US20220024956A1 - Psilocin derivatives as serotonergic psychedelic agents for the treatment of cns disorders - Google Patents

Psilocin derivatives as serotonergic psychedelic agents for the treatment of cns disorders Download PDF

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US20220024956A1
US20220024956A1 US17/387,883 US202117387883A US2022024956A1 US 20220024956 A1 US20220024956 A1 US 20220024956A1 US 202117387883 A US202117387883 A US 202117387883A US 2022024956 A1 US2022024956 A1 US 2022024956A1
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Abdelmalik Slassi
Joseph Araujo
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Mindset Pharma Inc
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Priority to US17/833,341 priority patent/US11591353B2/en
Priority to US18/079,617 priority patent/US12054505B2/en
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Definitions

  • the application relates to novel psilocin derivatives of Formula (I) for the treatment of different conditions that are treated by activation of serotonin receptor, for example, mental illnesses and other neurological diseases, disorders and conditions, in the fields of psychiatry, neurobiology and pharmacotherapy.
  • the present application further comprises methods for making the compounds of Formula (I) and corresponding intermediates.
  • Mental health disorders 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.
  • the severity of symptoms varies such that some individuals experience debilitating disease that precludes normal social function, while others suffer with intermittent repeated episodes across their lifespan.
  • endophenotypes of note across the diseases, and often comorbidities exist. Specifically, there exist phenotypic endophenotypes associated with alterations in mood, cognition and behavior. Interestingly, many of these endophenotypes extend to neurological conditions as well.
  • attentional deficits are reported in patients with attention deficit disorder, attention deficit hyperactivity disorder, eating disorders, substance use disorders, schizophrenia, depression, obsessive compulsive disorder, traumatic brain injury, Fragile X, Alzheimer's disease, Parkinson's disease and frontotemporal dementia.
  • serotonin reuptake inhibitors include serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, antidepressants, monoamine oxidase inhibitors, and, while primarily developed for depressive disorders, many of these therapeutics are used across multiple medical indications including, but not limited to, depression in Alzheimer's disease and other neurodegenerative disease, chronic pain, existential pain, bipolar disorder, obsessive compulsive disorder, anxiety disorders and smoking cessation.
  • the marketed drugs show limited benefit compared to placebo, can take six weeks to work and for some patients, and are associated with several side effects including trouble sleeping, drowsiness, fatigue, weakness, changes in blood pressure, memory problems, digestive problems, weight gain and sexual problems.
  • Psychedelics are one of the oldest classes of psychopharmacological agents known to man and cannot be fully understood without reference to various fields of research, including anthropology, ethnopharmacology, psychiatry, psychology, sociology, and others.
  • Psychedelics serotonergic hallucinogens
  • They are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts.
  • 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 are linked to epigenetic modifications, gene expression changes and modulation of pre- and post-synaptic receptor densities.
  • 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.
  • treatment resistant psychiatric and neurological diseases e.g., depression, post-traumatic stress disorder, dementia and addiction
  • psychedelic drugs are dangerous, from a physiologic safety standpoint, they are one of the safest known classes of CNS drugs. They do not cause addiction, and no overdose deaths have occurred after ingestion of typical doses of classical psychotic agents, such as LSD, psilocybin, or mescaline (Scheme 1).
  • 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].
  • Psilocybin (4-phosphoryloxy-N,N-dimethyltrypatmine (iii, Scheme 1) has the chemical formula C 12 H 17 N 2 O 4 P. It is a tryptamine 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, and later synthesized by him in 1958 [Passie et al.
  • Addict Biol., 2002, 7(4):357-364 was used in psychiatric and psychological research and in psychotherapy during the early to mid-1960s up until its controlled drug scheduling in 1970 in the US, 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.
  • psilocybin In humans as well as other mammals, psilocybin is transformed into the active metabolite psilocin, or 4-hydroxy-N,N-dimethyltryptamine (iv, Scheme 1). 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 confirms the 5HT2A activity of psilocybin and psilocin, and provides some support for indirect effects on dopamine through 5HT2A 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.
  • 5-HT1A receptors are colocalized with 5-HT2A receptors on cortical pyramidal cells [Martin-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].
  • 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.
  • a majority of known 5HT2A agonists produce hallucinogenic effects in humans, and rodents generalize from one 5HT2A 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 5HT2A receptor than for the rat receptor and it has a lower K(i) for both 5HT2A and 5HT2C receptors than LSD. Moreover, results from a series of drug-discrimination studies in rats found that 5HT2A antagonists, and not 5HT1A antagonists, prevented rats from recognizing psilocybin [Winter et al., Pharmacol Biochem Behav., 2007, 87(4):472-480]. Daily doses of LSD and psilocybin reduce 5HT2 receptor density in rat brain.
  • Psilocybin produces an altered state of consciousness with subjective symptoms such as “marked alterations in perception, mood, and thought, changes in experience of time, space, and self.”
  • Psilocybin was used in experimental research for the understanding of etiopathogenesis of selective mental disorders and showed psychotherapeutic potential [Rucker et al., Psychopharmacol., 2016, 30(12):1220-1229].
  • Psilocybin became increasingly popular as a hallucinogenic recreational drug and was eventually classed as a Schedule I controlled drug in 1970.
  • 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.
  • 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.
  • psilocybin has shown varying degrees of success in neurotic disorders, alcoholism, depression in terminally ill cancer patients, obsessive compulsive disorder, addiction, anxiety, post-traumatic stress disorder and even cluster headaches. It could also be useful as a psychosis model for the development of new treatments for psychotic disorders. [Dubovyk and Monahan-Vaughn, ACS Chem. Neurosci., 2018, 9(9):2241-2251].
  • 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].
  • 5HT2A agonism is widely recognized as the primary action of classic psychedelic agents
  • psilocybin has lesser 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 5HT1A 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. According to the World Health Organization, the discovery of mainstream antidepressants has largely revolutionized the management of depression, yet up to 60% of patients remain inadequately treated. This is often due to the drugs' delayed therapeutic effect (generally 6 weeks from treatment onset), side effects leading to non-compliance, or inherent non-responsiveness to them. 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.
  • This form of anxiety affects up to 40% of individuals diagnosed with life-threatening diseases like cancer. It manifests as apprehension regarding future danger or misfortune accompanied by feelings of dysphoria or somatic symptoms of tension, and often coexists with depression. It is associated with decreased quality of life, reduced treatment adherence, prolonged hospitalization, increased disability, and hopelessness, which overall contribute to decreased survival rates.
  • 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.
  • the psychedelic treatment model consists of administering the orally-active drug to induce a mystical experience lasting 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.
  • Psychedelic treatment is generally well-tolerated with no persisting adverse effects. Regarding their mechanisms of action, 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.
  • Regular doses of psychedelics also ameliorate sleep disturbances, which are highly prevalent in depressive patients with more than 80% of them 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.
  • sleep problems often appear before other depression symptoms, and subjective sleep quality worsens before the onset of an episode in recurrent depression.
  • Brain areas showing increased functional connectivity with poor sleep scores and higher depressive symptomatology scores included prefrontal and limbic areas, areas involved in the processing of emotions. Sleep disruption in healthy participants has demonstrated that sleep is indeed involved in mood, emotion evaluation processes and brain reactivity to emotional stimuli.
  • microdosing For psychedelics such as psilocybin and LSD referred to colloquially as microdosing.
  • 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, and so on.
  • this dosing paradigm more consistent with current standards in pharmacological care, but may be particularly beneficial for certain conditions, such as Alzheimer's disease and other neurodegenerative diseases, attention deficit disorder, attention deficit hyperactivity disorder, and for certain patient populations such as elderly, juvenile and patients that are fearful of or opposed to psychedelic assisted therapy.
  • this approach may be particularly well suited for managing cognitive deficits and preventing neurodegeneration.
  • subpopulations of low attentive and low motivated rats demonstrate improved performance on 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).
  • treatment of patients with hallucinogenic doses of 5HT2A 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.
  • 5HT2A agonists also show similar neuroprotective and increased neuroplasticity effects (neuroplastogens) and reduced neuroinflammation, which could be beneficial in 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 playful 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 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.
  • the present application includes compounds having the general structural Formula (I) or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • R 1 is selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 6 alkyleneP(O)(OR 12 ) 2 , C(O)R 12 , CO 2 R 12 , C(O)N(R 12 ) 2 , S(O)R 12 and SO 2 R 12 ;
  • the compounds of Formula (I) and pharmaceutically acceptable salts, solvates and/or prodrugs thereof are isotopically enriched with deuterium.
  • one or more of A, X, Q′, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 comprises one or more deuterium or one or more of A, X, Q′, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 is deuterium.
  • the compounds of the application are used as medicaments. Accordingly, the application also includes a compound of the application for use as a medicament.
  • the present application 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 application to the cell.
  • the present application also includes a method of treating a mental illness comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
  • the present application also includes a method of treating a mental illness comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
  • the present application also includes a method of treating a CNS disease, disorder or condition and/or a neurological disease, disorder or condition comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
  • the application additionally provides a process for the preparation of compounds of the application.
  • General and specific processes are discussed in more detail below and set forth in the examples below.
  • FIG. 1 is a graph showing the effect of various doses of exemplary compound of Formula I, I-28, on head-twitch response (HTR) in male C57BL6 mice.
  • the induction of head twitches elicited by 5-HT2A receptor agonists is believed to represent a behavioural proxy of their psychedelic effects.
  • MSP metabolite
  • the induction of head twitches elicited by 5-HT2A receptor agonists is believed to represent a behavioural proxy of their psychedelic effects.
  • compound(s) of the application or “compound(s) of the present application” and the like as used herein refers to a compound of Formula (I) and compounds of Formula (I-A) to (I-I) and pharmaceutically acceptable salts, solvates and/or prodrugs thereof.
  • composition(s) of the application or “composition(s) of the present application” and the like as used herein refers to a composition, such a pharmaceutical composition, comprising one or more compounds of the application.
  • 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 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.
  • suitable 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.
  • 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.
  • prodrug means a compound, or salt of a compound, that, after administration, is converted into an active drug.
  • 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 “C n1-n2 ”.
  • C 1-6 alkyl (or “C 1 -C 6 alkyl”) means an alkyl group having 1, 2, 3, 4, 5, or c carbon atoms and includes, for example, any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and ter-butyl, n- and iso-propyl, ethyl and methyl.
  • C 4 alkyl refers to n-, iso-, sec- and tert-butyl, n- and isopropyl, ethyl and methyl.
  • alkenyl whether it is used alone or as part of another group, means a straight or branched chain, saturated alkylene group, that is, a saturated carbon chain that contains substituents on two of its ends.
  • the number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “C n1-n2 ”.
  • C 2-6 alkylene means an alkylene group having 2, 3, 4, 5 or 6 carbon atoms.
  • alkynyl as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkynyl groups containing at least one triple bond.
  • the number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “C n1-n2 ”.
  • C 2-6 alkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms.
  • cycloalkyl as used herein, whether it is used alone or as part of another group, means a saturated carbocyclic group containing from 3 to 20 carbon atoms and one or more rings. The number of carbon atoms that are possible in the referenced cycloalkyl group are indicated by the numerical prefix “C n1-n2 ”.
  • C 3-10 cycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • aryl refers to carbocyclic groups containing at least one aromatic ring and contains either 6 to 20 carbon atoms.
  • available refers to atoms that would be known to a person skilled in the art to be capable of replacement by a substituent.
  • heterocycloalkyl refers to cyclic groups containing at least one non-aromatic ring containing from 3 to 20 atoms in which one or more of the atoms are a heteromoiety selected from O, S, S(O), SO 2 and N and the remaining atoms are C.
  • Heterocycloalkyl groups are either saturated or unsaturated (i.e. contain one or more double bonds).
  • heterocycloalkyl group contains the prefix C n1-n2 or “n1 to 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 heteromoeity as selected from O, S, S(O), SO 2 and N and the remaining atoms are C.
  • Heterocycloalkyl groups are optionally benzofused.
  • heteroaryl refers to cyclic groups containing at least one heteroaromatic ring containing 5-20 atoms in which one or more of the atoms are a heteroatom selected from O, S and N and the remaining atoms are C.
  • a heteroaryl group contains the prefix C n1-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 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.
  • benzofused 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.
  • halogen refers to a halogen atom and includes fluoro, chloro, bromo and iodo.
  • haloalkyl refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been replaced with a halogen.
  • C 1-6 haloalkyl refers to a C 1 to C 6 linear or branched alkyl group as defined above with one or more halogen substituents.
  • haloalkenyl refers to an alkenyl group as defined above in which one or more of the available hydrogen atoms have been replaced with a halogen.
  • C 1-6 haloalkenyl refers to a C 1 to C 6 linear or branched alkenyl group as defined above with one or more halogen substituents.
  • haloalkynyl refers to an alkynyl group as defined above in which one or more of the available hydrogen atoms have been replaced with a halogen.
  • C 1-6 haloalkynyl refers to a C 1 to C 6 linear or branched alkynyl group as defined above with one or more halogen substituents.
  • alkoxy as used herein, alone or in combination, includes an alkyl group connected to an oxygen connecting atom.
  • one or more item includes a single item selected from the list as well as mixtures of two or more items selected from the list.
  • substituted means, unless otherwise indicated, that the referenced group is substituted with one or more substituents independently selected from halogen, CO 2 H, CO 2 CH 3 , C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)NHCH 3 , SO 2 CH 3 , SOCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N, NH and NCH 3 .
  • alternative isotope thereof refers to an isotope of an element that is other than the isotope that is most abundant in nature.
  • 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 general Formula (I) and pharmaceutically acceptable salts, solvates and/or prodrug thereof.
  • different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H) and tritium (3H). Protium is the predominant hydrogen isotope found in nature.
  • all available atoms are optionally substituted with alternate isotope means that available atoms are optionally substituted with an isotope of that atom of having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • a “compound” refers to the compound and, in certain embodiments, to the extent they are stable, any hydrate or solvate thereof.
  • a hydrate is the compound complexed with water and a solvate is the compound complexed with a solvent, which may be an organic solvent or an inorganic solvent.
  • a “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).
  • the compounds of the present application are limited to stable compounds embraced by general Formula (I), or pharmaceutically acceptable salts, solvates and/or prodrug thereof.
  • pharmaceutically acceptable means compatible with the treatment of subjects.
  • 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.
  • 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
  • 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.
  • subject as used herein includes all members of the animal kingdom including mammals, and suitably refers to humans. Thus the methods of the present application are applicable to both human therapy and veterinary applications.
  • treating 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.
  • a subject with early cancer can be treated to prevent progression, or alternatively a subject in remission can be treated with a compound or composition of the application to prevent recurrence.
  • Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the application and optionally consist of a single administration, or alliteratively comprise a series of administrations.
  • an effective amount or “therapeutically effective amount” means an amount of one or more compounds of the application that is effective, at dosages and for periods of time necessary to achieve the desired result.
  • 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.
  • administered means administration of a therapeutically effective amount of one or more compounds or compositions of the application to a cell, tissue, organ or subject.
  • prevention 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.
  • disease, disorder or condition refers to a disease, disorder or condition treated or treatable by activation a serotonin receptor, for example 5-HT 2A and particularly using a serotonin receptor agonist, such as one or more compounds of the application herein described.
  • treating a disease, disorder or condition by activation of a serotonin receptor 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 favourably when serotonergic activity associated with the disease, disorder or condition is agonized by one or more of the compounds or compositions of the application.
  • activation includes agonism, partial agonist and positive allosteric modulation of a serotonin receptor.
  • 5-HT 2A as used herein mean the 5-HT 2A receptor subtype of the 5-HT 2 serotonin receptor.
  • therapeutic agent refers to any drug or active agent that has a pharmacological effect when administered to a subject.
  • the present application includes a compound of Formula (I) or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • R 1 is selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 6 alkyleneP(O)(OR 12 ) 2 , C(O)R 12 , CO 2 R 12 , C(O)N(R 12 ) 2 , S(O)R 12 and SO 2 R 12 ;
  • the present application includes a compound of Formula (I) or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • the halogen atom when, in the compounds of Formula I, all available hydrogen atoms in a group are optionally replaced with a halogen atom, the halogen atom is F, CI or Br. In some embodiments, when all available hydrogen atoms in a group are optionally replaced with a halogen atom, the halogen atom is F or Br. In some embodiments, when all available hydrogen atoms in a group are optionally replaced with a halogen atom, the halogen atom is F.
  • all available hydrogen atoms are optionally substituted with a fluorine, chlorine or bromine atom and/or all available atoms are optionally substituted with an alternate isotope thereof. In some embodiments, all available hydrogen atoms are optionally substituted with a halogen or bromine atom and/or all available atoms are optionally substituted with an alternate isotope thereof. In some embodiments, all available hydrogen atoms are optionally substituted with a halogen or chlorine atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof. In some embodiments, all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogen atoms are optionally substituted with deuterium. In some embodiments, all available hydrogen atoms are optionally substituted with a fluorine atom and/or all available atoms are optionally substituted with deuterium. In some embodiments, all available atoms are optionally substituted with deuterium.
  • all available hydrogen atoms are optionally substituted with an alternate isotope thereof.
  • the alternate isotope of hydrogen is deuterium. Accordingly, in some embodiments, the compounds of the application are isotopically enriched with deuterium.
  • one or more of A, X, Q′, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 comprises one or more deuterium or one or more of A, X, Q′, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 is deuterium.
  • R 1 is selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkyleneP(O)(OR 12 ) 2 , C(O)R 12 , CO 2 R 12 , C(O)N(R 12 ) 2 , S(O)R 12 and SO 2 R 12 ; wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 1 is selected from S(O)R 12 and SO 2 R 12 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 1 is selected from hydrogen, C 1 -C 3 alkyl, CH 2 P(O)(OR 12 ) 2 , CH 2 CH 2 P(O)(OR 12 ) 2 , CH 2 CH(CH 3 )P(O)(OR 12 ) 2 , CH(CH 3 )CH 2 P(O)(OR 12 ) 2 , CH(CH 3 )P(O)(OR 12 ) 2 , CH(CH 2 CH 3 )P(O)(OR 12 ) 2 , C(O)R 12 , CO 2 R 12 and C(O)N(R 9 ) 2 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 1 is selected from hydrogen, C 1 -C 3 alkyl, CH 2 P(O)(OR 12 ) 2 , CH 2 CH 2 P(O)(OR 12 ) 2 , CH 2 CH(CH 3 )P(O)(OR 12 ) 2 , CH(CH 3 )CH 2 P(O)(OR 12 ) 2 , CH(CH 3 )P(O)(OR 12 ) 2 , CH(CH 2 CH 3 )P(O)(OR 12 ) 2 , C(O)R 12 and CO 2 R 12 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 1 is selected from hydrogen, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 P(O)(OR 12 ) 2 and CH(CH 3 )P(O)(OR 12 ) 2 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 1 is selected from hydrogen, deuterium, F, CH 3 , CF 3 , CD 3 , CH 2 CH 3 , CD 2 CD 3 , CF 2 CF 3 , CH(CH 3 ) 2 , CD(CD 3 ) 2 , CF(CF 3 ) 2 , C(CD 3 ) 3 , C(CF 3 ) 3 , and C(CH 3 ) 2 .
  • R 1 is selected from hydrogen, deuterium, CH 3 , CF 3 and CD 3 .
  • R 1 is hydrogen.
  • R 1 is selected from CH 2 P(O)(OR 12 ) 2 and CH(CH 3 )P(O)(OR 12 ) 2 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 1 is CH(CH 3 )P(O)(OR 12 ) 2 .
  • R 1 is CH 2 P(O)(OR 12 ) 2 .
  • R 2 to R 6 are independently selected from hydrogen and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 2 is selected from hydrogen, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and C(CH 3 ) 3 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 2 is selected from hydrogen, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and C(CH 3 ) 3 , wherein all available hydrogen atoms are optionally substituted with a fluorine atom and/or all available hydrogen atoms are optionally substituted with deuterium.
  • R 2 is selected from hydrogen and deuterium, Br, F, CH 3 , CF 3 , CH 2 CH 3 , CD 2 CD 3 , CF 2 CF 3 , CH(CH 3 ) 2 , CD(CD 3 ) 2 , CF(CF 3 ) 2 , C(CD 3 ) 3 , C(CF 3 ) 3 , and C(CH 3 ) 3 .
  • R 2 is selected from hydrogen and deuterium.
  • R 2 is hydrogen.
  • R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and C(CH 3 ) 3 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and C(CH 3 ) 3 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogen atoms are optionally substituted with deuterium.
  • At least one of R 3 , R 4 , R 5 and R 6 is deuterium or at least one of R 3 , R 4 , R 5 and R 6 comprises deuterium. In some embodiments, at least one of R 3 and R 4 or R 5 and R 6 is deuterium or at least one of R 3 and R 4 or R 5 and R 6 comprises deuterium. In some embodiments, R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, deuterium, Br, F, CH 3 , CD 2 H, CDH 2 , CD 3 , CH 2 CH 3 , CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 .
  • R 3 , R 4 , R 5 and R 6 and R 4 are independently selected from hydrogen, deuterium, F, CH 3 , CD 2 H, CDH 2 and CD 3 . In some embodiments, R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, deuterium, F, CH 3 and CD 3 . In some embodiments, R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, deuterium and F. In some embodiments, at least one of R 3 , R 4 , R 5 and R 6 is F. In some embodiments, at least one of R 3 and R 4 or R 5 and R 6 is deuterium.
  • R 3 , R 4 , R 5 and R 6 is deuterium. In some embodiments, R 3 , R 4 , R 5 and R 6 are all hydrogen. In some embodiments, R 3 , R 4 , R 5 and R 6 are all deuterium.
  • R 7 and R 8 are independently selected from hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 4 haloalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • the C 3 -C 7 cycloalkyl in R 7 and R 8 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • the heterocycloalkyl in R 7 and R 8 is, independently, a saturated or unsaturated heterocycle. In some embodiments heterocycloalkyl in R 7 and R 8 is, independently, a saturated or unsaturated bridged bicyclic heterocycle. In some embodiments, the saturated or unsaturated bridged bicyclic heterocycle is independently selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl and oxobicycloheptanenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • the heterocycloalkyl in R 7 and R 8 independently, a saturated or unsaturated heterocycle.
  • heterocycloalkyl in R 7 and R 8 is, independently, a saturated or unsaturated bridged bicyclic heterocycle.
  • the saturated or unsaturated bridged bicyclic heterocycle is independently, selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl and oxobicycloheptanenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • the heterocycloalkyl in R 7 and R 8 independently selected from aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydr
  • the heteroaryl in R 7 and R 8 is independently selected from, azepinyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl
  • R 7 and R 8 are independently selected from hydrogen, C 1 -C 4 alkyl and C 2 -C 6 alkenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof. In some embodiments, R 7 and R 8 are independently selected from hydrogen and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 7 and R 8 are independently from hydrogen and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogen atoms are optionally substituted with deuterium.
  • R 7 and R 8 are independently selected from hydrogen, deuterium, Br, F, CH 3 , CF 3 , CD 2 H, CDH 2 , CD 3 , CH 2 CH 3 , CF 2 CF 3 , and CD 2 CD 3 .
  • R 7 and R 8 are independently selected from hydrogen, deuterium, CH 3 , CD 2 H, CDH 2 , CD 3 , CH 2 CH 3 and CD 2 CD 3 .
  • R 7 and R 8 are independently selected from hydrogen, deuterium, CH 3 , CD 3 , CH 2 CH 3 and CD 2 CD 3 . In some embodiments, R 7 and R 8 are independently selected from CH 3 , CD 3 , CH 2 CH 3 and CD 2 CD 3 . In some embodiments, R 7 and R 8 are both CH 3 , CD 3 , CH 2 CH 3 or CD 2 CD 3 . In some embodiments, R 7 and R 8 are both CH 3 . In some embodiments, R 7 and R 8 are both CD 3 . In some embodiments, R 7 and R 8 are both CH 2 CH 3 . In some embodiments, R 7 and R 8 are both CD 2 CD 3 .
  • R 7 and R 8 are taken together with the nitrogen atom therebetween to form a 3- to 7-membered heterocyclic ring optionally including 1 to 2 additional ring heteromoities selected from O, S, S(O), SO 2 , N and NR 13 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 7 and R 8 are taken together with the nitrogen atom therebetween to form a 4- to 7-membered heterocyclic ring optionally including 1 to 2 additional ring heteromoieties selected from O, S, S(O), SO 2 , N and NR 13 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 7 and R 8 are taken together with the nitrogen atom therebetween to form azetidinyl, diazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiozolidinyl, piperidinyl, diazinanyl (e.g. piperazinyl), morpholinyl or azepanyl ring, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 7 and R 8 are taken together with the nitrogen atom therebetween to form pyrrolidinyl, piperidinyl or diazinanyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 7 and R 8 are taken together with the nitrogen atom therebetween to form pyrrolidinyl, piperidinyl or diazinanyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogens are optionally substituted with deuterium.
  • R 7 and R 8 are taken together with the nitrogen atom therebetween to form pyrrolidinyl, piperidinyl or diazinanyl, wherein all available hydrogens are optionally substituted with deuterium.
  • the substituents are independently selected from one or more of Br, CI, F, CO 2 H, CO 2 CH 3 , C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)NHCH 3 , SO 2 CH 3 , C 1 -C 4 alkyl, C 1 -C 4 fluoralkyl, C 2 -C 6 alkenyl, C 2 -C 6 fluoroalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 fluoroalkynyl, C 3 -C 6 cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N, NH and NCH 3 .
  • the substituents on R 7 and R 8 are independently selected from one to three of Br, CI, F, C 1 -C 4 alkyl, C 1 -C 4 fluoralkyl, C 2 -C 6 alkenyl, C 2 -C 6 fluoroalkenyl, C 2 -C 6 alkynyl and C 2 -C 6 fluoroalkynyl. In some embodiments, the substituents on R 7 and R 8 are independently selected from one or two of Br, CI, F, CH 3 and CF 3 .
  • R 9 , R 10 and R 11 are independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 ) 2 , SR 13 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 6 haloalkenyl, CO 2 R 13 , C(O)N(R 13 ) 2 , S(O)R 13 , SO 2 R 13 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl and a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N and NR 13 , wherein said C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 -C 6 al
  • R 9 , R 10 and R 11 are independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 ) 2 , SR 13 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 6 haloalkenyl, CO 2 R 13 , C(O)N(R 13 ) 2 , S(O)R 13 , SO 2 R 13 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C 2 -C 6 haloalkynyl, wherein said C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl and C 2 -C 6 haloalkynyl groups are optionally substituted by one or more substituents independently selected from CN, OR 13 , N(R 13 )
  • R 9 , R 10 and R 11 are independently selected from hydrogen, F, CI, Br, CN, OR 13 , N(R 13 ) 2 , SR 13 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 6 haloalkenyl, CO 2 R 13 , C(O)N(R 13 ) 2 , S(O)R 13 , SO 2 R 13 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C 2 -C 6 haloalkynyl, wherein said C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl and C 2 -C 6 haloalkynyl groups are optionally substituted by one to three substituents independently selected from CN, OR 13 , N(R
  • R 9 , R 10 and R 11 are independently selected from hydrogen, F, CI, Br, CN, OR 13 , N(R 13 ) 2 , SR 13 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , C 1 -C 4 haloalkyl, C 2 -C 6 haloalkenyl, CO 2 R 13 , S(O)R 13 , SO 2 R 13 , C(O)N(R 13 ) 2 , C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, wherein said C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl and C 2 -C 6 alkynyl groups are optionally substituted by one or two substituents independently selected from CN, OR 13 , N(R 13 ) 2 and SR 13
  • R 9 , R 10 and R 11 are independently selected from hydrogen, F, CI, Br, CN, OR 13 , N(R 13 ) 2 , SR 13 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , C 1 -C 4 haloalkyl, C 2 -C 6 haloalkenyl, CO 2 R 13 , S(O)R 13 , SO 2 R 13 and C 2 -C 6 alkenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 9 , R 10 and R 11 are independently selected from hydrogen, F, CI, Br and CN wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 9 , R 10 and R 11 are independently selected from hydrogen, deuterium, F, CI, Br and CN.
  • R 9 , R 10 and R 11 are independently selected from hydrogen and deuterium.
  • R 9 , R 10 and R 11 are all hydrogen.
  • R 9 , R 10 and R 11 are all deuterium.
  • R 10 is selected from hydrogen, deuterium, F, CI, Br and CN and R 9 and R 11 are selected from hydrogen and deuterium. In some embodiments, R 10 is selected from hydrogen, deuterium, F and CN and R 9 and R 11 are selected from hydrogen and deuterium. In some embodiments, R 10 is selected from hydrogen, F and CN and R 9 and R 11 are selected from hydrogen and deuterium. In some embodiments, R 10 is selected from hydrogen, F and CN and R 9 and R 11 both hydrogen.
  • the C 3 -C 7 cycloalkyl in R 9 , R 10 and R 11 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • the 3- to 7-membered heterocyclic ring in R 9 , R 10 and R 11 is, independently, a saturated or unsaturated heterocycle. In some embodiments, the 3- to 7-membered heterocyclic ring in R 9 , R 10 and R 11 is, independently, a saturated or unsaturated bridged bicyclic heterocycle.
  • the saturated or unsaturated bridged bicyclic heterocycle is independently selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl and oxobicycloheptanenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • the 3- to 7-membered heterocyclic ring in R 9 , R 10 and R 11 is, independently, a saturated or unsaturated heterocycle. In some embodiments, the 3- to 7-membered heterocyclic ring in R 9 , R 10 and R 11 is, independently, a saturated or unsaturated bridged bicyclic heterocycle.
  • the saturated or unsaturated bridged bicyclic heterocycle is independently, selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl and oxobicycloheptanenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • the 3- to 7-membered heterocyclic ring in R 9 , R 10 and R 11 is independently selected from aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, ox
  • each R 12 is independently selected from hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 4 haloalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 4 alkyleneC 3 -C 7 cycloalkyl, substituted or unsubstituted C 1 -C 4 alkyleneC 3 -C 7 heterocycloalkyl, substituted or unsubstituted C 1 -C 4 alkylenearyl and substituted or unsubstituted C 1 -C 4 al
  • the C 3 -C 7 cycloalkyl each R 12 is independently is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • the heterocycloalkyl each R 12 is independently is a saturated or unsaturated heterocycle.
  • heterocycloalkyl in R 12 is a saturated or unsaturated bridged bicyclic heterocycle.
  • the saturated or unsaturated bridged bicyclic heterocycle is independently selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl and oxobicycloheptanenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • the heterocycloalkyl each R 12 is independently is selected from aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydro
  • the heteroaryl in each R 12 is independently is selected from, azepinyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,
  • each R 12 is independently selected from hydrogen, C 1 -C 4 alkyl and C 2 -C 6 alkenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof. In some embodiments, each R 12 is independently selected from hydrogen and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • each R 12 is independently selected from hydrogen and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with fluorine atom and/or all available hydrogen atoms are optionally substituted with deuterium. In some embodiments, each R 12 is independently selected from hydrogen, deuterium, CH 3 , CD 2 H, CDH 2 , CD 3 , CH 2 CH 3 and CD 2 CD 3 . In some embodiments, each R 12 is independently selected from hydrogen, deuterium, CH 3 , CD 3 , CH 2 CH 3 and CD 2 CD 3 . In some embodiments each R 12 is independently selected from hydrogen, CH 3 , CD 3 , CH 2 CH 3 and CD 2 CD 3 . In some embodiments, R 12 is CH 3 . In some embodiments, R 12 is CD 3 . In some embodiments, each R 12 is independently CH 2 CH 3 . In some embodiments, R 12 is CD 2 CD 3 . In some embodiments, each R 12 is independently CH 2 CH 3 . In some embodiments, R 12 is CD 2 CD 3
  • each R 12 is independently selected from substituted or unsubstituted C 1 -C 4 alkyleneC 3 -C 7 cycloalkyl, substituted or unsubstituted C 1 -C 4 alkyleneC 3 -C 7 heterocycloalkyl, substituted or unsubstituted C 1 -C 4 alkylenearyl, substituted or unsubstituted C 1 -C 4 alkyleneheteroaryl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • each R 12 is independently selected from substituted or unsubstituted C 1 -C 4 alkylenearyl and substituted or unsubstituted C 1 -C 4 alkyleneheteroaryl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof. In some embodiments, each R 12 is independently substituted or unsubstituted C 1 -C 4 alkylenearyl wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • each R 12 is independently substituted or unsubstituted CH 2 aryl wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof. In some embodiments, each R 12 is independently substituted or unsubstituted CH 2 phenyl.
  • the substituents are independently selected from one or more of Br, CI, F, CO 2 H, CO 2 CH 3 , C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)NHCH 3 , SO 2 CH 3 , C 1 -C 4 alkyl, C 1 -C 4 fluoralkyl, C 2 -C 6 alkenyl, C 2 -C 6 fluoroalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 fluoroalkynyl, C 3 -C 6 cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N, NH and NCH 3 .
  • the substituents on R 12 are independently selected from one to three of Br, CI, F, C 1 -C 4 alkyl, C 1 -C 4 fluoralkyl, C 2 -C 6 alkenyl, C 2 -C 6 fluoroalkenyl, C 2 -C 6 alkynyl and C 2 -C 6 fluoroalkynyl. In some embodiments, the substituents on R 12 are independently selected from one or two of Br, CI, F, CH 3 and CF 3 .
  • Y is halogen. In some embodiments, the halogen in Y is selected from F, CI and Br. In some embodiments, the halogen in Y is selected from F and Cl. In some embodiments, the halogen in Y is F.
  • Y is X-A.
  • X is selected from S, S(O) and SO 2 . In some embodiments, X is selected from O, NR 13 and S, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof. In some embodiments, X is selected from NR 13 and O. In some embodiments, X is O.
  • A is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, P(O)(OR 12 ) 2 , C 1 -C 3 alkyleneP(O)(OR 12 ) 2 , C 1 -C 3 alkyleneC 3 -C 7 cycloalkyl, C 1 -C 3 alkyleneC 4 -C 6 cycloalkenyl, C 1 -C 3 alkyleneheterocycloalkyl, C 1 -C 3 alkylenearyl, C 1 -C 3 alkyleneheteroaryl, C(O)Q′, CO 2 Q′, C(O)N(Q′) 2 , S(O)Q′ and SO 2 Q′, wherein all available hydrogen atoms are optional
  • A is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 3 alkyleneC 3 -C 7 cycloalkyl, C 1 -C 3 alkyleneC 4 -C 6 cycloalkenyl, C 1 -C 3 alkyleneheterocycloalkyl, C 1 -C 3 alkylenearyl, C 1 -C 3 alkyleneheteroaryl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • A is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl, heterocycloalkyl, C 1 -C 3 alkyleneC 3 -C 7 cycloalkyl, C 1 -C 3 alkyleneC 4 -C 6 cycloalkenyl, C 1 -C 3 alkyleneheterocycloalkyl, C 1 -C 3 alkylenearyl, C 1 -C 3 alkyleneheteroaryl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • A is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and heterocycloalkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • A is selected from hydrogen, C 1 -C 4 alkyl and C 2 -C 4 alkenyl, wherein all available hydrogen atoms are optionally substituted with halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • A is selected from hydrogen and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof. In some embodiments, A is selected from hydrogen and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with a fluorine atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • A is selected from hydrogen, CH 3 , CF 3 , CH 2 CH 3 , CD 2 CD 3 , CF 2 CF 3 , CH(CH 3 ) 2 , CD(CD 3 ) 2 , CF(CF 3 ) 2 , C(CD 3 ) 3 , C(CF 3 ) 3 , and C(CH 3 ) 3 .
  • A is selected from hydrogen, CH 3 , CH 2 CH 3 , CD 2 CD 3 , CH(CH 3 ) 2 , CD(CD 3 ) 2 , C(CD 3 ) 3 , and C(CH 3 ) 3 .
  • A is selected from C 1 -C 3 alkyleneC 3 -C 7 cycloalkyl, C 1 -C 3 alkyleneC 4 -C 6 cycloalkenyl, C 1 -C 3 alkyleneheterocycloalkyl, C 1 -C 3 alkylenearyl and C 1 -C 3 alkyleneheteroaryl, wherein all available hydrogen atoms are optionally substituted with halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • A is selected CH 2 C 3 -C 7 cycloalkyl, CH 2 C 4 -C 6 cycloalkenyl, CH 2 heterocycloalkyl, CH 2 aryl and CH 2 heteroaryl, wherein all available hydrogen atoms are optionally substituted with halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • A is selected from CH 2 C 3 -C 7 cycloalkyl, CH 2 aryl and CH 2 heteroaryl, wherein all available hydrogen atoms are optionally substituted with halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • A is CH 2 aryl, wherein all available hydrogen atoms are optionally substituted with halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof. In some embodiments, A is CH 2 phenyl.
  • A is selected from hydrogen, P(O)(OR 12 ) 2 , CH 2 P(O)(OR 12 ) 2 , CH 2 CH 2 P(O)(OR 12 ) 2 , CH 2 CH(CH 3 )P(O)(OR 12 ) 2 , CH(CH 3 )CH 2 P(O)(OR 12 ) 2 , CH(CH 3 )P(O)(OR 12 ) 2 , CH(CH 2 CH 3 )P(O)(OR 12 ) 2 , C(O)Q′, CO 2 Q′, C(O)N(Q′) 2 S(O)Q′ and SO 2 Q′, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • A is selected from hydrogen, P(O)(OR 12 ) 2 , CH 2 P(O)(OR 12 ) 2 , CH(CH 3 )P(O)(OR 12 ) 2 , C(O)N(Q′) 2 , C(O)Q′, S(O)Q′ and SO 2 Q′, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • A is selected from S(O)Q′ and SO 2 Q′, wherein all available hydrogen atoms are optionally substituted with halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • A is selected from hydrogen, P(O)(OR 12 ) 2 , CH 2 P(O)(OR 12 ) 2 , CH(CH 3 )P(O)(OR 12 ) 2 , C(O)N(Q′) 2 and C(O)Q′. In some embodiments, A is selected from hydrogen, P(O)(OR 12 ) 2 and C(O)Q′. In some embodiments, A is hydrogen. In some embodiments, A is C(O)N(Q′) 2 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • A is P(O)(OR 11 ) 2 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • A is C(O)Q′, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is selected from C 1 -C 20 alkyl, C 1 -C 20 haloalkyl, C 2 -C 20 alkenyl, C 2 -C 20 haloalkenyl, C 2 -C 20 alkynyl and C 2 -C 20 haloalkynyl wherein said C 1 -C 20 alkyl, C 2 -C 20 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 20 haloalkenyl, C 2 -C 20 alkynyl and C 2 -C 20 haloalkynyl groups are optionally substituted by one to three substituents independently selected from CN, OR 13 , N(R 13 ) 2 , CO 2 R 13 , SR 13 , C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and a 3- to 7-membered heterocyclic ring, and/or are disubstitute
  • Q′ is selected from C 1 -C 20 alkyl, C 2 -C 20 alkenyl and C 2 -C 20 alkynyl wherein said C 1 -C 20 alkyl, C 2 -C 6 alkenyl and C 2 -C 20 alkynyl are optionally substituted by one to three substituents independently selected from CN, OR 13 , N(R 13 ) 2 , CO 2 R 13 and SR 13 , and/or are disubstituted on the same carbon atom with C 1-6 alkyl, or with C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, and wherein each of said C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and 3- to 7-membered heterocyclic ring are further optionally substituted with a substituent selected from C 1 -C 3 alkyl and C 1 -C 3 haloalkyl, wherein all available hydrogen
  • Q′ is selected from C 1 -C 20 alkyl, C 2 -C 20 alkenyl and C 2 -C 20 alkynyl wherein said C 1 -C 20 alkyl, C 2 -C 6 alkenyl and C 2 -C 20 alkynyl are optionally substituted by one to three substituents independently selected from N(R 13 ) 2 and CO 2 R 13 , and/or disubstituted on the same carbon atom with C 1-6 alkyl, or with C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, wherein said C 3 -C 7 cycloalkyl is further optionally substituted with a substituent selected from C 1 -C 3 alkyl and C 1 -C 3 haloalkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is selected from C 1 -C 20 alkyl, C 2 -C 20 alkenyl and C 2 -C 20 alkynyl optionally substituted with one or two substituents independently selected from N(R 13 ) 2 and CO 2 R 13 , and/or disubstituted on the same carbon atom with C 1-6 alkyl, or with C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, wherein said C 3 -C 7 cycloalkyl ring is further optionally substituted with a substituent selected from C 1 -C 3 alkyl and C 1 -C 3 haloalkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is C 1 -C 20 alkyl or C 2 -C 20 alkenyl substituted by N(R 13 ) 2 and/or disubstituted on the same carbon with C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, wherein said C 3 -C 7 cycloalkyl ring is further optionally substituted with a substituent selected from C 1 -C 3 alkyl and C 1 -C 3 haloalkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is C 1 -C 20 alkyl or C 2 -C 20 alkenyl substituted by N(R 13 ) 2 wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof. In some embodiments, Q′ is C 1 -C 20 alkyl substituted by N(R 13 ) 2 wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is C 1 -C 10 alkyl substituted by N(R 13 ) 2 wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof. In some embodiments, Q′ is C 1 -C 10 alkyl substituted by N(R 13 ) 2 wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogen atoms are optionally substituted with deuterium.
  • Q′ is C 1 -C 20 alkyl or C 2 -C 20 alkenyl substituted by N(R 13 ) 2 and disubstituted on the same carbon atom with C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, wherein said C 3 -C 7 cycloalkyl ring is further optionally substituted with a substituent selected from C 1 -C 3 alkyl and C 1 -C 3 haloalkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is C 1 -C 20 alkyl substituted by N(R 13 ) 2 and disubstituted on the same carbon atom with C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, wherein said C 3 -C 7 cycloalkyl ring is further optionally substituted with a substituent selected from C 1 -C 3 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is C 1 -C 10 alkyl substituted by N(R 13 ) 2 and disubstituted on the same carbon atom with C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, wherein said C 3 -C 7 cycloalkyl ring is further optionally substituted with a substituent selected from C 1 -C 3 alkyl and wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogen atoms are optionally substituted with deuterium.
  • Q′ is C 1 -C 10 alkyl substituted by N(R 13 ) 2 and disubstituted on the same carbon atom with C 2-6 alkylene to form a C 5 -C 6 cycloalkyl ring, wherein said C 3 -C 7 cycloalkyl ring is further optionally substituted with a substituent selected from C 1 -C 3 alkyl and wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogen atoms are optionally substituted with deuterium.
  • Q′ is C 1 -C 10 alkyl substituted by N(R 13 ) 2 and disubstituted on the same carbon atom with C 2-6 alkylene to form a spirocyclohexanyl ring, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogen atoms are optionally substituted with deuterium.
  • Q′ is C 1 -C 20 alkyl or C 2 -C 20 alkenyl optionally substituted by CO 2 R 13 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is C 1 -C 20 alkyl or C 2 -C 20 alkenyl substituted by CO 2 R 13 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogens are optionally substituted with a deuterium.
  • Q′ is C 1 -C 10 alkyl or C 2 -C 10 alkenyl substituted by CO 2 R 13 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogens are optionally substituted with a deuterium.
  • Q′ is C 1 -C 6 alkyl or C 2 -C 6 alkenyl substituted by CO 2 R 13 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogens are optionally substituted with a deuterium.
  • Q′ is C 1 -C 20 alkyl or C 2 -C 20 alkenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is C 1 -C 20 alkyl or C 2 -C 20 alkenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogen atoms are optionally substituted with deuterium.
  • Q′ when Q′ is C 1 -C 20 alkyl, Q′ is a saturated fatty acid derivative, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogens are optionally substituted with a deuterium. In some embodiments, when Q′ is C 2 -C 20 alkenyl, Q′ is an unsaturated fatty acid derivative, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogens are optionally substituted with a deuterium.
  • Q′ is C 1 -C 10 alkyl or C 2 -C 10 alkenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is C 1 -C 6 alkyl or C 2 -C 6 alkenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is C 1 -C 4 alkyl or C 2 -C 4 alkenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is selected from CH 3 , CF 3 , CD 2 H, CDH 2 , CD 3 , CH 2 CH 3 , CF 2 CF 3 , and CD 2 CD 3 .
  • Q′ is selected from C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N and NR 13 , wherein said C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and 3- to 7-membered heterocyclic ring groups are optionally substituted by one to three substituents independently selected from CN, OR 13 , N(R 13 ) 2 , CO 2 R 13 , SR 13 , C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and a 3- to 7-membered heterocyclic ring and wherein each of said C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and 3- to 7-membered heterocyclic rings are each further
  • Q′ is selected from C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, N, S(O), SO 2 and NR 13 , wherein said C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and 3- to 7-membered heterocyclic ring groups are optionally substituted by one to three substituents independently selected from N(R 13 ) 2 and CO 2 R 13 , and wherein said C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and 3- to 7-membered heterocyclic ring are each further optionally substituted with a substituent selected from C 1 -C 3 alkyl; wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with
  • Q′ is selected from C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from N and NR 13 , wherein said C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and 3- to 7-membered heterocyclic ring groups are optionally substituted by one to three substituents independently selected from CN, OR 13 , N(R 13 ) 2 , CO 2 R 13 , SR 13 and a 3- to 7-membered heterocyclic ring and wherein each of said C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and 3- to 7-membered heterocyclic rings are each further optionally substituted with a substituent selected from C 1 -C 3 alkyl and C 1 -C 3 haloalkyl; wherein all available hydrogen
  • Q′ is a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from N and NR 13 , wherein said 3- to 7-membered heterocyclic ring group is optionally substituted by one to three substituents independently selected from CN, OR 13 , N(R 13 ) 2 , CO 2 R 13 , SR 13 and a 3- to 7-membered heterocyclic ring and wherein each of said 3- to 7-membered heterocyclic rings are each further optionally substituted with a substituent selected from C 1 -C 3 alkyl; wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from N and NR 13 , wherein said 3- to 7-membered heterocyclic ring group is optionally substituted by a 3- to 7-membered heterocyclic ring and wherein each of said 3- to 7-membered heterocyclic rings are each further optionally substituted with a substituent selected from C 1 -C 3 alkyl; wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is a 5- to 6-membered heterocyclic ring including 1 ring heteromoiety selected from N and NR 13 , wherein said 5 to 6-membered heterocyclic ring group is optionally substituted by a 5- to 6-membered heterocyclic ring, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is a piperidinyl or a pyrrolidinyl substituted by a piperidinyl or a pyrrolidinyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is a piperidinyl substituted by a piperidinyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • the C 3 -C 7 cycloalkyl in Q′ is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • the C 4 -C 7 cycloalkenyl in Q′ is selected from cyclobutenyl, cyclopentenyl and cyclohexenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • the 3- to 7-membered heterocyclic ring in Q′ is selected from aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, t
  • the 3- to 7-membered heterocyclic ring in Q′ is a saturated or unsaturated heterocycle.
  • the 3- to 7-membered heterocyclic ring in Q′ is a saturated or unsaturated bridged bicyclic heterocycle.
  • the saturated or unsaturated bridged bicyclic heterocycle is selected from azabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl and oxobicycloheptanenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • the heteroaryl in Q′ is selected from, azepinyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxazolyl,
  • Q′ is selected from the groups listed below:
  • A is C(O)Q′ and Q′ is selected from the groups listed above.
  • A is C(O)N(Q′) 2 and each Q′ is C 1 -C 4 alkyl or C 2 -C 4 alkenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • each Q′ is C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is selected from CH 3 , CF 3 , CD 2 H, CDH 2 , CD 3 , CH 2 CH 3 , CF 2 CF 3 , and CD 2 CD 3 .
  • A is C(O)N(Q′) 2 and each Q′ is CH 3 or CD 3 .
  • each R 13 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl, and a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N and N(R 14 ), wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl and 3- to 7-membered heterocyclic ring groups are optional
  • each R 13 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl, and a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N and N(R 14 ), wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • each R 13 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, and a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N and N(R 14 ), wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • each R 13 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof. In some embodiments, each R 13 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogen atoms are optionally substituted with deuterium.
  • each R 13 is independently selected from hydrogen and C 1 -C 6 alkyl wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogen atoms are optionally substituted with deuterium.
  • each R 13 is independently selected from hydrogen, deuterium, F, CH 3 , CF 3 , CD 2 H, CDH 2 , CD 3 , CH 2 CH 3 , CF 2 CF 3 , and CD 2 CD 3 .
  • each R 13 is independently selected from hydrogen, deuterium, CH 3 , CD 2 H, CDH 2 , CD 3 , CH 2 CH 3 , and CD 2 CD 3 .
  • each R 13 is hydrogen.
  • each R 13 is independently CH 3 or CD 3 .
  • R 14 is selected from hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 4 haloalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 14 is selected from hydrogen, C 1 -C 4 alkyl and C 2 -C 6 alkenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof. In some embodiments, R 14 is selected from hydrogen and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 14 is selected from hydrogen and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogen atoms are optionally substituted with deuterium.
  • R 14 is hydrogen, deuterium, F, CH 3 , CF 3 , CD 2 H, CDH 2 , CD 3 , CH 2 CH 3 , CF 2 CF 3 , and CD 2 CD 3 .
  • R 14 is selected is from hydrogen, deuterium, CH 3 , CD 2 H, CDH 2 , CD 3 , CH 2 CH 3 and CD 2 CD 3 .
  • R 14 is selected from hydrogen, deuterium, CH 3 and CD 3 .
  • R 14 is hydrogen.
  • the substituents are independently selected from one or more of Br, CI, F, CO 2 H, CO 2 CH 3 , C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)NHCH 3 , SO 2 CH 3 , C 1 -C 4 alkyl, C 1 -C 4 fluoralkyl, C 2 -C 6 alkenyl, C 2 -C 6 fluoroalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 fluoroalkynyl, C 3 -C 6 cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N, NH and NCH 3 .
  • the substituents on R 14 are independently selected from one to three of Br, CI, F, C 1 -C 4 alkyl, C 1 -C 4 fluoralkyl, C 2 -C 6 alkenyl, C 2 -C 6 fluoroalkenyl, C 2 -C 6 alkynyl and C 2 -C 6 fluoroalkynyl. In some embodiments, the substituents on R 14 are independently selected from one or two of Br, CI, F, CH 3 and CF 3 .
  • the compound of Formula (I) when Y is X-A and X is O, the compound of Formula (I) is a compound of Formula (I-A). Accordingly, the application includes a compound of Formula (I-A) or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • the compound of Formula (I) is a compound of Formula (I-B). Accordingly, the application includes a compound of Formula (I-B) or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • the compound of Formula (I) is a compound of Formula (I-C).
  • the application includes a compound of Formula (I-C) or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • the compound of Formula (I) is a compound of Formula (I-E). Accordingly, the application includes a compound of Formula (I-E) or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • the compound of Formula (I) is a compound of Formula (I-F). Accordingly, the application includes a compound of Formula (I-F) or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • the compound of Formula (I) is a compound of Formula (I-G). Accordingly, the application includes a compound of Formula (I-G) or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • Y is X-A and the compound of Formula (I) is a compound of Formula (I-H). Accordingly, in some embodiments, the application includes a compound of Formula (I-H) or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • Y is halogen and the compound of Formula (I) is a compound of Formula (I-I). Accordingly, in some embodiments, the application includes a compound of Formula (I-I) or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • Y is selected from F, CI and Br. In some embodiments, in the compounds of Formula (I-I), Y is selected from F and Br. In some embodiments, in the compounds of Formula (I-I), Y is F
  • Y is X-A and A is C 1-6 alkyl and the compound of Formula (I) is a compound of Formula (I-J). Accordingly, in some embodiments, the application includes a compound of Formula (I-H) or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • a in the compound of Formula (I-J) is selected from CH 3 , CD 2 H, CDH 2 , CD 3 , CH 2 CH 3 , CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 . In some embodiments, A in the compound of Formula (I-J) selected from CH 3 , CD 3 , CH 2 CH 3 and CD 2 CD 3 . In some embodiments, A in the compound of Formula (I-J) selected from CH 3 , and CD 3 .
  • R 1 in the compounds of Formula (I-A) to (I-C) and (I-H) to (I-J) is selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkyleneP(O)(OR 12 ) 2 , C(O)R 12 , CO 20 R 12 , C(O)N(R 12 ) 2 , S(O)R 12 and SO 2 R 12 ; wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 1 in the compounds of Formula (I-A) to (I-C) and (I-H) to (I-J) is selected from hydrogen, C 1 -C 3 alkyl, CH 2 P(O)(OR 12 ) 2 , CH 2 CH 2 P(O)(OR 12 ) 2 , CH 2 CH(CH 3 )P(O)(OR 12 ) 2 , CH(CH 3 )CH 2 P(O)(OR 12 ) 2 , CH(CH 3 )P(O)(OR 12 ) 2 , CH(CH 2 CH 3 )P(O)(OR 12 ) 2 , C(O)R 12 and CO 2 R 12 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 1 in the compounds of Formula (I-A) to (I-C) and (I-H)to (I-J) is selected from hydrogen, CH 3 , CH 2 CH 3 , and CH(CH 3 ) 2 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 1 in the compounds of Formula (I-A) to (I-C) and (I-H) to (I-J) is selected from hydrogen, deuterium, Br, F, CH 3 , CF 3 , CD 3 , CH 2 CH 3 , CD 2 CD 3 , CF 2 CF 3 , CH(CH 3 ) 2 , CD(CD 3 ) 2 , CF(CF 3 ) 2 , C(CD 3 ) 3 , C(CF 3 ) 3 , and C(CH 3 ) 2
  • R 1 in the compounds of Formula (I-A) to (I-C) and (I-H)to (I-J) is selected from hydrogen, deuterium, CH 3 , CF 3 and CD 3 .
  • R 1 in the compounds of Formula (I-A) to (I-C) and (I-H) to (I-J) is hydrogen. In some embodiments, R 1 in the compounds of Formula (I-A) to (I-C) and (I-H) to (I-J) is selected from CH 2 P(O)(OR 12 ) 2 and CH(CH 3 )P(O)(OR 12 ) 2 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 1 in the compounds of Formula (I-A) to (I-C) and (I-H) to (I-J is CH(CH 3 )P(O)(OR 12 ) 2 . In some embodiments, R 1 in the compounds of Formula (I-A), (I-C) and (I-H) is CH 2 P(O)(OR 12 ).
  • R 2 to R 6 are independently selected from hydrogen and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • at least one of R 3 , R 4 , R 5 and R 6 is deuterium or at least one of R 3 , R 4 , R 5 and R 6 comprises deuterium.
  • R 3 and R 4 or R 5 and R 6 are deuterium or at least one of R 3 and R 4 or R 5 and R 6 comprises deuterium.
  • R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, deuterium, Br, F, CH 3 , CD 2 H, CDH 2 , CD 3 , CH 2 CH 3 , CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 .
  • R 3 , R 4 , R 5 and R 6 and R 4 are independently selected from hydrogen, deuterium, F, CH 3 , CD 2 H, CDH 2 and CD 3 .
  • R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, deuterium, F, CH 3 and CD 3 .
  • R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, deuterium and F. In some embodiments, in the compounds of Formula to (I-C) and (I-E) to (I-J), at least one of R 3 , R 4 , R 5 and R 6 is F. In some embodiments, in the compounds of Formula (I-A) to (I-C) and (I-E) to (I-J), at least one of R 3 and R 4 or R 5 and R 6 is deuterium.
  • R 3 , R 4 , R 5 and R 6 are all hydrogen. In some embodiments, in the compounds of Formula (I-A) to (I-C) and (I-E) to (I-J), R 3 , R 4 , R 5 and R 6 are all deuterium.
  • R 7 and R 8 are independently selected from hydrogen, deuterium, Br, F, CH 3 , CF 3 , CD 2 H, CDH 2 , CD 3 , CH 2 CH 3 , CF 2 CF 3 , and CD 2 CD 3 .
  • R 7 and R 8 are independently selected from hydrogen, deuterium, CH 3 , CD 3 , CH 2 CH 3 and CD 2 CD 3 .
  • R 7 and R 8 are both hydrogen, deuterium, CH 3 , CD 3 , CH 2 CH 3 or CD 2 CD 3 .
  • R 7 and R 8 are both hydrogen.
  • R 7 and R 8 are both CH 3 .
  • R 7 and R 8 are both CD 3 . In some embodiments, in the compounds of Formula (I-A) to (I-C) and (I-E) to (I-J), R 7 and R 8 are both CH 2 CH 3 . In some embodiments, in the compounds of Formula (I-A) to (I-C) and (I-E) to (I-J), R 7 and R 8 are both CD 2 CD 3 .
  • At least one of R 3 , R 4 , R 5 and R 6 is deuterium or at least one of R 3 , R 4 , R 5 and R 6 comprises deuterium and R 7 and R 8 are independently selected from hydrogen, deuterium, CH 3 , CD 3 , CH 2 CH 3 and CD 2 CD 3 .
  • R 3 and R 4 or R 5 and R 6 are deuterium and R 7 and R 8 are both hydrogen, deuterium, CH 3 , CD 3 , CH 2 CH 3 or CD 2 CD 3 .
  • R 3 , R 4 , R 5 and R 6 are all hydrogen or R 3 , R 4 , R 5 and R 6 are all deuterium and R 7 and R 8 are both hydrogen, deuterium, CH 3 , CD 3 , CH 2 CH 3 or CD 2 CD 3 .
  • R 7 and R 8 are taken together with the nitrogen atom therebetween to form pyrrolidinyl, piperidinyl or diazinanyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogens are optionally substituted with deuterium.
  • R 3 , R 4 , R 5 and R 6 are all hydrogen or R 3 , R 4 , R 5 and R 6 are all deuterium and R 7 and R 8 are taken together with the nitrogen atom therebetween to form pyrrolidinyl, piperidinyl or diazinanyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogens are optionally substituted with deuterium
  • R 9 , R 10 and R 11 are independently selected from hydrogen, F, CI, Br, CN, OR 13 , N(R 13 ) 2 , SR 13 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , C 1 -C 4 haloalkyl, C 2 -C 6 haloalkenyl, CO 2 R 13 , S(O)R 13 , SO 2 R 13 and C 2 -C 6 alkenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • R 9 , R 10 and R 11 are independently selected from hydrogen, F, CI, Br and CN wherein all available atoms are optionally substituted with an alternate isotope thereof.
  • R 9 , R 10 and R 11 are independently selected from hydrogen, deuterium, F, CI, Br and CN.
  • R 9 , R 10 and R 11 are independently selected from hydrogen and deuterium.
  • R 9 , R 10 and R 11 are all hydrogen. In some embodiments, in the compound of Formula (I-A), (I-H) to (I-J), R 9 , R 10 and R 11 are all deuterium. In some embodiments, in the compound of Formula (I-A), (I-H) to (I-J), R 10 is selected from hydrogen, deuterium, F, CI, Br and CN and R 9 and R 11 are selected from hydrogen and deuterium.
  • R 10 is selected from hydrogen, deuterium, F and CN and R 9 and R 11 are selected from hydrogen and deuterium. In some embodiments, in the compound of Formula (I-A), (I-H) to (I-J), R 10 is selected from hydrogen, F and CN and R 9 and R 11 are selected from hydrogen and deuterium. In some embodiments, in the compound of Formula (I-A), (I-H) to (I-J), R 10 is selected from hydrogen, F and CN and R 9 and R 11 both hydrogen. In some embodiments, in the compound of Formula (I-A), (I-H) to (I-J), R 10 is selected from hydrogen, deuterium, F, CI, Br and CN.
  • Q′ is selected from hydrogen, C 1 -C 20 alkyl, C 2 -C 20 alkenyl and a 3 to 7-membered heterocyclic group wherein said C 1 -C 20 alkyl and C 2 -C 6 alkenyl are optionally substituted by one to three substituents independently selected from N(R 13 ) 2 and CO 2 R 13 and wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is C 1 -C 10 alkyl or C 2 -C 10 alkenyl substituted by CO 2 R 10 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogens are optionally substituted with a deuterium.
  • Q′ is C 1 -C 6 alkyl or C 2 -C 6 alkenyl substituted by CO 2 R 10 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogens are optionally substituted with a deuterium.
  • Q′ is selected from
  • Q′ is selected from C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, N, S(O), SO 2 and NR 10 , wherein said C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and 3- to 7-membered heterocyclic ring groups are optionally substituted by one to three substituents independently selected from N(R 10 ) 2 and CO 2 R 10 , and wherein said C 3 -C 7 cycloalkyl, C 4 -C 7 cyclo
  • Q′ is
  • Q′ is C 1 -C 4 alkyl or C 2 -C 4 alkenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is selected from CH 3 , CF 3 , CD 2 H, CDH 2 , CD 3 , CH 2 CH 3 , CF 2 CF 3 , and CD 2 CD 3 .
  • Q′ is C 1 -C 20 alkyl or C 2 -C 20 alkenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogen atoms are optionally substituted with deuterium.
  • Q′ is selected from
  • Q′ is
  • Q′ is C 1 -C 20 alkyl substituted by N(R 10 ) 2 wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is C 1 -C 10 alkyl substituted by N(R 10 ) 2 wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogen atoms are optionally substituted with deuterium.
  • Q′ is selected from
  • Q′ is C 1 -C 20 alkyl substituted by N(R 10 ) 2 and disubstituted on the same carbon atom with C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, wherein said C 3 -C 7 cycloalkyl ring is further optionally substituted with a substituent selected from C 1 -C 3 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is C 1 -C 10 alkyl substituted by N(R 10 ) 2 and disubstituted on the same carbon atom with C 2-6 alkylene to form a spirocyclohexanyl ring, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available hydrogen atoms are optionally substituted with deuterium.
  • Q′ is a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from N and NR 10 , wherein said 3- to 7-membered heterocyclic ring group is optionally substituted by one to three substituents independently selected from CN, OR 10 , N(R 10 ) 2 , CO 2 R 10 , SR 10 and a 3- to 7-membered heterocyclic ring and wherein each of said 3- to 7-membered heterocyclic rings are each further optionally substituted with a substituent selected from C 1 -C 3 alkyl; wherein all available hydrogen atoms are optionally substituted with a halogen atom
  • Q′ is a 5- to 6-membered heterocyclic ring including 1 ring heteromoiety selected from N and NR 10 , wherein said 5 to 6-membered heterocyclic ring group is optionally substituted by a 5- to 6-membered heterocyclic ring, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • Q′ is a piperidinyl substituted by a piperidinyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.
  • the compounds of Formula (I) are selected from:
  • the compounds of Formula (I) are selected from the compounds listed below:
  • the compounds of the present application 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 application.
  • the compounds of the present application may further exist in varying polymorphic forms and it is contemplated that any polymorphs, or mixtures thereof, which form are included within the scope of the present application.
  • the compounds of the present application may further be radiolabeled and accordingly all radiolabeled versions of the compounds of the application are included within the scope of the present application.
  • the compounds of the application also include those in which one or more radioactive atoms are incorporated within their structure.
  • the compounds of the present application are suitably formulated in a conventional manner into compositions using one or more carriers. Accordingly, the present application also includes a composition comprising one or more compounds of the application and a carrier. The compounds of the application are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application further includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier. In embodiments of the application the pharmaceutical compositions are used in the treatment of any of the diseases, disorders or conditions described herein.
  • the compounds of the application 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.
  • a compound of the application 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.
  • 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 NF19) 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.
  • a compound of the application 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.
  • the compound is incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions and the like.
  • carriers that are used include lactose, com 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); or wetting agents (e.g., sodium lauryl sulphate), or solvents (e.g. medium chain triglycerides, ethanol, water).
  • 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 star
  • Oral dosage forms also include modified release, for example immediate release and timed-release, formulations.
  • 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.
  • SR sustained-release
  • ER extended-release
  • CR controlled-release
  • Contin continuous-release
  • 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.
  • liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • useful carriers, solvents or diluents include lactose, medium chain triglycerides, ethanol and dried com starch.
  • 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.
  • aqueous suspensions and/or emulsions are administered orally, the compound of the application 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 preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • 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
  • preservatives e.g., methyl or propyl p-hydroxybenzoates or sorbic acid.
  • a compound of the application is administered parenterally.
  • solutions of a compound of the application are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • 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.
  • sterile solutions of the compounds of the application are usually prepared and the pH's of the solutions are suitably adjusted and buffered.
  • ointments or droppable liquids are delivered, for example, by ocular delivery systems known to the art such as applicators or eye droppers.
  • 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.
  • diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.
  • a compound of the application 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.
  • 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.
  • the compounds of the application are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders.
  • the compounds of the application are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped 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.
  • 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.
  • 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.
  • a propellant include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas.
  • the dosage unit is suitably determined by providing a valve to deliver a metered amount.
  • 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 application 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 application 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 application 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.
  • a compound of the application is coupled with soluble polymers as targetable drug carriers.
  • soluble polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • a compound of the application 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 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 application 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 application (the active ingredient) is in association with a pharmaceutically acceptable carrier.
  • 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.
  • the compounds of the application including pharmaceutically acceptable salts, solvates and/or prodrugs thereof are used are administered in a composition comprising an additional therapeutic agent. Therefore the present application also includes a pharmaceutical composition comprising one of more compounds of the application, or pharmaceutically acceptable salts, solvates and/or prodrugs thereof and an additional therapeutic agent, and optionally one or more pharmaceutically acceptable excipients.
  • 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.
  • the additional therapeutic agent is a psychoactive drug.
  • a compound also includes embodiments wherein one or more compounds are referenced.
  • the compounds of the application are serotonergic binding agents that act as agonists or partial agonists at a serotonin receptor.
  • the present application 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 application to the cell.
  • the application also includes a use of one or more compounds of the application for activating a serotonin receptor in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for activating a serotonin receptor in a cell.
  • the application further includes one or more compounds of the application for use in activating a serotonin receptor in a cell.
  • the compounds of the application are capable of activating a serotonin receptor
  • the compounds of the application are useful for treating diseases, disorders or conditions by activating a serotonin receptor. Therefore, the compounds of the present application are useful as medicaments. Accordingly, the application also includes a compound of the application for use as a medicament.
  • the present application 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 application to a subject in need thereof.
  • the present application also includes a use of one or more compounds of the application for treatment of a disease, disorder or condition by activation of a serotonin receptor as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a disease, disorder or condition by activation of a serotonin receptor.
  • the application further includes one or more compounds of the application for use in treating a disease, disorder or condition by activation of a serotonin receptor.
  • the serotonin receptor is 5-HT 2A .
  • the present application includes a method for activating 5-HT 2A in a cell, either in a biological sample or in a patient, comprising administering an effective amount of one or more compounds of the application to the cell.
  • the application also includes a use of one or more compounds of the application for activating 5-HT 2A in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for activating 5-HT 2A in a cell.
  • the application further includes one or more compounds of the application for use in activating 5-HT 2A in a cell.
  • the present application also includes a method of treating a disease, disorder or condition by activation of 5-HT 2A comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
  • the present application also includes a use of one or more compounds of the application for treatment of a disease, disorder or condition by activation of 5-HT 2A as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a disease, disorder or condition by activation of 5-HT 2A .
  • the application further includes one or more compounds of the application for use in treating a disease, disorder or condition by activation of 5-HT 2A .
  • the compounds of the application 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 application also includes a method of treating a mental illness comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof. The present application also includes a use of one or more compounds of the application for treatment a mental illness, as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a mental illness. The application further includes one or more compounds of the application for use in treating a mental illness.
  • 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, anxiety and cyclothymic disorder; psychotic disorders, such as hallucinations, delusions, schizophrenia; impulse control and addiction disorders, such as pyromania (starting fires), kleptomania (stealing) and compulsive gambling; alcohol addiction; drug addiction, such as opioid addiction; personality disorders, such as antisocial personality disorder, obsessive-compulsive personality disorder and paranoid personality disorder; obsessive-compulsive disorder (OCD), 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
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is neurodegeneration. In some embodiments, the disease, disorder or condition that is treated by activation of a serotonin receptor is reduced brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR) activation and/or inflammation.
  • BDNF brain-derived neurotrophic factor
  • mTOR mammalian target of rapamycin
  • the disease, disorder or condition that is treated by activation of a serotonin receptor comprises cognitive impairment; 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; or a combination thereof.
  • the mental illness is selected from hallucinations and delusions and a combination thereof.
  • the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations and chronoceptive hallucinations, and a combination thereof.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is psychosis or psychotic symptoms.
  • the present application also includes a method of treating psychosis or psychotic symptoms comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
  • the present application also includes a use of one or more compounds of the application for treatment of psychosis or psychotic symptoms, as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of psychosis or psychotic symptoms.
  • the application further includes one or more compounds of the application for use in treating psychosis or psychotic symptoms.
  • administering to said subject in need thereof a therapeutically effective amount of the compounds of the application 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 application 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 application results in an improvement of psychosis or psychotic symptoms.
  • the compounds of the application are useful for treating a central nervous system (CNS) disease, disorder or condition and/or a neurological disease, disorder or condition in a subject in need of therapy, comprising administering a therapeutically effective amount of a compound of general formula (I), or a pharmaceutically acceptable salt thereof to the subject.
  • CNS central nervous system
  • 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.
  • CNS central nervous system
  • the present application also includes a method of treating a CNS disease, disorder or condition and/or a neurological disease, disorder or condition comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
  • the present application also includes a use of one or more compounds of the application for treatment a CNS disease, disorder or condition and/or a neurological disease, disorder or condition, as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a CNS disease, disorder or condition and/or a neurological disease, disorder or condition.
  • the application further includes one or more compounds of the application for use in treating a CNS disease, disorder or condition and/or a neurological disease, disorder or condition.
  • 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
  • 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 application are directed to both human and veterinary diseases, disorders and conditions.
  • the compounds of the application are useful for treating behavioral problems in subjects that are felines or canines.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is behavioral problems in subjects that are felines or canines.
  • the present application also includes a method of treating a behavioral problem comprising administering a therapeutically effective amount of one or more compounds of the application to a non-human subject in need thereof.
  • the present application also includes a use of one or more compounds of the application for treatment a behavioral problem in a non-human subject, as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a behavioral problem in a non-human subject.
  • the application further includes one or more compounds of the application for use in treating a behavioral problem in a non-human subject.
  • 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.
  • the non-human subject is canine. In some embodiments, the non-human subject is feline.
  • the present application 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 application 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 application also includes a use of one or more compounds of the application 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 a use of one or more compounds of the application 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 application further includes one or more compounds of the application 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.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is a mental illness. 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. 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.
  • CNS central nervous system
  • 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 application are administered in combination with one or more additional treatments for a mental illness.
  • 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 carbamazepine, divalproex (valproic acid), lamotrigine, gabapentin and topiramate.
  • benzodiazepines such as alprazolam
  • mood stabilizers such as lithium
  • anticonvulsants such carbamazepine, divalproex (valproic acid), lamotrigine, gabapentin and topiramate.
  • 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.
  • 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 application are administered in combination with one or more additional treatments for attention deficit hyperactivity disorder and/or attention deficit disorder and a combination thereof.
  • the additional treatments for attention deficit hyperactivity disorder and/or attention deficit disorder and a combination thereof are selected from methylphenidate, atomoxetine and amphetamine and a combination thereof.
  • 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 application are administered in combination with one or more additional treatments for dementia or Alzheimer's disease.
  • the additional treatments for dementia and Alzheimer's disease are selected acetylcholinesterase inhibitors, NMDA antagonists and nicotinic agonists.
  • the acetylcholinesterase inhibitors are selected from donepezil, galantamine, rivastigmine, and phenserine, and combinations thereof.
  • the NMDA antagonists are selected from MK-801, ketamine, phencyclidine, and memantine, and combinations thereof.
  • the nicotinic agonists is nicotine, nicotinic acid, nicotinic alpha7 agonists, or nicotinic alpha2 beta4 agonists, or combinations thereof.
  • the muscarinic agonists is a muscarinic M1 agonist, or a muscarinic M4 agonist, or combinations thereof.
  • the muscarinic antagonist is a muscarinic M2 antagonist.
  • 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 application are administered in combination with one or more additional treatments for psychosis or psychotic symptoms.
  • the additional treatments for psychosis or psychotic symptom are selected typical antipsychotics and atypical antipsychotics.
  • 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
  • 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 and zotepine, and combinations thereof.
  • effective amounts vary according to factors such as the disease state, age, sex and/or weight of the subject or species.
  • 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.
  • the compounds of the application are administered one, two, three or four times a year. In some embodiments, the compounds of the application are administered at least once a week. However, in another embodiment, the compounds are administered to the subject from about one time per 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 application 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.
  • the compounds of the application 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.
  • 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 application is either used alone or in combination with other known agents useful for treating diseases, disorders or conditions by activation of a serotonin receptor, such as the compounds of the application.
  • a compound of the application is administered contemporaneously with those agents.
  • “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.
  • two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances.
  • a combination of agents is administered to a subject in a non-contemporaneous fashion.
  • a compound of the present application is administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present application provides a single unit dosage form comprising one or more compounds of the application, an additional therapeutic agent and a pharmaceutically acceptable carrier.
  • the dosage of a compound of the application 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.
  • one or more compounds of the application 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 application from about 0.01 ⁇ g/cc to about 1000 ⁇ g/cc, or about 0.1 ⁇ g/cc to about 100 ⁇ g/cc.
  • oral dosages of one or more compounds of the application will range between about 10 ⁇ g per day to about 1000 mg per day for an adult, suitably about 10 ⁇ g per day to about 500 mg per day, more suitably about 10 ⁇ g per day to about 200 mg per day.
  • 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.
  • a representative amount is from about 0.001 ⁇ g/kg to about 10 mg/kg, about 0.1 ⁇ g/kg to about 10 mg/kg, about 0.01 ⁇ g/kg to about 1 mg/kg or about 0.1 ⁇ g/kg to about 1 mg/kg.
  • 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.
  • 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 application) per tablet.
  • the one or more compounds of the application are administered in a single daily, weekly or monthly dose or the total daily dose is divided into two, three or four daily doses.
  • the compounds of the application 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 application 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-HT 2A 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-HT 2A human CNS receptor occupancy of 30% or less.
  • the compounds of the application 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.
  • the compounds of the application are generally prepared according to the process illustrated in Schemes II-IV.
  • the compounds of Formula (I) are prepared as shown in Scheme II. 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.
  • the compounds of Formula (I) are synthesized according to Scheme III. Therefore, a substituted indole compound of Formula (C) is coupled with a suitable amino compound of Formula (E) in the present of suitable coupling reagents such as oxalyl chloride to provide compounds of Formula (D).
  • suitable coupling reagents such as oxalyl chloride
  • suitable reducing agents such as Al-based reducing agents
  • Salts of compounds of the application may be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the application 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.
  • solvates will vary depending on the compound and the solvate.
  • 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.
  • 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 application will vary depending on the compound and the solvate.
  • 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.
  • suitable conditions to form a particular solvate can be made by a person skilled in the art.
  • Isotopically-enriched compounds of the application 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.
  • 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.
  • the reaction was treated with aminopropyl silica gel (1.3 g) and diluted with ethyl acetate (50 mL). The reaction was filtered though a pad of celite and washed with ethyl acetate (2 ⁇ 20 mL). Combined organic layer was evaporated and dried under vacuum to obtain crude dibenzyl (3-(2-(bis(methyl-d 3 )amino)ethyl-1,1,2,2-d4)-1H-indol-4-yl) phosphate as light brown semi-solid.
  • % ⁇ ⁇ Activation ( RFUcompound - RFU ⁇ ⁇ low ⁇ ⁇ control ) ( RFU ⁇ ⁇ top ⁇ ⁇ concentration ⁇ ⁇ of ⁇ ⁇ reference ⁇ agonist - RFU ⁇ ⁇ low ⁇ ⁇ control ) * 100 ⁇ %
  • the exemplary compounds of the application were found to be 5-HT2A agonists.
  • the results of representative compounds are presented as EC50 provided in Table 1.
  • Table 1 Effect of compounds of Formula 1 (I-28) and its metabolite targeting on human 5-HT2A (h5-HT2A) receptor under agonist mode:
  • Exemplary compound of Formula I, I-46, I-28, and the metabolite of I-28 (I-45) were evaluated functionally using FLIPR assay for their effect on h5-HT2A receptor under agonist mode.
  • EC 50 (nM) concentrations are illustrated in Table 1. This assay confirms that either the compounds of the application and/or their major metabolites are effective agonists of the target human 5-HT2A receptors.
  • the metabolite of the I-28 prodrug is the active agonist of the target human 5-HT2A receptor.
  • Ketanserin Hydrochloride PerkinElmer NET791250UC [Ethylene-3H]- Ketanserin MedChemExpress HY-10562 Bovine Serum Albumin (BSA) Sigma A1933 Calcium chloride (CaCl 2 ) Sigma C5670 Tris(hydroxymethyl)aminomethane (Tris) Alfa Aesar A18494 Polyethylenimine, branched (PEI) Sigma 408727
  • iii Prepare (v/v) DMSO: a. Add 50 ⁇ l/well of 0.5% (v/v) PEI to UniFilter-96 GF/B plates. Seal the plates and incubate at 4 oC for 3 hrs; b. After incubation, wash the plates 3 times with ice-cold wash buffer (50 mM Tris, pH7.4);
  • iv. Preparation of assay plates a. Dilute cell membrane with assay buffer and add 330 ⁇ l/well to 96 round deep well plates to reach a concentration of 20 ⁇ g/well; b. Prepare 8 concentrations of reference or test compounds and add 110 ⁇ l/well to 96 round deep well plates; c. Dilute [3H]-ketanserin with assay buffer to 5 nM (5 ⁇ final concentration) and add 110 ⁇ l/well to 96 round deep well plates.
  • X Read the plate by using a Microbeta2 microplate counter.
  • the IC50 is determined by fitting percentage of inhibition as a function of compound concentrations with Hill equation using XLfit.
  • Exemplary compounds of Formula I were evaluated using radioligand binding assay on human 5-HT2A receptor. EC 50 (nM) concentrations are illustrated in Table 2. This assay confirms that compounds or metabolites of the application are effective ligands of the target human 5-HT2A receptors. Specifically, the metabolite of the exemplary compound (I-28) demonstrates greater binding affinity at the target receptor.
  • the objective of this study was to estimate in vitro metabolic stability of I-12 in pooled human, male rat and male mouse liver microsomes.
  • concentrations of parent 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.
  • a master solution in the “Incubation Plate” containing phosphate buffer, ultra-pure H 2 O, MgCl 2 solution and liver microsomes was made according to Table-3. The mixture was pre-warmed at 37° C. water bath for 5 minutes.
  • reaction was started with the addition of 4 ⁇ L of 200 ⁇ M exemplary test compounds of the application or control compounds to each master solution to get the final concentration of 2 ⁇ M. This study was performed in duplicate.
  • 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 an Triple QuadTM 5500 instrument.
  • Peak area ratios of test compound to internal standard were determined from extracted ion chromatograms.
  • in vitro half-life (in vitro t1/2) was determined from the slope value:
  • 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.
  • Exemplary compounds of the application were evaluated for their stability in human, rat and mouse liver microsomes. A majority of the exemplary compounds of the application 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 4 for Exemplary compounds of Formula I).
  • Group ID Formulation Storage 1 3, 5, 7 & 9 A 0.2 mg/mL formulation of the appropriate TA ⁇ 80° C. will be freshly prepared in saline on the day of dosing. 2, 4, 6, 8 & 10 A 1 mg/mL formulation of the appropriate TA will be freshly prepared in saline on the day of dosing.
  • Group ID Blood collection time (h) Volume/time-point 1, 3, 5, 7 & 9 0.0833, 0.25, 0.5, 1, 2, ⁇ 0.03 mL (tail snip) 4, 6 & 8 24 ⁇ 0.4 mL blood via cardiac puncture 2, 4, 6, 8 & 10 0.25, 0.5, 1, 2, 4, 6, & ⁇ 0.03 mL (tail snip) 8 24 ⁇ 0.4 mL blood via cardiac puncture
  • mice Male C57BL/6 mice (25-30 g) from Charles River Labs were acclimatized for a minimum of 5 days prior to dosing. Body weights were recorded on the day of dosing.
  • Formulations were administered intravenously (i.v.) via the tail vein or orally (p.o.) by gavage with disposable feeding needles.
  • Serial blood samples were collected via tail snip. Terminal blood samples were collected under isoflurane anesthesia by cardiac puncture.
  • test compounds i. selection of the ion transition for the test compounds (i.e. identification of the parent and product ions).
  • V sample clean-up method using protein precipitation.
  • STDs non-zero calibration standards
  • LLOQ lower level of quantitation
  • the correlation coefficient (r) of the calibration curve must be greater than or equal to 0.99.
  • PK parameters C 0 , t 1/2 , AUC 0-tlast .
  • nc denotes not calculable as the terminal phase was not defined.
  • nc The properties of the metabolite following dosing of the exemplary prodrug I-28.
  • HTR head-twitch response
  • mice Male, C57BL/6J mice (body weight range 20-30 g) were dosed with the appropriate dose of test article, and following a 1-minute pre-treatment time, placed in individual observation chambers. Animals were visually assessed for the incidence head twitches continuously over a 1 hr period. Head twitches were defined as a rapid jerk of the head which was not elicited by an external tactile stimulus (Come and Pickering, Psychopharmacologia, 1967, 11(1): 65-78). Each head twitch was individually counted by a trained observer, and the data expressed as the mean ⁇ SEM of 6-10 mice per group. Mice were used in a single experiment only.
  • mice Male, Sprague-Dawley rats (body weight range 250-400 g) were dosed with the appropriate dose of test article and following a 1-minute pre-treatment time, placed in locomotor activity boxes (dimensions 17′′ W ⁇ 17′′ L ⁇ 12′′ H) and continuously monitored for a 1 hr period with data collected into 10 minute time bins. Animals were visually assessed for overt behavioural signs, including behaviours characteristic of 5-HT2A receptor activation (wet dog shakes, back muscle contractions), 5-HT2A receptor activation (yawning, penile grooming) and 5-HT1A behaviours (forepaw treading, hindlimb abduction) (Halberzettl et al, Behav Brain Res. 256: 328-345, 2013).
  • the rats were trained to associate one lever to a psilocybin training dose of 1 mg/kg SC, and the second lever to a neutral stimulus (saline, SC) (Winter et al, Pharmacol Biochem Behav. 87(4): 472-480, 2007). Training sessions lasted 30-min or until the delivery of 50 pellets and continued until the animals attained appropriate stimulus control (defined as six consecutive sessions where animals made no more than 16 lever presses before the delivery of the first reward, and at least 95% total responses on the appropriate lever). The rats continued to receive daily food ration in their home cage at day end.
  • FIG. 1 is a graph showing the effect of various doses of exemplary compound of Formula I, I-28, on head-twitch response (HTR) in male C57BL6 mice.
  • the induction of head twitches elicited by 5-HT2A receptor agonists is believed to represent a behavioural proxy of their psychedelic effects. Also locomotor activity and other 5-HT receptor signs measured ( FIG. 1 ).
  • the metabolite of I-28 (I-45) demonstrates greater efficacy to induce head twitch than the exemplary prodrug I-28 ( FIG. 2 ).

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