WO2024044847A1 - Dérivés d'indoline utilisés en tant qu'agents sérotoninergiques utiles pour le traitement de troubles associés - Google Patents

Dérivés d'indoline utilisés en tant qu'agents sérotoninergiques utiles pour le traitement de troubles associés Download PDF

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WO2024044847A1
WO2024044847A1 PCT/CA2023/051143 CA2023051143W WO2024044847A1 WO 2024044847 A1 WO2024044847 A1 WO 2024044847A1 CA 2023051143 W CA2023051143 W CA 2023051143W WO 2024044847 A1 WO2024044847 A1 WO 2024044847A1
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alkyl
independently selected
compound
formula
halo
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PCT/CA2023/051143
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Abdelmalik Slassi
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Mindset Pharma Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the application relates to methods of activating serotonin receptors in a cell using indoline derivatives of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof as well as to the treatment of different conditions that are treated by activation of serotonin receptors, for example, mental illnesses and neurological disease, in the fields of psychiatry, neurobiology and pharmacotherapy.
  • the present application also relates to indoline derivatives of Formula l-A and to compositions and uses thereof
  • 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.
  • Many mental health disorders, as well as neurological disorders are impacted by alterations, dysfunction, degeneration, and/or damage to the brain’s serotonergic system, which may explain, in part, common endophenotypes and comorbidities among neuropsychiatric and neurological diseases.
  • 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
  • Psilocybin (4-phosphoryloxy-N,N-dimethyltrypatmine) 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], and 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.
  • psilocybin In humans as well as other mammals, psilocybin is transformed into the active metabolite psilocin, or 4-hydroxy-N,N-dimethyltryptamine. It is likely that psilocin partially or wholly produces most of the subjective and physiological effects of psilocybin in humans and non-human animals. Recently, human psilocybin research confirmed the 5- HT2A activity of psilocybin and psilocin, and provides some support for indirect effects on dopamine through 5-HT2A activity and possible activity at other serotonin receptors. In fact, the most consistent finding for involvement of other receptors in the actions of psychedelics is the 5-HT1A receptor.
  • 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.
  • 5-HT2A 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 5-HT1A receptors, which may contribute to antidepressant/anti-anxiety effects.
  • Depression and anxiety are two of the most common psychiatric disorders worldwide. Depression is a multifaceted condition characterized by episodes of mood disturbances alongside other symptoms such as anhedonia, psychomotor complaints, feelings of guilt, attentional deficits and suicidal tendencies, all of which can range in severity. Similarly, anxiety disorders are a collective of etiologically complex disorders characterized by intense psychosocial distress and other symptoms depending on the subtype. Anxiety associated with life-threatening disease is the only anxiety subtype that has been studied in terms of psychedelic-assisted therapy. Pharmacological and psychosocial interventions are commonly used to manage this type of anxiety, but their efficacy is mixed and limited such that they often fail to provide satisfactory emotional relief. Recent interest into the use of psychedelic-assisted therapy may represent a promising alternative for patients with depression and anxiety that are ineffectively managed by conventional methods.
  • 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.
  • 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 , Higgins et al., Front. Pharmacol., 2001 , DOI: 10.3389).
  • 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
  • Neuroplastogens neuroplasticity effects
  • 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.
  • indoline derivatives modulate the activity of serotonin receptor subtypes, in particular 5-HT2A, by direct binding to these receptors.
  • the present application 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, to a subject in need thereof, wherein:
  • R 1 and R 1 ' are independently selected from H, halo, OH, NH 2 , C 1 _ 6 alkyl, C 1 . 6 alkoxyl, NH(C1- 6alkyl) and N(C 1 - 6 alkyl) 2 ;
  • R 2 and R 2 ' are independently selected from H, halo, NH 2 , C 1-6 alkyl, Ci-ealkoxyl, NH(C1- 6alkyl) and N(C 1-6 alkyl) 2 ;
  • Q is selected from Q1 , Q2, Q3, Q4, Q5 and Q6: is a single bond or a double bond provided that when in Q1 is a double bond then R 9 and R 15 are not present, when in Q2 is a double bond then R 17 and R 25 are not present, and when in Q5 is a double bond then R 48 and R 57 are not present; one or both of R 4 and R 5 is independently selected from H, halo, C 1 _ 6 alkyl and C 1-6 alkoxy, or
  • R 4 and R 5 are linked together to form O-(CH 2 ) 1-2 O, or one of R 4 and R 5 is selected from X-L-A and the other of R 4 and R 5 is selected from H, halo, C 1-6 alkyl and C 1-6 alkoxy, X is selected from a direct bond, O, C(O), NR a , NR a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and NR a C(O)NR a ; L is selected from a direct bond, C 1-6 alkylene, C 2-6 alkenylene, C 1-6 alkyleneO, C 2- 6 alkenyleneO, C 1-6 alkyleneC(O), C 2-6 alkenyleneC(O), C 1-6 alkyleneNR b C(O), C 2- 6 alkenyleneNR b C(O), C 1-6 alkylene
  • 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. 10 [0025] The present application also includes a method of treating a mental illness comprising administering a therapeutically effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof to a subject in need thereof. [0026] The present application also includes a method of treating a CNS disease, 15 disorder or condition and/or a neurological disease comprising administering a therapeutically effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof to a subject in need thereof.
  • the present application includes one or more compounds of Formula I-A or 20 a pharmaceutically acceptable salt, solvate and/or prodrug thereof wherein: R 1 and R 1' are independently selected from H, halo, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxyl, NH(C 1- 6 alkyl) and N(C 1-6 alkyl) 2 ; 25 R 2 and R 2' are independently selected from H, halo, NH 2 , C 1-6 alkyl, C 1-6 alkoxyl, NH(C 1- 6 alkyl) and N(C 1-6 alkyl) 2 ; Q is selected from Q1, Q2, Q3, Q4, Q5 and 6: (Q1), (Q2), (Q3), (Q4) (Q5) and (Q6); a single bond or a double bond provided that when in Q1 is a double bond then R 9 and R 15 are not present, when in Q2 is a double bond then R 17 and R 25 are not present, and when in Q5
  • R 36 and R 37 are not both D, when R 39 is CD3.
  • 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.
  • 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 l-A and includes pharmaceutically acceptable salts, solvates and/or prodrugs thereof as well as all stereoisomers and regioisomers.
  • 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 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 means a compound, or a salt and/or prodrug of a compound, wherein molecules of a suitable solvent are incorporated in the 5 crystal lattice.
  • 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 10 atoms that are possible in the referenced alkyl group are indicated by the prefix “Cn1-n2”.
  • C1-6alkyl (or “C1-C6alkyl”) means an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.
  • alkenyl as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkenyl groups containing at 15 least one double bond. The number of carbon atoms that are possible in the referenced alkenyl group are indicated by the prefix “Cn1-n2”.
  • C2-6alkyl (or “C2-C6alkyl”) means an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms.
  • alkenylene as used herein, whether it is used alone or as part of another group, means a straight or branched chain, unsaturated alkylene group, that is, an 20 unsaturated carbon chain that contains substituents on two of its ends and at least one double bond.
  • the number of carbon atoms that are possible in the referenced alkenylene group are indicated by the prefix “Cn1-n2”.
  • C2-6alkenylene means an alkenylene group having 2, 3, 4, 5 or 6 carbon atoms.
  • alkoxy as used herein, alone or in combination, 25 includes an alkyl group connected to an oxygen-connecting atom.
  • cycloalkyl as used herein, whether it is used alone or as part of another group, means a saturated carbocyclic group containing from 3 to 6 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 “Cn1-n2”.
  • Cn1-n2 the numerical prefix “Cn1-n2”.
  • C3- 30 6 cycloalkyl means a cycloalkyl group having 3, 4, 5 or 6 carbon atoms.
  • heterocycloalkyl refers to cyclic grou s containing at least one non-aromatic ring c ontaining from 3 to 6 atoms in which one or more of the atoms are a heteromoiety selected from O, S, S(O), SO 2 , NH, NC 1-6 alkyl 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 5 which one or more, suitably 1 to 4, of the ring atoms is replaced with a heteromoeity as selected from O, S, S(O), SO 2 , NH, NC 1-6 alkyl and N and the remaining atoms are C.
  • aryl as used herein, whether it is used alone or as part of another group, refers to carbocyclic groups containing at least one aromatic ring and contains from 6 to 10 carbon atoms.
  • heteroaryl refers to cyclic groups containing at least one heteroaromatic ring containing 5-6 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 Cn1-n2 this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in 15 which one or more, suitably 1 to 4, of the ring atoms is replaced with a heteroatom as defined above.
  • halogen refers to a halogen atom and includes fluoro, chloro, bromo and iodo.
  • haloalkyl refers to an alkyl group as defined above 20 in which one or more of the available hydrogen atoms have been replaced with a halogen.
  • C1-6haloalkyl refers to a C 1 to C 6 linear or branched alkyl group as defined above with one or more halogen substituents.
  • deuteroalkyl refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been replaced with a 25 deuterium.
  • C1-6deuteroalkyl refers to a C 1 to C 6 linear or branched alkyl group as defined above with one or more deuterium substituents.
  • available as in “available hydrogen atoms” or “available atoms” refers to atoms that would be known to a person skilled in the art to be capable of replacement by a substituent.
  • the term “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.
  • the term “alternate isotope thereof’ as used herein refers to an isotope of an element that is other than the isotope that is most abundant in nature.
  • the 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 application is meant to include all suitable isotopic variations of the compounds of general Formula I and l-A and pharmaceutically acceptable salts, solvates and/or prodrugs thereof.
  • different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H).
  • Protium is the predominant hydrogen isotope found in nature.
  • the term “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 (l-A), or pharmaceutically acceptable salts, solvates and/or prodrugs 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.
  • the term "protecting group” or "PG” and the like as used herein refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule. The selection of a suitable protecting group can be made by a person skilled in the art.
  • subject 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.
  • Treatment as used herein also include prophylactic treatment.
  • a subject with early neurological disease 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 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 or “prophylaxis”, or synonym thereto, as used herein refers to a reduction in the risk or probability of a patient becoming afflicted with a disease, disorder or condition or manifesting a symptom associated with a disease, disorder or condition.
  • the "disease, disorder or condition” as used herein refers to a disease, disorder or condition treated or treatable by activation a serotonin receptor, for example 5- HT 2 A and particularly using a serotonin receptor agonist, such as one or more compounds of the application herein described.
  • the disease, disorder or condition may also be treated or treatable via alternative mechanisms, for example by modulation, deactivation, antagonism or reverse agonism of a serotonin receptor, including 5-HT 2 A and/or 5-HTIA.
  • 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 modulated, for example 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-HTIA and “5-HT 2A ” are used herein mean the 5-HTIA and 5- HT 2A receptor subtypes of the 5-HT serotonin receptor, respectively.
  • therapeutic agent refers to any drug or active agent that has a pharmacological effect when administered to a subject.
  • indoline derivatives are useful for treating diseases, disorders or conditions by modulating, for example activating, a serotonin receptor. Therefore, the indoline derivatives are useful as medicaments. Accordingly, the application also includes indoline derivates for use as a medicament.
  • the present application includes a method of treating a disease, 5 disorder or condition by activation of a serotonin receptor comprising administering a therapeutically effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, to a subject in need thereof, I 10 wherein: R 1 and R 1' are independently selected from H, halo, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxyl, NH(C 1- 6alkyl) and N(C1-6alkyl)2; R 2 and R 2' are independently selected from H, halo, NH2, C1-6alkyl, C1-6alkoxyl, NH(C1- 6alkyl) and N(C1-6alkyl)2; 15 Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6: (Q1), (Q2), (Q3), (Q4), (Q5) and (Q6); - is a single bond or a double bond provided that
  • R 4 and R 5 are linked together to form O-(CH 2 )I-2O, or one of R 4 and R 5 is selected from X-L-A and the other of R 4 and R 5 is selected from H, halo, Ci_ 6 alkyl and C 1-6 alkoxy;
  • X is selected from a direct bond, O, C(O), NR a , NR a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and NR a C(O)NR a ;
  • L is selected from a direct bond, C 1-6 alkylene, C 2 -6alkenylene, C 1-6 alkyleneO, C 2 . salkenyleneO, Ci-6alkyleneC(O), C 2 .6alkenyleneC(O), Ci-6alkyleneNR b C(O), C 2 .
  • R a is selected from H and Ci-salkyl
  • R b is selected from H, C 1-6 alkyl and A;
  • A is selected from H, Ci- 30 alkyl, C 2.3 oalkenyl, phenyl, C 3 -6cycloalkyl, 3- to 6-membered heterocycloalkyl comprising 1 to 4 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 and 5- to 6-membered heteroaryl comprising 1 to 4 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 , wherein the phenyl, C 3 - iocycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, Ci. 4 alkyl and OCi. 4 alkyl;
  • R 3 and R 6 are independently selected from H, halo, OH, Ci salkyl and Ci-ealkoxy;
  • R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently selected from H, halo and Ci- ea Iky I;
  • R 12 , R 20 , R 29 , R 39 and R 51 are independently selected from H, C 1-6 alkyl, C(O)C 1-6 alkyl and C(O)-A;
  • R 60 and R 61 are independently selected from H and Ci-salkyl ; or one of R 60 and R 61 is C(O)-A' and the other is selected from H and Ci_ 6 alkyl; wherein A' is selected from Y, O-Y and O-Ci- 4 alkylene-O-C(O)-Y; and
  • Y is selected from C -soalkyl and C -soalkenyl
  • R 60 and R 61 together with the N atom to which they are bound, form a 3- to 6-membered heterocyclic ring which optionally comprises one or two additional heteromoieties independently selected from O, S, S(O), SO 2 , N, and NR 65 and which is optionally substituted with one or more substituents independently selected from halo, OH, Ci. 4 alkyl and OCi. 4 alkyl;
  • R 64 and R 65 are independently selected from H and C 1-6 alkyl; and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof, provided when Q is Q6 then the compound of Formula I comprises D.
  • the present application also includes a use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof to the cell.
  • the application also includes a use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for activating 5-HT 2 A in a cell as well as a use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for the preparation of a medicament for activating 5-HT 2 A in a cell.
  • the application further includes one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for use in activating 5-HT 2A in a cell.
  • the serotonin receptor is 5-HTI A .
  • the present application includes a method for activating 5-HTIA receptors in a cell, either in a biological sample or in a patient, comprising administering an effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof to the cell.
  • the application also includes a use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for activating 5-HT i A receptors in a cell as well as a use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for the preparation of a medicament for activating 5-HTIA receptors in a cell.
  • the application further includes one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for use in activating 5-HTIA receptors 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof to a subject in need thereof.
  • the present application also includes a use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for the preparation of a medicament for treatment of a disease, disorder or condition by activation of 5-HT 2 A.
  • the application further includes one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for use in treating a disease, disorder or condition by activation of 5-HT 2 A.
  • the present application also includes a method of treating a disease, disorder or condition by activation of 5-HTIA comprising administering a therapeutically effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof to a subject in need thereof.
  • the present application also includes a use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for treatment of a disease, disorder or condition by activation of 5-HT i A as well as a use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for the preparation of a medicament for treatment of a disease, disorder or condition by activation of 5-HTIA.
  • the application further includes one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for use in treating a disease, disorder or condition by activation of 5-HTIA.
  • the disease, disorder or condition may also be treated or treatable via alternative mechanisms, for example by modulation, deactivation, antagonism or reverse agonism of a serotonin receptor, including 5-HT 2 A and/or 5-HTIA.
  • the compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof to a subject in need thereof.
  • the present application also includes a use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for treatment a mental illness, as well as a use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for the preparation of a medicament for treatment of a mental illness.
  • the application further includes one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 disorders; sexual dysfunction, sexual disorder,
  • 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof to a subject in need thereof.
  • the present application also includes a use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for treatment of psychosis or psychotic symptoms, as well as a use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for the preparation of a medicament for treatment of psychosis or psychotic symptoms.
  • the application further includes one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for use in treating psychosis or psychotic symptoms.
  • administering to said subject in need thereof a therapeutically effective amount of the compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof does not result in a worsening of psychosis or psychotic symptoms such as, but not limited to, hallucinations and delusions.
  • administering to said subject in need thereof a therapeutically effective amount of the compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof results in an improvement of psychosis or psychotic symptoms such as, but not limited to, hallucinations and delusions.
  • administering to said subject in need thereof a therapeutically effective amount of the compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof results in an improvement of psychosis or psychotic symptoms.
  • the compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof are useful for treating a central nervous system (CNS) disorder 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof to a subject in need thereof.
  • the present application also includes a use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof to a non-human subject in need thereof.
  • the present application also includes a use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for treatment a behavioral problem in a non-human subject, as well as a use of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof for the preparation of a medicament for treatment of a behavioral problem in a non-human subject.
  • the application further includes one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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.
  • the mental illness is selected from hallucinations and delusions and a combination thereof.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is a central nervous system (CNS) disorder.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is psychosis or psychotic symptoms.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is behavioral problems in a non-human subject.
  • 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 muscarinic agonists and 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 alpha? agonists or 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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,
  • 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, suitopride, tiapride, veralipride, ziprasidone and zotepine, and combinations thereof.
  • 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof are administered in combination with one or more additional treatments for a mental illness.
  • the additional treatments for a mental illness is selected typical antipsychotics and atypical antipsychotics.
  • effective amounts vary according to factors such as the disease state, age, sex and/or weight of the subject or species.
  • 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof are administered one, two, three or four times a year. In some embodiments, the compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof from about 0.01 pg/cc to about 1000 pg/cc, or about 0.1 pg/cc to about 100 pg/cc.
  • oral dosages of one or more compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof will range between about 10 pg per day to about 1000 mg per day for an adult, suitably about 10 pg per day to about 500 mg per day, more suitably about 10 pg 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 pg/kg to about 10 mg/kg, about 0.1 pg/kg to about 10 mg/kg, about 0.01 pg/kg to about 1 mg/kg or about 0.1 pg/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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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 Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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.
  • the compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof are used or administered in an effective amount which comprises administration of doses or dosage regimens that provide clinical effects similarto those exhibited by a human plasma psilocin Cmax of 4 ng/mL or less and/or human 5-HT 2 A human CNS receptor occupancy of 40% or less orthose exhibited by a human plasma psilocin Cmax of 1 ng/mL or less and/or human 5-HT 2 A human CNS receptor occupancy of 30% or less.
  • the compounds of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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.
  • a compound also includes embodiments wherein one or more compounds are referenced.
  • compounds of the application also includes embodiments wherein only one compound is referenced.
  • all available hydrogen atoms in a group are optionally replaced with deuterium.
  • Q is Q1 , K , and - is a single bond and the compound of Formula I has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are as defined for
  • R 1 , R 1 ', R 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 10 , R 11 , R 12 , R 13 and R 14 are as defined for Formula I, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • single bond and the compound of Formula I has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 1 , R 1 ', R 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 and R 25 are as defined for Formula I, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • double bond and the compound of Formula I has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 1 , R 1 ', R 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 are as defined for Formula I, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • the compound of Formula I has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 and R 35 are as defined for Formula I, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • Formula I has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 1 , R 1 ', R 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 and R 47 are as defined for Formula I, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • R 1 , R 1 ', R 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 and R 57 are as defined for Formula I, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • double bond and the compound of Formula I has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 1 , R 1 ', R 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 48 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 and R 56 are as defined for
  • the compound of Formula I has the following structure:
  • R 1 , R 1 ', R 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 58 , R 59 , R 60 , R 61 , R 62 and R 63 are as defined for Formula I, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof, provided the compound of Formula I comprises D.
  • R 1 , R 2 , R 2 , R 2 ”, R 3 , R 5 and R 6 are all H and the compound Formula I has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 4 and Q are as defined for Formula I, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • R 1 , R 1 , R 2 , R 2 , R 3 , R 4 and R 6 are all H and the compound Formula I has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 5 and Q are as defined for Formula I, and wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • R 1 , R 1 ', R 2 , R 2 ', R 3 and R 6 are all H and the compound Formula I has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 4 , R 5 and Q are as defined for Formula I, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • R 1 , R 1 ', R 2 and R 2 ' are all H and R 3 , R 4 , R 5 and R 6 are all D and the compound of Formula I has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein: Q is as defined for Formula I, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • R 48 R 49
  • R 50 R 52
  • R 54 R 55
  • R 63 a re independently selected from H, D, F, Cl, C 1-6 alkyl, C 1-6 fluoroalkyl and C 1-6 deuteroalkyl.
  • R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently selected from H, F, D, CH 3 , CD 2 H, CDH 2 , CD 3 , CF 3 , CHF 2 , CH 2 CH 3 , CH 2 CH 2 D, CH 2 CD 2 H and CD2CD3.
  • R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently selected from H and D.
  • R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 and R 57 are independently selected from H and D.
  • R 58 , R 59 , R 62 and R 63 are independently selected from H and D. In some embodiments, R 58 , R 59 , R 62 and R 63 are H. In some embodiments, R 58 , R 59 , R 62 and R 63 are D. In some embodiments, R 58 and R 59 are H and R 62 and R 63 are D. In some embodiments, R 58 and R 59 are D and R 62 and R 63 are H.
  • Q3 is (Q3) or is either R or S. Therefore in some embodiments, Q3 is (Q3) or is either R or S. Therefore in some embodiments, Q3 is (Q3) or is either R or S. Therefore in some embodiments, Q3 is (Q3) or is either R or S. Therefore in some embodiments, Q3 is (Q3) or is either R or S. Therefore in some embodiments, Q3 is (Q3) or is either R or S. Therefore in some embodiments, Q3 is (Q3) or is either R or S. Therefore in some embodiments, Q3 is (Q3) or is either R or S. Therefore in some embodiments, Q3 is (Q3) or is either R or S. Therefore in some embodiments, Q3 is (Q3) or is either R or S. Therefore in some embodiments, Q3 is (Q3) or is either R or S. Therefore in some embodiments, Q3 is (Q3) or is either R or S. Therefore in some embodiments, Q3 is (Q3) or is either R or S. Therefore in some embodiments, Q3 is (Q3) or
  • the stereochemistry at the carbon to which R 28 or R 38 is bonded is R. In some embodiments, the stereochemistry at the carbon to which R 28 or R 38 is bonded is S.
  • the stereochemistry at the carbon to which R 15 , R 25 or R 48 is bonded is R. In some embodiments, the stereochemistry at the carbon to which R 15 , R 25 or R 48 is bonded is S.
  • Q is selected from one of the following groups:
  • R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 are independently selected from H, D, C 1-6 alkyl, C 1 _ 6 fluoroalkyl, C 1-6 deuteroalkyl and C(O)-A’.
  • R 12 , R 20 , R 29 and R 39 are independently selected from H, Ci_ 4 alkyl, Ci. 4 fluoroalkyl, Ci. 4 deuteroalkyl and C(O)-A’.
  • R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 are independently selected from H, CH 3 , CD 3 , CD 2 H, CF 2 H and CF 3 .
  • R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 are independently selected from H, CH 3 and CD 3 . In some embodiments, R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 are independently selected from CH 3 and CD 3 .
  • Q is selected from one of the following groups: wherein R 29 is selected from H, D, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 deuteroalkyl and C(O)-A’. In some embodiments, R 29 is selected from H, Ci- 4 alkyl, Ci. 4 fluoroalkyl, Ci. 4 deuteroalkyl and C(O)-A’. In some embodiments, R 29 is selected from H, C 1-4 alkyl , C 1-4 fluoroalkyl and C 1 . 4 deuteroalkyl. In some embodiments, R 29 is selected from H, CH 3 , CD 3 , CD 2 H, CF 2 H and CF 3 . In some embodiments, R 29 is selected from H, CH 3 and CD 3 . In some embodiments, R 29 is selected from CH 3 and CD 3 .
  • R 60 and R 61 together with the N atom to which they are bound, form a 3- to 6-membered heterocyclic ring which optionally comprises one or two additional heteromoieties independently selected from O, N and NR 65 and which is optionally substituted with one or more substituents independently selected from halo, OH, Ci_ 4 alkyl and OCi. 4 alkyl.
  • R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 are independently selected from C(O)-A.
  • one of R 60 and R 61 is C(O)-A' and the other is selected from H and C 1_6 alkyl. In some embodiments, one of R 60 and R 61 is C(O)-A' and the other is selected from H and C 1 _ 4 alkyl .
  • A' is selected from Y, O-Y and O-Ci- 2 alkylene-O- C(O)-Y, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom. In some embodiments, A' is selected from Y, O-Y and O-Cialkylene-O-C(O)-Y, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • Y is Cio-25alkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom. In some embodiments, Y is Ci3-2ialkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • Y is Cio-25alkenyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom. In some embodiments, Y is Ci 3.2 ialkenyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom. In some embodiments, Y is Cio-25alkenyl and comprises 1 , 2, 3, 4, 5 or 6 double bonds.
  • the alkyl or alkene group of Y is an alkyl or alkenyl group present in a fatty acid, wherein all available H atoms are optionally replaced with deuterium.
  • Y is an alkenyl group present in a fatty acid, wherein all available H atoms are optionally replaced with deuterium.
  • the fatty acid is an omega-6 fatty acid (i.e. an unsaturated or polyunsaturated fatty acid wherein the double bond that is closest to the methyl end of the molecule is located at carbon numbered 6 starting from the end methyl group) or an omega-3 fatty acid (i.e.
  • Y is an alkyl group present in a fatty acid wherein all available H atoms are optionally replaced with deuterium.
  • the alkyl or alkene group of Y is an alkyl or alkene group present in a fatty acid selected from the list of fatty acids in Table 1 :
  • the alkene group of Y is an alkyl or alkenyl group present in linoleic acid, eicosadienoic acid or decosahexanoic acid.
  • Y is the alkyl or alkenyl group of a fatty acid wherein 1-10, 2-8, 2-6 or 2-4 H atoms are replaced with deuterium.
  • A' is Y.
  • A' is -O-Y.
  • A is -O-C 3 alkylene-O-C(O)-Y.
  • R 1 and R 1 ' are independently selected from H, OH, halo, NH 2 , Ci-4alkyl, Ci. 4 alkoxy, NH(Ci-4alkyl) and N(Ci-4alkyl).
  • R 1 and’R 1 ' are independently selected from H, D, Cl, F, OH, NH 2 , Ci. 4 alkyl, Ci. 4 alkoxy, Ci.
  • R 1 and’R 1 ' are independently selected from H, D, Cl, F, OH, NH2, Ci- 2 alkyl, C ⁇ alkoxy, C1- 2 fluoroalkyl and C ⁇ deuteroalkyl, NH(Ci. 2 alkyl), NH(Ci. 2 deuteroalkyl), NH(Ci. 2 flouroalkyl), N(Ci. 2 alkyl) 2 , N(Ci. 2 fluoroalkyl) 2 , N(Ci. 2 deuteroalkyl) 2 , N(Ci.2fluoroalkyl)(Ci. 2 alkyl), N(Ci.
  • R 1 is selected from H, D, F, NH 2 , CH 3 , CF 2 H, CD 2 H, CH 3 O, CF 3 , CD 3 , NH(CH 3 ), NH(CD 3 ), NH(CF 3 ), N(CH 3 ) 2 , N(CF 3 ) 2 and N(CD 3 ) 2 .
  • R 1 and’R 1 ' are independently selected from H, D, F, NH 2 , CH 3 , CF 2 H, CD 2 H, CH 3 O, CF 3 and CD 3 .
  • R 1 and R 1 ' are independently selected from H, D, F, OH, CH 3 , CF 2 H, CD 2 H, CH 3 O, CF 3 and CD 3 .
  • R 1 and R 1 ' are independently H, D or F.
  • R 1 and R 1 ' are all H or are all D.
  • R 1 and R 1 ' are both H.
  • R 2 and R 2 ' are independently selected from H, halo, NH 2 , Ci. 4 alkyl, Ci. 4 alkoxy, NH(Ci. 4 alkyl) and N(Ci. 4 alkyl).
  • R 2 and R 2 ' are independently selected from H, D, Cl, F, NH 2 , Ci- 4 alkyl, Ci. 4 alkoxy, Ci. 4 fluoroalkyl, Ci. 4 deuteroalkyl, NH(Ci. 4 alkyl), NH(Ci. 4 deuteroalkyl), NH(Ci. 4 flouroalkyl), N(Ci. 4 alkyl) 2 , N(Ci.
  • R 2 and R 2 ' are independently selected from H, D, Cl, F, Ci_ 2 alkyl, Ci. 2 alkoxy, Ci. 2 fluoroalkyl, Ci. 2 deuteroalkyl, NH(Ci. 2 alkyl), NH(Ci. 2 deuteroalkyl), NH(Ci.
  • N(Ci. 2 alkyl) 2 N(Ci. 2 fluoroalkyl) 2 , N(Ci. 2 deuteroalkyl) 2 , N(Ci. 2 fluoroalkyl)(Ci. 2 alkyl), N(Ci. 2 fluoroalkyl)(Ci. 2 deuteroalkyl) and N(Ci. 2 deuteroalkyl)(Ci. 2 alkyl).
  • R 2 and R 2 ' are independently selected from H, D, F, NH 2 , CH 3 , CF 2 H, CD 2 H, CH 3 O, CF 3 , CD 3 , NH(CH 3 ), NH(CD 3 ), NH(CF 3 ), N(CH 3 ) 2 , N(CF 3 ) 2 and N(CD 3 ) 2 .
  • R 1 is selected from H, D, F, NH 2 , CH 3 , CF 2 H, CD 2 H, CH 3 O, CF 3 and CD 3 .
  • R 2 and R 2 ' are independently selected from H, D, F, CH 3 , CF 2 H, CD 2 H, CH 3 O, CF 3 and CD 3 .
  • R 2 and R 2 ' are independently H, D or F.
  • R 2 and R 2 ' are all H or are all D.
  • R 2 and R 2 ' are all H.
  • R 1 , R 1 ', R 2 and’ R 2 ' are independently H, D or F. In some embodiments, R 1 , R 1 ', R 2 and R 2 ' are all H or are all D. In some embodiments, R 1 , R 1 ', R 2 and R 2 ' are all H.
  • R 3 and R 6 are independently selected from H, D, Cl, F, OH, Ci_ 4 alkyl, Ci. 4 alkoxy, Ci. 4 fluoroalkoxy, Ci. 4 deuteroalkoxy, Ci. 4 fluoroalkyl and Ci- 4 deuteroalkyl.
  • R 3 and R 6 are independently selected from H, D, Cl, F, OH, Ci_ 4 alkyl , Ci. 4 alkoxy, Ci. 4 fluoroalkyl and Ci. 4 deuteroalkyl.
  • R 3 and R 6 are independently selected from H, D, Cl, F, OH, Ci_ 2 alkyl, Ci. 2 alkoxy, Ci.
  • R 3 and R 6 are independently selected from H, D, Cl, F, OH, Ci- 2 alkyl, Ci- 2 alkoxy, Ci. 2 fluoroalkyl and Ci. 2 deuteroalkyl.
  • R 3 and R 6 are independently selected from H, D, F, OH, CH 3 , CH 3 O, CF 2 HO, CD 2 HO, CF 3 O, CD 3 O, CF 2 H, CD 2 H, CF 3 and CD 3 .
  • R 3 and R 6 are independently selected from H, D, F, OH, CH 3 , CH 3 O, CF 2 H, CD 2 H, CF 3 and CD 3 . In some embodiments, R 3 and R 6 are independently selected from H, D, F, OH, CH 3 , CH 3 O, CF 2 HO, CF 3 O and CD 3 O. In some embodiments, R 3 and R 6 are independently selected from H and D. In some embodiments, at least one of R 3 and R 6 is D. In some embodiments, each of R 3 and R 6 are D. In some embodiments, each of R 3 and R 6 are H.
  • R 4 and R 5 is independently selected from H, D, F, Cl, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1 _ 6 fluoroalkoxy and Ci-6deuteroalkoxy.
  • both of R 4 and R 5 are independently selected from H, D, F, Cl, Ci. 4 alkyl, Ci. 4 fluoroalkyl, Ci. 4 deuteroalkyl, Ci. 4 alkoxy, Ci. 4 fluoroalkoxy and Ci. 4 deuteroalkoxy.
  • R 4 and R 5 is independently selected from H, D, F, Cl, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CH 2 CF 2 H, CH 2 CF 3 , CH 2 CFH 2 , CH(CF 3 ) 2 , CD 3 , CH(CH 3 ) 2 O, CH 3 CH 2 CH 2 O, CH 3 CH 2 O, CH 3 O, CF 3 O, CHF 2 O, CF 2 HCH 2 O, CF 3 CH 2 O, (CF 3 ) 2 CHO, and CD 3 O.
  • R 4 and R 5 is independently selected from H, D, F, Cl, CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CD 3 , CH 3 O, CH(CH 3 ) 2 O, CF 3 O, CHF 2 O, and CD 3 O.
  • both of R 4 and R 5 are independently selected from H, D, F, Cl, Ci-salkyl, Ci-efluoroalkyl, Ci-edeuteroalkyl, Ci-ealkoxy, Ci-efluoroalkoxy and Ci- 6 deuteroalkoxy.
  • both of R 4 and R 5 are independently selected from D, F, Cl, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 fluoroalkoxy and Ci. edeuteroalkoxy.
  • both of R 4 and R 5 are independently selected from H, D, F, Cl, Ci_ 4 alkyl, Ci.
  • R 4 and R 5 are independently selected from H, D, F, Cl, CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CD 3 , CH(CH 3 ) 2 O, CH 3 O, CF 3 O, CHF 2 O, and CD 3 O.
  • both of R 4 and R 5 are independently selected from D, F, Cl, CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CD 3 , CH(CH 3 ) 2 O, CH 3 O, CF 3 O, CHF 2 O, and CD 3 O. In some embodiments both of R 4 and R 5 are independently selected from CH 3 O, CF 3 O, CHF 2 O, and CD 3 O. In some embodiments both of R 4 and R 5 are CD 3 O or both of R 4 and R 5 are CH 3 O.
  • R 4 is H or D and R 5 is selected from H, D, F, Cl, Ci- 6 alkyl, C 1 _ 6 fluoroalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 fluoroalkoxy and C 1-6 deuteroalkoxy.
  • R 4 is H or D and R 5 is selected from H, D, F, Cl, Ci_ 4 alkyl, Ci. 4 fluoroalkyl, Ci. 4 deuteroalkyl, Ci. 4 alkoxy, Ci. 4 fluoroalkoxy and Ci. 4 deuteroalkoxy.
  • R 4 is H or D and R 5 is selected from H, D, F, Cl, CH(CH 3 ) 2 , CH 3 , CF 3 , CF 2 H, CD 3 , CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O.
  • R 4 is H or D and R 5 is selected from D, F, Cl, CH(CH 3 ) 2 , CH 3 , CF 3 , CF 2 H, CD 3 , CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O.
  • R 4 is H or D and R 5 is selected from CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O. In some embodiments, R 4 is H and R 5 is selected from CH 3 O and CD 3 O.
  • R 5 is H or D and R 4 is selected from H, D, F, Cl, C1- salkyl, Ci-efluoroalkyl, Ci-edeuteroalkyl, Ci-ealkoxy, Ci-efluoroalkoxy and Ci-edeuteroalkoxy.
  • R 5 is H or D and R 4 is selected from H, D, F, Cl, Ci_ 4 alkyl, C1- 4 fluoroalkyl, Ci. 4 deuteroalkyl, Ci. 4 alkoxy, Ci. 4 fluoroalkoxy and Ci.
  • R 5 is H or D and R 4 is selected from D, F, Cl, CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CD 3 , CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O.
  • R 5 is H or D and R 4 is selected from CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O.
  • R 5 is H and R 4 is selected from CH 3 O and CD 3 O.
  • R 4 and R 5 are linked together to form O-CH 2 O.
  • R 3 , R 4 R 5 and R 6 are selected from D, F, Cl, CH 3 ,
  • R 3 , R 4 , R 5 and R 6 are all H or in some embodiments, R 3 , R 4 , R 5 and R 6 are all D. In some embodiments, R 3 , R 4 , R 5 and R 6 are selected from CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O.
  • two of R 3 , R 4 , R 5 and R 6 are selected from H or D and the remaining of R 3 , R 4 R 5 and R 6 are selected from CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O. In some embodiments, two of R 3 , R 4 R 5 and R 6 are selected from H or D and the remaining of R 3 , R 4 , R 5 and R 6 are selected from CH 3 O and CD 3 O.
  • one of R 3 , R 4 , R 5 and R 6 is selected from H or D and the remaining of R 3 , R 4 R 5 and R 6 are selected from CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O. In some embodiments, one of R 3 , R 4 , R 5 and R 6 is selected from H or D and the remaining of R 3 , R 4 , R 5 and R 6 are selected from CH 3 O and CD 3 O.
  • one of R 4 and R 5 is selected from X-L-A and the other of R 4 and R 5 is selected from H, halo, C 1-6 alkyl and C 1-6 alkoxy.
  • X is a direct bond and one of R 4 and R 5 is selected from L-A and the other of R 4 and R 5 is selected from H, halo, Ci_ 6 alkyl and C 1-6 alkoxy.
  • X is selected from O, C(O), NR a , NR a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and NR a C(O)NR a .
  • X is selected from O, C(O), OC(O), C(O)O and OC(O)O.
  • X is selected from O, OC(O) and C(O)O. In some embodiments, X is O. In some embodiments, X is selected from OC(O) and C(O)O. In some embodiments, X is selected from O, NR a , NR a C(O), C(O)NR a , NR a C(O)O, OC(O)NR a and NR a C(O)NR a . In some embodiments, X is selected from NR a C(O), C(O)NR a , NR a C(O)O, OC(O)NR a and NR a C(O)NR a .
  • X is selected from NR a C(O), and C(O)NR a . In some embodiments, X is selected from NR a C(O)O, OC(O)NR a and NR a C(O)NR a . In some embodiments, X is selected from O, OC(O), C(O)O, NR a C(O), and C(O)NR a .
  • L is selected from a direct bond, Ci- 4 alkylene, C 2 . 4 alkenylene, Ci. 4 alkyleneO, C 2.4 alkenyleneO, Ci. 4 alkyleneC(O), C 2.4 alkenyleneC(O) C1- 4 alkyleneNR b C(O), C 2.4 alkenyleneNR b C(O), Ci. 4 alkyleneC(O)NR b , C 2 . 4 alkenyleneC(O)NR b , Ci. 4 alkyleneOC(O), C 2.4 alkenyleneOC(O), Ci. 4 alkyleneC(O)O, C 2 . 4 alkenyleneC(O), Ci.
  • L is selected from a direct bond, Ci. 2 alkylene, C 2.4 alkenylene, Ci. 2 alkyleneO, C 2.4 alkenyleneO, Ci. 2 alkyleneC(O), C 2.4 alkenyleneC(O) Ci.
  • L is selected from a direct bond, C1- 2 alkylene, Ci. 2 alkyleneO, Ci. 2 alkyleneC(O), Ci. 2 alkyleneNR b C(O), Ci. 2 alkyleneC(O)NR b , Ci. 2 alkyleneOC(O), Ci. 2 alkyleneC(O)O, Ci.
  • L is selected from a direct bond, CH 2 , CF 2 , CD 2 , CH 2 -O, CF 2 -O, CD 2 -O, CH 2 -C(O), CF 2 -C(O), CD 2 -C(O), CH 2 -NR b C(O), CD 2 -NR b C(O), CH 2 -C(O)NR b , CF 2 -C(O)NR b , CD 2 -C(O)NR b , CH 2 -OC(O), CD 2 -OC(O), CF 2 -OC(O), CH 2 -C(O)O, CF 2 -C(O)O, CD 2 -C(O)O, CD 2 -C(O)NR b , CH 2 -OC(O), CD 2 -OC(O), CF 2 -OC(O), CH 2 -C(O)O, CF 2 -C(O)O, CD 2 -C(O)O, CD
  • X is a direct bond and L is a direct bond and one of R 4 and R 5 is selected from A and the other of R 4 and R 5 is selected from H, halo, Ci_ 4 alkyl and Ci. 4 alkoxy.
  • X is selected from O, OC(O), C(O)O, NR a C(O), and C(O)NR a and one of R 4 and R 5 is selected from O-Ci. 2 alkylene-A, O-Ci. 2 alkyleneO-A, O- Ci. 2 alkyleneC(O)-A, O-Ci. 2 alkyleneNR b C(O)-A, O-Ci. 2 alkyleneC(O)NR b -A, O-C1. 2 alkyleneOC(O)-A, O-Ci. 2 alkyleneC(O)O-A, O-Ci. 2 alkyleneOC(O)NR b -A, O-C1-
  • 2 alkyleneNR b C(O)NR b -A and the other of R 4 and R 5 is selected from H, halo, Ci. 4 alkyl and Ci. 4 alkoxy wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • X is selected from O, OC(O), C(O)O, NR a C(O), and C(O)NR a and one of R 4 and R 5 is selected from O-Ci. 2 alkylene-A, O-Ci. 2 alkyleneO-A, O-Ci. 2 alkyleneC(O)-A, 0-0. 2 alkyleneNR b C(O)-A, O-Ci.
  • R 4 and R 5 is selected from H, F, Cl, Ci. 4 alkyl, Ci. 4 haloalkyl, Ci. 4 deuteroalkyl and Ci. 4 alkoxy wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • the other of R 4 and R 5 is selected from D, F, Cl, CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CD 3 , CH(CH 3 ) 2 O, CH 3 O, CF 3 O, CHF 2 O, and CD 3 O wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom, and the other of R 4 and R 5 is H or D.
  • R 4 is X-L-A and R 5 is selected from H, halo, Ci .ealky I and C 1-6 alkoxy. In some embodiments, of R 5 is X-L-A and R 4 is selected from H, halo, Ci. 6 alkyl and C 1-6 alkoxy.
  • R a is selected from H and Ci_ 4 alkyl.
  • R b is selected from H, Ci. 4 alkyl and A.
  • A is H, and one of R 4 and R 5 is selected OH, C(O)H, NHR a , NHR a C(O), C(O)NHR a , OC(O)H, C(O)OH, OC(O)OH, NR a C(O)OH, OC(O)NHR a , NHR a C(O)NR a , X-Ci. 4 alkylene, X-C 2.4 alkenylene, X-Ci. 4 alkyleneOH, X-C 2.4 alkenyleneOH, X-Ci.
  • A is H, and one of R 4 and R 5 is selected OH, C(O)H, NHR a , NHR a C(O), C(O)NHR a , OC(O)H, C(O)OH, OC(O)OH, NR a C(O)OH, OC(O)NHR a , NHR a C(O)NR a , X-Ci. 2 alkylene, X-C 2.4 alkenylene, X-Ci. 2 alkyleneOH, X-C 2 .
  • R 4 and R 5 is selected from H, halo, Ci. 4 alkyl and Ci. 4 alkoxy, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • A is H and X is a direct bond. Therefore, in some embodiments, and one of R 4 and R 5 is selected from Ci_ 4 alkyl, C 2.4 alkenyl, Ci. 4 alkyleneOH, C 2.6 alkenyleneOH, Ci. 4 alkyleneC(O)H, C 2.4 alkenyleneC(O)H, Ci. 4 alkyleneNR b C(O)H, C 2 . 4 alkenyleneNR b C(O)H, Ci. 4 alkyleneC(O)NHR b , C 2.4 alkenyleneC(O)NHR b , Ci. 4 alkyleneOC(O)H, C 2.4 alkenyleneOC(O)H, Ci.
  • A is H and X is selected from O, C(O), NR a , NR a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and NR a C(O)NR a .
  • A is H and X is selected from O, C(O), OC(O), C(O)O and OC(O)O.
  • A is H and X is selected from O, OC(O) and C(O)O.
  • A is H and X is O.
  • A is H and X is selected from OC(O) and C(O)O. In some embodiments, A is H and X is selected from NR a , NR a C(O), C(O)NR a , NR a C(O)O, OC(O)NR a and NR a C(O)NR a . In some embodiments, A is H and X is selected from NR a C(O), C(O)NR a , NR a C(O)O, OC(O)NR a and NR a C(O)NR a . In some embodiments, A is H and X is selected from NR a C(O), and C(O)NR a . In some embodiments, A is H and X is selected from NR a C(O), OC(O)NR a and NR a C(O)NR a .
  • A is H
  • L is a direct bond
  • one of R 3 and R 4 is selected from X-H. Therefore, in some embodiments, and one of R 3 and R 4 is selected from OH, C(O)H, NHR a , NHR a C(O), C(O)NHR a , OC(O)H, C(O)OH, OC(O)OH, NR a C(O)OH, OC(O)NHR a and NHR a C(O)NR a , wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • R b is selected from H and Ci_ 4 alkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • one of R 4 and R 5 is selected from A, O-A, C(O)-A, C(O)-A, C(O)O-A, Ci. 4 alkylene-A, Ci. 4 alkylene-C(O)-A, Ci. 4 alkylene-C(O)O-A, 0-0. 4 alkylene-A, O-Ci. 4 alkylene-C(O)-A, and O-Ci. 4 alkylene-C(O)O-A and the other of R 4 and R 5 is selected from H, halo, C 1-6 alkyl and C 1-6 alkoxy, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • one of R 4 and R 5 is selected from A, O-A, C(O)-A, C(O)-A, and C(O)O-A and the other of R 4 and R 5 is selected from H, halo, C 1-6 alkyl and Ci. ealkoxy, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • one of R 4 and R 5 is A.
  • one of R 4 and R 5 is O-A.
  • one of R 4 and R 5 is C(O)-A.
  • one of R 4 and R 5 is C(O)O-A.
  • one of R 4 and R 5 is selected from Ci. 4 alkylene-A, Ci. 4 alkylene-C(O)-A, Ci. 4 alkylene-C(O)O-A, O-Ci. 4 alkylene-A, O-Ci. 4 alkylene-C(O)-A, and O- Ci. 4 alkylene-C(O)O-A and the other of R 4 and R 5 is selected from H, halo, Ci-salkyl and Ci- 6 alkoxy, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • one of R 4 and R 5 is Ci. 4 alkylene-A.
  • one of R 4 and R 5 is Ci. 4 alkylene-C(O)-A. In some embodiments, one of R 4 and R 5 is Ci. 4 alkylene-C(O)O-A. In some embodiments, one of R 4 and R 5 is O-Ci. 4 alkylene-A. In some embodiments, one of R 4 and R 5 is O-Ci. 4 alkylene- C(O)-A. In some embodiments, one of R 4 and R 5 is O-Ci. 4 alkylene-C(O)O-A.
  • one of R 4 and R 5 is selected from A, O-A, C(O)-A, C(O)O-A, Ci. 4 alkylene-A, Ci. 4 alkylene-C(O)-A, Ci. 4 alkylene-C(O)O-A, O-Ci. 4 alkylene-A, O- Ci. 4 alkylene-C(O)-A, and O-Ci. 4 alkylene-C(O)O-A and the other of R 4 and R 5 is selected from H, F, Cl, Ci. 4 alkyl and Ci. 4 alkoxy, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • one of R 4 and R 5 is selected from A, O-A, C(O)-A, C(O)O-A, Ci. 4 alkylene-A, Ci. 4 alkylene- C(O)-A, Ci. 4 alkylene-C(O)O-A, O-Ci. 4 alkylene-A, O-Ci. 4 alkylene-C(O)-A, and O-Ci. 4 alkylene-C(O)O-A and the other of R 4 and R 5 is selected from H, F, Cl, Ci- 4 alkyl, Ci- 4 haloalkyl, Ci. 4 deuteroalkyl and Ci.
  • R 4 and R 5 is selected from A, O-A, C(O)-A, C(O)O-A, , Ci. 2 alkylene- A, Ci. 2 alkylene-C(O)-A, Ci. 2 alkylene-C(O)O-A, O-Ci. 2 alkylene-A, O-Ci. 2 alkylene-C(O)-A, and O-Ci.
  • R 4 and R 5 is selected from D, F, Cl, CH3, CH(CH 3 ) 2 , CF 3 , CF 2 H, CD 3 , CH(CH 3 ) 2 O, CH 3 O, CF 3 O, CHF 2 O, and CD 3 O wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • one of R 4 and R 5 is selected from A, O-A, C(O)- A, C(O)O-A, Ci. 2 alkylene-A, Ci. 2 alkylene-C(O)-A, Ci. 2 alkylene-C(O)O-A, O-Ci.
  • R 4 and R 5 is H or D, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • one of R 4 and R 5 is selected from A, O-A, C(O)-A, C(O)O-A, CH 2 -A, CD 2 -A, CF 2 -A, CH 2 -C(O)-A, CF 2 -C(O)-A, CD 2 -C(O)-A, CH 2 -C(O)O-A, CD 2 -C(O)O-A, CF 2 -C(O)O-A, O-CH 2 A, O-CF 2 A, O-CD 2 A, -CH 2 -C(O)-A, O- CD 2 -C(O)-A, O-CF 2 -C(O)-A, O- CH 2 -C(O)O-A, O-CF 2 -C(O)O-A, O-CD 2 -C(O)O-A, and the other of R 4 and R 5 is H or D.
  • R 4 is selected from A, O-A, C(O)-A, C(O)O-A, Ci- 2 alkylene-A, Ci. 2 alkylene-C(O)-A, Ci. 2 alkylene-C(O)O-A, O-Ci. 2 alkylene-A, O-Ci. 2 alkylene- C(O)-A, and O-Ci. 2 alkylene-C(O)O-A and R 5 is H or D, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • R 4 is selected from A, O-A, C(O)-A, C(O)O-A, CH 2 -A, CD 2 -A, CF 2 - A, CH 2 -C(O)-A, CF 2 -C(O)-A, CD 2 -C(O)-A, CH 2 -C(O)O-A, CD 2 -C(O)O-A, CF 2 -C(O)O-A, O- CH 2 A, O-CF 2 A, O-CD 2 A, O-CH 2 -C(O)-A, O-CD 2 -C(O)-A, O-CF 2 -C(O)-A, O- CH 2 -C(O)O-A, O-CF 2 -C(O)O-A, and O- CD 2 -C(O)O-A and R 5 is H or D.
  • R 5 is selected from A, O-A, C(O)-A, C(O)O-A, Ci. 2 alkylene-A, Ci. 2 alkylene-C(O)-A, Ci. 2 alkylene- C(O)O-A, O-Ci. 2 alkylene-A, O-Ci. 2 alkylene-C(O)-A, and O-Ci. 2 alkylene-C(O)O-A and R 4 is H or D, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • R 5 is selected from A, O-A, C(O)-A, C(O)O-A, CH 2 -A, CD 2 -A, CF 2 -A, CH 2 -C(O)-A, CF 2 -C(O)-A, CD 2 -C(O)-A, CH 2 - C(O)O-A, CD 2 -C(O)O-A, CF 2 -C(O)O-A, O-CH 2 A, O-CF 2 A, O-CD 2 A, O-CH 2 -C(O)-A, O-CD 2 - C(O)-A, O-CF 2 -C(O)-A, O- CH 2 -C(O)O-A, O- CF 2 -C(O)O-A, and O- CD 2 -C(O)O-A and R 4 is H or D.
  • A is selected from Ci. 30 alkyl, C 2.30 alkenyl, phenyl, C 3 - 6 cycloalkyl, 3- to 6-membered heterocycloalkyl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 and 5- to 6-membered heteroaryl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 , wherein the phenyl, C 3 -iocycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6- membered heteroaryl are optionally substituted with one or two substituents independently selected from F, Cl, OH, Ci.
  • Ci. 4 deuteroalkyl Ci. 4 fluoroalkyl, OCi. 4 alkyl, OCi. 4 deuteroalkyl and OCi. 4 fluoroalkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • A is selected from Ci.
  • A is selected from phenyl, C 3.6 cycloalkyl, 3- to 6- membered heterocycloalkyl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 and 5- to 6-membered heteroaryl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 , wherein the phenyl, C 3 -iocycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are optionally replaced with one or two substituents independently selected from F, Cl, Ci_ 4 alkyl, Ci. 4 deuteroalkyl, Ci.
  • A is selected from phenyl, C 3 .6cycloalkyl, 5- to 6- membered heterocycloalkyl comprising 1 to 2 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 48 and 5- to 6-membered heteroaryl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 , wherein the phenyl, C 3 -iocycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from F, Cl, Ci. 4 alkyl, Ci. 4 deuteroalkyl, Ci. 4 fluoroalkyl, OCi. 4 alkyl, OCi. 4 deutero
  • the C 3.6 cycloalkyl in A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • the C 3 .6cycloalkyl in A is cyclopropyl which is optionally substituted with one ortwo substituents independently selected from F, Cl, Ci_ 4 alkyl, Ci. 4 deuteroalkyl, Ci. 4 fluoroalkyl, OCi. 4 alkyl, OCi. 4 deuteroalkyl and OCi. 4 fluoroalkyl.
  • the 3- to 6-membered heterocycloalkyl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 in A 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
  • the 3- to 6-membered heterocycloalkyl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 in A is selected from tetra hydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, , piperidinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl oxide, tetrahydrothiopyranyl dioxide, dihydropyranyl, piperidinyl, piperazinyl, morph
  • the 5- to 6-membered heteroaryl in A is selected from furyl, imidazolyl, isothiazolyl, thiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyrrolyl, thienofuryl, triazolyl and thienyl, each of which is optionally substituted with one or two substituents independently selected from F, C, Ci_ 4 alkyl, Ci. 4 deuteroalkyl, Ci. 4 fluoroalkyl, OCi. 4 alkyl, OCi. 4 deuteroalkyl and OCi. 4 fluoroalkyl.
  • the 5- to 6- membered heteroaryl in A is selected from furyl, isothiazolyl, thiazolyl, pyridyl and pyrrolyl, each of which is optionally substituted with one or two substituents independently selected from F, C, Ci_ 4 alkyl , Ci. 4 deuteroalkyl, Ci. 4 fluoroalkyl, OCi. 4 alkyl, OCi. 4 deuteroalkyl and OCi. 4 fluoroalkyl.
  • the phenyl, C 3 -iocycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl in A is optionally substituted with one or two substituents independently selected from F, Cl, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CH 2 CF 2 H, CH 2 CF 3 , CH 2 CFH 2 , CH(CF 3 ) 2 , CD 3 , CH(CH 3 ) 2 O, CH 3 CH 2 CH 2 O, CH 3 CH 2 O, CH 3 O, CF 3 O, CHF 2 O, CF 2 HCH 2 O, CF 3 CH 2 O, (CF 3 ) 2 CHO, and CD 3 O.
  • A is selected from Ci- 30 alkyl and C 2 -3oalkenyl wherein all available hydrogen atoms are optionally and independently replaced with a fluoride
  • A is Cio-25alkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom. In some embodiments, A is Ci 3.2 ialkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • A is Cio-25alkenyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom. In some embodiments, A is Ci 3.2 ialkenyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom. In some embodiments, A is Cio-25alkenyl and comprises 1 , 2, 3, 4, 5 or 6 double bonds.
  • the alkyl or alkene group of A is an alkyl or alkenyl group present in a fatty acid, wherein all available H atoms are optionally replaced with deuterium.
  • A is an alkenyl group present in a fatty acid, wherein all available H atoms are optionally replaced with deuterium.
  • the fatty acid is an omega-6 fatty acid (i.e. an unsaturated or polyunsaturated fatty acid wherein the double bond that is closest to the methyl end of the molecule is located at carbon numbered 6 starting from the end methyl group) or an omega-3 fatty acid (i.e.
  • A is an alkyl group present in a fatty acid wherein all available H atoms are optionally replaced with deuterium.
  • the alkyl or alkene group of A is an alkyl or alkene group present in a fatty acid selected from the list of fatty acids in Table 1 wherein all available H atoms are optionally replaced with deuterium.
  • the alkene group of A is an alkyl or alkenyl group present in linoleic acid, eicosadienoic acid or decosahexanoic acid acid.
  • A is the alkyl or alkenyl group of a fatty acid wherein 1-10, 2-8, 2-6 or 2-4 H atoms are replaced with deuterium.
  • R 64 and R 65 are independently selected from H, D, Ci_ 4 alkyl, Ci. 4 fluoroalkyl and Ci. 4 deuteroalkyl. In some embodiments, R 64 and R 65 are independently selected from H, D, CH3, CF3 and CD3. In some embodiments, R 64 and R 65 are independently selected from CH 3 and CD 3 .
  • the compound of Formula I is defined as follows: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • Q is selected from Q1 , Q2, Q3, Q4, Q5 and Q6:
  • - is a single bond or a double bond provided that when - in Q1 is a double bond then R 9 and R 15 are not present, when in Q2 is a double bond then R 17 and R 25 are not present and when in Q5 is a double bond then R 48 and R 57 are not present;
  • R 1 , R 1 ', R 2 , R 2 ', R 3 and R 6 are independently selected from H, D and F; one or both of R 4 and R 5 is selected from H, Ci. 4 alkoxy, Ci. 4 fluoralkoxy and Ci. 4 deuteroalkoxy, or
  • R 4 and R 5 are linked together to form O-(CH2)I-2O;
  • R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently selected from H and D;
  • R 12 , R 20 , R 29 , R 39 and R 51 are independently selected from H, Ci_ 4 alkyl, Ci. 4 fluoroalkyl and
  • R 60 and R 61 are independently selected from H and C 1-6 alkyl, provided when Q is Q6 then the compound of Formula I comprises D.
  • the compound of Formula I is defined as follows: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 1 and R 1 ' are independently selected from H, halo, OH, NH 2 , Ci_ 6 alkyl, C 1-6 alkoxyl, NH(Ci. 6 alkyl) and N(C 1 _ 6 alkyl) 2 ;
  • R 2 and R 2 ' are independently selected from H, halo, NH 2 , Ci-salkyl, Ci-ealkoxyl, NH(Ci. 6 alkyl) and N(C 1-6 alkyl) 2 ;
  • Q is selected from Q1 , Q2, Q3, Q4, Q5 and Q6: - is a single bond or a double bond provided that when - in Q1 is a double bond then R 9 and R 15 are not present, when in Q2 is a double bond then R 17 and R 25 are not present, and when in Q5 is a double bond then R 48 and R 57 are not present; one or both of R 4 and R 5 is independently selected from H, halo, Ci_ 6 alkyl and C 1-6 alkoxy, or
  • R 4 and R 5 are linked together to form O-(CH 2 )I-2O, or one of R 4 and R 5 is selected from X-L-A and the other of R 4 and R 5 is selected from H, halo, Ci_ 6 alkyl and C 1-6 alkoxy,
  • X is selected from a direct bond, O, C(O), NR a , NR a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and NR a C(O)NR a ;
  • L is selected from a direct bond, C 1-6 alkylene, C 2 -6alkenylene, C 1-6 alkyleneO, C 2 . salkenyleneO, Ci-6alkyleneC(O), C 2 .6alkenyleneC(O) Ci-6alkyleneNR b C(O), C 2 . 6 alkenyleneNR b C(O), C 1-6 alkyleneC(O)NR b , C 2.6 alkenyleneC(O)NR b , C 1-6 alkyleneOC(O), C 2.6 alkenyleneOC(O), C 1-6 alkyleneC(O)O, C 2.6 alkenyleneC(O), C 1-6 alkyleneOC(O)NR b , C 2 .
  • R a is selected from H and Ci-salkyl
  • R b is selected from H, Ci_ 6 alkyl and A;
  • A is selected from H, Ci- 30 alkyl, C 2.3 oalkenyl, phenyl, C 3 -6cycloalkyl, 3- to 6-membered heterocycloalkyl comprising 1 to 4 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 and 5- to 6-membered heteroaryl comprising 1 to 4 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 , wherein the phenyl, C 3 - iocycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, Ci. 4 alkyl and OCi. 4 alkyl;
  • R 3 and R 6 are independently selected from H, halo, OH, Ci salkyl and Ci-ealkoxy;
  • R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently selected from H, halo and Ci- ea Iky I;
  • R 12 , R 20 , R 29 , R 39 and R 51 are independently selected from H, C 1-6 alkyl, C(O)C 1 _ 6 alkyl and C(O)-A;
  • R 60 and R 61 are independently selected from H and Ci-salkyl ; or one of R 60 and R 61 is C(O)-A' and the other is selected from H and Ci_ 6 alkyl; wherein A' is selected from Y, O-Y and O-Ci- 4 alkylene-O-C(O)-Y; and
  • Y is selected from C -soalkyl and C -soalkenyl
  • R 60 and R 61 together with the N atom to which they are bound, form a 3- to 6-membered heterocyclic ring which optionally comprises one or two additional heteromoieties independently selected from O, S, S(O), SO 2 , N, and NR 65 and which is optionally substituted with one or more substituents independently selected from halo, OH, Ci. 4 alkyl and OCi. 4 alkyl;
  • R 64 and R 65 are independently selected from H and C 1-6 alkyl; and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof, provided one of R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 is C(O)-A'; or one of R 4 and R 5 is selected from X-L-A and the other of R 4 and R 5 is selected from H, halo, Ci_ 6 alkyl and C 1-6 alkoxy provided A is not H, Ci_ 6 alkyl or C 1-6 alkeynyl when X and L are both direct bonds
  • the compounds of Formula I are selected from the compounds listed below, or a pharmaceutically acceptable salt, solvate and/or prodrug thereof: oz ZL
  • the compounds of Formula I are novel and therefore the present application includes these compounds and compositions comprising these compounds and uses thereof. Therefore, in some embodiments, the compounds of Formula I are compounds of Formula l-A. Accordingly, the present application includes compounds of Formula l-A: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 5 and Q are as defined above for Formula I, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof, provided when Q is Q6 then the compound of Formula l-A comprises D, when Q is Q3 or Q4, then R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 6 , R 26 , R 27 , R 28 , R 30 to R 35 , R 36 , R 37 , R 38 and R 40 to R 47 are not all H, when R 5 is H or OCH 3 , and R 29 or R 39 is CH 3 ; and when Q is Q4 and R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 6 , R 38 and R 40 to R 47 are all H, then
  • all available hydrogen atoms are optionally and independently replaced with a fluorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • Q is Q1 , R , and - is a single bond and the compound of Formula l-A has the following structure:
  • R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are as defined for Formula l-A, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • double bond and the compound of Formula l-A has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 8 , R 10 , R 11 , R 12 , R 13 and R 14 are as defined for Formula l-A, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • the halogen atom when all available hydrogen atoms in a group are optionally replaced with a halogen atom, the halogen atom is F, Cl 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 are replaced with a halogen atom, the halogen atom is F or Cl. 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 in a group are optionally replaced with deuterium.
  • Q is Q2
  • bond and the compound of Formula l-A has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 and R 25 are as defined for Formula l-A, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • double bond and the compound of Formula l-A has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 16 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 are as defined for Formula l-A, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • Q is Q3, , and the compound of Formula l-A has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 and R 35 are as defined for Formula l-A, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof, provided R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 6 , R 26 , R 27 , R 28 , R 30 to R 35 , R 36 , R 37 , R 38 and R 40 to R 47 are not all H, when R 5 is H or OCH 3 , and R 29 is CH 3 .
  • Formula l-A has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 and R 47 are as defined for Formula l-A, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof, provided R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 6 , R 36 , R 37 , R 38 and R 40 to R 47 are not all H, when R 5 is H or OCH 3 , and R 39 is CH 3 , and when R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 6 , R 38 and R 40 to R 47 are all H, then R 36 and R 37 are
  • R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 and R 57 are as defined for Formula l-A, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • double bond and the compound of Formula l-A has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 and R 56 are as defined for Formula l-A, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • Q is Q6, R 63 R 62 (Q6), and the compound of
  • Formula l-A has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 58 , R 59 , R 60 , R 61 , R 62 and R 63 are as defined for Formula I- A, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof, provided the compound of Formula l-A comprises D.
  • R 1 , R 2 , R 2 , R 2 ”, R 3 , R 5 and R 6 are all H and the compound Formula l-A has the following structure: l-A or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 4 and Q are as defined for Formula l-A, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof, provided when Q is Q6 then the compound of Formula l-A comprises D, when Q is Q3 or Q4, then R 4 , R 26 , R 27 , R 28 , R 30 to R 35 , R 36 , R 37 , R 38 and R 40 to R 47 are not all H, when R 5 is H or OCH 3 , and R 29 or R 39 is CH 3 , and when Q is Q4 and R 4 , R 38 and R 40 to R 47 are all H, then R 36 and R 37 are not both D, when R 39 is CD 3 .
  • R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 and R 6 are all H and the compound Formula l-A has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 5 and Q are as defined for Formula l-A, and wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof, provided when Q is Q6 then the compound of Formula l-A comprises D, when Q is Q3 or Q4, R 26 , then R 27 , R 28 , R 30 to R 35 , R 36 , R 37 , R 38 and R 40 to R 47 are not all H, when R 5 is H or OCH 3 , and R 29 or R 39 is CH 3 , and when Q is Q4 and R 38 and R 40 to R 47 are all H, then R 36 and R 37 are not both D, when R 39 is CD 3 .
  • R 1 , R 1 ', R 2 , R 2 ', R 3 and R 6 are all H and the compound Formula l-A has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 4 , R 5 and Q are as defined for Formula I, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof, provided when Q is Q6 then the compound of Formula l-A comprises D, when Q is Q3 or Q4 then R 4 , R 26 , R 27 , R 28 , R 30 to R 35 , R 36 , R 37 , R 38 and R 40 to R 47 are not all H, when R 5 is H or OCH 3 , and R 29 or R 39 is CH 3 , and when Q is Q4 and R 4 , R 38 and R 40 to R 47 are all H, then R 36 and R 37 are not both D, when R 39 is CD 3 .
  • R 1 , R 1 ', R 2 and R 2 ' are all H and R 3 , R 4 , R 5 and R 6 are all D and the compound of Formula l-A has the following structure: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • Q is as defined for Formula I, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof.
  • R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently selected from H, D, F, Cl, C 1-6 alkyl, C 1-6 fluoroalkyl and C 1-6 deuteroalkyl.
  • R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently selected from H, F, D, CH 3 , CD 2 H, CDH 2 , CD 3 , CF 3 , CHF 2 , CH 2 CH 3 , CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 .
  • R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently selected from H and D.
  • R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 52 , R 53 , R 54 , R 55 , R 56 and R 57 are independently selected from H and D.
  • R 58 , R 59 , R 62 and R 63 are independently selected from H and D. In some embodiments, R 58 , R 59 , R 62 and R 63 are H. In some embodiments, R 58 , R 59 , R 62 and R 63 are D. In some embodiments, R 58 and R 59 are H and R 62 and R 63 are D. In some embodiments, R 58 and R 59 are D and R 62 and R 63 are H.
  • Q3 is either R or S. Therefore in some embodiments, Q3 is
  • the stereochemistry at the carbon to which R 28 or R 38 is bonded is R. In some embodiments, the stereochemistry at the carbon to which R 28 or R 38 is bonded is S.
  • the stereochemistry at the carbon to which R 15 , R 25 or R 48 is bonded is either R or S. Therefore in some embodiments, Q1 is [00227] In some embodiments, the stereochemistry at the carbon to which R 15 , R 25 or R 48 is bonded is R. In some embodiments, the stereochemistry at the carbon to which R 15 , R 25 or R 48 is bonded is S.
  • Q is selected from one of the following groups:
  • R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 are independently selected from H, D, C 1-6 alkyl, C 1 _ 6 fluoroalkyl, C 1-6 deuteroalkyl and C(O)-A’.
  • R 12 , R 20 , R 29 and R 39 are independently selected from H, Ci_ 4 alkyl , Ci. 4 fluoroalkyl, Ci. 4 deuteroalkyl and C(O)-A’.
  • R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 are independently selected from H, CH 3 , CD 3 , CD 2 H, CF 2 H and CF 3 .
  • R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 are independently selected from H, CH 3 and CD 3 . In some embodiments, R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 are independently selected from CH 3 and CD 3 .
  • Q is selected from one of the following groups: wherein R 29 is selected from H, D, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 deuteroalkyl and C(O)-A’. In some embodiments, R 29 is selected from H, Ci_ 4 alkyl, Ci. 4 fluoroalkyl, Ci. 4 deuteroalkyl and C(O)-A’. In some embodiments, R 29 is selected from H, Ci- 4 alkyl , Ci. 4 fluoroalkyl and Ci. 4 deuteroalkyl. In some embodiments, R 29 is selected from H, CH 3 , CD 3 , CD 2 H, CF 2 H and CF 3 . In some embodiments, R 29 is selected from H, CH 3 and CD 3 . In some embodiments, R 29 is selected from CH 3 and CD 3 .
  • R 60 and R 61 together with the N atom to which they are bound, form a 3- to 6-membered heterocyclic ring which optionally comprises one or two additional heteromoieties independently selected from O, N and NR 65 and which is optionally substituted with one or more substituents independently selected from halo, OH, Ci-4alkyl and OCi-4alkyl.
  • R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 are independently selected from C(O)-A’.
  • one of R 60 and R 61 is C(O)-A' and the other is selected from H and Ci_ 6 alkyl. In some embodiments, one of R 60 and R 61 is C(O)-A' and the other is selected from H and Ci. 4 alkyl.
  • A' is selected from Y, O-Y and O-Ci- 2 alkylene-O- C(O)-Y, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom. In some embodiments, A' is selected from Y, O-Y and O-Cialkylene-O-C(O)-Y, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • Y is Cio-25alkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom. In some embodiments, Y is Ci 3-2 ialkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • Y is Cio- 2 5alkenyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom. In some embodiments, Y is Ci 3.2 ialkenyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom. In some embodiments, Y is Cio. 25 alkenyl and comprises 1 , 2, 3, 4, 5 or 6 double bonds.
  • the alkyl or alkene group of Y is an alkyl or alkenyl group present in a fatty acid, wherein all available H atoms are optionally replaced with deuterium.
  • Y is an alkenyl group present in a fatty acid, wherein all available H atoms are optionally replaced with deuterium.
  • the fatty acid is an omega-6 fatty acid (i.e. an unsaturated or polyunsaturated fatty acid wherein the double bond that is closest to the methyl end of the molecule is located at carbon numbered 6 starting from the end methyl group) or an omega-3 fatty acid (i.e.
  • Y is an alkyl group present in a fatty acid wherein all available H atoms are optionally replaced with deuterium.
  • the alkyl or alkene group of Y is an alkyl or alkene group present in a fatty acid selected from the list of fatty acids in Table 1 wherein all available H atoms are optionally replaced with deuterium.
  • the alkene group of Y is an alkyl or alkenyl group present in linoleic acid, eicosadienoic acid or decosahexanoic acid.
  • Y is the alkyl or alkenyl group of a fatty acid wherein 1-10, 2-8, 2-6 or 2-4 H atoms are replaced with deuterium.
  • A' is Y.
  • A' is -O-Y.
  • A is -O-C 3 alkylene-O-C(O)-Y.
  • R 1 and R 1 ' are independently selected from H, OH, halo, NH 2 , Ci_ 4 alkyl, Ci. 4 alkoxy, NH(Ci. 4 alkyl) and N(Ci. 4 alkyl).
  • R 1 and R 1 ' are independently selected from H, D, Cl, F, OH, NH 2 , Ci- 4 alkyl, Ci. 4 alkoxy, Ci- 4 fluoroalkyl, Ci. 4 deuteroalkyl, NH(Ci. 4 alkyl), NH(Ci. 4 deuteroalkyl), NH(Ci. 4 flouroalkyl), N(Ci. 4 alkyl) 2 , N(Ci.
  • R 1 and R 1 ' are independently selected from H, D, Cl, F, OH, NH 2 , Ci_ 2 alkyl, Ci. 2 alkoxy, Ci. 2 fluoroalkyl and Ci. 2 deuteroalkyl, NH(Ci. 2 alkyl), NH(Ci.
  • R 1 is selected from H, D, F, NH 2 , CH 3 , CF 2 H, CD 2 H, CH 3 O, CF 3 , CD 3 , NH(CH 3 ), NH(CD 3 ), NH(CF 3 ), N(CH 3 ) 2 , N(CF 3 ) 2 and N(CD 3 ) 2 .
  • R 1 and R 1 ' are independently selected from H, D, F, NH 2 , CH 3 , CF 2 H, CD 2 H, CH 3 O, CF 3 and CD 3 .
  • R 1 and R 1 ' are independently selected from H, D, F, OH, CH 3 , CF 2 H, CD 2 H, CH 3 O, CF 3 and CD 3 .
  • R 1 and R 1 ' are independently H, D or F.
  • R 1 and R 1 ' are all H or are all D.
  • R 1 and R 1 ' are both H.
  • R 2 and R 2 ' are independently selected from H, halo, NH 2 , Ci. 4 alkyl, Ci. 4 alkoxy, NH(Ci. 4 alkyl) and N(Ci. 4 alkyl).
  • R 2 and R 2 ' are independently selected from H, D, Cl, F, NH 2 , Ci_ 4 alkyl , Ci. 4 alkoxy, Ci. 4 fluoroalkyl, Ci. 4 deuteroalkyl, NH(Ci. 4 alkyl), NH(Ci. 4 deuteroalkyl), NH(Ci. 4 flouroalkyl), N(Ci. 4 alkyl) 2 , N(Ci.
  • R 2 and R 2 ' are independently selected from H, D, Cl, F, Ci_ 2 alkyl, Ci. 2 alkoxy, Ci. 2 fluoroalkyl, Ci. 2 deuteroalkyl, NH(Ci. 2 alkyl), NH(Ci. 2 deuteroalkyl), NH(Ci.
  • N(Ci. 2 alkyl) 2 N(Ci. 2 fluoroalkyl) 2 , N(Ci. 2 deuteroalkyl) 2 , N(Ci. 2 fluoroalkyl)(Ci. 2 alkyl), N(Ci. 2 fluoroalkyl)(Ci. 2 deuteroalkyl) and N(Ci. 2 deuteroalkyl)(Ci. 2 alkyl).
  • R 2 and R 2 ' are independently selected from H, D, F, NH 2 , CH 3 , CF 2 H, CD 2 H, CH 3 O, CF 3 , CD 3 , NH(CH 3 ), NH(CD 3 ), NH(CF 3 ), N(CH 3 ) 2 , N(CF 3 ) 2 and N(CD 3 ) 2 .
  • R 1 is selected from H, D, F, NH 2 , CH 3 , CF 2 H, CD 2 H, CH 3 O, CF 3 and CD 3 .
  • R 2 and R 2 ' are independently selected from H, D, F, CH 3 , CF 2 H, CD 2 H, CH 3 O, CF 3 and CD 3 .
  • R 2 and R 2 ' are independently H, D or F.
  • R 2 and R 2 ' are all H or are all D.
  • R 2 and R 2 ' are all H.
  • R 1 , R 1 ', R 2 and R 2 ' are independently H, D or F. In some embodiments, R 1 , R 1 ', R 2 and R 2 ' are all H or are all D. In some embodiments, R 1 , R 1 ', R 2 and R 2 ' are all H.
  • R 3 and R 6 are independently selected from H, D, Cl, F, OH, Ci_ 4 alkyl, Ci. 4 alkoxy, Ci. 4 fluoroalkoxy, Ci. 4 deuteroalkoxy, Ci. 4 fluoroalkyl and Ci. 4 deuteroalkyl.
  • R 3 and R 6 are independently selected from H, D, Cl, F, OH, Ci_ 4 alkyl, Ci. 4 alkoxy, Ci. 4 fluoroalkyl and Ci. 4 deuteroalkyl.
  • R 3 and R 6 are independently selected from H, D, Cl, F, OH, Ci- 2 alkyl, Ci.
  • R 3 and R 6 are independently selected from H, D, Cl, F, OH, Ci_ 2 alkyl, Ci. 2 alkoxy, Ci. 2 fluoroalkyl and Ci. 2 deuteroalkyl.
  • R 3 and R 6 are independently selected from H, D, F, OH, CH 3 , CH 3 O, CF 2 HO, CD 2 HO, CF 3 O, CD 3 O, CF 2 H, CD 2 H, CF 3 and CD 3 .
  • R 3 and R 6 are independently selected from H, D, F, OH, CH 3 , CH 3 O, CF 2 H, CD 2 H, CF 3 and CD 3 . In some embodiments, R 3 and R 6 are independently selected from H, D, F, OH, CH 3 , CH 3 O, CF 2 HO, CF 3 O and CD 3 O. In some embodiments, R 3 and R 6 are independently selected from H and D. In some embodiments, at least one of R 3 and R 6 is D. In some embodiments, each of R 3 and R 6 are D. In some embodiments, each of R 3 and R 6 are H.
  • R 4 and R 5 is independently selected from H, D, F, Cl, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 fluoroalkoxy and C 1-6 deuteroalkoxy.
  • both of R 4 and R 5 are independently selected from H, D, F, Cl, Ci-4alkyl, Ci-4fluoroalkyl, Ci-4deuteroalkyl, Ci-4alkoxy, Ci-4fluoroalkoxy and Ci- 4 deuteroalkoxy.
  • R 4 and R 5 is independently selected from H, D, F, Cl, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CH 2 CF 2 H, CH 2 CF 3 , CH 2 CFH 2 , CH(CF 3 ) 2 , CD 3 , CH(CH 3 ) 2 O, CH 3 CH 2 CH 2 O, CH 3 CH 2 O, CH 3 O, CF 3 O, CHF 2 O, CF 2 HCH 2 O, CF 3 CH 2 O, (CF 3 ) 2 CHO, and CD 3 O.
  • R 4 and R 5 is independently selected from H, D, F, Cl, CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CD 3 , CH 3 O, CH(CH 3 ) 2 O, CF 3 O, CHF 2 O, and CD 3 O.
  • both of R 4 and R 5 are independently selected from D, F, Cl, Ci_ 6 alkyl, C 1-6 fluoroalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 fluoroalkoxy and Ci. edeuteroalkoxy.
  • both of R 4 and R 5 are independently selected from H, D, F, Cl, CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CD 3 , CH(CH 3 ) 2 O, CH 3 O, CF 3 O, CHF 2 O, and CD 3 O.
  • both of R 4 and R 5 are independently selected from D, F, Cl, Ci-salkyl , C 1 _ 6 fluoroalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 fluoroalkoxy and C 1-6 deuteroalkoxy. In some embodiments both of R 4 and R 5 are independently selected from H, D, F, Cl, Ci. 4alkyl, Ci-4fluoroalkyl, Ci-4deuteroalkyl, Ci-4alkoxy, Ci-4fluoroalkoxy and Ci-4deuteroalkoxy.
  • both of R 4 and R 5 are independently selected from H, D, F, Cl, CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CD 3 , CH(CH 3 ) 2 O, CH 3 O, CF 3 O, CHF 2 O, and CD 3 O.
  • both of R 4 and R 5 are independently selected from D, F, Cl, CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CD 3 , CH(CH 3 ) 2 O, CH 3 O, CF 3 O, CHF 2 O, and CD 3 O.
  • both of R 4 and R 5 are independently selected from CH 3 O, CF 3 O, CHF 2 O, and CD 3 O.
  • R 4 and R 5 are CD 3 O or both of R 4 and R 5 are CH 3 O.
  • R 4 is H or D and R 5 is selected from H, D, F, Cl, Ci- 6 alkyl, C 1 _ 6 fluoroalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 fluoroalkoxy and C 1-6 deuteroalkoxy.
  • R 4 is H or D and R 5 is selected from H, D, F, Cl, Ci- 4 alkyl, Ci. 4fluoroalkyl, Ci- deuteroalkyl, Ci- alkoxy, Ci- fluoroalkoxy and Ci- deuteroalkoxy.
  • R 4 is H or D and R 5 is selected from H, D, F, Cl, CH(CH 3 ) 2 , CH 3 , CF 3 , CF 2 H, CD 3 , CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O.
  • R 4 is H or D and R 5 is selected from D, F, Cl, CH(CH 3 ) 2 , CH 3 , CF 3 , CF 2 H, CD 3 , CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O.
  • R 4 is H or D and R 5 is selected from CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O. In some embodiments, R 4 is H and R 5 is selected from CH 3 O and CD 3 O.
  • R 5 is H or D and R 4 is selected from H, D, F, Cl, Ci- 6 alkyl, C 1 _ 6 fluoroalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 fluoroalkoxy and C 1-6 deuteroalkoxy.
  • R 5 is H or D and R 4 is selected from D, F, Cl, CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CD 3 , CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O.
  • R 5 is H or D and R 4 is selected from CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O. In some embodiments, R 5 is H and R 4 is selected from CH 3 O and CD 3 O.
  • R 3 , R 4 R 5 and R 6 are selected from D, F, Cl, CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CD 3 , CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O.
  • R 3 , R 4 R 5 and R 6 are all H or In some embodiments, R 3 , R 4 R 5 and R 6 are all D. In some embodiments, R 3 , R 4 R 5 and R 6 are selected from CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O.
  • two of R 3 , R 4 R 5 and R 6 are selected from H or D and the remaining of R 3 , R 4 R 5 and R 6 are selected from CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O. In some embodiments, two of R 3 , R 4 R 5 and R 6 are selected from H or D and the remaining of R 3 , R 4 R 5 and R 6 are selected from CH 3 O and CD 3 O. In some embodiments, one of R 3 , R 4 R 5 and R 6 is selected from H or D and the remaining of R 3 , R 4 R 5 and R 6 are selected from CH(CH 3 ) 2 O CH 3 O, CF 3 O, CHF 2 O, and CD 3 O. In some embodiments, one of R 3 , R 4 R 5 and R 6 is selected from H or D and the remaining of R 3 , R 4 R 5 and R 6 are selected from CH 3 O and CD 3 O.
  • R 4 and R 5 are linked together to form O-CH 2 O.
  • one of R 4 and R 5 is selected from X-L-A and the other of R 4 and R 5 is selected from H, halo, C 1-6 alkyl and C 1-6 alkoxy.
  • X is a direct bond and one of R 4 and R 5 is selected from L-A and the other of R 4 and R 5 is selected from H, halo, Ci-salkyl and Ci-ealkoxy.
  • X is selected from O, C(O), NR a , NR a C(O), C(O)NR a , OC(O), C(O)O, 0C(0)0, NR a C(O)O, OC(O)NR a and NR a C(O)NR a .
  • X is selected from O, C(O), OC(O), C(O)O and OC(O)O.
  • X is selected from O, OC(O) and C(O)O. In some embodiments, X is O. In some embodiments, X is selected from OC(O) and C(O)O. In some embodiments, X is selected from NR a , NR a C(O), C(O)NR a , NR a C(O)O, OC(O)NR a and NR a C(O)NR a . In some embodiments, X is selected from NR a C(O), C(O)NR a , NR a C(O)O, OC(O)NR a and NR a C(O)NR a .
  • X is selected from NR a C(O), and C(O)NR a . In some embodiments, X is selected from NR a C(O)O, OC(O)NR a and NR a C(O)NR a . In some embodiments, X is selected from O, OC(O), C(O)O, NR a C(O), and C(O)NR a .
  • L is selected from a direct bond, Ci- 4 alkylene, C 2 . 4 alkenylene, Ci. 4 alkyleneO, C 2.4 alkenyleneO, Ci. 4 alkyleneC(O), C 2.4 alkenyleneC(O) C1- 4 alkyleneNR b C(O), C 2.4 alkenyleneNR b C(O), Ci. 4 alkyleneC(O)NR b , C 2 . 4 alkenyleneC(O)NR b , Ci. 4 alkyleneOC(O), C 2.4 alkenyleneOC(O), Ci. 4 alkyleneC(O)O, C 2 . 4 alkenyleneC(O), Ci.
  • L is selected from a direct bond, Ci. 2 alkylene, C 2.4 alkenylene, Ci. 2 alkyleneO, C 2.4 alkenyleneO, Ci. 2 alkyleneC(O), C 2.4 alkenyleneC(O) Ci.
  • L is selected from a direct bond, C1- 2 alkylene, Ci. 2 alkyleneO, Ci. 2 alkyleneC(O), Ci. 2 alkyleneNR b C(O), Ci. 2 alkyleneC(O)NR b , Ci. 2 alkyleneOC(O), Ci. 2 alkyleneC(O)O, Ci.
  • L is selected from a direct bond, CH 2 , CF 2 , CD 2 , CH 2 -O, CF 2 -O, CD 2 -O, CH 2 -C(O), CF 2 -C(O), CD 2 -C(O), CH 2 -NR b C(O), CD 2 -NR b C(O), CH 2 -C(O)NR b , CF 2 -C(O)NR b , CD 2 -C(O)NR b , CH 2 -OC(O), CD 2 -OC(O), CF 2 -OC(O), CH 2 -C(O)O, CF 2 -C(O)O, CD 2 -C(O)O, CD 2 -C(O)NR b , CH 2 -OC(O), CD 2 -OC(O), CF 2 -OC(O), CH 2 -C(O)O, CF 2 -C(O)O, CD 2 -C(O)O, CD
  • X is a direct bond and L is a direct bond and one of R 4 and R 5 is selected from A and the other of R 4 and R 5 is selected from H, halo, Ci_ 4 alkyl and Ci- 4 alkoxy.
  • X is selected from O, OC(O), C(O)O, NR a C(O), and C(O)NR a and one of R 4 and R 5 is selected from O-Ci. 2 alkylene-A, O-Ci. 2 alkyleneO-A, O- Ci. 2 alkyleneC(O)-A, O-Ci. 2 alkyleneNR b C(O)-A, O-Ci.
  • 2 alkyleneC(O)NR b -A O-C1.
  • R 4 and R 5 is selected from H, halo, Ci. 4 alkyl and Ci. 4 alkoxy wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • X is selected from O, OC(O), C(O)O, NR a C(O), and C(O)NR a and one of R 4 and R 5 is selected from O-Ci.
  • R 4 and R 5 is selected from H, halo, Ci_ 4 alkyl and Ci. 4 alkoxy wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • R 4 and R 5 is selected from H, F, Cl, C1- 4 alkyl, Ci. 4 haloalkyl, Ci. 4 deuteroalkyl and Ci. 4 alkoxy wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • the other of R 4 and R 5 is selected from D, F, Cl, CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CD 3 , CH(CH 3 )2O, CH 3 O, CF 3 O, CHF2O, and CD 3 O wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium Atom, and the other of R 4 and R 5 is H or D.
  • R 4 is X-L-A and R 5 is selected from H, halo, C 1-6 alkyl and Ci-ealkoxy. In some embodiments, of R 5 is X-L-A and R 4 is selected from H, halo, C1- 6 alkyl and C 1-6 alkoxy.
  • R a is selected from H and Ci_ 4 alkyl.
  • R b is selected from H, Ci. 4 alkyl and A.
  • A is H, and one of R 4 and R 5 is selected OH, C(O)H, and the other of R 4 and R 5 is selected from H, halo, Ci. 4 alkyl and Ci. 4 alkoxy, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • A is H, and one of R 4 and R 5 is selected OH, C(O)H, NHR a , NHR a C(O), C(O)NHR a , OC(O)H, C(O)OH, OC(O)OH, NR a C(O)OH, OC(O)NHR a , NHR a C(O)NR a , X-Ci. 2 alkylene, X-C 2.4 alkenylene, X-Ci. 2 alkyleneOH, X-C 2 . 4 alkenyleneOH, X-Ci. 2 alkyleneC(O)H, X-C 2.4 alkenyleneC(O)H, X-Ci.
  • R 4 and R 5 is selected from H, halo, Ci. 4 alkyl and Ci. 4 alkoxy, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • A is H and X is a direct bond. Therefore, in some embodiments, and one of R 4 and R 5 is selected from Ci_ 4 alkyl, C 2.4 alkenyl, Ci. 4 alkyleneOH, C 2.6 alkenyleneOH, Ci. 4 alkyleneC(O)H, C 2.4 alkenyleneC(O)H, Ci. 4 alkyleneNR b C(O)H, C 2 . 4 alkenyleneNR b C(O)H, Ci. 4 alkyleneC(O)NHR b , C 2.4 alkenyleneC(O)NHR b , Ci- 4 alkyleneOC(O)H, C 2.4 alkenyleneOC(O)H, Ci.
  • A is H and X is selected from O, C(O), NR a , NR a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and NR a C(O)NR a .
  • A is H and X is selected from O, C(O), OC(O), C(O)O and OC(O)O.
  • A is H and X is selected from O, OC(O) and C(O)O.
  • A is H and X is O.
  • A is H and X is selected from OC(O) and C(O)O. In some embodiments, A is H and X is selected from NR a , NR a C(O), C(O)NR a , NR a C(O)O, OC(O)NR a and NR a C(O)NR a . In some embodiments, A is H and X is selected from NR a C(O), C(O)NR a , NR a C(O)O, OC(O)NR a and NR a C(O)NR a . In some embodiments, A is H and X is selected from NR a C(O), and C(O)NR a .
  • A is H and X is selected from NR a C(O)O, OC(O)NR a and NR a C(O)NR a .
  • A is H, and L is a direct bond, and one of R 3 and R 4 is selected from X-H.
  • R 3 and R 4 is selected from OH, C(O)H, NHR a , NHR a C(O), C(O)NHR a , OC(O)H, C(O)OH, OC(O)OH, NR a C(O)OH, OC(O)NHR a and NHR a C(O)NR a , wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • R b is selected from H and Ci. 4 alkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • one of R 4 and R 5 is selected from A, O-A, C(O)-A, C(O)-A, C(O)O-A, Ci. 4 alkylene-A, Ci. 4 alkylene-C(O)-A, Ci. 4 alkylene-C(O)O-A, 0-0. 4 alkylene-A, O-Ci. 4 alkylene-C(O)-A, and O-Ci. 4 alkylene-C(O)O-A and the other of R 4 and R 5 is selected from H, halo, C 1-6 alkyl and C 1-6 alkoxy, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • one of R 4 and R 5 is selected from A, O-A, C(O)-A, C(O)-A, and C(O)O-A and the other of R 4 and R 5 is selected from H, halo, C 1-6 alkyl and C 1-6 alkoxy, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • one of R 4 and R 5 is A.
  • one of R 4 and R 5 is O-A.
  • one of R 4 and R 5 is C(O)-A.
  • one of R 4 and R 5 is C(O)O-A.
  • one of R 4 and R 5 is selected from Ci. 4 alkylene-A, Ci. 4 alkylene-C(O)-A, Ci. 4 alkylene-C(O)O-A, O-Ci. 4 alkylene-A, O-Ci. 4 alkylene-C(O)-A, and O- Ci. 4 alkylene-C(O)O-A and the other of R 4 and R 5 is selected from H, halo, Ci-salkyl and Ci- 6 alkoxy, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • one of R 4 and R 5 is Ci- 4 alkylene-A.
  • one of R 4 and R 5 is Ci. 4 alkylene-C(O)-A. In some embodiments, one of R 4 and R 5 is Ci. 4 alkylene-C(O)O-A. In some embodiments, one of R 4 and R 5 is O-Ci. 4 alkylene-A. In some embodiments, one of R 4 and R 5 is O-Ci. 4 alkylene- C(O)-A. In some embodiments, one of R 4 and R 5 is O-Ci. 4 alkylene-C(O)O-A.
  • one of R 4 and R 5 is selected from A, O-A, C(O)-A, C(O)O-A, C(O)-A, C(O)O-A, Ci. 4 alkylene-A, Ci. 4 alkylene-C(O)-A, Ci. 4 alkylene-C(O)O-A, O-Ci. 4 alkylene-A, O-Ci. 4 alkylene-C(O)-A, and O-Ci. 4 alkylene-C(O)O-A and the other of R 4 and R 5 is selected from H, F, Cl, Ci. 4 alkyl and Ci.
  • R 4 and R 5 is selected from A, O-A, C(O)-A, C(O)O-A, C(O)- A, C(O)O-A, Ci. 4 alkylene-A, Ci. 4 alkylene-C(O)-A, Ci. 4 alkylene-C(O)O-A, O-Ci. 4 alkylene-A, O-Ci. 4 alkylene-C(O)-A, and O-Ci.
  • R 4 alkylene-C(O)O-A and the other of R 4 and R 5 is selected from H, F, Cl, Ci_ 4 alkyl, Ci. 4 haloalkyl, Ci. 4 deuteroalkyl and Ci. 4 alkoxy wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • one of R 4 and R 5 is selected from A, O-A, C(O)-A, C(O)O-A, C(O)-A, C(O)O-A, Ci. 2 alkylene-A, Ci. 2 alkylene-C(O)-A, Ci. 2 alkylene-C(O)O-A, O-Ci.
  • R 4 and R 5 is selected from D, F, Cl, CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CD 3 , CH(CH 3 ) 2 O, CH 3 O, CF 3 O, CHF 2 O, and CD 3 O wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • one of R 4 and R 5 is selected from A, O-A, C(O)-A, C(O)O-A, Ci. 2 alkylene-A, Ci.
  • R 4 and R 5 is H or D, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • one of R 4 and R 5 is selected from A, O-A, C(O)-A, C(O)O-A, CH 2 -A, CD 2 -A, CF 2 -A, CH 2 - C(O)-A, CF 2 -C(O)-A, CD 2 -C(O)-A, CH 2 -C(O)O-A, CD 2 -C(O)O-A, CF 2 -C(O)O-A, O-CH 2 A, O-CF 2 A, O-CD 2 A, -CH 2 -C(O)-A, O-CD 2 -C(O)-A, O-CF 2 -C(O)-A, O- CH 2 -C(O)O-A, O- CF 2 - C(O)O-A, O- CD 2 -C(O)O-A, and the other of R 4 and R 5 is H or D.
  • R 4 is selected from A, O-A, C(O)-A, C(O)O-A, Ci- 2 alkylene-A, Ci. 2 alkylene-C(O)-A, Ci. 2 alkylene-C(O)O-A, O-Ci. 2 alkylene-A, O-Ci. 2 alkylene- C(O)-A, and O-Ci. 2 alkylene-C(O)O-A and R 5 is H or D, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • R 4 is selected from A, O-A, C(O)-A, C(O)O-A, CH 2 -A, CD 2 -A, CF 2 - A, CH 2 -C(O)-A, CF 2 -C(O)-A, CD 2 -C(O)-A, CH 2 -C(O)O-A, CD 2 -C(O)O-A, CF 2 -C(O)O-A, O- CH 2 A, O-CF 2 A, O-CD 2 A, O-CH 2 -C(O)-A, O-CD 2 -C(O)-A, O-CF 2 -C(O)-A, O- CH 2 -C(O)O-A, O- CF 2 -C(O)O-A, and O- CD 2 -C(O)O-A and R 5 is H or D.
  • R 5 is selected from A, O-A, C(O)-A, C(O)O-A, Ci. 2 alkylene-A, Ci. 2 alkylene-C(O)-A, Ci. 2 alkylene- C(O)O-A, O-Ci. 2 alkylene-A, O-Ci. 2 alkylene-C(O)-A, and O-Ci. 2 alkylene-C(O)O-A and R 4 is H or D, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • R 5 is selected from A, O-A, C(O)-A, C(O)O-A, CH 2 -A, CD 2 -A, CF 2 -A, CH 2 -C(O)-A, CF 2 -C(O)-A, CD 2 -C(O)-A, CH 2 - C(O)O-A, CD 2 -C(O)O-A, CF 2 -C(O)O-A, O-CH 2 A, O-CF 2 A, O-CD 2 A, O-CH 2 -C(O)-A, O-CD 2 - C(O)-A, O-CF 2 -C(O)-A, O- CH 2 -C(O)O-A, O- CF 2 -C(O)O-A, and O- CD 2 -C(O)O-A and R 4 is H or D.
  • A is selected from Ci. 30 alkyl , C 2 -3oalkenyl, phenyl, C 3 - 6 cycloalkyl, 3- to 6-membered heterocycloalkyl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 and 5- to 6-membered heteroaryl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 , wherein the phenyl, C 3 -iocycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6- membered heteroaryl are optionally substituted with one or two substituents independently selected from F, Cl, OH, Ci.
  • Ci. 4 deuteroalkyl Ci. 4 fluoroalkyl, OCi. 4 alkyl, OCi. 4 deuteroalkyl and OCi. 4 fluoroalkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • A is selected from Ci.
  • A is selected from phenyl, C 3 -6cycloalkyl, 3- to 6- membered heterocycloalkyl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 and 5- to 6-membered heteroaryl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 , wherein the phenyl, C 3 -iocycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from F, C, Ci- 4 alkyl, Ci.
  • A is selected from phenyl, C 3-6 cycloalkyl, 5- to 6- membered heterocycloalkyl comprising 1 to 2 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 and 5- to 6-membered heteroaryl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 , wherein the phenyl, C 3 -iocycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from F, C, Ci- 4 alkyl, Ci. 4 deuteroalkyl, Ci. 4 fluoroalkyl, OCi. 4 alkyl
  • the C 3.6 cycloalkyl in A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • the C 3.6 cycloalkyl in A is cyclopropyl which is optionally substituted with one ortwo substituents independently selected from F, C, Ci_ 4 alkyl, Ci. 4 deuteroalkyl, Ci. 4 fluoroalkyl, OCi. 4 alkyl, OCi. 4 deuteroalkyl and OCi. 4 fluoroalkyl.
  • the 3- to 6-membered heterocycloalkyl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 in A 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
  • the 3- to 6-membered heterocycloalkyl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 in A is selected from tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, piperidinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, tetrahydropyranyl, tetrahydrothiopyranyl, dihydropyranyl, tetrahydrothiopyranyl oxide, tetrahydrothiopyranyl dioxide, piperidinyl, piperazinyl, morpholin
  • the 5- to 6-membered heteroaryl in A is selected from furyl, imidazolyl, isothiazolyl, thiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyrrolyl, thienofuryl, triazolyl and thienyl, each of which is optionally substituted with one or two substituents independently selected from F, C, Ci_ 4 alkyl, Ci. 4 deuteroalkyl, Ci. 4 fluoroalkyl, OCi. 4 alkyl, OCi. 4 deuteroalkyl and OCi. 4 fluoroalkyl.
  • the 5- to 6- membered heteroaryl in A is selected from furyl, isothiazolyl, thiazolyl, pyridyl and pyrrolyl, each of which is optionally substituted with one or two substituents independently selected from F, C, Ci_ 4 alkyl , Ci. 4 deuteroalkyl, Ci. 4 fluoroalkyl, OCi. 4 alkyl, OCi. 4 deuteroalkyl and OCi. 4 fluoroalkyl.
  • the phenyl, C 3 -iocycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl in A is optionally substituted with one or two substituents independently selected from F, Cl, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CF 3 , CF 2 H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF 3 ) 2 , CD 3 , CH(CH 3 ) 2 O, CH 3 CH 2 CH 2 O, CH 3 CH 2 O, CH 3 O, CF 3 O, CHF2O, CF2HCH2O, CF 3 CH 2 O, (CF 3 ) 2 CHO, and CD 3 O.
  • A is selected from Ci. 30 alkyl and C 2.3 oalkenyl wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • A is Cio-25alkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom. In some embodiments, A is Ci 3.2 ialkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom.
  • A is Cio-25alkenyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom. In some embodiments, A is Ci 3.2 ialkenyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or deuterium atom. In some embodiments, A is Cio-25alkenyl and comprises 1 , 2, 3, 4, 5 or 6 double bonds.
  • the alkyl or alkene group of A is an alkyl or alkenyl group present in a fatty acid, wherein all available H atoms are optionally replaced with deuterium.
  • A is an alkenyl group present in a fatty acid, wherein all available H atoms are optionally replaced with deuterium.
  • the fatty acid is an omega-6 fatty acid (i.e. an unsaturated or polyunsaturated fatty acid wherein the double bond that is closest to the methyl end of the molecule is located at carbon numbered 6 starting from the end methyl group) or an omega-3 fatty acid (i.e.
  • A is an alkyl group present in a fatty acid wherein all available H atoms are optionally replaced with deuterium.
  • the alkyl or alkene group of A is an alkyl or alkene group present in a fatty acid selected from the list of fatty acids in Table 1 wherein all available H atoms are optionally replaced with deuterium.
  • the alkene group of A is an alkyl or alkenyl group present in linoleic acid, eicosadienoic acid or decosahexanoic acid.
  • A when A is the alkyl or alkenyl group of a fatty acid wherein 1-10, 2-8, 2-6 or 2-4 H atoms are replaced with deuterium.
  • R 64 and R 65 are independently selected from H, D, Ci_ 4 alkyl, Ci. 4 fluoroalkyl and Ci. 4 deuteroalkyl. In some embodiments, R 64 and R 65 are independently selected from H, D, CH 3 , CF 3 and CD 3 . In some embodiments, R 64 and R 65 are independently selected from CH3 and CD3.
  • the compound of Formula l-A is defined as follows: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • Q is selected from Q1 , Q2, Q3, Q4, Q5 and Q6: is a single bond or a double bond provided that when in Q1 is a double bond then R 9 and R 15 are not present, when in Q2 is a double bond then R 17 and R 25 are not present and when in Q5 is a double bond then R 48 and R 57 are not present;
  • R 1 , R 1 ', R 2 , R 2 ', R 3 and R 6 are independently selected from H, D and F; one or both of R 4 and R 5 is selected from H, Ci. 4 alkoxy, Ci- 4 fluoralkoxy and Ci. 4 deuteroalkoxy, or
  • R 4 and R 5 are linked together to form O-(CH 2 )I-2O;
  • R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently selected from H and D;
  • R 12 , R 20 , R 29 , R 39 and R 51 are independently selected from H, Ci. 4 alkyl, Ci- 4 fluoroalkyl and Ci- 4 deuteroalkyl, and
  • R 60 and R 61 are independently selected from H and C 1-6 alkyl; provided when Q is Q6 then the compound of Formula I comprises D; when Q is Q3 or Q4, then R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 6 , R 26 , R 27 , R 28 , R 30 to R 35 , R 36 , R 37 , R 38 and R 40 to R 47 are not all H, when R 5 is H or OCH 3 , and R 29 or R 39 is CH 3 and when Q is Q4 and R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 6 , R 38 and R 40 to R 47 are all H, then R 36 and R 37 are not both D, when R 39 is CD 3 .
  • the compound of Formula l-A is defined as follows: or a pharmaceutically acceptable salt, solvate and/or prodrug thereof, wherein:
  • R 1 and R 1 ' are independently selected from H, halo, OH, NH 2 , Ci_ 6 alkyl, C 1-6 alkoxyl, NH(Ci. 6 alkyl) and N(C 1 _ 6 alkyl) 2 ;
  • R 2 and R 2 ' are independently selected from H, halo, NH 2 , Ci_ 6 alkyl, C 1-6 alkoxyl, NH(Ci. 6 alkyl) and N(C 1 _ 6 alkyl) 2 ;
  • Q is selected from Q1 , Q2, Q3, Q4, Q5 and Q6: is a single bond or a double bond provided that when in Q1 is a double bond then R 9 and R 15 are not present, when in Q2 is a double bond then R 17 and R 25 are not present, and when in Q5 is a double bond then R 48 and R 57 are not present; one or both of R 4 and R 5 is independently selected from H, halo, Ci-salkyl and O-ealkoxy, or
  • R 4 and R 5 are linked together to form O-(CH 2 )I-2O, or one of R 4 and R 5 is selected from X-L-A and the other of R 4 and R 5 is selected from H, halo, Ci_ 6 alkyl and C 1-6 alkoxy,
  • X is selected from a direct bond, O, C(O), NR a , NR a C(O), C(O)NR a , OC(O), C(O)O, OC(O)O, NR a C(O)O, OC(O)NR a and NR a C(O)NR a ;
  • L is selected from a direct bond, C 1-6 alkylene, C 2 -6alkenylene, C 1-6 alkyleneO, C 2 . 6 alkenyleneO, C 1-6 alkyleneC(O), C 2.6 alkenyleneC(O), C 1-6 alkyleneNR b C(O), C 2 .
  • R a is selected from H and C 1-6 alkyl
  • R b is selected from H, Ci_ 6 alkyl and A;
  • A is selected from Ci- 30 alkyl, C 2.3 oalkenyl, phenyl, C 3 -6cycloalkyl, 3- to 6-membered heterocycloalkyl comprising 1 to 4 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 and 5- to 6-membered heteroaryl comprising 1 to 4 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 64 , wherein the phenyl, C 3 - locycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, Ci- 4 alkyl and OCi. 4 alkyl;
  • R 3 and R 6 are independently selected from H, halo, OH, Ci_ 6 alkyl and C 1-6 alkoxy;
  • R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 62 and R 63 are independently selected from H, halo and Ci- ea Iky I;
  • R 12 , R 20 , R 29 , R 39 and R 51 are independently selected from H, Ci-ealkyl, C(O)Ci-ealkyl and C(O)-A;
  • R 60 and R 61 are independently selected from H and Ci_ 6 alkyl; or one of R 60 and R 61 is C(O)-A' and the other is selected from H and Ci-ealkyl; wherein A' is selected from Y, O-Y and O-Ci- 4 alkylene-O-C(O)-Y; and
  • Y is selected from C7-soalkyl and C7-soalkenyl
  • R 60 and R 61 together with the N atom to which they are bound, form a 3- to 6-membered heterocyclic ring which optionally comprises one or two additional heteromoieties independently selected from O, S, S(O), SO 2 , N, and NR 65 and which is optionally substituted with one or more substituents independently selected from halo, OH, Ci- 4 alkyl and OCi. 4 alkyl;
  • R 64 and R 65 are independently selected from H and C 1-6 alkyl; and all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with alternate isotope thereof, provided one of R 12 , R 20 , R 29 , R 39 , R 51 , R 60 and R 61 is C(O)-A'; or one of R 4 and R 5 is selected from X-L-A and the other of R 4 and R 5 is selected from H, halo, C 1 _ 6 alkyl and C 1-6 alkoxy provided A is not H, Ci_ 6 alkyl or C 1-6 alkeynyl when X and L are both direct bonds. [00288] A person skilled in the art would appreciate that the carbon to which R 2 and R 2 are bonded, when R 2 and R 2 are different, is chiral. Therefore, the present application includes all stereoisomers at this carbon center and mixtures thereof.
  • the compounds of Formula l-A are selected from the compounds listed below, or a pharmaceutically acceptable salt, solvate and/or prodrug thereof: £4
  • the pharmaceutically acceptable salt is an acid addition salt or a base addition salt.
  • Suitable salts include acid addition salts that may, for example, be formed by mixing a solution of a compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Additionally, acids that are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) and Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley VCH; S.
  • An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound.
  • Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids.
  • organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2- phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid.
  • exemplary acid addition salts also include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates (“mesylates”), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like.
  • the mono- or di-acid salts are formed and such salts exist in either a hydrated, solvated or substantially anhydrous form.
  • acid addition salts are more soluble in water and various hydrophilic organic solvents and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection criteria for the appropriate salt will be known to one skilled in the art.
  • Other non-pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • a base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound.
  • Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclo
  • Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
  • the selection of the appropriate salt may be useful, for example, so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed.
  • the selection criteria for the appropriate salt will be known to one skilled in the art.
  • exemplary basic salts also include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, Abutyl amine, choline and salts with amino acids such as arginine, lysine and the like.
  • alkali metal salts such as sodium, lithium and potassium salts
  • alkaline earth metal salts such as calcium and magnesium salts
  • salts with organic bases for example, organic amines
  • organic bases for example, organic amines
  • alkali metal salts such as sodium, lithium and potassium salts
  • alkaline earth metal salts such as calcium and magnesium salts
  • salts with organic bases for example, organic amines
  • organic bases for example, organic amines
  • amino acids such as arginine, lysine and the like.
  • Basic nitrogen containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl and dibutyl sulfates), long chain halides (e.g., decyl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides) and others.
  • lower alkyl halides e.g., methyl, ethyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl and dibutyl sulfates
  • long chain halides e.g., decyl, lauryl and stearyl chlorides,
  • Compounds carrying an acidic moiety can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts) and salts formed with suitable organic ligands such as quaternary ammonium salts.
  • suitable pharmaceutically acceptable salts for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts) and salts formed with suitable organic ligands such as quaternary ammonium salts.
  • suitable pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
  • Solvates of compounds of Formula I or l-A or a pharmaceutically salt and/or prodrug thereof include, for example, those made with solvents that are pharmaceutically acceptable.
  • solvents include water (resulting solvate is called a hydrate) and ethanol and the like. Suitable solvents are physiologically tolerable at the dosage administered.
  • Prodrugs of the compounds of Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof include, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates and amino acid esters.
  • compounds of Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof may have at least one chiral center and therefore can exist as enantiomers and/or diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of Formula I or I- A or a pharmaceutically salt, solvate and/or prodrug thereof having an alternate stereochemistry. It is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present application.
  • the compounds of Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof 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 Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof may further exist in varying amorphous and polymorphic forms and it is contemplated that any amorphous forms, polymorphs, or mixtures thereof, which form are included within the scope of the present application.
  • the compounds of the present application may further be radiolabeled and accordingly all radiolabeled versions of the compounds of Formula I Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof are included within the scope of the present application. Therefore, the compounds of Formula I Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof also include those in which one or more radioactive atoms are incorporated within their structure.
  • the compounds of Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof 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 Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof and a carrier.
  • the compounds of Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo.
  • the present application further includes a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions are used in the treatment of any of the diseases, disorders or conditions described herein.
  • the compounds of Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof 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 Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof 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 (Gl) 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 Formula I or l-A or a pharmaceutically acceptable salt, solvate and/or prodrug thereof 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
  • the tablets are coated by methods well known in the art.
  • pH sensitive enteric coatings such as EudragitsTM designed to control the release of active ingredients are optionally used.
  • Oral dosage forms also include modified release, for example immediate release and timed-release, formulations.
  • modified-release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), timerelease 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 Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof 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).
  • Useful diluents include lactose and high molecular weight polyethylene glycols.
  • a compound of Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof is administered parenterally.
  • solutions of a compound of Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof 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 Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof are usually prepared and the pH's of the solutions are suitably adjusted and buffered.
  • the total concentration of solutes should be controlled to render the preparation isotonic.
  • ointments or droppable liquids are delivered, for example, by ocular delivery systems known to the art such as applicators or eye droppers.
  • 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.
  • mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol
  • preservatives such as sorbic acid, EDTA or benzyl chromium chloride
  • diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.
  • a compound of Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof 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.
  • compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders.
  • the compounds of Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof 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 nonaqueous 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 Formula I Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof 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 Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine.
  • 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 Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof 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 Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof 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 Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof 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.
  • biodegradable polymers useful in achieving controlled release of a drug
  • 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
  • the compounds of Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof are particularly amenable to administration with the air of nano-carrier systems, such as liposomes, micelles, nanoparticles, nano-emulsions, lipidic nanosystems and the like (see for example, Bhat, M. et al., Chem. and Phys, of Lipids, 2021 , 236, 105053). Accordingly the present application includes a composition comprising one or more compounds of Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof and one or more components of a nano-carrier system.
  • a compound of Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof 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 Formula I or l-A or a pharmaceutically salt, solvate and/or prodrug thereof (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 Formula I or l-A including pharmaceutically acceptable salts , solvates and/or prodrugs thereof are used are administered in a composition comprising an additional therapeutic agent.
  • the present application also includes a pharmaceutical composition
  • a pharmaceutical composition comprising one of more compounds of Formula I or l-A, 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.
  • Compounds of Formula I or a pharmaceutically salt, solvate and/or prodrug thereof including compounds of Formula l-A or a pharmaceutically salt, solvate and/or prodrug thereof can be prepared by various synthetic processes. The choice of particular structural features and/or substituents may influence the selection of one process over another. The selection of a particular process to prepare a given compound of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof is within the purview of the person of skill in the art. Some starting materials for preparing compounds of Formula I or a pharmaceutically salt, solvate and/or prodrug thereof are available from commercial chemical sources or may be extracted from cells, plants, animals or fungi. Other starting materials, for example as described below, are readily prepared from available precursors using straightforward transformations that are well known in the art. In the Schemes below showing some embodiments of methods of preparation of compounds of the application, all variables are as defined in Formula I, unless otherwise stated.
  • compounds of Formula A wherein R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 and R 6 are as defined in Formula I, are reacted under basic conditions using, for example, pyridine with compounds of Formula B, wherein R 28 and R 30 -R 35 are as defined in Formula I, R 29 is as defined in Formula I or is a suitable protecting group and LG is a suitable leaving group, such as chloro or OH, to provide compounds of Formula C.
  • Reduction of keto group in the compounds of Formula C for example using Al-based reducing agents such as lithium borohydride, lithium aluminum hydride or lithium aluminum deuteride, provides the compounds of Formula (I), wherein R 33 and R 34 are either H or D. If R 29 is a protecting group, it is removed in a separate step or, wherein the protecting group is removed in the presence of Al-based reducing agents is removed during the reduction of the compounds of Formula C.
  • Al-based reducing agents such as lithium borohydride, lithium aluminum hydride or lithium aluminum deuteride
  • the compounds of Formula A wherein R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 and R 6 are as defined in Formula I, are reacted with keto compounds of Formula D, wherein R 7 - R 10 , R 12 , R 13 are as defined in Formula I, R 11 is as defined in Formula I or is a suitable protecting group in the presence of a suitable reducing agent such as sodium triacetoxyborohydride (STAB) to provide the compounds of Formula A
  • STAB sodium triacetoxyborohydride
  • R 14 is either H or D. If R 11 is a protecting group, it is removed in a separate step.
  • Q is (Q1) and is a single bond and R 14 is either H or D
  • Q is (Q2) and is a single bond and R 25 is either H or D
  • Q is (Q3)
  • Q is (Q4) or Q is (Q5) and is a single bond the compounds of Formula I are prepared as shown using methods known in the art, for example, the methods described in W02013122107, US20080234237, US20070099913 and/or Annedi S. C et al., European Journal of Medicinal Chemistry, 55, 94-107, 2012.
  • R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 and R 6 are as defined in Formula I, are reacted with compounds of Formula E, wherein R 26 - R 28 , R 30 -R 36 are as defined in Formula I, R 29 is as defined in
  • Formula I or is a suitable protecting group and LG is a suitable leaving group, such as chloro, bromo, iodo, mesylate or tosylate, in the presence of a suitable base such as N,N- diisopropylethylamine (DIPEA) to provide compounds of Formula I.
  • DIPEA N,N- diisopropylethylamine
  • Suitable inert organic solvents include, but are not limited to, 2- propanol, dimethylformamide (DMF), 1 ,4-dioxane, methylene chloride, chloroform, tetra hydrofuran (THF), toluene, and the like.
  • a desired compound salt is achieved using standard techniques. For example, the neutral compound is treated with an acid or base in a suitable solvent and the formed salt is isolated by filtration, extraction or any other suitable method.
  • 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. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.
  • Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups.
  • available hydroxy or amino groups may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine).
  • reaction step of the present application is carried out in a variety of solvents or solvent systems
  • said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
  • reaction was treated with (R)-2-(2-(6- methoxyindoline-1-carbonyl)pyrrolidin-1-yl)-1-phenyl-2 2 -ethan-1-one (1.5 g, 3.94 mmol) in dry THF (20 mL) over a period of 5 min. after stirring for 15 min. The reaction was brought to room temperature and stirred for additional 4 h. The reaction was cooled to 0 °C, quenched with water (1.0 mL), 2 N NaOH solution (1 mL) and water (1 mL). The reaction was brought to room temperature and stirred for additional 30 min.
  • reaction was brought to room temperature and stirred for additional 4 h.
  • the reaction was cooled to 0 °C, quenched with water (1.0 mL), 2 N NaOH solution (1 mL) and water (1 mL).
  • the reaction was brought to room temperature and stirred for additional 30 min.
  • the reaction was diluted with THF (50 mL), filtered through a pad of Na 2 SO 4 , followed by a pad of silica gel.
  • Solvent was evaporated and crude was purified by column chromatography (2 M NH 3 in MeOH: CH 2 CI 2 , 5:95) on silica gel to obtain the title compound (R)-l-58 (0.8 g, 82.5%) as an off- white solid.
  • reaction was brought to room temperature and stirred for additional 4 h.
  • the reaction was cooled to 0 °C, quenched with water (1.34 mL), 2 N NaOH solution (1.34 mL) and water (1.34 mL).
  • the reaction was brought to room temperature and stirred for additional 30 min.
  • the reaction was diluted with THF (50 mL), filtered through a pad of Na 2 SO 4 , followed by a pad of silica gel.
  • Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH: CH 2 CI 2 , 5:95) on silica gel to obtain the title compound (S)-l-58 (1.14 g, 65.5%) as an off-white solid.
  • reaction was brought to room temperature and stirred for additional 4 h.
  • the reaction was cooled to 0 °C, quenched with water (0.8 mL), 2 N NaOH solution (0.8 mL) and water (0.8 mL).
  • the reaction was brought to room temperature and stirred for additional 30 min.
  • the reaction was diluted with THF (50 mL), filtered through a pad of Na 2 SO 4 , followed by a pad of silica gel. Solvent was evaporated and crude was purified by column chromatography (2 M NH 3 in MeOH: CH 2 CI 2 , 5:95) on silica gel to obtain the title compound (R)-l-46 (0.77 g, 74.7%) as colourless oil.
  • reaction was brought to room temperature and stirred for additional 4 h.
  • the reaction was cooled to 0 °C, quenched with water (1 .0 mL), 2 N NaOH solution (1 .0 mL) and water (1 .0 mL).
  • the reaction was brought to room temperature and stirred for additional 30 min.
  • the reaction was diluted with THF (50 ml_), filtered through a pad of Na 2 SO 4 , followed by a pad of silica gel.
  • Solvent was evaporated and crude was purified by column chromatography (2 M NH 3 in MeOH: CH 2 CI 2 , 5:95) on silica gel to obtain the title compound (R)-l-47 (0.98 g, 76%) as an off-white solid.
  • the reaction was cooled to 0 °C, quenched with water (0.6 mL), 2 N NaOH solution (0.6 mL) and water (0.6 mL). The reaction was brought to room temperature and stirred for additional 30 min. The reaction was diluted with THF (50 mL), filtered through a pad of Na 2 SO 4 , followed by a pad of silica gel. Solvent was evaporated and crude was purified by column chromatography (2 M NH 3 in MeOH: CH 2 CI 2 , 5:95) on silica gel to obtain the title compound (R)-l-59 (0.6 g, 89.5%) as a pale-yellow glue.
  • Example 12 FLIPR assay: human 5-HT2A
  • Electro-thermal incubator Shanghai Yiheng DHP-9031 plate shaker IKA MS3 digital
  • HTR2A&Ga15-HEK293 cells were cultured in DMEM medium containing 10% dialyzed FBS and 1 * penicillin-streptomycin, 100 pg/mL Hygromycin B and 300 pg/mL G418. The cells were passaged about three times a week, maintained between ⁇ 30% to ⁇ 90% confluence.
  • the cell culture medium (DMEM medium containing 10% dialyzed
  • the cell suspension was transferred into a 15 mL centrifuge tube, and then centrifuged at 1 ,200 rpm for 5 minutes.
  • Serotonin HCI was prepared to the concentration of 10 mM with
  • test compounds were prepared to the concentration of 10 mM with DMSO.
  • Cells are cultured in cell culture medium (DMEM containing 10% FBS ,1 * penicillin-streptomycin 300 pg/ml G418 and 100 pg/ml hygromycin B) at 37°C, 5% (v/v) CO2.
  • DMEM cell culture medium
  • penicillin-streptomycin 300 pg/ml G418 and 100 pg/ml hygromycin B penicillin-streptomycin 300 pg/ml G418 and 100 pg/ml hygromycin B
  • FLIPR® Calcium 6 Assay Kit i.
  • the dye is diluted with assay buffer (20mM HEPES in 1x HBSS, PH7.4); ii. Probenecid is added to the final concentration of 5 mM; Hi. Vortex vigorously for 1-2 minutes.
  • 3xcompound in assay buffer is prepared: a. Reference compounds are diluted to required concentration with DMSO. The compounds are added to a 384-well compound plate; b. Serial dilutions are performed; c. 10mM test compounds are added to the compound plate, and 3-fold serial dilutions are performed, d. Transfer 60 nl/well of compounds from source plate to a 384-well compound plate (Corning, 3657) by using an Echo; e. Add 20pl/well assay buffer to the compound plate; f. Mix the plate on plate shaker for 2 mins;
  • Exemplary compounds of Formula I were evaluated functionally using FLIPR assay for their effect on h5-HT2A receptor under agonist mode.
  • the results of potential competition binding properties of the exemplary compounds of the application targeting the human 5-hydroxytryptamine receptor 2A (5-HT2A) are summarized in Table 2.
  • the results of exemplary compounds of the application are presented as IC 5 o is provided in Table 2.
  • Exemplary compounds of Formula I were evaluated using radioligand binding assay on human 5-HT2A receptor. EC 5 o (nM) concentrations are illustrated in Table 2. This assay confirms that compounds of the application are effective ligands of the target human 5-HT2A receptors.
  • Exemplary compounds of Formula I were evaluated functionally using FLIPR assay for their effect on h5-HT 2 A receptor under agonist mode.
  • the objective of this study was to evaluate the binding properties of exemplary compounds of Formula I on 5- hydroxytryptamine receptor 2A (5-HT2A).
  • Ketanserin Hydrochloride [Ethylene- PerkinElmer NET791250UC
  • N 100-100x(U-C2)/(C1-C2), where U is the unknown value, C1 is the average of high controls, and C2 is the average of low controls.
  • Exemplary compounds of Formula I were evaluated using radioligand binding assay on human 5-HT2A receptor.
  • IC50 (nM) concentrations are illustrated in Table 3. This assay confirms that compounds of the application are effective ligands of the target human 5-HT2A receptors.
  • HTR1A&Ga15-CHO cells were cultured in DMEM/F12 medium containing 10% dialyzed FBS, 1 x penicillin-streptomycin and 600 pg/mL Hygromycin B. The cells were passaged about three times a week, maintained between ⁇ 30% to ⁇ 90% confluence.
  • the cell culture medium (DMEM/F12 medium containing 10% dialyzed FBS, 1 x penicillin-streptomycin and 600 pg/mL Hygromycin B), TrypLETM Express and DPBS was warmed to R.T. in advance.
  • the cell suspension was transferred into a 15 mL centrifuge tube, and then centrifuged at 1 ,200 rpm for 5 minutes.
  • probenecid was added to the final concentration of 5 mM.
  • Serotonin was prepared to the concentration of 10 mM with DMSO,
  • Exemplary compounds of Formula I were evaluated using functional FLIPR assay on human 5-HT1A receptor. EC50 (nM) concentrations are illustrated in Table 4. This assay confirms that compounds of the application have moderate functional activity at the target human 5-HT 1 A receptors.

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Abstract

La présente demande concerne des procédés d'activation de récepteurs de sérotonine dans une cellule à l'aide de dérivés d'indoline de formule générale (I) ou d'un sel, solvate et/ou promédicament pharmaceutiquement acceptable de ceux-ci, ainsi que le traitement de maladies, de troubles ou d'états par activation d'un récepteur de sérotonine dans une cellule. Parmi ces maladies, ces troubles ou ces états figurent, par exemple, la psychose, les maladies mentales et les troubles du SNC. La présente demande concerne également de nouveaux dérivés d'indoline et des compositions et des utilisations de ceux-ci. Q étant choisi parmi (Q1), (Q2), (Q3), (Q4) (Q5) et (Q6).
PCT/CA2023/051143 2022-08-29 2023-08-29 Dérivés d'indoline utilisés en tant qu'agents sérotoninergiques utiles pour le traitement de troubles associés WO2024044847A1 (fr)

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WO2023019366A1 (fr) * 2021-08-20 2023-02-23 Mindset Pharma Inc. Dérivés d'indole n-substitués utilisés en tant qu'agents sérotoninergiques utiles pour le traitement de troubles associés
WO2023201423A1 (fr) * 2022-04-19 2023-10-26 Mindset Pharma Inc. Dérivés d'indoline utilisés en tant qu'agents sérotoninergiques utiles pour le traitement de troubles associés

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Publication number Priority date Publication date Assignee Title
WO2023019366A1 (fr) * 2021-08-20 2023-02-23 Mindset Pharma Inc. Dérivés d'indole n-substitués utilisés en tant qu'agents sérotoninergiques utiles pour le traitement de troubles associés
WO2023201423A1 (fr) * 2022-04-19 2023-10-26 Mindset Pharma Inc. Dérivés d'indoline utilisés en tant qu'agents sérotoninergiques utiles pour le traitement de troubles associés

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