins. The reaction was brought to room temperature, then refluxed for additional 16 hrs. The reaction was brought back to room temperature, then cooled to 0° C. and quenched with the sequential addition of water (1.0 mL), 4N NaOH solution (1.0 mL) and water (1.0 mL). The reaction was brought to room temperature and stirred for an additional 30 mins. The reaction was filtered and washed with THF (2×50 mL). The combined THF layer was evaporated, and the crude product was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) on silica gel to obtain the title compound (R) I-254 (0.75 g, 94.5%) as an off-white solid. 1H NMR (DMSO-d6): δ 10.45 (s, 1H), 7.08 (s, 1H), 6.98 (s, 1H), 6.93 (s, 1H), 3.79 (s, 3H), 3.01-2.95 (m, 2H), 2.49-2.43 (m, 1H), 2.38-2.32 (m, 4H), 2.22 (s, 3H), 2.10-2.06 (m, 1H), 1.76-1.41 (m, 4H); ESI-MS (m/z, %): 259 (MH+, 100).
Example 13D: Synthesis of (R)-5-Methoxy-6-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole (R) I-255




Synthesis of (R)-2-(2-((5-methoxy-6-methyl-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenylethan-1-one 9A
A solution of (R)-2-(2-(5-methoxy-6-methyl-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenylethan-1-one (2.0 g, 5.10 mmol) in dry THF (30 mL) was treated with a solution of lithium borohydride (10.2 mL, 20.38 mmol, 2 M solution in THF) at room temperature over a period of 5 mins. and the reaction was refluxed for additional 4 hrs. The reaction was cooled to 0° C., quenched with the careful addition of methanol (25 mL) over a period of 15 mins. The reaction was brought to room temperature and stirred for an additional 1 hr. The reaction was treated with saturated NaHCO3 solution (30 mL) and the product was extracted into ethyl acetate (3×50 mL). The combined ethyl acetate layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by flash column chromatography (MeOH; CH2Cl2, 2:98) on silica gel to obtain the title compound 9A (1.32 g, 68.7%) as a pale-yellow foam. The compound was used in the subsequent step without any characterization.
Synthesis of (R)-5-methoxy-6-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole (R) I-255
A solution of (R)-2-(2-((5-methoxy-6-methyl-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenylethan-1-one (1.3 g, 3.43 mmol) in dry THF (20 mL) was treated with lithium aluminum deuteride (0.36 g, 8.58 mmol) at 0° C. over a period of 10 mins. The reaction was brought to room temperature, then refluxed for additional 16 hrs. The reaction was brought to room temperature, then cooled to 0° C. and quenched with the sequential addition of water (1.0 mL), 4N NaOH solution (1.0 mL) and water (1.0 mL). The reaction was brought to room temperature and stirred for additional 30 mins. The reaction was filtered and washed with THF (2×50 mL). The combined THF layer was evaporated, and the crude product was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) on silica gel to obtain the title compound (R) I-255 (0.75 g, 84.6%) as an off-white solid. 1H NMR (DMSO-d6): δ10.46 (s, 1H), 7.08 (s, 1H), 6.98 (s, 1H), 6.93 (s, 1H), 3.79 (s, 3H), 3.01-2.95 (m, 2H), 2.49-2.43 (m, 4H), 2.37-2.32 (m, 1H), 2.22 (s, 3H), 2.11-2.07 (m, 1H), 1.76-1.41 (m, 4H); ESI-MS (m/z, %): 262 (MH+, 100).
Example 13E: Synthesis of (R)-6-Fluoro-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (R) I-256




Synthesis of (R)-2-(2-(6-fluoro-5-methoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenylethan-1-one 12A
A solution of 1-(2-oxo-2-phenylethyl)-D-proline (4.6 g, 18.45 mmol) in dry THF (50 mL) was treated with thionyl chloride (2.7 mL, 36.90 mmol) at 0° C. The reaction was brought to room temperature, then refluxed for 2 hrs. The reaction was brought to room temperature, solvent was evaporated, and the crude product was dried under vacuum to obtain the corresponding acid chloride.
A solution of 6-fluoro-5-methoxy-1H-indole (3.0 g, 18.45 mmol) in dry CH2Cl2 (50 mL) at 5-10° C. was treated with above crude acid chloride in dry CH2Cl2 (20 mL) and ethyl magnesium bromide (12.9 mL, 38.74 mmol, 3 M in diethyl ether) simultaneously over a period of 5 mins. and stirred at same temperature for a further 15 mins. The reaction was quenched with concentrated HCl (10 mL) followed by water (50 mL) and product was extracted into CH2Cl2 (2×100 mL). The CH2Cl2 layer was washed with saturated NaHCO3 solution (50 mL), brine (25 mL) and dried (Na2SO4). Solvent was evaporated and the crude product was purified by crystallization from a mixture of CH2Cl2, Hexanes 1:5 to obtain the title compound 12A (5.7 g, 78.8%) as a beige solid. 1H NMR (DMSO-d6): δ 11.96, 11.95 (2s, 1H), 8.40 (dd, 1H, J=3.0, 6.0 Hz), 7.85, 7.84 (2d, 1H, J=6.0 Hz), 7.39-7.34 (m, 3H), 7.15-7.02 (m, 3H), 5.24-4.91 (m, 3H), 3.87 (s, 3H), 3.56-3.49 (m, 2H), 2.40-2.28 (m, 1H), 1.92-1.84 (m, 3H); ESI-MS (m/z, %): 397 (MH+), 419 (M+Na).
Synthesis of (R)-6-fluoro-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (R) I-256
A solution of (R)-2-(2-(6-fluoro-5-methoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenylethan-1-one (2.0 g, 5.04 mmol) in dry THF (30 mL) was treated with lithium aluminum hydride (25.2 mL, 25.22 mmol, 1M solution in THF) at 0° C. over a period of 10 mins. The reaction was brought to room temperature, then refluxed for additional 16 hrs. The reaction was brought to room temperature, then cooled to 0° C. and quenched with the sequential addition of water (1.0 mL), 4N NaOH solution (1.0 mL) and water (1.0 mL). The reaction was brought back to room temperature and stirred for an additional 30 mins. The reaction was filtered and washed with THF (2×50 mL). The combined THF layer was evaporated and the crude product was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) on silica gel to obtain the title compound (R) I-256 (0.93 g, 70.4%) as an off-white foam. 1H NMR (DMSO-d6): δ 10.69 (s, 1H), 7.16-7.08 (m, 3H), 3.84 (s, 3H), 3.02-2.95 (m, 2H), 2.47-2.42 (m, 1H), 2.38-2.30 (m, 4H), 2.14-2.08 (m, 1H), 1.75-1.41 (m, 4H); ESI-MS (m/z, %): 263 (MH+, 100).
Example 13F: Synthesis of (R)-6-Fluoro-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole (R) I-257




Synthesis of (R)-2-(2-((6-fluoro-5-methoxy-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenylethan-1-one 14A
A solution of (R)-2-(2-(6-fluoro-5-methoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenylethan-1-one (2.5 g, 6.31 mmol) in dry THF (30 mL) was treated with a solution of lithium borohydride (12.6 mL, 25.22 mmol, 2 M solution in THF) at room temperature over a period of 5 mins. and the reaction was refluxed for additional 4 hrs. The reaction was cooled to 0° C. and quenched with the careful addition of methanol (25 mL) over a period of 15 mins. The reaction was brought to room temperature and stirred for additional 1 hr. The reaction was treated with saturated NaHCO3 solution (30 mL) and product was extracted into ethyl acetate (3×50 mL). Combined ethyl acetate layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by flash column chromatography (MeOH; CH2Cl2, 2:98) on silica gel to obtain the title compound 14A (1.65 g, 68.5%) as a pale-yellow glue. The compound was used in the subsequent step with out any characterization.
Synthesis of (R)-6-fluoro-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indole (R) I-257
A solution of (R)-2-(2-((6-fluoro-5-methoxy-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenylethan-1-one (1.65 g, 4.31 mmol) in dry THF (25 mL) was treated with lithium aluminum deuteride (0.45 g, 10.78 mmol) at 0° C. over a period of 10 mins. The reaction was brought to room temperature, then refluxed for additional 16 hrs. The reaction was brought to room temperature, then cooled to 0° C. and quenched with the sequential addition of water (1.0 mL), 4N NaOH solution (1.0 mL) and water (1.0 mL). The reaction was brought back to room temperature and stirred for additional 30 mins. The reaction was filtered and washed with THF (2×50 mL). The combined THF layer was evaporated and the crude product was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) on silica gel to obtain the title compound (R) I-257 (0.97 g, 85.1%) as an off-white solid. 1H NMR (DMSO-d6): δ10.69 (s, 1H), 7.16-7.08 (m, 3H), 3.84 (s, 3H), 3.01-2.95 (m, 2H), 2.49-2.45 (m, 1H), 2.38-2.29 (m, 1H), 2.14-2.07 (m, 1H), 1.77-1.40 (m, 4H); ESI-MS (m/z, %): 266 (MH+, 100).
B. Biological Testing
Example 14: Human 5-HT2A: Functional FLIPR Assay
Objective
The potential excitatory effects of compounds targeting human 5-hydroxytryptamine receptor 2A (5-HT2A) under agonist mode was assessed.
1. Materials and Instrumentation







TABLE 40







1.1 Cell line











Cell line Name
Target
Host cell







HTR2A&Gα15-HEK293
5-HT2A
Flp-In-293

















TABLE 41







1.2 Materials











Regents
Vendor
Cat#







DMEM
Gibco
10569-010



Dialyzed FBS
BIOSUN
BS-0005-500



Penicillin-Streptomycin
Invitrogen
15140



Hygromycin B
Invivogen
Ant-hg-5



Tetracycline
Abcam
ab141223



hydrochloride



TrypLE ™Express
Gibco
12604-013



DPBS
Gibco
14190250



DMSO
Millipore
1029312500



Probenecid
Sigma
P8761



FLIPR Calcium 6 Assay
Molecular Device
R8191



Kit



HEPES
Invitrogen
15630



Hank's Buffered Saline
Invitrogen
14025



Solution



Serotonin HCl
Selleck
S4244

















TABLE 42







1.3 Instrumentation and consumables









Item
Supplier
Cat#





Fluorometric Imaging Plate Reader
Molecular Device
Tetra


(FLIPR)


Countess Automated Cell Counter
Invitrogen
Countess


Cell Counting Chamber Slides
Invitrogen
C10312


STERI-CYCLE CO2 Incubator
Thermo
371


1300 Series Class II Biological Safety
Thermo
1389


Cabinet


Table-type Large Capacity Low Speed
Cence
L550


Centrifuge


Centrifuge
Eppendorf
5702


Echo
Labcyte
550


Echo
Labcyte
655


Electro-thermal incubator
Shanghai Yiheng
DHP-9031


plate shaker
IKA
MS3 digital


Water Purification System
ULUPURE
UPH-III-20T


Versatile and Universal pH and
Mettler Toledo
S220


Conductivity Meters


384-Well plate
Corning
3764


384-Well LDV Clear microplate
LABCYTE
LP-0200


384-Well Polypropylene microplate
LABCYTE
PP-0200


384-well compound plate
Corning
3657


T25 cell culture flask
Corning
430639


50 mL Polypropylene Centrifuge Tube
JET
CFT011500


15 mL Polypropylene Centrifuge Tube
JET
CFT011150









2. Experimental Methods
2.1 Cell Culture
HTR2A&Gα15-HEK293 cells were cultured in DMEM medium containing 10% dialyzed FBS and 1× penicillin-streptomycin, 100 μg/mL Hygromycin B and 300 μg/mL G418. The cells were passaged about three times a week, maintained between ˜30% to ˜90% confluence.
2.2 Cell Plating
1. The 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 to room temperature was warmed in advance.
2. For induction, 1 μg/ml tetracycline (final concentration) was added to cell culture medium and incubated for 48 hours prior to seeding cells into plate at 37° C., 5% (v/v) CO2. The cell culture medium was removed from flask. Cells were washed with DP BS.
3. 2 mL TrypLE™ Express was added to the flask, mixed well by gentle shaking and cells were incubated at 37° C. for a few minutes.
4. The cells were checked for morphological change under microscope, the digestion was stopped by adding 4 mL cell culture medium to the flask when most of cells turned to round.
5. The cell suspension was transferred into a 15 mL centrifuge tube, and then centrifuged at 1,200 rpm for 5 minutes.
6.
The supernatant was removed. The cell pellet was resuspended with 2 ml cell culture medium.
7. The cell density was counted using cell counter. Only cells with >85% viability were used for the assay.
8. Cells were diluted to 6.67×105/mL with cell culture medium.
9. 30 μL/well cell suspensions added into a 384-well cell plate (The cell density was 20,000 cells/well).
10. The cell plate was incubated overnight at 37° C., 5% (v/v) CO2.
2.3 Cell Handling
1. On the day of experiments, culture medium was removed from the cell plate.
2. 10 μL of assay buffer (20 mM HEPES, in 1×HBSS, pH 7.4) was added to each well of the cell plate.
3. 2× dye solution was prepared following the manual of the FLIPR® Calcium 6 Assay Kit:

    
    
        i. The dye was diluted with assay buffer.
        ii. Probenecid was added to the final concentration of 5 mM.
        iii. Vortexed vigorously for 1-2 minutes.
    
    


4. 10 μL of 2× dye solution was added to each well of the cell plate
5. The cell plate was placed on plate shaker, followed by shaking at 600 rpm for 2 minutes.
6. The plate was incubated at 37° C. for 2 hours followed by an additional 15-minute incubation at 25° C.
2.4 Prepare 3× Compound.
1. Serotonin HCl was prepared to the concentration of 10 mM with DMSO.
2. The test compounds were prepared to the concentration of 10 mM with DMSO.
3. The compounds were added to a 384-well compound source plate.
4. 3-folds serial dilutions were performed with DMSO.
5. 90 nL/well of serial diluted compounds was transferred from source plate to a 384-well compound plate by using an Echo.
6. 30 μL/well of assay buffer (20 mM HEPES in 1×HBSS, pH 7.4) was added to the compound plate.
7. The plate was mixed on-plate shaker for 2 minutes.
2.5 FLIPR Assay:
1. After the cells were incubated with dye solution, the cell plate, compound plate containing 3× compounds and FLIPR tips were placed into FLIPR.
2. 10 μL of 3× compounds transferred from the compound plate to the cell plate by FLIPR.
3. The plate was read for 160 sec with 1 sec interval and the data of agonist mode was obtained.
3. Data Analysis
1. The normalized fluorescence reading (RFU) was calculated as shown below, wherein Fmax and Fmin stand for maximum and minimum of calcium signal during defined time window:

RFU=Fmax−Fmin 

2. EC50 by fitting RFU against log of compound concentrations with Hill equation was calculated using XLfit.
Results and Discussion
The results of potential competition binding properties of the exemplary compounds of the disclosure targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A) are summarized in Table 43. The results of exemplary compounds of the disclosure are presented as EC50 is provided in Table 43.







TABLE 43







Effect of exemplary compounds of Formula (I) using


FLIPR functional assay on human 5-HT2A receptor











Example
h5-HT2A, EC50 [nM]
RFU@10 μM (1)















5-MeO-DMT
63
5,667



DMT
163
3,493



(R) I-98
13
8,298



(R) I-244
50
7,945



(R) I-245
120
8,322



Rac (R) I-248
54
8,240







(1) Curve fitting with activation (%) @ 10 mM with RFU






II. Results and Discussion
Exemplary compounds of Formula (I) were evaluated using FLIPR functional assay on human 5-HT2A receptor. EC50 (nM) concentrations are illustrated in Table 43. This assay confirms that compounds of the disclosure are effective agonists of the target human 5-HT2A receptors.
Example 15: Human 5-HT2A: Radioligand Binding Assay
Objective
The objective of this study was to evaluate the binding properties of exemplary compounds of Formula (I) on 5-hydroxytryptamine receptor 2A (5-HT2A).
1. Materials and Instrumentation







TABLE 44







1.1 Regents









Items
Vendor
Cat#





Ketanserin Hydrochloride,
PerkinElmer
NET791250UC


[Ethylene-3H]—


Ketanserin
MedChemExpress
HY-10562


Bovine Serum Albumin (BSA)
Sigma
A1933


Calcium chloride (CaCl2)
Sigma
C5670


Tris(hydroxymethyl)aminomethane
Alfa Aesar
A18494


(Tris)


Polyethylenimine, branched (PEI)
Sigma
408727
















TABLE 45







1.2 Instrumentation and Consumables









Item
Supplier
Cat#





Microbeta2 Microplate Counter
PerkinElmer
2450-0060


UniFilter-96 GF/B
PerkinElmer
6005177


TopSeal
Biotss
SF-800


MicroBeta Filtermate-96
PerkinElmer
D961962


Seven Compact pH meter
Mettler Toledo
S220


Ultrapure Water Meter
Sichuan Ulupure
UPH-III-20T


Benchtop Centrifuge
Hunan Xiangyi
L550


Microplate Shaker
Allsheng
MX100-4A


384-Well Polypropylene
Labcyte
PP-0200


Microplate


96 Round Well Plate
Corning
3799


96 Round Deep Well Plate
Axygen
P-DW-11-C


Echo
LABCYTE
550









2. Experimental Methods
1. The assay buffer was prepared following Table 46 below.










TABLE 46







Reagent
Concentration









Tris
50 mM



CaCl2
 4 mM



BSA
0.1% (w/v)







Adjust pH to 7.4 followed by 0.2 μM sterile filtration






2. 8 doses of reference and test compounds starting from 10 mM stock solution as required was prepared by 5-fold serial dilutions with 100% (v/v) DMSO.
3. UniFilter-96 GF/B plate was pretreated:

    
    
        i. 50 μl/well of 0.5% (v/v) PEI was added to UniFilter-96 GF/C plates. The plates were sealed and incubated at 4° C. for 3 hrs.
        ii. After incubation, the plates were washed 3 times with ice-cold wash buffer (50 mM Tris, pH 7.4).
    
    


4. The assay plate was prepared:

    
    
        i. Cell membrane was diluted with assay buffer and 330 μl/well was added to 96 round deep well plates to reach a concentration of 20 μg/well.
        ii. 8 concentrations of reference or test compounds were prepared and 110 μl/well was added to 96 round deep well plates.
        iii. [3H]-ketanserin was diluted with assay buffer to 5 nM (5× final concentration) and 110 μl/well was added to 96 round deep well plates.
    
    


5. The plate was centrifuged at 1000 rpm for 30 secs and then agitated at 600 rpm at room temperature for 5 mins.
6. The plates were sealed and the plate incubated at 27° C. for 90 min.
7. The incubation was stopped by vacuum filtration onto GF/B filter plates followed by 4 times washing with ice-cold wash buffer (50 mM Tris, pH7.4).
8. The plates were dried at 37° C. for 45 min.
9. The filter plates were sealed and 40 μl/well of scintillation cocktail was added.
10. The plate was read by using a Microbeta2 microplate counter.
3. Data Analysis
1. For reference and test compounds, the results were expressed as % Inhibition, using the normalization equation: N=100−100×(U−C2)/(C1−C2), where U is the unknown value, C1 is the average of high controls, and C2 is the average of low controls.
2. The IC50 was determined by fitting percentage of inhibition as a function of compound concentrations with Hill equation using XLfit.
Results and Discussion
The results of potential competition binding properties of the exemplary compound of the disclosure targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A) are summarized in Table 47. The results of exemplary compounds of the disclosure are presented as IC50 provided in Table 47.







TABLE 47







Effect of exemplary compounds of Formula (I) using


Radioligand binding assay on human 5- receptor










Compound ID
h5-HT2A, IC50 [nM]







5-MeO-DMT
603



DMT
954



(R) I-98
350



(R) I-244
129



(R) I-245
225



rac (R) I-248
310










II. Results and Discussion
Exemplary compounds of Formula (I) were evaluated using radioligand binding assay on human 5-HT2A receptor. IC50 (nM) concentrations are illustrated in Table 47. This assay confirms that exemplary compounds of the disclosure are effective ligands of the target human 5-HT2A receptors.
Example 15A: Human-5HT2A-β-Arrestin Assay
Protocol
Compound potency (EC50) and efficacy (Max response) against the human 5-HT2A receptor in stably transfected U2OS cells was determined in a GPCR cell based β-arrestin reporter assay.
Cells were seeded in a total volume of 20 μL into white walled, 384-well microplates and incubated at 37° C. overnight before analysis. For agonist determination, cells were incubated with sample to induce response. Intermediate dilution of sample stocks was performed to generate 5× samples in assay buffer. 5 μL of 5× samples were added to cells and incubated at 37° C. for 120 mins. The final assay vehicle concentration was 1%. The results are expressed as percent efficacy relative to the maximum response of the control ligand (serotonin) in Table 48.







TABLE 48







Effect of exemplary compounds of Formula (I) using


a β-arrestin reporter assay on human 5-HT2A receptor











Compound ID
EC50 (μM)
Emax (% of serotonin)















DMT
0.1136
38.86



5MeO-DMT
0.02945
72.41



(R) I-98
0.025792
81.67



(R) I-244
0.0067093
79.58



(R) I-245
0.028375
82.18



Cis (R) I-248
0.11174
84.4










Example 16: Human 5-HT1A: Functional FLIPR Assay
1. Objective
The potential excitatory effects of compounds targeting on 5-hydroxytryptamine receptor 1A (5-HT1A) under agonist mode was assessed.
2. Materials and Instrumentation







TABLE 49







2.1 Cell line











Cell line Name
Target
Host cell







HTR1A&Gα15-CHO
5-HT1A
Flp-in CHO

















TABLE 50







2.2 Materials









Regents
Vendor
Cat#












DMEM/F12
Gibco
11330057


Dialyzed FBS
BIOSUN
BS-0005-500


Penicillin-Streptomycin
Invitrogen
15140


Hygromycin B
Invivogen
Ant-hg-5


TrypLE ™Express
Gibco
12604-013


DPBS
Gibco
14190250


DMSO
Millipore
1029312500


Probenecid
Sigma
P8761


FLIPR Calcium 6 Assay Kit
Molecular Device
R8191


HEPES
Invitrogen
15630


Hank's Buffered Saline
Invitrogen
14025


Solution


Serotonin HCl
Selleck
S4244
















TABLE 51







2.3 Instrumentation and consumables









Item
Supplier
Cat#





Fluorometric Imaging Plate Reader
Molecular Device
Tetra


(FLIPR)


Countess Automated Cell Counter
Invitrogen
Countess


Cell Counting Chamber Slides
Invitrogen
C10312


STERI-CYCLE CO2 Incubator
Thermo
371


1300 Series Class II Biological Safety
Thermo
1389


Cabinet


Table-type Large Capacity Low Speed
Cence
L550


Centrifuge


Centrifuge
Eppendorf
5702


Echo
Labcyte
550


Echo
Labcyte
655


Electro-thermal incubator
Shanghai Yiheng
DHP-9031


plate shaker
IKA
MS 3 digital


Water Purification System
ULUPURE
UPH-III-20T


Versatile and Universal pH and
Mettler Toledo
S220


Conductivity Meters


384-Well plate
Corning
3764


384-Well LDV Clear microplate
LABCYTE
LP-0200


384-Well Polypropylene microplate
LABCYTE
PP-0200


384-well compound plate
Corning
3657


T25 cell culture flask
Corning
430639


50 mL Polypropylene Centrifuge Tube
JET
CFT011500


15 mL Polypropylene Centrifuge Tube
JET
CFT011150









3. Experimental Methods
3.1 Cell Culture
HTR1A&Gα15-CHO cells were cultured in DMEM/F12 medium containing 10% dialyzed FBS, 1× penicillin-streptomycin and 600 μg/mL Hygromycin B. The cells were passaged about three times a week, maintained between ˜30% to ˜90% confluence.
3.2 Cell Plating
1. The cell culture medium (DME M/F12 medium containing 10% dialyzed FBS, 1× penicillin-streptomycin and 600 μg/mL Hygromycin B), TrypLE™ Express and DPBS was warmed to R.T. in advance.
2. The cell culture medium was removed from flask. Washed cells with DPBS.
3. 1 mL TrypLE™ Express was added to the flask, mixed well by gentle shaking and cells were incubated at 37° C. for a few minutes.
4. The cells were checked for morphological change under microscope, the digestion was stopped by adding 2 mL cell culture medium to the flask when most of cells turned to round.
5. The cell suspension was transferred into a 15 mL centrifuge tube, and then centrifuged at 1,200 rpm for 5 minutes.
6. The supernatant was removed. The cell pellets were resuspended with 2 mL cell culture medium.
7. The cell density was counted using cell counter. Only cells with >85% viability were used for the assay.
8. Cells were diluted to 4×105/mL with cell culture medium.
9. 30 μL/well cell suspensions were added into a 384-well cell plate (The cell density was 12,000 cells/well).
10. The cell plate was incubated overnight at 37° C., 5% (v/v) CO2.
3.3 Cell Handling
1. On the day of experiments, culture medium was removed from the cell plate.
2. 10 μL of assay buffer (20 mM HEPES, in 1×HBSS, pH 7.4) was added to each well of the cell plate.
3. 2× dye solution was prepared following the manufacture's instruction of the FLIPR® Calcium 6 assay kit:

    
    
        i. The dye was diluted with assay buffer.
        ii. probenecid was added to the final concentration of 5 mM.
        iii. Vortexed vigorously for 1-2 minutes, adjust pH to 7.4.
    
    


4. 10 μL of 2× dye solution was added to each well of the cell plate.
5. The cell plate was placed on plate shaker, followed by shaking at 600 rpm for 2 minutes.
6. The plate was incubated at 37° C. for 2 hours followed by an additional 15-minute incubation at 25° C.
3.4 Prepare 3× Compounds.
1. Serotonin was prepared to the concentration of 10 mM with DMSO, 3-folds serial dilutions were performed with DMSO.
2. Prepare the test compound to the concentration of 10 mM with DMSO, preform 3-folds serial dilutions with DMSO.
3. The compounds were added to a 384-well compound source plate.
4. 90 nL/well of serial diluted compounds were transferred from source plate to a 384-well compound plate by using an Echo.
5. 30 μL/well of assay buffer was added to the compound plate.
6. The plate was mixed on-plate shaker for 2 minutes.
3.5 FLIPR Assay
1. After the cells were incubated with dye solution, the cell plate, compound plate containing 3× compounds and FLIPR tips were placed into FLIPR.
2. 10 μL of 3× compounds were transferred from the compound plate to the cell plate by FLIPR.
3. The plate was read for 160 sec with 1 sec interval to obtain the data of agonist mode.
4. Data Analysis
1. The normalized fluorescence reading (RFU) was calculated as shown below, wherein Fmax and Fmin stand for maximum and minimum of calcium signal during defined time window:



 
  RFU
  =
  
   
    F
    max
   
   -
   
    F
    min
   
  
 



2. EC50 was calculated by fitting RFU against log of compound concentrations with Hill equation using XLfit.
Results and Discussion
The results of potential competition binding properties of the exemplary compounds of the disclosure targeting the human 5-hydroxytryptamine receptor 1A (5-HT1A) are summarized in Table 52. The results of exemplary compounds of the disclosure are presented as EC50 provided in Table 52.







TABLE 52







Effect of exemplary compounds of Formula (I) using


FLIPR functional assay on human 5-HT1A receptor











Compound ID
h5-HT1A, EC50 [nM]
RFU@10 μM (1)















5-MeO-DMT
1,066
3,891



DMT
 ND(2)
204



(R) I-98
3,171
1,666



(R) I-244
ND
616



(R) I-245
ND
899



rac (R) I-248
ND
601







(1) Curve fitting with activation (%) @ 10 mM with RFU






(2) Not detected
Exemplary compounds of Formula (I) were evaluated using functional FLIPR assay on human 5-HT1A receptor. EC50 (nM) concentrations are illustrated in Table 52. This assay confirms that compounds of the disclosure are functionally active at the target human 5-HT1A receptors.
Example 17: Human 5-HT1A: Radioligand Binding Assay
1. Objective
The objective of this study was to evaluate the binding properties of test compounds on 5-hydroxytryptamine receptor 1A (5-HT1A).
2. Materials and Instrumentation







TABLE 53







2.1 Regents









Items
Vendor
Cat#





[3H]-8-Hydroxy-DPAT
PE
NET929250UC


Serotonin HCl
Selleck
S4244


Bovine Serum Albumin (BSA)
Sigma
A1933


Calcium chloride (CaCl2)
Sigma
C5670


MgCl2
Sigma
M1028


Tris(hydroxymethyl)aminomethane (Tris)
Alfa Aesar
A18494


Polyethylenimine, branched (PEI)
Sigma
408727
















TABLE 54







2.2 Instrumentation and Consumables









Item
Supplier
Cat#





Microbeta2 Microplate Counter
PerkinElmer
2450-0060


UniFilter-96 GF/B
PerkinElmer
6005177


TopSeal
Biotss
SF-800


MicroBeta Filtermate-96
PerkinElmer
D961962


Seven Compact pH meter
Mettler Toledo
S220


Ultrapure Water Meter
Sichuan Ulupure
UPH-III-20T


Benchtop Centrifuge
Hunan Xiangyi
L550


Microplate Shaker
Allsheng
MX100-4A


384-Well Polypropylene
Labcyte
PP-0200


Microplate


96 Round Well Plate
Corning
3799


96 Round Deep Well Plate
Axygen
P-DW-11-C


Echo
LABCYTE
550









3 Experimental Methods
1. The assay buffer was prepared following Table 55 below.










TABLE 55







Reagent
Concentration









Tris
25 mM



MgCl2
10 mM



CaCl2
 1 mM



BSA
0.5% (w/v)







Adjust pH to 7.4 followed by 0.2 μM sterile filtration






2. 8 doses of reference and test compounds were prepared starting from 10 mM stock solution as required by 5-fold serial dilutions with 100% (v/v) DMSO.
3. UniFilter-96 GF/B plate was pretreated:

    
    
        i. 50 μL/well of 0.5% (v/v) PEI was added to UniFilter-96 GF/B plates. The plates were sealed and incubated at 4° C. for 3 hrs.
        ii. After incubation, the plates were washed 3 times with ice-cold wash buffer (50 mM Tris, pH7.4).
    
    


4. Assay plate was prepared:

    
    
        i. Cell membrane was diluted with assay buffer and 100 μl/well was added to 96 round well plates to reach a concentration of 20 μg/well.
        ii. 8 concentrations of reference or test compounds were prepared and 50 μl/well was added to 96 round deep well plates.
        iii. [3H]-8-Hydroxy-DPAT was diluted with assay buffer to 2 nM (4× final concentration) and 50 μL/well was added to 96 round well plates.
    
    


5. The plate was centrifuged at 1000 rpm for 30 secs and then agitated at 600 rpm at room temperature for 5 min.
6. The plates were sealed and the plate was incubated at 27° C. for 90 min.
7. The incubation was stopped by vacuum filtration onto GF/B filter plates followed by 4 times washing with ice-cold wash buffer (50 mM Tris, pH7.4).
8. The plates were dried at 37° C. for 45 min.
9. The filter plates were sealed and 40 μl/well of scintillation cocktail was added.
10. The plate was read by using a Microbeta2 microplate counter.
4 Data Analysis
1. For reference and test compounds, the results were expressed as % Inhibition, using the normalization equation: N=100−100×(U−C2)/(C1−C2), where U is the unknown value, C1 is the average of high controls, and C2 is the average of low controls.
2. The IC50 was determined by fitting percentage of inhibition as a binding of compound concentrations with Hill equation using XLfit.
Results and Discussion
The results of potential competition binding properties of the exemplary compounds presented as IC50 of the disclosure targeting the human 5-hydroxytryptamine receptor (5-HT1A) are summarized in Table 56.







TABLE 56







Effect of exemplary compounds of Formula (I) using


Radioligand binding assay on human 5-HT1A receptor











h5-HT1A,



Compound ID
IC50 [nM]














5-MeO-DMT
6



DMT
689



(R) I-98
5



(R) I-244
15



(R ) I-245
5



rac (R) I-248
8.3










Results and Discussion
Exemplary compounds of Formula (I), thereof were evaluated using radioligand binding assay on human 5-HT1A receptor. IC50 (nM) concentrations are illustrated in Table 56. This assay confirms that compounds of Formula (I) of the disclosure are effective ligands of the target human 5-HT1A receptors.
Example 17A: Human 5-HT2B: Radioligand Binding Assay
The objective of this study is to evaluate the binding properties of test compounds on 5-HT2B.










Materials and Instruments (Table 57)









Materials
Vendor
Cat#





[3H]-LSD
PerkinElmer
NET638250UC


Yohimbine
MedChemExpress
HY-N0127


Bovine Serum Albumin (BSA)
Sigma
A1933


Calcium chloride (CaCl2)
Sigma
C5670


Tris(hydroxymethyl)aminomethane
Alfa Aesar
A18494


(Tris)


Polyethylenimine, branched (PEI)
Sigma
408727



















Instrumentation and Consumables (Table 58)









Item
Supplier
Cat#





Microbeta2 Microplate Counter
PerkinElmer
2450-0060


UniFilter-96 G F/B
PerkinElmer
6005177


TopSeal
Biotss
SF-800


MicroBeta Filtermate-96
PerkinElmer
D961962


Seven Compact pH meter
Mettler Toledo
S 220


Ultrapure Water Meter
Sichuan Ulupure
UPH-III-20T


Benchtop Centrifuge
Hunan Xiangyi
L550


Microplate Shaker
Allsheng
MX100-4A


384-Well Polypropylene Microplate
Labcyte
PP-0200


96 Round Well Plate
Corning
3799


96 Round Deep Well Plate
Axygen
P-DW-11-C


Echo
LABCYTE
550









Experimental Methods
1) The assay buffer was prepared following Table 59 below.










TABLE 59







Reagent
Concentration









Tris
50 mM



CaCl2
 4 mM



BSA
0.1% (w/v)







Adjust pH to 7.4 followed by 0.2 μM sterile filtration






2) Eight doses of reference and test compounds starting from 10 mM stock solution as requested by 5-fold serial dilutions with 100% (v/v) DMSO.
3) UniFilter-96 GF/B plate was pretreated:

    
    
        a. 50 μL/well of 0.5% (v/v) PEI to UniFilter-96 GF/B plates. The plates were sealed and incubate at 4° C. for 3 hrs.
        b. After incubation, the plates were washed three times with ice-cold wash buffer (50 mM Tris, pH7.4).
    
    


4) Assay plate preparation:

    
    
        a. Cell membrane was diluted with assay buffer and 330 μL/well added to 96 round deep well plates to reach a concentration of 1 unit/well.
        b. Eight concentrations of reference or test compounds were prepared and 110 μL/well added to 96 round deep well plates.
        c. [3H]-LSD was diluted with assay buffer to 5 nM (5× final concentration) and 110 μL/well was added to 96 round deep well plates.
    
    


5) The plate was centrifuged at 1000 rpm for 30 secs and then agitated at 600 rpm at room temperature for 5 min.
6) The plates were sealed and incubated at 37° C. for 90 mins.
7) The incubation was stopped by vacuum filtration onto GF/B filter plates followed by washing four times with ice-cold wash buffer (50 mM Tris, pH7.4).
8) The plates were dried at 37° C. for 45 mins.
9) The filter plates were sealed and 40 μL/well of scintillation cocktail was added.
10) The plate was read using a Microbeta2 microplate counter.
Data Analysis
For reference and test compounds, the results are expressed as % Inhibition, using the normalization equation: N=100−100×(U−C2)/(C1−C2), where U is the unknown value, C1 is the average of the high controls, and C2 is the average of the low controls. The IC50 is determined by fitting percentage of inhibition as a function of compound concentrations with Hill equation.











TABLE 60







Compound ID
5-HT2B, IC50 [nM]
5-HT2B, Ki [nM]




















5-MeO-DMT
248.92
128.79



DMT
423.14
218.92



(R) I-98
45.56
23.57



(R) I-244
21.44
11.09



rac (R) 1-248
46.30
23.95










Example 17B: Human-5HT1A-CAMP Assay
Protocol
Compound potency (EC50) and efficacy (Max response) against the human 5-HT1A receptor in stably transfected CHO-K1 cells were determined in a GPCR cell-based CAMP assay.
Cells were seeded in a total volume of 20 μL into white walled, 384-well microplates and incubated at 37° C. overnight before analysis. Prior to testing, cell plating media was exchanged with 10 μL of Assay buffer (HBSS+10 mM HEPES). Briefly, intermediate dilution of sample stocks was performed to generate 4× samples in assay buffer. 5 μL of 4× samples+5 μL of 4× forskolin was added to cells and incubated at 37° C. for 30 mins. The final assay vehicle concentration was 1%. The results are expressed as percent efficacy relative to the maximum response of the control ligand (serotonin) in Table 61.







TABLE 61







Effect of exemplary compounds of Formula (I) using


CAMP functional assay on human 5-HT1A receptor











Compound ID
EC50 (μM)
Emax (% of serotonin)















DMT
0.97437
87.1



5MeO-DMT
0.012699
99.98



(R) I-98
0.040309
96.42



(R) 1-244
0.0063038
99.01



(R) 1-245
0.01948
99.14



Cis (R) 1-248
0.052683
96.76










Example 17C: Human-5HT2B FLIPR Assay
Protocol
Compound potency (EC50) and efficacy (Max response) against the human 5-HT2B receptor in stably transfected HE K293 cells was determined in a calcium mobilization-based assay.
Cells were seeded in a total volume of 20 μL into white walled, 384-well microplates and incubated at 37° C. overnight. Prior to testing, cell plating media was exchanged with 20 μL of Dye Loading buffer (HBSS+20 mM HEPES containing 1× Dye, 1× Additive A, and 2.5 mM Probenecid). Plates were incubated at 37° C. for 45 mins followed by 15 mins at room temperature.
10 μL of assay buffer (HBSS+20 mM HEPES) was added to cells. Intermediate dilution of sample stocks was performed to generate 4× samples in assay buffer. Assay plates and compound plates were loaded into the FLIPR instrument. 10 μL of samples were added using the FLIPR onboard robotics after 5 secs of starting calcium measurement. The final assay vehicle concentration was 1%. The results are expressed as percent efficacy relative to the maximum response of the control ligand (serotonin) in Table 62.







TABLE 62







Effect of exemplary compounds of Formula (I) using


FLIPR functional assay on human-5-HT2B receptor











Compound ID
EC50 (μM)
Emax (% of serotonin)















DMT
>10
13.4



5MeO-DMT
0.015452
28.88



(R) I-98
0.0028832
52.7



(R) I-244
0.0024999
92.75



(R) I-245
0.011171
53.91



Cis (R) I-248
0.02494
69.85










Example 17D: Human-5HT2C FLIPR Assay
Protocol
Compound potency (EC50) and efficacy (Max response) against the human 5-HT2B receptor in stably transfected U2OS cells was determined in a calcium mobilization-based assay.
Cells were seeded in a total volume of 20 μL into white walled, 384-well microplates and incubated at 37° C. overnight. Prior to testing, cell plating media was exchanged with 20 μL of Dye Loading buffer (HBSS+20 mM HEPES containing 1× Dye, 1× Additive A, and 2.5 mM Probenecid). Plates were incubated at 37° C. for 45 mins followed by 15 mins at room temperature.
10 μL of assay buffer (HBSS+20 mM HEPES) was added to the cells. Intermediate dilution of sample stocks was performed to generate 4× samples in assay buffer. Assay plates and compound plates were loaded into the FLIPR instrument 10 μL of samples were added using the FLIPR onboard robotics after 5 seconds of starting calcium measurement. The final assay vehicle concentration was 1%. The results are expressed as percent efficacy relative to the maximum response of the control ligand (serotonin) in Table 63.







TABLE 63







Effect of exemplary compounds of Formula (I) using


FLIP R functional assay on human 5-HT2c receptor











Compound ID
EC50 (μM)
Emax (% of serotonin)















DMT
0.01112
94.56



5MeO-DMT
0.0027312
95.42



(R) I-98
0.0065076
95.23



(R) I-244
0.0025278
87.27



(R) I-245
0.042251
83.29



Cis (R) I-248
0.15081
89.99










Example 17E: Human-5HT2B Positive Allosteric Modulator (PAM) Assay
Protocol
Compound potency (EC50) and efficacy (Max response) against the human 5-HT2B receptor in stably transfected HEK293 cells was determined in a GPCR cell-based assay.
For Positive Allosteric Modulator determination, cells were pre-incubated with sample followed by EC20 addition. Intermediate dilution of sample stocks was performed to generate 5× samples in assay buffer. 5 μL of 5× samples were added to cells and incubated at 37° C. for 10 mins. 5 μL of agonist at 6×EC20 concentration was added and the cells were incubated at 37° C. for 120 mins. The final assay vehicle concentration was 1%. The results are expressed as percent efficacy relative to the maximum response of the control ligand (serotonin) in Table 64.







TABLE 64







Effect of exemplary compounds of Formula (I) using


PAM functional assay on human 5-HT 2B receptor











Compound ID
EC50 (μM)
Emax (% of serotonin)















DMT
>10
0



5MeO-DMT
>10
0



(R) I-98
>10
0



(R) I-244
0.097371
26.89



(R) I-245
>3.3333
0



Cis (R) I-248
>10
7.97










Example 18: Psychedelic-Like Effect of Exemplary Compounds of Formula (I)
The effect of different doses of exemplary compounds of Formula (I) were evaluated on head-twitch response (HTR) as a behavior-based model of psychedelic activity.
Mouse Head Twitch Response (HTR) Test:
Protocols
Adult C57BL/6J mice (body weight range 20-30 g) were each placed into an open-top test cage made of transparent plastic for 20-30 min of habituation prior to testing. Habituation and testing were both conducted under low light conditions (˜100 lux). Mice received a subcutaneous (SC) injection of either vehicle, positive control substance (e.g., 2,5-dimethoxy-4-iodoamphetamine (DOI)), or test compound at appropriate doses and volumes (10 mL/kg). Immediately post-treatment each mouse was placed back in its respective test cage. The cages were placed at approximately 50 cm from each other on a white, adjustable height table/flat surface so that the experimenter could easily monitor fine behaviors of both mice within the testing environment. An opaque divider was placed between the cages to prevent animals from observing each other. Immediately after placing the mice back into the test cages, the experimenter sat directly in front of the two containers, and recorded in real time the number of head twitch responses (HTR, defined as rapid side-to-side rotational shaking of the head) performed by each mouse for 20 min, subdivided in 5 min intervals with the use of a silent timer. To ensure scoring accuracy and consistency, one experienced experimenter performed HTR recording for all mice included in a study. While mice were subjected to HTR testing, another mouse pair underwent habituation in a separate set of test cages, so that at the end of the HTR scoring period new animals were ready to undergo substance administration and testing. Between individual HTR tests, cages were cleaned with water, disinfected with a 70% ethanol aqueous solution, and dried using paper towels.
Results and Discussion
FIG. 2, FIG. 3, FIG. 4, and FIG. 5 are graphs showing the effect of various doses of exemplary compounds of Formula (I), specifically, (R) I-98, (R) I-244, (R) I-245, and Cis (R) I-248, on head-twitch response (HTR) in male C57BL6 mice. The mice were treated with exemplary compound (R) I-98, (R) I-244, (R) I-245, or Cis (R) I-248 by SC route, and the total number of head twitches were recorded over a 20 min period. Data is expressed as mean±SEM. The induction of head twitches elicited by 5-HT2A receptor agonists is believed to represent a behavioral proxy of their psychedelic effects. Also, locomotor activity and other 5-HT receptor signs were measured (FIGS. 2-5).
Example 19: Pharmacokinetic Studies in Rat
Protocol
Study Details:
Animals: Male Sprague-Dawley rats (˜225-350 g) from Charles River Labs were acclimatized for a minimum of 5 days prior to start of study procedures. Body weights were recorded on the day of dosing.
Food restriction: None.
Clinical observations: Animals were observed at the time of dosing and each sample collection. Any abnormalities were documented including presence/absence of wet dog shakes/back muscle contractions (WDS/BMC).
Dosing: Formulations were administered intravenously (i.v.) via the tail vein using a 25 G needle connected to a 1 cc syringe.
Formulation:
The Compounds of Formula (I) were freshly prepared at the appropriate concentrations in 5% Tween-80 in saline.
Sample Collection:
Blood collection time (h): 0, 25, 1 and 4
Volume/time-point: ˜0.25 mL (saphenous vein)
Bioanalytical Method Development and Sample Analysis:
Analytes: Compounds of Formula (I)
Matrix: Rat plasma.
Instrumentation: AB Sciex QTRAP 4000 or 6500 MS/MS system equipped with an LC system with a binary pump, a solvent degasser, a thermostated column compartment and a multiplate autosampler.
Bioanalytical method(s) development include:

    
    
        1. The selection of the ion transition for the test compounds and potential internal standards (i.e., identification of the parent and product ions).
        2. The optimization of mass spectrometric operating parameters.
        3. The establishment of the chromatographic condition for the analytes.
        4. The selection of an appropriate internal standard (IS).
        5. The development of sample clean-up method using protein precipitation.

Method(s) Qualification:

    
    


1. The determination of the quantification dynamic range using non-zero calibration standards (STDs) in singlet. The STDs will consist of a blank matrix sample (without IS), a zero sample (with IS), and at least 6 non-zero STDs covering the expected range and including the lower level of quantitation (LLOQ).
2. Triplicate injections of a system suitability sample (neat solution containing the analyte and IS) bracketing the batch.
Method(s) Acceptance Criteria:
1. At least 75% of non-zero STDs must be included in the calibration curve with all back-calculated concentrations within ±20% deviation from nominal concentrations (±25% for the lower level of quantification, LLOQ).
2. The correlation coefficient (r) of the calibration curve must be greater than or equal to 0.99 using quadratic regression analysis (1/x2 weighting).
3. The area ratio variation between the pre- and post-run injections of the system suitability samples is within ±25%.
Sample Analysis Batch:
1. Triplicate injections of a system suitability sample bracketing the batch.
2. The STDs in ascending order.
3. The study samples and the dosing solutions diluted as 3 independent dilutions into blank matrix (plasma).
4. For more than 40 study samples in a batch, two sets of STDs bracketing the samples will be utilized.
Samples which are 25% greater than the highest calibration standard, will be diluted and re-assayed along with a corresponding dilution quality control standard. Dilution standards will be acceptable if they are within 25% accuracy of the target concentration.
PK Analysis
Analysis software: Phoenix® WinNonlin® 8.3 (Pharsight, Certara, Mountainview, CA).
Analysis methods: non-compartmental analysis, linear up/log down trapezoidal rule.
PK parameters: t1/2 and AUC0-tlast will be estimated.
Results
Table 65 shows the plasma concentration of exemplary compounds of Formula (I) following i.v. administration.







TABLE 65







Plasma concentrations of exemplary compounds of Formula


(I) following 1.10 mg/kg i.v. administration (Group 2).










Experi-












Dose
mental



Exam-
(mg/
time (h)/


ple ID
kg)
Rat#
Plasma concentration (ng/mL)
















(R) I-98
1.32

R07
R08
R09
Mean ± SD  




0.25
411
479
449
446 ± 34.1




1
128
110
100
113 ± 14.2




4
2.48
2.25
2.23
 2.32 ± 0.139


rac (R)
2.09

R04
R05
R06
Mean ± SD  


I-248

0.25
235
437
459
377 ± 123 




1
134
135
162
144 ± 15.9




4
27.8
11.5
17.0
18.8 ± 8.29 


(R) I-
2.06

R01
R02
R03
Mean ± SD  


245

0.25
307
154
71.8
178 ± 119 




1
170
121
98.3
130 ± 36.6




4
39.9
43.6
48.3
43.9 ± 4.21 


(R) I-
2

R10
R11
R12
Mean ± SD  


244

0.25
252
360
263
292 ± 59.4




1
132
150
107
130 ± 21.6




4
20.7
23.8
21.4
22.0 ± 1.63 





*Values in italics are below the lower limit of quantitation (BLQ, 0.5 ng/mL) but were included in calculations.


*BLQ denotes below the lower limit of quantitation (0.5 ng/mL).






Table 66 is a summary of the plasma apparent t1/2 and AUC0-tlast for exemplary compounds of Formula (I) 1 following 1.10 mg/kg i.v. administration (Group 2).







TABLE 66







Summary of plasma apparent t1/2 and AUC0-tlast for I-1


following 1.10 mg/kg i.v. administration (Group 2).










Example
Dose




ID
(mg/kg)
Parameter
Parameter estimate for each animal
















(R) I-98
1.32

R07
R08
R09
Mean ± SD




Apparent t1/2
0.514
0.498
0.505
  0.506 ± 0.00788




(h)a




AUC0-tlast
403
426
397
  409 ± 15.1




(h*ng/mL)


rac (R) I-
2.09

R04
R05
R06
Mean ± SD


248

Apparent t1/2
1.25
0.747
0.823
 0.939 ± 0.269




(h)a




AUC0-tlast
402
477
544
  474 ± 71.0




(h*ng/mL)


(R) I-245
2.6

R01
R02
R03
Mean ± SD




Apparent t1/2
1.32
2.05
2.93
  2.10 ± 0.806




(h)a




AUC0-tlast
528
370
293
 397 ± 120




(h*ng/mL)


(R) I-244
2

R10
R11
R12
Mean ± SD




Apparent t1/2
1.06
1.00
1.10
  1.05 ± 0.0494




(h)a




AUC0-tlast
390
490
366
  415 ± 65.7




(h*ng/mL)





aApparent t1/2 was estimated from 2 points only






Discussion
Exemplary compounds of the disclosure were evaluated for pharmacokinetics profile rat via i.v. administration. Table 65 and Table 66 summarize the results of three representative compounds of formula 1 for plasma concentrations and plasma apparent t1/2 and AUC0-tlast, respectively. of. These results show that the compounds of the disclosure show a spectrum of plasma t1/2 and exposure profiles.
Example 20: Human, Rat and Mouse Liver Microsomes Stability
Objective
The objective of this study was to estimate in vitro metabolic stability of exemplary compounds of Formula (I) or a pharmaceutically acceptable salt, solvate and/or prodrug thereof in pooled human, male rat and male mouse liver microsomes. The concentrations of compounds in reaction systems were evaluated by LC-MS/MS for estimating the stability in pooled human, male rat and male mouse liver microsomes. The in vitro intrinsic clearances of test compounds were determined as well.
Protocol
A master solution in the “Incubation Plate” containing phosphate buffer, ultra-pure H2O, MgCl2 solution and liver microsomes was made according to Table 67. The mixture was pre-warmed at 37° C. water bath for 5 minutes.







TABLE 67







Preparation of master solution










Reagent
Stock Concentration
Volume
Final Concentration
















Phosphate buffer
200
mM
200
μL
100
mM











Ultra-pure H2O
—
106
μL
—













MgCl2 solution
50
mM
40
μL
5
mM


Microsomes
20
mg/mL
10
μL
0.5
mg/mL









40 μL of 10 mM NADPH solution was added to each well. The final concentration of NADPH was 1 mM. The negative control samples were prepared by replacing NADPH with 40 μL of ultra-pure H2O. Samples were prepared in duplicate. Negative controls were prepared in singlet
The reaction was started with the addition of 4 μL of 200 μM exemplary test compounds of the disclosure or control compounds to each master solution to get the final concentration of 2 μM. This study was performed in duplicate.
Aliquots of 50 μL were taken from the reaction solution at 0, 15, 30, 45 and 60 minutes. The reaction solutions were stopped by the addition of 4 volumes of cold methanol with IS (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol and 2 μM ketoprofen). Samples were centrifuged at 3,220 g for 40 minutes. Aliquot of 90 μL of the supernatant was mixed with 90 μL of ultra-pure H2O and then was used for LC-MS/MS analysis.
LC/MS analysis was performed for all samples from this study using a Shimadzu liquid chromatograph separation system equipped with degasser DGU-20A5R; solvent delivery unit LC-30AD; system controller SIL-30AC; column oven CTO-30A; CTC Analytics HTC PAL System. Mass spectrometric analysis was performed using a Triple Quad™ 5500 instrument.
All calculations were carried out using Microsoft Excel. Peak area ratios of test compound to internal standard (listed in the below table) were determined from extracted ion chromatograms.
All calculations were carried out using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The slope value, k, was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve.
The in vitro half-life (in vitro t1/2) was determined from the slope value:



 
  
   in
   ⁢
      
   vitro
   ⁢
      
   
    t
    
     1
     /
     2
    
   
  
  =
  
   -
   
    (
    
     0.693
     /
     k
    
    )
   
  
 



Conversion of the in vitro t1/2 (min) into the in vitro intrinsic clearance (in vitro C Lint, in μL/min/mg proteins) was done using the following equation (mean of duplicate determinations):



 
  
   in
   ⁢
      
   vitro
   ⁢
      
   
    CL
    int
   
  
  =
  
   
    (
    
     0.693
     
      (
      
       t
       
        1
        /
        2
       
      
      )
     
    
    )
   
   *
   
    (
    
     
      volume
      ⁢
         
      of
      ⁢
         
      incubation
      ⁢
         
      
       (
       
        μ
        ⁢
        L
       
       )
      
     
     
      amount
      ⁢
         
      of
      ⁢
         
      proteins
      ⁢
         
      
       (
       mg
       )
      
     
    
    )
   
  
 



For the exemplary compounds of the disclosure or control compound that showed an initial fast disappearance followed by a slow disappearance, only the time points that were within the initial rate were included in the calculation.
Results and Discussion
Human, rat and mouse liver microsomes contain a wide variety of drug metabolizing enzymes and are commonly used to support in vitro ADME (absorption, distribution, metabolism and excretion) studies. These microsomes are used to examine the potential first-pass metabolism by-products of orally administered drugs. Representative compounds of the disclosure were evaluated for their stability in human, rat and mouse liver microsomes.
Most of the exemplary compounds of the disclosure in three species, human, rat and mouse liver microsomes were recovered within a 60-minute time period indicating that the compounds were not rapidly cleared (see Table 68 for exemplary compounds of Formula (I)).







TABLE 68







Metabolic Stability of Compounds of Formula 1 in Liver


Microsomes of Different Species (Human, Rat and Mouse)















CLint
Scaled-up
Predicted


Compound

T1/2
(μL/min/mg
CLint
hepatic CL


ID
Species
(min)
protein)
(mL/min/Kg)
(mL/min/kg)















Diclofenac
Human
10.59
130.91
164.18
18.38



Rat
15.27
90.79
162.69
41.22



Mouse
40.69
34.06
149.03
56.11


(R) I-98
Human
64.33
21.55
27.02
11.72



Rat
10.04
138.11
247.50
45.13



Mouse
14.39
96.32
421.38
74.16


rac (R)
Human
<4.51
>307.01
>385.04
>19.64


I-248
Rat
<4.51
>307.01
>550.16
>50.17



Mouse
<4.51
>307.01
>1343.17
>84.35


(R) I-244
Human
5.98
231.63
290.50
19.32



Rat
6.89
201.05
360.28
47.87



Mouse
<4.51
>307.01
>1343.17
>84.35


(R) I-245
Human
12.00
115.46
144.81
18.11



Rat
<4.51
>307.01
>550.16
>50.17



Mouse
5.12
270.81
1184.81
83.65





Notes:


1. For the compounds that showed an initial fast disappearance followed by a slow disappearance, only the time points that were within the initial rate were included in the calculation.


2. If % remaining at 30 minutes was lower than 1%, then CLint and t1/2 will be reported as “>307.01” and “<4.51,” respectively.













TABLE 69







Metabolic Stability of Test Compounds in


Liver Microsomes of Different Species (b)








Compound
Remaining Percentage (%)












ID
Species
Assay Format
0 min
30 min
60 min















Diclofenac
Human
With Cofactors
100.00
5.01
1.77




Without Cofactors
100.00
112.67
96.67



Rat
With Cofactors
100.00
11.86
6.35




Without Cofactors
100.00
102.19
100.63



Mouse
With Cofactors
100.00
45.55
33.71




Without Cofactors
100.00
89.49
96.59


5-MeO-DMT
Human
With Cofactors
100.00
19.24
3.25




Without Cofactors
100.00
18.58
3.00



Rat
With Cofactors
100.00
2.57
0.36




Without Cofactors
100.00
49.55
23.82



Mouse
With Cofactors
100.00
61.84
39.30




Without Cofactors
100.00
104.76
95.24


(R) I-98
Human
With Cofactors
With
100.00
67.04





Cofactors




Without Cofactors
Without
100.00
98.21





Cofactors



Rat
With Cofactors
With
100.00
14.43





Cofactors




Without Cofactors
Without
100.00
103.23





Cofactors



Mouse
With Cofactors
With
100.00
14.54





Cofactors




Without Cofactors
Without
100.00
100.99





Cofactors


rac (R)
Human
With Cofactors
100.00
0.04
0.00


I-248

Without Cofactors
100.00
100.47
98.60



Rat
With Cofactors
100.00
0.95
0.19




Without Cofactors
100.00
94.04
94.04



Mouse
With Cofactors
100.00
0.15
0.19




Without Cofactors
100.00
99.54
95.85


(R) I-245
Human
With Cofactors
100.00
14.62
3.13




Without Cofactors
100.00
101.09
98.91



Rat
With Cofactors
100.00
0.62
0.00




Without Cofactors
100.00
95.83
94.10



Mouse
With Cofactors
100.00
1.72
0.25




Without Cofactors
100.00
100.00
93.17


(R) I-244
Human
With Cofactors
100.00
3.10
0.00




Without Cofactors
100.00
94.44
88.07



Rat
With Cofactors
100.00
4.90
0.57




Without Cofactors
100.00
94.87
87.40



Mouse
With Cofactors
100.00
0.00
0.00




Without Cofactors
100.00
98.38
86.59









Discussion
Exemplary compounds of the disclosure were evaluated for their stability in human, rat and mouse liver microsomes. Table 68 and Table 69 illustrate the results of the stability studies. These results show that the compounds of the disclosure show a spectrum of stability across different species, including human, rat and mouse.
Example 21: Protein Binding Measurements in Different Species, (Human, Rat, Mouse and Dog) Plasma Using Equilibrium Dialysis Method
Protocol
1. The Frozen Plasma (Stored at −80° C.) was Thawed Immediately in a 37° C. Water Bath.
2. Preparation of Working Solution
The working solution of test compounds and control compound was prepared in DMSO at the concentration of 200 μM, and then the working solution was spiked into plasma. The final concentration of compound was 1 M. The final concentration of DMSO was 0.5%. Ketoconazole was used as positive control in the assay.
3. Preparation of Dialysis Membranes
The dialysis membranes were soaked in ultrapure water for 60 minutes to separate strips, then in 20% ethanol for 20 minutes, finally in dialysis buffer for 20 minutes.
4. Procedure for Equilibrium Dialysis
The dialysis set up was assembled according to the manufacturer's instruction. Each Cell was with 150 μL of plasma sample and dialyzed against equal volume of dialysis buffer (PBS). The assay was performed in duplicate. The dialysis plate was sealed and incubated in an incubator at 37° C. with 5% CO2 at 100 rpm for 6 hours. At the end of incubation, 50 μL of samples from both buffer and plasma chambers were transferred to wells of a 96-well plate.
5. Procedure for Sample Analysis
50 μL of plasma was added to each buffer samples and an equal volume of PBS was supplemented to the collected plasma sample. 400 μL of precipitation buffer acetonitrile containing internal standards (IS, 200 nM labetalol, 100 nM tolbutamide and 100 nM ketoprofen) was added to precipitate protein and release compounds. Samples were vortexed for 2 minutes and centrifuged for 30 minutes at 3,220 g. Aliquot of 50 μL of the supernatant was diluted by 150 μL acetonitrile containing internal standards: ultra-pure H2O=1:1, and the mixture was used for LC-MS/MS analysis.
6. Data Analysis
All calculations were carried out using Microsoft Excel. The concentrations of test compounds in the buffer and plasma chambers were determined from peak area ratios. The percentages of bound compound were calculated as follows:



 
  
   %
   ⁢
      
   Free
  
  =
  
   
    (
    
     Peak
     ⁢
        
     Area
     ⁢
        
     
      Ratio
      
       buffer
       ⁢
         
       chamber
      
     
     /
     Peak
     ⁢
        
     Area
     ⁢
        
     
      Ratio
      
       plasma
       ⁢
         
       chamber
      
     
    
    )
   
   *
   100
   ⁢
   %
  
 




 
  
   %
   ⁢
      
   Bound
  
  =
  
   
    100
    ⁢
    %
   
   -
   
    %
    ⁢
       
    Free
   
  
 




 
  
   %
   ⁢
      
   Recovery
  
  =
  
   
    (
    
     
      Peak
      ⁢
         
      Area
      ⁢
         
      
       Ratio
       
        buffer
        ⁢
          
        chamber
       
      
     
     +
     

     
      Peak
      ⁢
         
      Area
      ⁢
         
      
       Ratio
       
        plasma
        ⁢
          
        chamber
       
      
     
    
    )
   
   /
   Peak
   ⁢
      
   Area
   ⁢
      
   
    Ratio
    
     total
     ⁢
       
     sample
    
   
   *
   100
   ⁢
   %
  
 



Materials










Plasma information (Table 70)










Species
Strain/Gender
Batch No.
Source





Human
Pooled; Male &
HUMANPLK2PNNV20230717
Healthy Asian volunteers



Female

from local vendor





(collected in domestic





hospital with Ethical





approval)


Dog
Beagle;
PH-Dog-20230612
Local Supplier



Pooled; Male &



Female


Rat
SD; Pooled;
RAT542174
BioIVT



Male & Female


Mouse
CD-1; Pooled;
MSE441125
BioIVT



Male & Female



















Bioanalytical Method (Table 71)






















A
Time (min)
0
0.2
0.6
1.1
1.2
1.4



% B
5
5
100
100
5
5


B
Time (min)
0
2.4
2.5
2.6
3



% B
5
100
100
5
5



















Injection Volume (Table 72)


















A
 3 μL



B
20 μL










    
    
        Column temperature: 40° C.
        MS parameters:
        Ion source: Turbo spray
        Ionization model: ESI
        Scan type: MRM
        Collision gas: 6 L/min
        Curtain gas: 30 L/min
        Nebulize gas: 50 L/min
        Auxiliary gas: 50 L/min
        Temperature: 500° C.
        Ion spray voltage: +5500 v (positive MRM)
    
    


Results and Discussion







TABLE 73







Protein Binding Results for Test Compounds and Control


Compound in Human, Dog, Rat and Mouse Plasma















% Remaining


Compound ID
Species
% Bound
% Recovery
@ 6 hours














Ketoconazole
Human
99.24
100.62
99.64



Dog
98.95
86.06
87.36



Rat
99.39
100.71
109.42



Mouse
99.32
94.67
108.54


(R) I-98
Human
83.24
101.48
104.64



Dog
84.26
103.74
110.92



Rat
43.14
87.98
96.55



Mouse
36.83
96.43
103.70


(R) I-244
Human
98.58
90.12
105.89



Dog
97.19
94.57
94.07



Rat
81.05
86.53
85.45



Mouse
89.89
84.79
94.96


rac (R)
Human
99.86
106.81
112.41


I-245
Dog
99.16
96.29
96.81



Rat
86.06
97.30
100.74



Mouse
87.49
95.03
111.37









Discussion
Exemplary compounds of the disclosure were evaluated for their protein Binding profile compared control compound, Ketoconazole, in Human, Dog, Rat and Mouse Plasma. These results show that the compounds of the disclosure illustrate high to moderate % bond with good recovery across different species.
Additional embodiments described herein include intermediate compounds, including but not limited to those in Table 74 below:









TABLE 74





Compound
Structure
IUPAC Name







Intermediate 1;




(R)-2-(2-(5- (methylthio)-1H- indole-3- carbonyl)pyrrolidin-1- yl)-1-phenylethan-1- one


 


Intermediate 2;




(R)-2-(2-(5- (benzyloxy)-1H- indole-3- carbonyl)pyrrolidin-1- yl)-1-phenylethan-1- one


 


Intermediate 3;




R)-5-(benzyloxy)-3- ((1-(methyl- d3)pyrrolidin-2- yl)methyl-d2)-1H- indole


 


Intermediate 4;




(R)-3-((1-(methyl- d3)pyrrolidin-2- yl)methyl-d2)-1H- indol-5-ol


 


Intermediate 2A




(R)-2-(2-(4-fluoro-5- methoxy-1H-indole-3- carbonyl)pyrrolidin-1- yl)-1-phenylethan-1- one


 


Intermediate 4A




(R)-2-(2-((4-fluoro-5- methoxy-1H-indol-3- yl)methyl)pyrrolidin-1- yl)-1-phenylethan-1- one


 


Intermediate 7A




(R)-2-(2-(5-methoxy- 6-methyl-1H-indole- 3-carbonyl)pyrrolidin- 1-yl)-1-phenylethan- 1-one


 


Intermediate 9A




(R)-2-(2-((5-methoxy- 6-methyl-1H-indol-3- yl)methyl)pyrrolidin-1- yl)-1-phenylethan-1- one


 


Intermediate 12A




(R)-2-(2-(6-fluoro-5- methoxy-1H-indole-3- carbonyl)pyrrolidin-1- yl)-1-phenylethan-1- one


 


Intermediate 14A




(R)-2-(2-((6-fluoro-5- methoxy-1H-indol-3- yl)methyl)pyrrolidin-1- yl)-1-phenylethan-1- one









EXEMPLARY EMBODIMENTS
E1: A compound of Formula (I)




    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof,
        wherein:
        X is absent or selected from O, S, S(O), and SO2;
        R1 is selected from H, C1-C6alkyl, C1-C6alkyleneP(O)(OR11)2, C1-C6alkyleneOP(O)(OR11)2, C(O)R11, CO2R11, C(O)N(R11)2, S(O)R11, and SO2R11;
        R2 is selected from H, halo, and C1-C6alkyl;
        R3, R4, and R5 are independently selected from H, CN, halo, C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl;
        R6 is selected from H, C1-C10alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZR12, C2-C6alkenyleneZR12, C2-C6alkynyleneZR12, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, and C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13;
        R7 and R8 are independently selected from H, halo, and C1-C6alkyl;
        each R9 is independently selected from halo, C1-C6alkyl, OH, OC1-C6alkyl, C1-C6alkyleneOH, and C1-C6alkyleneOC1-C6alkyl;
        R10 is selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6alkynyleneZ′R14, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyleneC3-C7cycloalkyl, C1-C6alkyleneC3-C10heterocycloalkyl, C1-C6alkyleneC6-C10aryl, and C1-C6alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR15, and C(O)R15;
        Z is selected from O, C(O), NR16C(O), NR16C(O)O, C(O)NR16, OC(O)NR16, and NR16.
        Z′ is selected from O, C(O), NR17C(O), NR17C(O)O, C(O)NR17, OC(O)NR17, and NR17.
        n is an integer selected from 0, 1, 2, 3, and 4;
        R11, R13, R15, R16, and R17 are independently selected from H and C1-C6alkyl;
        R12 and R14 are independently selected from H, C1-C6alkyl, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, and C5-C10heteroaryl, the latter four groups being optionally substituted with one to four substituents independently selected from halo, C1-C4alkyl, OC1-C4alkyl, and C(O)C1-C4alkyl, and
        available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof,
        provided when X is O, R1, R2, R3, R4, R5, R7, and R8 are H or D, n is 0, and R6 is H, CH3, or CD3, then R10 is not H, CH3, or CD3;
        when X is O, R1, R2, R3, R4, R5, R7, and R8 are H or D and n is 0, and R6 is CH3, or CHF2, then R10 is not H, CH3, or CD3; and
        when X is absent and R6 is H, then either n is not 0 or R10 is not H or C1-C6alkyl.
    
    


E2: The compound of E1, provided (1) when X is absent, then R6 is not H, D, or halogen, and (2) when X is O, S, S(O), or SO2, then each R9 is not independently selected from H, D, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, and C1-C6deuterohaloalkyl and/or R10 is not selected from H, D, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, and C1-C6deuterohaloalkyl.
E3: The compound of E1, provided when X is absent, then R6 is not H, D, or halogen.
E4: The compound of E1, provided when X is O, S, S(O), or SO2, each R9 is not independently selected from H, D, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, and C1-C6deuterohaloalkyl.
E5: The compound of E1, provided when X is O, S, S(O), or SO2, then R10 is not selected from H, D, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, and C1-C6deuterohaloalkyl.
E6: The compound of E1, provided (1) when X is absent, then R6 is not H, D, or halogen, and (2) when X is O, S, S(O), or SO2, then each R9 is not independently selected from H, D, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, and C1-C6deuterohaloalkyl.
E7: The compound of E1, when X is absent, then R6 is not H, D, or halogen, and (2) when X is O, S, S(O), or SO2, then R10 is not selected from H, D, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, and C1-C6deuterohaloalkyl.
E8: The compound of any one of E1 to E7, wherein available hydrogen atoms are optionally independently replaced with an iodine atom, a fluorine atom, and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E9: The compound of any one of E1 to E8, wherein X is S(O) or SO2.
E10: The compound of any one of E1 or E8, wherein X is S.
E11: The compound of any one of E1 to E8, wherein X is absent.
E12: The compound of any one of E1 to E8, wherein X is O.
E13: The compound of any one of E1 to E12, wherein R1 is selected from S(O)R11 and SO2R11.
E14: The compound of any one of E1 to E12, wherein R1 is selected from H, C1-C4alkyl, C1-C4alkyleneP(O)(OR11)2, C1-C4alkyleneOP(O)(OR11)2, C(O)R11, CO2R11, and C(O)N(R11)2, wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E15: The compound of E14, wherein R1 is selected from H, C1-C3alkyl, CH2P(O)(OR11)2, CH2CH2P(O)(OR11)2, CH2CH(CH3)P(O)(OR11)2, CH(CH3)CH2P(O)(OR11)2, CH(CH3)P(O)(OR11)2, CH(CH2CH3)P(O)(OR11)2, (CH2)OP(O)(OR11)2, C(O)R11, and CO2R11, wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E16: The compound of any one of E1 to E15, wherein R2 is selected from H, halo, and C1-C4alkyl, wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E17: The compound of E16, wherein R2 is selected from H, D, F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, and C1-C4deuterofluoroalkyl.
E18: The compound of E17, wherein R2 is selected from H, D, CH3, CF3, and CD3.
E19: The compound of any one of E1 to E18, wherein R3 is selected from H, D, halo, CN, C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl, wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E20: The compound of E19, wherein R3 is selected from H, D, CN, halo, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, C2-C4alkenyl, C2-C4fluoroalkenyl, C2-C4deuteroalkenyl, C2-C4deuterofluoroalkenyl, C2-C4alkynyl, C2-C4deuteroalkynyl, C2-C4fluoroalkynyl, and C2-C4deuterofluoroalkynyl.
E21: The compound of E20, wherein R3 is selected from H, D, CN, F, Br, Cl, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3, and CD2CD3.
E22: The compound of E21, wherein R3 is selected from H, F, and Cl.
E23: The compound of any one of E1 to E22, wherein R4 and R5 are independently selected from H, halo, CN, C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl, wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E24: The compound of E23, wherein R4 and R5 are independently selected from H, D, CN, halo, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, C2-C4alkenyl, C2-C4fluoroalkenyl, C2-C4deuteroalkenyl, C2-C4deuterofluoroalkenyl, C2-C4alkynyl, C2-C4deuteroalkynyl, C2-C4fluoroalkynyl, and C2-C4deuterofluoroalkynyl.
E25: The compound of E24, wherein R4 and R5 are independently selected from H, D, CN, F, Cl, Br, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3, and CD2CD3.
E26: The compound of E25, wherein R4 and R5 are independently selected from H and D.
E27: The compound of any one of E1 to E26, wherein R6 is selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZR12, C2-C6alkenyleneZR12, C2-C6alkynyleneZR12, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally replaced with a halogen atom and/or available atoms are optionally replaced with an alternate isotope thereof.
E28: The compound of E27, wherein R6 is C1-C6alkyl, wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E29: The compound of E28, wherein R6 is selected from C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl and C1-C6deuterofluoroalkyl.
E30: The compound of E29, wherein R6 is selected from CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2, CH(CHD2)2, CH(CDH2)2, C(CH3)3, C(CF3)3, C(CHF2)3, C(CFH2)3, C(CD3)3, C(CHD2)3, C(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2CH(CH3)CH3, CH2CH(CH3) CF3, CH2CH(CH3) CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3, and CH2CH2C(CD3)3.
E31: The compound of E30, wherein R6 is selected from H, D, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CF2H, CH2CH3, CH2CH2CH3, CH2CH2CF3, CH2CH2CH2CF3, CH(CH3)2, C(CH3)3, CH2CH(CH3)2, CH(CH3)CH2CH3, and CH2C(CH3)3.
E32: The compound of E27, wherein R6 is selected from C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZR12, C2-C6alkenyleneZR12, C2-C6alkynyleneZR12, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E33: The compound of E32, wherein R6 is selected from C4-C6alkenyl and C2-C6alkynyl, wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E34: The compound of E33, wherein R6 is selected from CH═CH2, CH2CH═CH2, CF2CH═CH2, CD2CH═CH2, CH═CH2CH3, CH═CH2CF3, CH═CH2CHF2, CH═CH2CH2F, CH═CH2CD3, CH═CH2CHD2, CH═CH2CH2D, C≡CH, C≡CCH3, C≡CCF3, C≡CCHF2, C≡CCFH2, C≡CCD3, C≡CCHD2, C≡CCDH2, CH2C≡CH, CF2C≡CH, CD2C≡CH, CH2C≡CCH3, CF2C≡CCH3, CD2C≡CCH3, CH2C≡CCD3, CF2C≡CCD3, CD2C≡CCD3, CH2C≡CCF3, CF2C≡CCF3, CD2C≡CCF3, CH2C≡CCHD2, CF2C≡CHD2, CD2C≡CHD2, CH2C≡CHF2, CF2C≡CHF2, and CD2C≡CHF2.
E35: The compound of E32, wherein R6 is selected from C1-C6alkyleneZR12, C2-C6alkenyleneZR12, and C2-C6alkynyleneZR12, wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E36: The compound of E35, wherein R6 is selected from C1-C6alkyleneZR12, C1-C6fluoroalkyleneZR12, C1-C6deuteroalkyleneZR12, C1-C6deuterofluoroalkyleneZR12, C2-C6alkenyleneZR12, C2-C6fluoroalkenyleneZR12, C2-C6deuteroalkenyleneZR12, C2-C6deuterofluoroalkenyleneZR12, C2-C6alkynyleneZR12, C2-C6fluoroalkynyleneZR12, C2-C6deuteroalkynyleneZR12, and C2-C6deuteroalkynyleneZR12.
E37: The compound of E36, wherein R6 is selected from CH2ZR12, CH2CH2ZR12, CH2CH2CH2ZR12, CH2CH2CH2CH2ZR12, CH(CH3)CH2ZR12, CH(CH3)CH2CH2ZR12, CH2CH(CH3) ZR12, CF2ZR12, CFHZR12, CH2CHFZR12, CH2CF2ZR12, CF2CF2ZR12, CH2CH2CF2ZR12, CH2CH2CFHZR12, CH2CH2CF2ZR12, CH(CH3) CF2ZR12, CH(CH3)CHFZR12, CH2CH2CH2CF2ZR12, CH2CH2CH2CHFZR12, CH(CH3)CH2CF2ZR12, CH(CH3)CH2CHFZR12, CD2ZR12, CDHZR12, CH2CHDZR12, CH2CD2ZR12, CD2CD2ZR12, CH2CH2CD2ZR12, CH2CH2CDHZR12, CH2CH2CD2ZR12, CH(CH3) CD2ZR12, CH(CH3)CHDZR12, CH2CH2CH2CD2ZR12, CH2CH2CH2CHDZR12, CH(CH3)CH2CD2ZR12, CH(CH3)CH2CHDZR12, CH═CHZR12, CH2CH═CHZR12, C≡CZR12, C≡CCH2ZR12, CH2C≡CZR12, and CH2C≡CH2ZR12.
E38: The compound of E37, wherein R6 is selected from CH2ZR12, CH2CH2ZR12, CH2CH2CH2ZR12, CH2CH2CH2CH2ZR12, CH(CH3)CH2ZR12, CH(CH3)CH2CH2ZR12, CH2CH(CH3) ZR12, CH═CHZR12, CH2CH═CHZR12, CH═CH2CHZR12, C≡CCH2ZR12, CH2C≡CZR12, and CH2C≡CH2ZR12.
E39: The compound of E32, wherein R6 is selected from C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, each of which is optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E40: The compound of E39, wherein R6 is selected from C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, C1-C4alkyleneC5-C10heteroaryl, C1-C4fluoroalkyleneC3-C7cycloalkyl, C1-C4fluoroalkyleneC3-C10heterocycloalkyl, C1-C4fluoroalkyleneC6-C10aryl, C1-C4fluoroalkyleneC5-C10heteroaryl, C1-C4deuteroalkyleneC3-C7cycloalkyl, C1-C4deuteroalkyleneC3-C10heterocycloalkyl, C1-C4deuteroalkyleneC6-C10aryl, C1-C4deuteroalkyleneC5-C10heteroaryl, C1-C4deuterofluoroalkyleneC3-C7cycloalkyl, C1-C4deuterofluoroalkyleneC3-C10heterocycloalkyl, C1-C4deuterofluoroalkyleneC6-C10aryl, and C1-C4deuterofluoroalkyleneC5-C10heteroaryl, in which each of the cyclic groups is optionally substituted with one to four substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR13, and C(O)R13, and wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E41: The compound of E40, wherein the substituents on R6 are independently selected from one to four of F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CD2H, CDH2, CD3, CF3, CHF2, CH2F, CH2CH2F, CF2CF3, CH2CH2D, CH2CD2H, CD2CD3, OR14, and C(O)R14.
E42: The compound of any one of E35 to E38, wherein Z is selected from NR16C(O), NR16C(O)O, C(O)NR16, OC(O)NR16, and NR16.
E43: The compound of any one of E35 to E38, wherein Z is selected from O, C(O), NR16C(O), and NR16C(O)O.
E44: The compound of any one of E1 to E43, wherein R7 and R8 are independently selected from H, halo, and C1-C4alkyl, wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E45: The compound of E44, wherein R7 and R8 are independently selected from H, D, F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, and C1-C4deuterofluoroalkyl.
E46: The compound of E45, wherein R7 and R8 are independently selected from H, F, Br, Cl, D, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3CF2CF3, CH2CH2D, CH2CD2H, and CD2CD3.
E47: The compound of E46, wherein R7 and R8 are independently selected from H, F, and D.
E48: The compound of E47, wherein R7 and R8 are independently selected from H and D.
E49: The compound of any one of E1 to E48, wherein each R9 is independently selected from D, halo, C1-C4alkyl, OH, OC1-C4alkyl, C1-C4alkyleneOH, and C1-C4alkyleneOC1-C6alkyl, wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E50: The compound of E49, wherein at least one R9 is selected from halo and C1-C4alkyl, wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E51: The compound of E50, wherein at least one R9 is selected from F, Cl, Br, OH, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2, CH(CHD2)2, CH(CDH2)2, C(CH3)3, C(CF3)3, C(CHF2)3, C(CFH2)3, C(CD3)3, C(CHD2)3, C(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3, and CH2CH2C(CD3)3.
E52: The compound of E49, wherein at least one R9 is selected from OH, OC1-C4alkyl, C1-C4alkyleneOH, and C1-C4alkyleneOC1-C6alkyl, wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E53: The compound of E52, wherein at least one R9 is selected from OH, OC1-C4alkyl, OC1-C4deuteroalkyl, OC1-C4fluoroalkyl, OC1-C4deuterofluoroalkyl, C1-C4alkyleneOH, C1-C4fluoroalkyleneOH, C1-C4deuteroalkyleneOH, C1-C4deuterofluoroalkyleneOH, C1-C4alkyleneOC1-C4alkyl, C1-C4alkyleneOC1-C4fluoroalkyl, C1-C4alkyleneOC1-C4deuteroalkyl, C1-C4alkyleneOC1-C4deuterofluoroalkyl, C1-C4fluoroalkyleneOC1-C4alkyl, C1-C4deuteroalkyleneOC1-C4alkyl, C1-C4deuterofluoroalkyleneOC1-C4alkyl, C1-C4fluoroalkyleneOC1-C4fluoroalkyl, C1-C4fluoroalkyleneOC1-C4deuteroalkyl, C1-C4deuteroalkyleneOC1-C4fluoroalkyl, C1-C4deuteroalkyleneOC1-C4deuteroalkyl, C1-C4deuterofluoroalkyleneOC1-C4fluoroalkyl, C1-C4fluoroalkyleneOC1-C4deuterofluoroalkyl, and C1-C4deuterofluoroalkyleneOC1-C4deuterofluoroalkyl.
E54: The compound of E53, wherein at least one R9 is selected from OH, OCH3, OCD2H, OCDH2, OCD3, OCF2H, OCFH2, OCF3, OCH2CH3, OCH2CH2F, OCH2CF2H, OCH2CF3, OCF2CF3, OCH2CH2D, OCH2CD2H, OCH2CD3OCD2CD3, OCH2CH2CH3, OCH2CH2CHF2, OCH2CH2CFH2, OCH2CH2CF3, OCH2CH2CHD2, OCH2CH2CDH2, OCH2CH2CD3, OCH(CH3)2, OCH(CF3)2, OCH(CHF2)2, OCH(CFH2)2, OCH(CD3)2, OCH(CHD2)2, OCH(CDH2)2, OC(CH3)3, OC(CF3)3, OC(CHF2)3, OC(CFH2)3, OC(CD3)3, OC(CHD2)3, OC(CDH2)3, OCH2CH2CH2CH3, OCH2CH2CH2CF3, OCH2CH2CH2CD3, OCH2CH(CH3)2, OCH2CH(CD3)2, OCH2CH(CF3)2, OCH(CH3)CH2CH3, OCH(CH3)CH2CF3, OCH(CH3)CH2CD3, OCH2C(CH3)3, OCH2C(CF3)3, OCH2C(CD3)3, OCH2CH2C(CH3)3, OCH2CH2C(CF3)3, OCH2CH2C(CD3)3, CH2OH, CF2OH, CD2OH, CH2CH2OH, CF2CF2OH, CH2CF2OH, CH2CD2OH, CD2CD2OH, CH2OCH3, CH2OCD2H, CH2OCDH2, CH2OCD3, CH2OCF3, CH2OCHF2, CH2OCH2F, CH2CH2OCH3, CH2CH2OCD2H, CH2CH2OCDH2, CH2CH2OCD3, CH2CH2OCF3, CH2CH2OCHF2, and CH2CH2OCH2F.
E55: The compound of E54, wherein at least one R9 is selected from OH, OCH3, OCF2H, OCFH2, OCF3, and OCD3.
E56: The compound of any one of E1 to E55, wherein n is an integer selected from 0 and 1.
E57: The compound of any one of E1 to E56, wherein R10 is selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6alkynyleneZ′R14, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted with one to four substituents independently selected from halo, C1-C6alkyl, OR15 and C(O)R15, and wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E58: The compound of E57, wherein R10 is selected from H, D, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, and C1-C6deuterofluoroalkyl.
E59: The compound of E58, wherein R10 is selected from H, D, CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2, CH(CHD2)2, CH(CDH2)2, C(CH3)3, C(CF3)3, C(CHF2)3, C(CFH2)3, C(CD3)3, C(CHD2)3, C(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2CH(CH3)CH3, CH2CH(CH3) CF3, CH2CH(CH3) CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3, and CH2CH2C(CD3)3 
E60: The compound of E57, wherein R10 is selected from C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, C2-C6alkynyleneZ′R14, C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, and C1-C4alkyleneC5-C10heteroaryl, the latter eight groups being optionally substituted one to four substituents independently selected from halo, C1-C6alkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E61: The compound of E57, wherein R10 is selected from C2-C6alkenyl, C2-C6fluoroalkenyl, C2-C6deuteroalkenyl, C2-C6deuterofluoroalkenyl, C2-C6alkynyl, C2-C6fluoroalkynyl, C2-C6deuteroalkynyl, and C2-C6deuterofluoroalkynyl.
E62: The compound of E61, wherein R10 is selected from CH═CH2, CH2CH═CH2, CF2CH═CH2, CD2CH═CH2, CH═CH2CH3, CH═CH2CF3, CH═CH2CHF2, CH═CH2CH2F, CH═CH2CD3, CH═CH2CHD2, CH═CH2CH2D, C≡CH, C≡CCH3, C≡CCF3, C≡CCHF2, C≡CCFH2, C≡CCD3, C≡CCHD2, C≡CCDH2, CH2C≡CH, CF2C≡CH, CD2C≡CH, CH2C≡CCH3, CF2C≡CCH3, CD2C≡CCH3, CH2C≡CCD3, CF2C≡CCD3, CD2C≡CCD3, CH2C≡CCF3, CF2C≡CCF3, CD2C≡CCF3, CH2C≡CCHD2, CF2C≡CHD2, CD2C≡CHD2, CH2C≡CHF2, CF2C≡CHF2, and CD2C≡CHF2.
E63: The compound of E57, wherein R10 is selected from C1-C6alkyleneZ′R14, C2-C6alkenyleneZ′R14, and C2-C6alkynyleneZ′R14, wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E64: The compound of E63, wherein R10 is selected from C1-C4alkyleneZ′R14, C1-C4fluoroalkyleneZ′R14, C1-C4deuteroalkyleneZ′R14, C1-C4deuterofluoroalkyleneZ′R14, C2-C4alkenyleneZ′R14, C2-C4fluoroalkenyleneZ′R14, C2-C4deuteroalkenyleneZ′R14, C2-C4deuterofluoroalkenyleneZ′R14, C2-C4alkynyleneZ′R14, C2-C4fluoroalkynyleneZ′R14, C2-C4deuteroalkynyleneZ′R14, and C2-C4deuterofluoroalkynyleneZ′R14.
E65: The compound of E64, wherein R10 is selected from CH2Z′R14, CH2CH2Z′R14, CH2CH2CH2Z′R14, CH2CH2CH2CH2Z′R14, CH(CH3)CH2Z′R14, CH(CH3)CH2CH2Z′R14, CH2CH(CH3)Z′R14, CF2Z′R14, CFHZ′R14, CH2CHFZ′R14, CH2CF2Z′R14, CF2CF2Z′R14, CH2CH2CF2Z′R14, CH2CH2CFHZ′R14, CH2CH2CF2Z′R14, CH(CH3)CF2Z′R14, CH(CH3)CHFZ′R14, CH2CH2CH2CF2Z′R14, CH2CH2CH2CHFZ′R14, CH(CH3)CH2CF2Z′R14, CH(CH3)CH2CHFZ′R14, CD2Z′R14, CDHZ′R14, CH2CHDZ′R14, CH2CD2Z′R14, CD2CD2Z′R14, CH2CH2CD2Z′R14, CH2CH2CDHZ′R14, CH2CH2CD2Z′R14, CH(CH3)CD2Z′R14, CH(CH3)CHDZ′R14, CH2CH2CH2CD2Z′R14, CH2CH2CH2CHDZ′R14, CH(CH3)CH2CD2Z′R14, CH(CH3)CH2CHDZ′R14, CH═CHZ′R14, CH2CH═CHZ′R14, C≡CZ′R14, C≡CCH2Z′R14, CH2C≡CZ′R14, and CH2C≡CH2Z′R14.
E66: The compound of E57, wherein R10 is selected from C3-C7cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C4alkyleneC3-C7cycloalkyl, C1-C4alkyleneC3-C10heterocycloalkyl, C1-C4alkyleneC6-C10aryl, C1-C4alkyleneC5-C10heteroaryl, C1-C4fluoroalkyleneC3-C7cycloalkyl, C1-C4fluoroalkyleneC3-C10heterocycloalkyl, C1-C4fluoroalkyleneC6-C10aryl, C1-C4fluoroalkyleneC5-C10heteroaryl, C1-C4deuteroalkyleneC3-C7cycloalkyl, C1-C4deuteroalkyleneC3-C10heterocycloalkyl, C1-C4deuteroalkyleneC6-C10aryl, C1-C4deuteroalkyleneC5-C10heteroaryl, C1-C4deuterofluoroalkyleneC3-C7cycloalkyl, C1-C4deuterofluoroalkyleneC3-C10heterocycloalkyl, C1-C4deuterofluoroalkyleneC6-C10aryl, and C1-C4deuterofluoroalkyleneC5-C10heteroaryl, in which each of the cyclic groups is optionally substituted with one to four substituents independently selected from F, Cl, Br, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4deuterofluoroalkyl, OR15, and C(O)R15, and wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E67: The compound of E66, wherein the substituents on R10 are independently selected from one to three of F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)2, CD2H, CDH2, CD3, CF3, CHF2, CH2F, OR15, and C(O)R15.
E68: The compound of one of E57, E60, and E63 to E65, wherein Z′ is selected from NR17C(O), NR17C(O)O, C(O)NR17, OC(O)NR17, and NR 17.
E69: The compound of one of E57, E60, and E63 to E65 wherein Z′ is selected from O, C(O), NR17C(O), and NR17C(O)O.
E70: The compound of one of E1 to E69, wherein R12 and R14 are independently selected from H, C1-C4alkyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, C6-C10aryl, and C5-C10heteroaryl, the latter four groups being optionally substituted with one to four substituents independently selected from F, Cl, Br, C1-C4alkyl, OC1-C4alkyl, and C(O)C1-C4alkyl, and wherein available hydrogen atoms are optionally independently replaced with a fluorine atom and/or a chlorine atom and/or available hydrogen atoms are optionally replaced with deuterium.
E71: The compound of one of E1 to E70, wherein R11, R13, R15, R16, and R17 are independently selected from H, D, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, and C1-C4deuterofluoroalkyl.
E72: The compound of any one of E1 to E26 and E44 to E71, wherein X is selected from S, S(O), and SO2, and wherein R6 is selected from

    
    
        CH3, CD3, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2,
        CH2C(CH3)3, CH2CH2C(CH3)3,
        CH2F, CHF2, CH2CHF2, CH2CF3, CH2CH2CF3,
    
    






E73: The compound of any one of E1 to E56 and E70 to E72, X is selected from S, S(O), and SO2, and wherein R10 is selected from

    
    
        CH3, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2,
        CH2C(CH3)3, CH2CH2C(CH3)3,
        CH2F, CHF2, CH2CHF2, CH2CF3, CH2CH2CF3,
        C1-C4alkyleneOCH3, C1-C4alkyleneOCHF2, C1-C4alkyleneOCH2F,
    
    






    
    
        C1-C4alkleneC(O)CHF2, C1-C4alkleneC(O)CF3,
    
    
























E74: The compound of any one of E1 to E26, E44 to E56, E70, and E71, wherein X is absent or oxygen, and wherein R6 and R10 are independently selected from

    
    
        CH3, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2,
        CH2C(CH3)3, CH2CH2C(CH3)3,
        CH2F, CHF2, CH2CHF2, CH2CF3, CH2CH2CF3,
        C1-C4alkyleneOCH3, C1-C4alkyleneOCHF2, C1-C4alkyleneOCH2F,
    
    






    
    
        C1-C4alkleneC(O)CHF2, C1-C4alkleneC(O)CF3,
    
    


















E75: The compound of any one of E1 to E8, wherein the compound of Formula (I) is selected from the table below:











Com-



pound
Structure







(R) I-1






 


(S) I-1






 


(R) I-2






 


(S) I-2






 


(R) I-3






 


(R) I-4






 


(R) I-5






 


(R) I-6






 


(R) I-7






 


(R, R) I-8






 


(R, S) I-8






 


(R, S) I-9






 


(R, R) I-9






 


(R) I-10






 


(R) I-11






 


(R) I-12






 


(R, S) I-13






 


(R, R) I-13






 


(R) I-14






 


trans (R) I-15






 


trans (R) I-16






 


(R, R) I-17






 


(R) I-18






 


(R) I-19






 


(R) I-20






 


(R) I-21






 


(R) I-22






 


(R) I-23






 


(R, S) I-24






 


(R, R) I-24






 


(R, S) I-25






 


(R, R) I-25






 


(R) I-26






 


(R) I-27






 


(R) I-28






 


(R) I-29






 


(R) I-30






 


(R) I-31






 


(R) I-32






 


(R) I-33






 


(R) I-34






 


(R) I-35






 


(R) I-36






 


(R) I-37






 


(R) I-38






 


(R) I-39






 


(R) I-40






 


(R, S) I-41






 


(R, R) I-41






 


(R, S) I-42






 


(R, R) I-42






 


(R) I-43






 


(R) I-44






 


(R) I-45






 


(R) I-46






 


(R) I-47






 


(R) I-48






 


(R) I-49






 


(R) I-50






 


(R) I-51






 


(R) I-52






 


(R) I-53






 


(R) I-54






 


(R) I-55






 


(R) I-56






 


(R) I-57






 


(R) I-58






 


(R) I-59






 


(R) I-60






 


(R) I-61






 


(R) I-62






 


(R) I-63






 


(R) I-64






 


(R) I-65






 


(R) I-66






 


(R) I-67






 


(R) I-68






 


(R) I-69






 


(R) I-70






 


(R) I-71






 


(R) I-72






 


(R) I-73






 


(R) I-74






 


(R) I-75






 


(R) I-76






 


(R) I-77






 


(R) I-78






 


(R) I-79






 


(R) I-80






 


(R) I-81






 


cis- (R) I-82






 


trans- (R) I-82






 


(R) I-83






 


(R) I-84






 


cis- (R) I-85






 


cis- (R) I-86






 


trans- (R) I-86






 


(R) I-87






 


(R) I-88






 


(R) I-89






 


(R) I-90






 


(R) I-91






 


(R) I-92






 


(R, S) I-93






 


(R, S) I-94






 


(R) I-95






 


(R) I-96






 


(R) I-97













    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof.
    
    


E76: The compound of any one of E1 to E8, wherein the compound of Formula (I) is selected from the table below:














Compound
Structure









II-1







 



(R) II-2







 



II-3







 



II-4







 



II-5







 



(R) II-6







 



(R) II-7







 



(R) II-8







 



(R) II-9







 



(R) II-10







 



(R) II-11







 



(R) II-12







 



(R) II-13







 



(R) II-14







 



(R) II-15







 



(R) II-16







 



(R) II-17







 



(R) II-18







 



(R) II-19







 



(R) II-20







 



(R) II-21







 



(R) II-22







 



(R) II-23







 



(R) II-24







 



(R) II-25







 



(R) II-26







 



(R) II-27







 



(R) II-28







 



(R) II-29







 



(R) II-30







 



(R) II-31







 



(R) II-32







 



(R) II-33







 



(R) II-34







 



(R) II-35







 



(R) II-36







 



(R) II-37







 



(R) II-38







 



(R) II-39







 



(R) II-40







 



(R) II-41







 



(R) II-42







 



(R) II-43







 



(R) II-44







 



(R) II-45







 



(R) II-46







 



(R) II-47







 



(R) II-48







 



(R) II-49







 



(R) II-50







 



(R) II-51







 



(R) II-52







 



(R) II-53







 



(R) II-54







 



(R) II-55







 



(R) II-56














    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof.
    
    


E77: The compound of any one of E1 to E8, wherein the compound of Formula (I) is selected from the table below:











Compound
Structure







(R) I-98






 


(R) I-99






 


(R) I-100






 


(R) I-101






 


(R, R) I-102






 


(R, S) I-102






 


(R, S) I-103






 


(R, R) I-103






 


(S) I-104






 


(R) I-105






 


(R) I-106






 


(R, S) I-107






 


(R, R) I-107






 


(R) I-108






 


Trans-(R) I-109






 


Trans (R) I-110






 


(R, R) I-111






 


(R) I-112






 


(R) I-113






 


(R) I-114






 


(R) I-115






 


(R) I-116






 


(R) I-117






 


(R, S) I-118






 


(R, R) I-118






 


(R, R) I-119






 


(R,S) I-119






 


(R) I-120






 


(R) I-121






 


(R) I-122






 


(R) I-123






 


(R) I-124






 


(R) I-125






 


(R) I-126






 


(R) I-127






 


(R) I-128






 


(R) I-129






 


(R) I-130






 


(R) I-131






 


(R) I-132






 


(R) I-133






 


(R) I-134






 


(R, S) I-135






 


(R, R) I-135






 


(R, S) I-136






 


(R, R) I-136






 


(R) I-137






 


(R) I-138






 


(R) I-139






 


(R) I-140






 


(R) I-141






 


(R) I-142






 


(R) I-143






 


(R) I-144






 


(R) I-145






 


(R) I-146






 


(R) I-147






 


(R) I-148






 


(R) I-149






 


(R) I-150






 


(R) I-151






 


(R) I-152






 


(R) I-153






 


(R) I-154






 


(R) I-155






 


(R) I-156






 


(R) I-157






 


(R) I-158






 


(R) I-159






 


(R) I-160






 


(R) I-161






 


(R) I-162






 


(R) I-163






 


(R) I-164






 


(R) I-165






 


Cis (R) I-166






 


Trans (R) I-167






 


(R) I-168






 


(R) I-169






 


Cis (R) I-170






 


Cis (R) I-171






 


Trans (R) I-172






 


(R) I-173






 


(R) I-174






 


(R) I-175






 


(R) I-176






 


(R) I-177






 


(R, S) I-178






 


(R, S) I-179






 


(R, R) I-180






 


(R) I-181






 


(R) I-182






 


(R) I-183






 


(R) I-184






 


(R) I-185






 


(R) I-186






 


(R) I-187






 


(R) I-188






 


(R) I-189






 


(R) I-190






 


(R) I-191






 


(R) I-192






 


(R) I-193






 


(R) I-194






 


(R) I-195






 


(R) I-196






 


(R) I-197






 


(R) I-198






 


(R) I-198-A






 


(R) I-199






 


(R) I-200






 


(R) I-201






 


(R) I-202






 


(R) I-203






 


(R) I-204






 


(R) I-205






 


(R) I-206






 


(R) I-207






 


(R) I-208






 


(R) I-209






 


(R) I-210






 


(R) I-211






 


(R) I-212






 


(R) I-213






 


(R) I-214






 


(R) I-215






 


(R) I-216






 


(R) I-217






 


(R) I-218






 


(R) I-219






 


(R) I-220






 


(R) I-221






 


(R) I-222






 


(R) I-223






 


(R) I-224






 


(R) I-225






 


(R) I-226






 


(R) I-227






 


(R) I-228






 


(R) I-229






 


(R) I-330






 


(R) I-231






 


(R) I-232






 


(R) I-233






 


(R) I-234






 


Cis (R) I-235






 


Cis (R) I-236






 


(R) I-237






 


(R) I-238






 


(R) I-239






 


Cis (R) I-240






 


Trans (R) I-241






 


(R) I-242






 


(R) I-243






 


(R) I-244






 


(R) I-245






 


Cis (R) I-246






 


Cis (R) I-247






 


Cis (R) I-248






 


Rac (R) I-248






 



and


 


(R) I-249













    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof.
    
    


E78: The compound of any one of E1 to E8, wherein the compound of Formula (I) is selected from the table below:











Compound
Structure







(R) I-250






 


(R) I-251






 


(R) I-252






 


(R) I-253






 


(R) I-254






 


(R) I-255






 


(R) I-256






 


(R) I-257






 


(R) I-258






 


(R) I-259






 


(R) I-260






 


(R) I-261






 


(R) I-262






 


(R) I-263






 


(R) I-264






 


(R) I-265






 


(R) I-266






 


(R) I-267






 


(R) I-268






 


(R) I-269






 


(R) I-270






 


(R) I-271






 


(R) I-272






 


(R) I-273






 


(R) I-274






 


(R) I-275






 


(R) I-276






 


(R) I-277






 


(R) I-278






 


(R) I-279






 


(R) I-280






 


(R) I-281






 


(R) I-282






 


(R) I-283






 


(R) I-284






 


(R) I-285






 


(R) I-286






 


(R) I-287






 


(R) I-288






 


(R) I-289






 


(R) I-290






 


(R) I-291






 


(R) I-292






 


(R) I-293






 


(R) I-294






 


(R) I-295






 


(R) I-296






 


(R) I-297






 


(R) I-298






 


(R) I-299






 


(R) I-300






 


(R) I-301






 


(R) I-302






 


(R) I-303






 


(R) I-304






 


(R) I-305






 


(R) I-306






 


(R) I-307






 


(R) I-308






 


(R) I-309






 


(R) I-310






 


(R) I-311






 


(R) I-312






 


(R) I-313






 


(R) I-314













    
    
        or a pharmaceutically acceptable salt, solvate, and/or prodrug thereof.
    
    


E79: A composition comprising one or more compounds of any one of E1 to E78 and a carrier.
E80: A pharmaceutical composition comprising one or more compounds of any one of E1 to E78 and a pharmaceutically acceptable carrier.
E81: A method for activating a serotonin receptor in a cell, either in a biological sample or in a patient, comprising administering an effective amount of one or more compounds of any one of E1 to E78 to the cell.
E82: A method of treating a disease, disorder, or condition by activation of a serotonin receptor comprising administering a therapeutically effective amount of one or more compounds of any one of E1 to E78 to a subject in need thereof.
E83: A method for activating a 5-HT1A and 5-HT2A in a cell, either in a biological sample or in a patient, comprising administering an effective amount of one or more compounds of any one of E1 to E78 to the cell.
E84: A method of treating a mental illness comprising administering a therapeutically effective amount of one or more compounds of any one of E1 to E78 to a subject in need thereof.
E85: The method of E84, wherein the mental illness is selected from hallucinations, delusions, and a combination thereof.
E86: The method of E84, wherein the mental illness is selected anxiety disorders; depression; mood disorders; psychotic disorders; impulse control and addiction disorders and behaviors; drug addiction; obsessive-compulsive disorder (OCD); post-traumatic stress disorder (PTSD); stress response syndromes; dissociative disorders; depersonalization disorder; factitious disorders; sexual and gender disorders; and somatic symptom disorders; and combinations thereof.
E87: A method of treating psychosis or psychotic symptoms comprising administering a therapeutically effective amount of one or more compounds of any one of E1 to E78 to a subject in need thereof.
E88: A method of treating a central nervous system (CNS) disease, disorder, or condition and/or a neurological disease, disorder, or condition comprising administering a therapeutically effective amount of one or more compounds of any one of E1 to E78 to a subject in need thereof.
E89: The method of E88, wherein the CNS disease, disorder, or condition and/or neurological disease, disorder, or condition is selected from neurological diseases including neurodevelopmental diseases and neurodegenerative diseases such as Alzheimer's disease; presenile dementia; senile dementia; vascular dementia; Lewy body dementia; cognitive impairment, Parkinson's disease and Parkinsonian related disorders such as Parkinson dementia, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infections; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disorders; Fragile X syndrome; Angelman syndrome; hereditary ataxias; neuro-otological and eye movement disorders; neurodegenerative diseases of the retina amyotrophic lateral sclerosis; tardive dyskinesias; hyperkinetic disorders; attention deficit hyperactivity disorder and attention deficit disorders; restless leg syndrome; Tourette's syndrome; schizophrenia; autism spectrum disorders; tuberous sclerosis; Rett syndrome; cerebral palsy; disorders of the reward system including eating disorders such as anorexia nervosa (“AN”) and bulimia nervosa (“BN”); and binge eating disorder (“BED”); pica; rumination disorder; avoidant/restrictive food intake disorder; trichotillomania, dermotillomania, nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology; reduction in convergent thinking; increase in spontaneous divergent thinking and goal-oriented divergent thinking; and combinations thereof.
E90: A method of treating a behavioral problem comprising administering a therapeutically effective amount of one or more compounds of any one of E1 to E78 to a non-human subject in need thereof.
E91: The method of E90, wherein the non-human subject is a canine or feline suffering from neurological diseases, behavioral problems, trainability problems, and/or a combination thereof.
E92: The method of E91, wherein and the neurological diseases, behavioral problems, and trainability problems are selected from anxiety, fear and stress, sleep disturbances, cognitive dysfunction, aggression, and a combination thereof.
E93: A method of treating a disease, disorder, or condition by activation of a serotonin receptor comprising administering a therapeutically effective amount of one or more compounds of any one of E1 to E78 in combination with another known agent useful for treatment of a disease, disorder, or condition by activation of a serotonin receptor to a subject in need thereof.
E94: A pharmaceutical composition comprising a compound of any one of E1 to E78 and an additional therapeutic agent.
E95: The composition of E94, wherein the additional therapeutic agent is a psychoactive drug.
While the present disclosure has been described with reference to examples, it is to be understood that the scope of the claims should not be limited by the embodiments set forth in the examples but should be given the broadest interpretation consistent with the description as a whole.
All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the application described and claimed herein.