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WO2025238416A1 - Dérivés d'indole, utilisations et compositions associées - Google Patents

Dérivés d'indole, utilisations et compositions associées

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Publication number
WO2025238416A1
WO2025238416A1 PCT/IB2025/000216 IB2025000216W WO2025238416A1 WO 2025238416 A1 WO2025238416 A1 WO 2025238416A1 IB 2025000216 W IB2025000216 W IB 2025000216W WO 2025238416 A1 WO2025238416 A1 WO 2025238416A1
Authority
WO
WIPO (PCT)
Prior art keywords
indol
amine
difluoromethoxy
methyl
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2025/000216
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English (en)
Inventor
Abdelmalik Slassi
Joseph A. ARAUJO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mindset Pharma Inc
Original Assignee
Mindset Pharma Inc
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Filing date
Publication date
Application filed by Mindset Pharma Inc filed Critical Mindset Pharma Inc
Publication of WO2025238416A1 publication Critical patent/WO2025238416A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • FIELD [0002] The application relates to analogs of psilocybin for the treatment of different conditions that are treated by activation of serotonin receptor, for example, mental illnesses and other neurological diseases, disorders and conditions, in the fields of psychiatry, neurobiology and pharmacotherapy.
  • Psychedelics have shown show promise in treating diseases such as major depressive disorder, treatment resistant depression, post-traumatic stress disorder (PTSD), and substance use disorder, in addition to end of life existential distress and others. However, many have hallucinogenic effects, impeding their use outside of a clinical setting. There is a need to develop new psychedelics.
  • the present application includes compounds of Formula I or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof: I or a pharmaceutically acceptab and/or prodrug thereof, wherein: X 1 is selected from O, NH, N(C 1-6 alkyl), S, S(O) and SO 2 ; R 1 is selected from R 12 and C 1-6 alkyleneR 12 , wherein the C 1-6 alkylene is optionally substituted with one or more of halo and C 1-6 alkyl; 1 Attorney Docket No.291.0024-WO00 R 2 is selected from H and halo; R 3 is selected from H and halo; R 4 is selected from H and halo; R 5 is selected from H and halo; R 6 is selected from H, halo and C 1-6 alkyl; R 7 is selected from H, halo and C 1-6 alkyl; R 8 is selected from H, halo and C 1-6 al
  • the present application includes a method for activating a serotonin receptor in and/or on a cell, either in a biological sample or in a subject, comprising administering an effective amount of one or more compounds of the application or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, to the cell.
  • 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, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, to a subject in need thereof. In some embodiments, the method of treating psychosis or psychotic symptoms effect in the subject.
  • the 5 Attorney Docket No.291.0024-WO00 method of treating psychosis or psychotic symptoms is without a hallucinogenic effect in the subject.
  • the present application also includes a method of treating a mental illness comprising administering a therapeutically effective amount of one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, to a subject in need thereof.
  • the method of treating a mental illness is without a hallucinogenic effect in the subject.
  • the method of treating a mental illness is with a reduced hallucinogenic effect in the subject.
  • the present application also includes a method of treating a CNS disease, disorder or condition and/or a neurological disease, disorder or condition comprising administering a therapeutically effective amount of one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, to a subject in need thereof.
  • the method of treating a CNS disease, disorder or condition and/or a neurological disease, disorder or condition is without a hallucinogenic effect in the subject.
  • the method of treating a CNS disease, disorder or condition and/or a neurological disease, disorder or condition is with a reduced hallucinogenic effect in the subject.
  • the application additionally provides a process for the preparation of compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof.
  • composition(s) of the application refers to a composition, such a pharmaceutical composition, comprising one or more compounds the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof.
  • an embodiment including “a compound” should be understood to present certain aspects with one compound, or two or more additional compounds.
  • the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), "including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”) are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
  • the second component as used herein is chemically different from the other components or first component.
  • a “third” component is different from the other, first and second components and further enumerated or “additional” components are similarly different.
  • suitable means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, the identity of the molecule(s) to be transformed and/or the specific use for the compound, but the selection would be well within the skill of a person trained in the art. All process/method steps described herein are to be conducted under conditions sufficient to provide the product shown.
  • reaction conditions including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.
  • the terms "about”, “substantially” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ⁇ 5% of the modified term if this deviation would not negate the meaning of the word it modifies or unless the context suggests otherwise to a person skilled in the art.
  • solvate means a compound, or a salt or prodrug of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered.
  • prodrug means a compound, or salt of a compound, that, after administration, is converted into an active drug.
  • zwitterion as used herein means a molecule that contains an equal number of positively- and negatively-charged functional groups.
  • alkyl as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cn1-n2”.
  • C 1-6 alkyl (or “C 1- C 6 alkyl”) means an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms and includes, for example, any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and tert-butyl, n- and iso-propyl, ethyl and methyl.
  • C1-4alkyl refers to n-, iso-, sec- and tert-butyl, n- and isopropyl, ethyl and methyl.
  • alkylene whether it is used alone or as part of another group, means straight or branched chain, saturated alkylene group, that is, a saturated carbon chain that contains substituents on two of its ends. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cn1-n2”.
  • Cn1-n2 the term C1-6alkylene means an alkylene group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkenyl whether it is used alone or as part of another group, means a straight or branched chain, unsaturated alkyl groups containing at least one double bond.
  • Cn1-n2 The number of carbon atoms that are possible in the referenced alkenyl group are indicated by the prefix “Cn1-n2”.
  • C2-6alkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms.
  • alkynyl as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkyl groups containing at least one triple bond.
  • C n1-n2 The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “C n1-n2 ”.
  • C 2-6 alkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms.
  • cycloalkyl as used herein, whether it is used alone or as part of another group, means a carbocyclic group containing one or more rings. Cycloalkyl groups are either saturated or unsaturated (i.e., contain one or more double bonds). The number of carbon atoms that are possible in the referenced cycloalkyl group are indicated by the numerical prefix “Cn1-n2”. For example, the term C3-10cycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • cycloalkyl also refers to cyclic groups containing at least one cycloalkyl group fused, spirofused or bridged to one or more cyclic groups (e.g. cycloalkyl groups are optionally fused, spirofused or bridged to aryl and cycloalkyl groups as defined herein).
  • aryl refers to carbocyclic groups containing at least one aromatic ring.
  • heterocyclyl refers to cyclic groups containing at least one non-aromatic ring in which one or more of the atoms are a heteromoiety selected from O, S, SO, SO 2, N, NH and substituted N and the remaining atoms are C. Heterocyclyl groups are either saturated or unsaturated (i.e., contain one or more double bonds).
  • heterocyclyl group contains the prefix Cn1- n2 this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, 9 Attorney Docket No.291.0024-WO00 in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteromoiety selected from O, S, SO, SO2, N, NH and substituted N and the remaining atoms are C.
  • Heterocyclyl groups are optionally benzofused.
  • heterocyclyl also refers to cyclic groups containing at least one heterocyclyl group fused, spirofused or bridged to one or more cyclic groups (e.g.
  • heterocyclyl groups are optionally fused, spirofused or bridged to aryl, heteroaryl, heterocycloalkyl and cycloalkyl groups as defined herein).
  • heteroaryl refers to cyclic groups containing at least one heteroaromatic ring in which one or more of the atoms are a heteromoiety selected from O, S, N, NH and substituted N and the remaining atoms are C.
  • heteroaryl group contains the prefix C n1-n2 this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteroatom as defined above.
  • Heteroaryl groups are optionally benzofused.
  • benzofused refers to a polycyclic group in which a benzene ring is fused with another ring.
  • a first ring being “fused” with a second ring means the first ring and the second ring share two adjacent atoms there between.
  • a first ring being “bridged” with a second ring means the first ring and the second ring share two non-adjacent atoms there between.
  • a first ring being “spirofused” with a second ring means the first ring and the second ring share one atom there between.
  • halogen refers to a halogen atom and includes fluoro, chloro, bromo and iodo.
  • haloalkyl refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been replaced with a halogen.
  • C 1-6 haloalkyl refers to a C 1 to C 6 linear or branched alkyl group as defined above with one or more halogen substituents.
  • haloalkenyl refers to an alkenyl group as defined above in which one or more of the available hydrogen atoms have been replaced with a halogen.
  • C1-6haloalkenyl or “C1-C6haloalkenyl” refers to a C1 to C6 linear or branched alkenyl group as defined above with one or more halogen substituents.
  • haloalkynyl refers to an alkynyl group as defined above in which one or more of the available hydrogen atoms have been replaced with a halogen.
  • C1-6haloalkynyl refers to a C1 to C6 linear or branched alkynyl group as defined above with one or more halogen substituents.
  • alkoxy as used herein, alone or in combination, includes an alkyl group connected to an oxygen connecting atom.
  • one or more item includes a single item selected from the list as well as mixtures of two or more items selected from the list.
  • substituted as used herein means that the referenced atom contains at least one substituent group other that a hydrogen atom.
  • substituted refers to any chemical grouping, including groups comprising carbon atoms and/or heteroatoms that is compatible with the reaction conditions of the processes of the application.
  • substituent refers to any chemical grouping, including groups comprising carbon atoms and/or heteroatoms that is compatible with the reaction conditions of the processes of the application.
  • a group is substituted with one or more substituents, it understood that the selection of those substituents is independent of each other. That is, the one or more substituents may be the same or different.
  • 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.
  • alternative isotope thereof refers to an isotope of an element that is other than the isotope that is most abundant in nature.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present application is meant to include all suitable isotopic variations of the compounds of general Formula (I) and compounds in Table 2, and pharmaceutically acceptable salts, solvates, zwitterions 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.
  • all available atoms are optionally replaced with alternate isotope” as used herein means that available atoms are optionally replaced with an isotope of that atom of having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • a “compound” refers to the compound and, in certain embodiments, to the extent they are stable, any hydrate or solvate thereof.
  • a hydrate is the compound complexed with water and a solvate
  • zwitterion is the compound complexed with a solvent, which may be an organic solvent or an inorganic solvent.
  • a “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).
  • the compounds of the present application are limited to stable compounds embraced by general Formula I or compounds in Table 2, or pharmaceutically acceptable salts, solvates, zwitterions 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.
  • 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.
  • a suitable protecting group can be made by a person skilled in the art.
  • Many conventional protecting groups are known in the art, for example as described in "Protective Groups in Organic Chemistry” McOmie, J.F.W. Ed., Plenum Press, 1973, in Greene, T.W. and Wuts, P.G.M., "Protective Groups in Organic Synthesis", John Wiley & Sons, 3 rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).
  • prodrug as used herein means a compound, or salt, and/or solvate, and/or zwitterion of a compound, that, after administration, is converted into an active drug. 12 Attorney Docket No.291.0024-WO00 [0061]
  • subject as used herein includes all members of the animal kingdom including mammals, and suitably refers to humans. Thus, the methods of the present application are applicable to both human therapy and veterinary applications.
  • treating or “treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results.
  • Beneficial or desired clinical results include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease and remission (whether partial or total), whether detectable or undetectable.
  • Treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Treatment as used herein also include prophylactic treatment.
  • a subject with early cancer can be treated to prevent progression, or alternatively a subject in remission can be treated with a compound or composition of the application to prevent recurrence.
  • Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the application and optionally consist of a single administration, or alliteratively comprise a series of administrations.
  • the term "effective amount” or “therapeutically effective amount” means an amount of one or more compounds of the application that is effective, at dosages and for periods of time necessary to achieve the desired result.
  • an effective amount is an amount that, for example, increases said activation compared to the activation without administration of the one or more compounds.
  • “Palliating” a disease, disorder or condition means that the extent and/or undesirable clinical manifestations of a disease, disorder or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to not treating the disorder.
  • administered means administration of a therapeutically effective amount of one or more compounds or compositions of the application to a cell, tissue, organ or subject.
  • prevention 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. 13 Attorney Docket No.291.0024-WO00 [0067]
  • the "disease, disorder or condition” as used herein refers to a disease, disorder or condition treated or treatable by activation a serotonin receptor and particularly using a serotonin receptor agonist, such as one or more compounds of the application herein described.
  • treating a disease, disorder or condition treatable by activation of a serotonin receptor means that the disease, disorder or condition to be treated is affected by, modulated by and/or has some biological basis, either direct or indirect, that includes serotonergic activity, in particular increases in serotonergic activity. These diseases respond favourably when serotonergic activity associated with the disease, disorder or condition is agonized by one or more of the compounds or compositions of the application.
  • activation as used herein includes agonism, partial agonist and positive allosteric modulation of a serotonin receptor.
  • serotonin receptors may include the 5-HT1 and /or the 5-HT2 serotonin receptor types.
  • 5-HT2 as used herein mean the serotonin receptor subtypes of the 5-HT2 serotonin receptor: 5-HT2A, 5-HT2B, 5HT2C.
  • therapeutic agent refers to any drug or active agent that has a pharmacological effect when administered to a subject.
  • hallucinogenic effects refers to the altered states of consciousness characterized by alterations in, for example, thought, mood and perception which a subject experiences upon administration or use of a psychedelic compound, such as psilocybin.
  • the term “equivalent dose of psilocybin” as used herein means that a compound is administered or used at a dose that is the same molar amount as a corresponding dose of psilocybin.
  • the present application includes a compound of Formula I or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof: 14 Attorney Docket No.291.0024-WO00 I or a pharmaceutically acceptab and/or prodrug thereof, wherein: X 1 is selected from O, NH, N(C1-6alkyl), S, S(O) and SO2; R 1 is selected from R 12 and C 1-6 alkyleneR 12 , wherein the C 1-6 alkylene is optionally substituted with one or more of halo and C 1-6 alkyl; R 2 is selected from H and halo; R 3 is selected from H and halo; R 4 is selected from H and halo; R 5 is selected from H
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , X 1 , X 2 , X 3 , X 4 and X 5 optionally comprise deuterium.
  • one or more R 2 to R 11 optionally comprise deuterium.
  • X1 is selected from O, NH, N(C1-4alkyl), S, S(O) and SO2.
  • X 1 is selected from O, S, NH, NC1-4alkyl, NC1-4fluoroalkyl, NC1- 4deuteroalkyl, S(O) and SO2. In some embodiments, X 1 is selected from O, S, NH, NCH3, NCD3, NCF3, S(O) and SO2. In some embodiments, X 1 is selected from O, NH and S. In some embodiments, X1 is selected from O, S, S(O) and SO2. In some embodiments, X1 is selected from O and S. In some embodiments, X1 is O. In some embodiments, X1 is S. [0078] In some embodiments, R1 is R12.
  • R1 is C1-6alkyleneR12, wherein the C1-6alkylene is optionally substituted with one or more of Cl, F, I, Br and C1-4alkyl, 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 is C 1-4 alkyleneR 12 , wherein the C 1-4 alkylene is optionally substituted with one or more of D, F, Cl, I, Br, C 1-2 alkyl, C 1-2 fluoroalkyl and C 1-2 deuteroalkyl.
  • R 1 is C1-4alkyleneR 12 , wherein the C1-4alkylene is optionally substituted with one or more of D, F, Cl, I, Br, CH3, CF3, CHF2, CH2F, CD2H, CDH2, CD3, CH2CH3, CF2CF3, and CD2CD3.
  • R 1 is C1-4alkyleneR 12 , wherein the C1-4alkylene is optionally substituted with one or more of D, F, I, Br, CH 3 , CF 3 , CF 2 H, CD 2 H, CDH 2 , CD 3, CH 2 CH 3 , CF 2 CF 3 , and CD 2 CD 3 .
  • R 1 is C 1-3 alkyleneR 12 , wherein the C 1-3 alkylene is optionally substituted with one or more of D, F, CH 3 , CF 3 , CD 2 H, CDH 2 , CD 3, CH2CH3, CF2CF3, and CD2CD3.
  • R 1 selected from R 12 and C1- 3alkyleneR 12 , wherein the C1-3alkylene is optionally substituted with one or more of D, F, CH3, CF3, CD2H, CDH2, CD3, CH2CH3, CF2CF3, and CD2CD3.
  • R1 is selected from R12, CH2R12, CH(CH3)R12, CH 2 CH 2 R 12 , CH 2 CH 2 CH 2 R 12 , CD 2 R 12 , CH(CD 3 )R 12 , CD 2 CD 2 R 12 and CD 2 CD 2 CD 2 R 12 .
  • R 1 is selected from R 12 , CH2R 12 , CH(CH3)R 12 , CH2CH2R 12 and CH2CH2CH2R 12 .
  • R2 is selected from H, D, Cl, F, I and Br.
  • R 2 is selected from H, D, Cl, Br and F.
  • R 2 is selected from H and D.
  • R 2 is D.
  • R 2 is H. 19 Attorney Docket No.291.0024-WO00
  • R3 is selected from H, D, Cl, Br, I and F.
  • R 3 is selected from H, D, Br, Cl and F.
  • R 3 is selected from H and D. In some embodiments, R 3 is D. In some embodiments, R 3 is H. [0082] In some embodiments, R4 is selected from H, D, Cl, Br, I and F. In some embodiments, R 4 is selected from H, D, Br, Cl and F. In some embodiments, R 4 is selected from H and D. In some embodiments, R 4 is D. In some embodiments, R 4 is H. [0083] In some embodiments, R5 is selected from H, D, Cl, Br, I and F. In some embodiments, R 5 is selected from H, D, Br, Cl and F. In some embodiments, R 5 is selected from H and D. In some embodiments, R 5 is D.
  • R 5 is H. [0084] In some embodiments, at least one of R2, R3, R4 and R5 is D. In some embodiments, all of R 2 , R 3 , R 4 and R 5 are D. In some embodiments, all of R 2 , R 3 , R 4 and R 5 are H. In some embodiments, R 2 , R 3 , R 4 and R 5 are independently selected from H, D and F. In some embodiments R 2 , R 3 and R 4 are independently selected from F, Cl and Br. In some embodiments one of R 2 , R 3 and R 4 is selected from F, Cl and Br and the other of R 2 , R 3 and R 4 are H.
  • R6 is selected from H, halo and C1-4alkyl.
  • R 6 is selected from H, Cl, F, Br, I and C 1-4 alkyl, 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 6 is selected from H, Cl, F and C1-4alkyl, 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 deuterium.
  • R 9 is selected from H, Cl, F, Br, I, C 1-4 alkyl, C 1-4 fluoroalkyl and C 1-4 deuteroalkyl.
  • R 6 is selected from H, Cl, F, Br, C 1-4 alkyl, C 1-4 fluoroalkyl and C 1-4 deuteroalkyl.
  • R 6 is selected from H, Cl, F, Br, C1-2alkyl, C1-2fluoroalkyl and C1- 2deuteroalkyl.
  • R6 is selected from H, D, Cl, Br, F, CH3, CF3, CF2H, CD 2 H, CDH 2 , CD 3, CH 2 CH 3 , CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 .
  • R 6 is selected from H, D, Cl, Br, F, CH 3 , CD 2 H, CDH 2 , CF 2 H, CFH 2 , CF 3 , CD 3, CH 2 CH 3 , CH 2 CH 2 D, CH2CD2H and CD2CD3.
  • R 6 is selected from H, D, Cl, F, CH3, CD2H, CDH2 and CD3.
  • R 6 is selected from H, D, F, CH3 and CD3. In some embodiments, R 6 is selected from H, D and F. In some embodiments, R 6 is selected from H and D. In some embodiments, R 6 is D. In some embodiments, R 6 is H. [0087] In some embodiments, R7 is selected from H, halo and C1-4alkyl. In some embodiments, R 7 is selected from H, Cl, F, Br, I and C 1-4 alkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and 20 Attorney Docket No.291.0024-WO00 all available atoms are optionally replaced with alternate isotope thereof.
  • R 7 is selected from H, Cl, F and C1-4alkyl, 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 deuterium.
  • R 7 is selected from H, Cl, F, Br, I, C 1-4 alkyl, C 1-4 fluoroalkyl and C 1-4 deuteroalkyl.
  • R 9 is selected from H, Cl, F, Br, C 1-4 alkyl, C 1-4 fluoroalkyl and C 1-4 deuteroalkyl.
  • R 7 is selected from H, Cl, F, lkyl and C 1- 2deuteroalkyl.
  • R 7 is selected fro 1-4fluoroalkyl and C1-4deuteroalkyl.
  • R 7 is sele F, CH3, CF3, CF2H, CD2H, CDH2, CD3, CH2CH3, CH2CH2D, CH2CD2H and C 2C 3.
  • R 7 is selected from H, D, Cl, Br, F, CH3, CD2H, CDH2, CF2H, CFH2, CF3, CD3, CH2CH3, CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 .
  • R 6 is selected from H, D, F, CH 3 , CD 2 H, CDH 2 and CD 3 .
  • R 7 is selected from H, D, Cl, F, CH 3 and CD 3 . In some embodiments, R 7 is selected from H, D and F. In some embodiments, R 7 is selected from H and D. In some embodiments, R 7 is D. In some embodiments, R 7 is H. [0088] In some embodiments, R8 is selected from H, halo and C1-4alkyl. In some embodiments, R 8 is selected from H, Cl, F, Br, I and C 1-4 alkyl, 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 8 is selected from H, Cl, F and C1-4alkyl, 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 deuterium. In some embodiments, R 8 is selected from H, Cl, F, Br, I, C 1-4 alkyl, C 1-4 fluoroalkyl and C 1-4 deuteroalkyl. In some embodiments, R 8 is selected from H, Cl, F, Br, C 1-4 alkyl, C 1-4 fluoroalkyl and C 1-4 deuteroalkyl.
  • R 8 is selected from H, D, Cl, Br, F, CH3, CF3, CF2H, CD2H, CDH2, CD3, CH2CH3, CH2CH2D, CH2CD2H and CD2CD3. In some embodiments, R 8 is selected from H, D, Cl, Br, F, CH3, CD2H, CDH2, CF2H, CFH2, CF3, CD3, CH2CH3, CH2CH2D, CH2CD2H and CD 2 CD 3 . In some embodiments, R 8 is selected from H, D, Cl, F, CH 3 , CD 2 H, CDH 2 and CD 3 . In some embodiments, R 8 is selected from H, D, F, CH 3 and CD 3 .
  • R 8 is selected from H, D and F. In some embodiments, R 8 is selected from H and D. In some embodiments, R 8 is D. In some embodiments, R 8 is H. [0089] In some embodiments, R9 is selected from H, halo and C1-4alkyl. In some embodiments, R 9 is selected from H, Cl, F, Br, I and C1-4alkyl, 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 9 is selected from H, Cl, F and C 1-4 alkyl, wherein all available hydrogen 21 Attorney Docket No.291.0024-WO00 atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally replaced with deuterium.
  • R 9 is selected from H, Cl, F, I, Br, C1-4alkyl, C1-4fluoroalkyl and C1-4deuteroalkyl.
  • R 9 is selected from H, Cl, F, Br, C1-4alkyl, C1-4fluoroalkyl and C1-4deuteroalkyl.
  • R 9 is selected from H, Cl, F, Br, C 1-2 alkyl, C 1-2 fluoroalkyl and C 1- 2 deuteroalkyl. In some embodiments, R 9 is selected from H, D, Cl, Br, F, CH 3 , CF 3 , CF 2 H, CD 2 H, CDH 2 , CD 3, CH 2 CH 3 , CH 2 CH 2 D, CH 2 CD 2 H and CD 2 CD 3 . In some embodiments, R 9 is selected from H, D, Cl, Br, F, CH3, CD2H, CDH2, CF2H, CFH2, CF3, CD3, CH2CH3, CH2CH2D, CH2CD2H and CD2CD3.
  • R 9 is selected from H, D, Cl, F, CH3, CD2H, CDH2 and CD3. In some embodiments, R 9 is selected from H, D, F, CH3 and CD3. In some embodiments, R 9 is selected from H, D and F. In some embodiments, R 9 is selected from H and D. In some embodiments, R 9 is D. In some embodiments, R 9 is H. [0090] In some embodiments, at least one of R6, R7, R8 and R9 is D or at least one of R6, R7, R8 and R9 comprises D. In some embodiments, at least one of R6 and R7 or R8 and R9 is D or at least one of R6 and R7 or R8 and R9 comprises D.
  • one of R6 and R7 or R8 and R9 is D or one of R6 and R7 or R8 and R9 comprises D In some embodiments, at least one of R6, R7, R8 and R9 is F. In some embodiments, at least one of R6 and R7 or R8 and R 9 is D. In some embodiments, one of R 6 and R 7 orR 8 and R 9 is D. In some embodiments, at least one of R6, R7, R8 and R9 is D. In some embodiments, one, two or three of R6 and R7 or R8 and R9 is D. In some embodiments, R6 and R7 are both D and R8 and R9 are both H.
  • R6 and R7 are both H and R8 and R9 are both D. In some embodiments, R6, R7, R8 and R9 are all H. In some embodiments, R6, R7, R8 and R9 are all D. [0091] In some embodiments, R10 is selected from H, C1-4alkyl, C1-4alkyleneOC1- 4 alkyl, C 1-4 alkyleneSC 1-4 alkyl, C 1-6 alkyleneS(O)C 1-4 alkyl and C 1-6 alkyleneSO 2 C 1-4 alkyl 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 10 is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1- 4 deuteroalkyl, C 1-4 alkyleneOC 1-4 alkyl, C 1-4 alkyleneOC 1-4 fluoroalkyl, C 1-4 alkyleneOC 1- 4 deuteroalkyl, C 1-4 fluoroalkyleneOC 1-4 alkyl, C 1-4 fluoroalkyleneOC 1-4 fluoroalkyl, C 1- 4fluoroalkyleneOC1-4deuteroalkyl, C1-4deuteroalkyleneOC1-4alkyl, C1-4deuteroalkyleneOC1- 4fluoroalkyl, C1-4deuteroalkyleneOC1-4deuteroalkyl, C1-4alkyleneSC1-4alkyl, C1-4alkyleneSC1- 4fluoroalkyl, C1-4alkyleneSC1-4deuteroalkyl, C1-4fluoroalkyleneSC1-4alkyl, C1- 4fluoroalkyleneSC1-4fluoroalkyl
  • R 10 is selected from H, C 1- 4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuteroalkyl, C 1-4 alkyleneOC 1-4 alkyl, C 1-4 alkyleneOC 1-4 fluoroalkyl, C1-4alkyleneOC1-4deuteroalkyl, C1-4alkyleneSC1-4alkyl, C1-4alkyleneSC1-4fluoroalkyl, C1- 4alkyleneSC1-4deuteroalkyl, C1-4alkyleneS(O)C1-4alkyl, C1-4alkyleneS(O)C1-4fluoroalkyl, C1- 4alkyleneS(O)C1-4deuteroalkyl, C1-4alkyleneSO2C1-4alkyl, C1-4alkyleneSO2C1-4fluoroalkyl and C1-4alkyleneSO2C1-4deuteroalkyl.
  • R 10 is selected from H, C1-4alkyl, C1- 4 fluoroalkyl, C 1-4 deuteroalkyl, C 1-4 alkyleneOC 1-4 alkyl, C 1-4 alkyleneOC 1-4 fluoroalkyl and C 1- 4 alkyleneOC 1-4 deuteroalkyl.
  • R 10 is selected from H, D, CH 3 , CD 2 H, CDH2, CD3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH2D, CH2CD2H, CD2CD3, C1-3alkyleneOCH3, C1-3alkyleneOCD2H, C1-3alkyleneOCDH2, C1- 3alkyleneOCD3, C1-3alkyleneOCF3, C1-3alkyleneOCHF2, C1-3alkyleneOCH2CH3, C1- 3alkyleneO CH2CH2CH3, C1-3alkyleneOCH(CH3)2, C1-3alkyleneOCH2CH2D, C1- 3alkyleneOCH2CD2H, and C1-3alkyleneOCD2CD3.
  • R10 is selected from H, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3, C1-3alkyleneOCH3, C1-3alkyleneOCD2H, C1-3alkyleneOCDH2, C1- 3alkyleneOCD3, C1-3alkyleneOCF3 and C1-3alkyleneOCHF2.
  • R 10 is selected from H, CH3, CD3, CD2H, CDH2, CH2CH3, CH2CH2CH3, CH(CH3)2, CF2H, CF3, C1- 3 alkyleneOCH 3 , C 1-3 alkyleneOCF 3 and C 1-3 alkyleneOCHF 2 .
  • R 10 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, C1-3alkyleneOCH3, C1-3alkyleneOCF3 and C1-3alkyleneOCHF2.
  • R11 is selected from H, C1-4alkyl and C1-4alkyleneOC1- 4alkyl, 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 11 is selected from H, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1- 4 deuteroalkyl, C 1-4 alkyleneOC 1-4 alkyl, C 1-4 alkyleneOC 1-4 fluoroalkyl, C 1-4 alkyleneOC 1- 4 deuteroalkyl, C 1-4 fluoroalkyleneOC 1-4 alkyl, C 1-4 fluoroalkyleneOC 1-4 fluoroalkyl, C 1- 4fluoroalkyleneOC1-4deuteroalkyl, C1-4deuteroalkyleneOC1-4alkyl, C1-4deuteroalkyleneOC1- 4fluoroalkyl and C1-4deuteroalkyleneOC1-4deuteroalkyl, C1-4alkyleneSC1-4alkyl, C1- 4alkyleneSC1-4fluoroalkyl, C1-4alkyleneSC1-4deuteroalkyl, C1-4fluoroalkyleneSC1-4alkyl, C1- 4fluoroalkyleneSC1-4fluoroalky
  • R 11 is selected from H, C1- 4alkyl, C1-4fluoroalkyl, C1-4deuteroalkyl, C1-4alkyleneOC1-4alkyl, C1-4alkyleneOC1-4fluoroalkyl, C1-4alkyleneOC1-4deuteroalkyl, C1-4alkyleneSC1-4alkyl, C1-4alkyleneSC1-4fluoroalkyl, C1- 4alkyleneSC1-4deuteroalkyl, C1-4alkyleneS(O)C1-4alkyl, C1-4alkyleneS(O)C1-4fluoroalkyl, C1- 4 alkyleneS(O)C 1-4 deuteroalkyl, C 1-4 alkyleneSO 2 C 1-4 alkyl, C 1-4 alkyleneSO 2 C 1-4 fluoroalkyl and C 1-4 alkyleneSO 2 C 1-4 deuteroalkyl.
  • R11 is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1- 4deuteroalkyl, C1-4alkyleneOC1-4alkyl, C1-4alkyleneOC1-4fluoroalkyl and C1-4alkyleneOC1- 4deuteroalkyl.
  • R11 is selected from H, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH2CH3)CH3, CH(CH3)3, CH 2 CH 2 D, CH 2 CD 2 H, CD 2 CD 3 , C 1-3 alkyleneOCH 3 , C 1-3 alkyleneOCD 2 H, C 1-3 alkyleneOCDH 2 , C1-3alkyleneOCD3, C1-3alkyleneOCF3, C1-3alkyleneOCHF2, C1-3alkyleneOCH2CH3, C1- 3alkyleneO CH2CH2CH3, C1-3alkyleneOCH(CH3)2, C1-3alkyleneOCH2CH2D, C1- 3alkyleneOCH2CD2H, and C1-3alkyleneOCD2CD3.
  • R11 is selected from H, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2D, CH 2 CD 2 H, CD 2 CD 3 , C 1-3 alkyleneOCH 3 , C 1-3 alkyleneOCD 2 H, C 1-3 alkyleneOCDH 2 , C 1- 3 alkyleneOCD 3 , C 1-3 alkyleneOCF 3 and C 1-3 alkyleneOCHF 2 .
  • R 11 is selected from H, CH3, CD2H, CDH2, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF2H, CF3, C1- 3alkyleneOCH3, C1-3alkyleneOCF3 and C1-3alkyleneOCHF2.
  • R 11 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, C1-3alkyleneOCH3, C 1-3 alkyleneOCF 3 and C 1-3 alkyleneOCHF 2 .
  • R10 and R11 are both CH(CH3)2, both CH3 or both CD3.
  • one of R 10 and R 11 is CH3 or CD3 and the other is CH(CH3)2. In some embodiments, one of R 10 and R 11 is CH3 and the other is CH2CH3, CH2CH2CH3, CH(CH3)2, C1-2alkyleneOCH3 or C1-2alkyleneOCHF2. In some embodiments, one of R 10 and R 11 is CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2 and the other is C1-2alkyleneOCH3 or C1-2alkyleneOCHF2.
  • R10 and R11 is C1-6alkyleneOC1-6alkyl, C 1-6 alkyleneSC 1-6 alkyl, C 1-6 alkyleneS(O)C 1-6 alkyl or C 1-6 alkyleneSO 2 C 1-6 alkyl.
  • one of R 10 and R 11 is C1-6alkyleneOC1-6alkyl, C1-6alkyleneSC1-6alkyl, C1- 24 Attorney Docket No.291.0024-WO00 6 alkyleneS(O)C 1-6 alkyl or C 1-6 alkyleneSO 2 C 1-6 alkyl.
  • both R 10 and R 11 are independently sel.
  • one of R 10 and R 11 is selected from H and C1- 6alkyl, and the other is C1-6alkyleneOC1-6alkyl. In some embodiments, one of R 10 and R 11 is selected from H and C1-4alkyl, and the other is C1-4alkyleneOC1-4alkyl. In some embodiments, one of R 10 and R 11 is selected from H and C 1-4 alkyl, and the other is C 1-3 alkyleneOC 1-4 alkyl. In some embodiments, one of R 10 and R 11 is selected from H and C 1-4 alkyl, and the other is C 1-3 alkyleneOC 1-2 alkyl.
  • At least one of R10 and R11 is selected from C1- 6alkyleneOC1-6alkyl, C1-6alkyleneSC1-6alkyl, C1-6alkyleneS(O)C1-6alkyl and C1- 6alkyleneSO2C1-6alkyl.
  • one of R 10 and R 11 is selected from C1- 6 alkyleneOC 1-6 alkyl, C 1-6 alkyleneSC 1-6 alkyl, C 1-6 alkyleneS(O)C 1-6 alkyl and C 1- 6 alkyleneSO 2 C 1-6 alk.
  • both R 10 and R 11 are independently selected from C 1-6 alkyleneOC 1-6 alkyl, C 1-6 alkyleneSC 1-6 alkyl, C 1-6 alkyleneS(O)C 1-6 alkyl and C 1- 6alkyleneSO2C1-6alk.
  • one of R 10 and R 11 is selected from H and C1- 6alkyl, and the other is selected from C1-6alkyleneOC1-6alkyl, C1-6alkyleneSC1-6alkyl, C1- 6alkyleneS(O)C1-6alkyl and C1-6alkyleneSO2C1-6alkyl.
  • one of R 10 and R 11 is C 1-6 alkyleneOC 1-6 alkyl.
  • one of R 10 and R 11 is selected from H and C 1-6 alkyl, and the other is C 1-6 alkyleneOC 1-6 alkyl. In some embodiments, one of R 10 and R 11 is selected from H and C 1-4 alkyl, and the other is C 1-3 alkyleneOC 1-4 alkyl. In some embodiments, one of R 10 and R 11 is selected from H and C1-4alkyl, and the other is C1- 3alkyleneOC1-2alkyl.
  • R10 and R11 together with the N atom to which they are bonded, form a 3- to 6-membered heterocyclic ring which optionally comprises one or more additional heteroatoms independently selected from O, S, S(O), SO 2 , N, and NR 13 and optionally substituted with one to three substituents selected from OH, halo, CN, SH, SO3H, C1-4alkyl, OC1-4alkyl, SC1-4alkyl, C1-4alkyleneOC1-4alkyl, C1-6alkyleneSC1-4alkyl, C1- 6alkyleneS(O)C1-4alkyl and C1-6alkyleneSO2C1-4alkyl, 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 10 and R 11 together with the N atom to which they are bonded, form a 3- to 6-membered heterocyclic ring which optionally comprises one or more additional heteroatoms independently selected from O, S, S(O), SO2, N, and NR 13 and optionally substituted with one to three substituents selected from OH, halo, CN, SH, SO3H, C1-4alkyl, C1-4fluoroalkyl, C 1-4 deuteroalkyl, OC 1-4 alkyl, OC 1-4 fluoroalkyl, OC 1-4 deuteroalkyl, SC 1-4 alkyl, SC 1-4 fluoroalkyl, SC 1-4 deuteroalkyl, C 1-4 alkyleneOC 1-4 alkyl, C 1-4 alkyleneOC 1-4 fluoroalkyl, C 1-4 alkyleneOC 1- 4 deuteroalkyl, C 1-4 fluoroalkyleneOC 1-4 alkyl, C 1-4 fluoroalkyleneOC 1-4 fluoroalkyl,
  • R10 and R11 together with the N atom to which they are bonded, form a 3- to 6-membered heterocyclic ring which optionally comprises one or more additional heteroatoms independently selected from O, S, S(O), SO2, N, and NR 13 and optionally substituted with one to three substituents selected from OH, halo, C 1-4 alkyl, C 1- 4 fluoroalkyl, C 1-4 deuteroalkyl, OC 1-4 alkyl, OC 1-4 fluoroalkyl, OC 1-4 deuteroalkyl, C 1- 4 alkyleneOC 1-4 alkyl, C 1-4 alkyleneOC 1-4 fluoroalkyl, C 1-4 alkyleneOC 1-4 deuteroalkyl, C 1- 4fluoroalkyleneOC1-4alkyl, C1-4fluoroalkyleneOC1-4fluoroalkyl, C1-4fluoroalkyleneOC1- 4deuteroalkyl, C1-4deuteroalkyleneOC
  • R10 and R11 together with the N atom to which they are bonded, form a 5- or 6-membered heterocyclic ring which optionally comprises one or more additional heteroatoms independently selected from O, S, S(O), SO2, N, and NR 13 and optionally substituted with one to three substituents selected from OH, F, C1-4alkyl and OC1- 4alkyl, 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 10 and R 11 together with the N atom to which they are bonded, form a 5- or 6-membered heterocyclic ring which optionally comprises one or more additional heteroatoms independently selected from O, S, S(O), SO2, N, and NR13, and optionally substituted with one to three substituents selected from OH, halo, C1-4alkyl, C1- 4fluoroalkyl, C1-4deuteroalkyl, OC1-4alkyl, OC1-4fluoroalkyl, OC1-4deuteroalkyl C1- C 1- C1- C 1- Attorney Docket No.291.0024-WO00 4 deuteroalkyleneOC 1-4 deuteroalkyl.
  • R 10 and R 11 together with the N atom to which they are bonded, form a 5- or 6-membered heterocyclic ring which optionally comprises one or more additional heteroatoms independently selected from O, S, S(O), SO2, N, and NR 13 and optionally substituted with one to three substituents selected from OH, F, I, Cl, Br, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuteroalkyl, OC 1-4 alkyl, OC 1-4 fluoroalkyl, OC 1- 4 deuteroalkyl, C 1-4 alkyleneOC 1-4 alkyl, C 1-4 alkyleneOC 1-4 fluoroalkyl, and C 1-4 alkyleneOC 1- 4 deuteroalkyl.
  • R 10 and R 11 together with the N atom to which they are bonded, form a 5- or 6-membered heterocyclic ring which optionally comprises 1 to 3 additional heteroatoms independently selected from O, S, S(O), SO2, N, and NR 13 and optionally substituted with one to three substituents selected from OH, F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CD3, CFD 2 , CHD 2 , OCH 3 , OCH(CH 3 ) 2 , OCF 3 , OCFH 2 , OCHF 2 , OCH 2 CF 2 H, OCH 2 CF 3 , OCH 2 CFH 2 , C 1-3 alkyleneOCH 3 , C 1-3 alkyleneOCD 2 H, C 1-3 alkyleneOCDH 2 , C 1-3 alkyleneOCD 3 , C 1- 3alkyleneOCF
  • R10 and R11 together with the N atom to which they are bonded, form a 5- or 6-membered heterocyclic ring which optionally comprises 1 or 2 additional heteroatoms independently selected from O, N and NR 13 and optionally substituted with one to three substituents selected from OH, F, Cl, Br, CH 3 , CH 2 CH 3 , CH2CH2CH3, CH(CH3)2, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CD3, CFD2, CHD2, OCH3, OCH(CH3)2, OCF3, OCFH2, OCHF2, OCH2CF2H, OCH2CF3, OCH2CFH2, C1- 3alkyleneOCH3, C1-3alkyleneOCD2H, C1-3alkyleneOCDH2, C1-3alkyleneOCD3, C1- 3 alkyleneOCF 3 and C 1-3 alkyleneOCHF 2 .
  • R 10 and R 11 together with the N atom to which they are bonded, form a 5- or 6-membered heterocyclic ring which optionally comprises 1 or 2 additional heteroatoms independently selected from O, N and NR 13 and optionally substituted with one to three substituents selected from OH, F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CD3, CFD2, CHD2, OCH3, OCH(CH3)2, OCF3, OCFH2, OCHF2, OCH2CF2H, OCH2CF3, OCH2CFH2, C1-3alkyleneOCH3, C1-3alkyleneOCF3 and C1-3alkyleneOCHF2.
  • R10 and R11 together with the N atom to which they are bonded, form a pyrrolidinyl or a piperidinyl ring and optionally substituted with one or two of OH, F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CD3, CFD2, CHD2, OCH3, OCH(CH3)2, OCF3, OCFH2, OCHF2, OCH2CF2H, OCH2CF3, OCH2CFH2, C1-3alkyleneOCH3, C1-3alkyleneOCF3 and C1- 3alkyleneOCHF2.
  • R 10 and R 11 together with the N atom to which they are bonded, form a pyrrolidinyl or a piperidinyl ring and optionally substituted with one or two 27 Attorney Docket No.291.0024-WO00 of OH, F, CH 3 , CF 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH(CH 3 ) 2 , OCF 3 , OCFH 2 , OCHF2, OCH2CF2H, OCH2CF3, OCH2CFH2, C1-3alkyleneOCH3, C1-3alkyleneOCF3 and C1- 3alkyleneOCHF2.
  • R 10 and R 11 together with the N atom to which they are bonded, form a pyrrolidinyl or a piperidinyl ring and optionally substituted with one or two of OH, F, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCF 3 , OCHF 2 , C 1-3 alkyleneOCH 3 , C 1-3 alkyleneOCF 3 and C 1-3 alkyleneOCHF 2 .
  • R 10 and R 11 together with the N atom to which they are bonded, form a pyrrolidinyl or a piperidinyl ring and optionally substituted with one of CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCHF2, C1-3alkyleneOCH3 and C1-3alkyleneOCHF2.
  • R10 and R11 together with the N atom to which they are bonded, form a pyrrolidinyl ring selected from: , oint
  • R10 and R11, together with the N atom to which they are bonded form a 3- to 6-membered heterocyclic ring which optionally comprises one or more additional heteroatoms independently selected from O, S, S(O), SO 2 , N, and NR 13 and is substituted with one to three substituents selected from OH, CN, SH, SO 3 H, OC 1-6 alkyl, SC 1-6 alkyl, C 1-6 alkyleneOC 1-6 alkyl, C 1-6 alkyleneSC 1-6 alkyl, C 1-6 alkyleneS(O)C 1-6 alkyl and C 1- 6alkyleneSO2C1-6alkyl, wherein all available hydrogen atoms are optionally and 28 Attorney Docket No.291.0024-WO00 independently replaced with a fluorine
  • R 10 and R 11 together with the N atom to which they are bonded, form a 5- to 6-membered heterocyclic ring which optionally comprises one or more additional heteroatoms independently selected from O, S, S(O), SO 2 , N, and NR 13 and is substituted with one to three substituents selected from OH, CN, SH, SO 3 H, OC 1-6 alkyl, SC 1-6 alkyl, C 1-6 alkyleneOC 1-6 alkyl, C 1-6 alkyleneSC 1- 6 alkyl, C 1-6 alkyleneS(O)C 1-6 alkyl and C 1-6 alkyleneSO 2 C 1-6 alkyl, 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 [00103]
  • R12 is selected from substituted phenyl, substituted or unsubstituted 2-naphthyl, substituted or un
  • R 12 is selected from substituted phenyl, substituted or unsubstituted C3-10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO2, N and NR 14 and substituted or unsubstituted 5- to 10-membered heteroaryl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 15 , and the substituents on R 12 are selected from one to three of halo, X 2 H, X 2 C1-6alkyl, CN, C1-6alkyleneX 3 C1-6alkyl and X 2 C1-6alkyleneX 3 C1-6alkyl, 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.
  • R12 is substituted phenyl or is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, azetidinyl, oxetanyl, theitanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, azepanyl, oxepanyl, thianyl, thianyl oxide, thianyl dioxide, thiepanyl, indanyl, thiophenyl, thiazolyl, furanyl, benzo
  • R 12 is substituted phenyl or is selected from substituted or unsubstituted cyclopentyl, cyclohexyl, indanyl, thiophenyl, tetrahydropyranyl, thianyl, thianyl oxide, thianyl dioxide, thiazolyl, pyridinyl, furanyl and pyrrolyl, and the substituents on R 12 are selected from one or two of halo, X 2 H, X 2 C 1-6 alkyl, CN, C 1-6 alkyleneX 3 C 1-6 alkyl and X 2 C 1-6 alkyleneX 3 C 1-6 alkyl, 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.
  • R12 is selected from substituted phenyl, substituted 2- naphthyl, substituted 1-naphthyl, substituted C3-12cycloalkyl, substituted 3- to 10-membered heterocyclyl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 14 and substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteromoeities independently selected from O, S, S(O), SO 2 , N and NR 15 , and the substituents on R 12 are selected from one to four of halo, X 2 H, X 2 C1-6alkyl, CN, C1-6alkyleneX 3 C1-6alkyl and X 2 C1- 6alkyleneX 3 C1-6alkyl, 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.
  • R12 is substituted phenyl, substituted 2-naphthyl, substituted 1-naphthyl, substituted cyclopropyl, substituted cyclobutyl, substituted cyclopentyl, substituted cyclohexyl, substituted cycloheptyl, substituted aziridinyl, substituted oxiranyl, substituted thiiranyl, substituted oxaxiridinyl, substituted azetidinyl, substituted oxetanyl, substituted theitanyl, substituted tetrahydrofuranyl, substituted tetrahydrothiophenyl, substituted pyrrolidinyl, substituted pyrrolyl, substituted pyrazolidinyl, imidazolidinyl, substituted piperidinyl, substituted piperazinyl, substituted tetrahydropyranyl, substituted azepanyl, substituted o
  • R12 is substituted 2-naphthyl or substituted 1-naphthyl, and the substituents are selected from one to three, or one or two substituents of halo, X 2 H, X 2 C1-6alkyl, CN, C1-6alkyleneX 3 C1-6alkyl and X 2 C1-6alkyleneX 3 C1-6alkyl, wherein all available 30 Attorney Docket No.291.0024-WO00 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 12 is substituted phenyl and the substituents are selected from one to three, or one or two of halo, X 2 H, X 2 C1-6alkyl, CN, C1-6alkyleneX 3 C1-6alkyl and X 2 C1-6alkyleneX 3 C1- 6 alkyl, 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.
  • R12 is substituted phenyl and the substituents are selected from one to three, or one or two of halo, X 2 H, X 2 C1-6alkyl, CN, C1-6alkyleneX 3 C1- 6alkyl and X 2 C1-6alkyleneX 3 C1-6alkyl, 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 12 is substituted phenyl substituted with one to three, or one or two substituents selected from halo, X 2 H, X 2 C1-6alkyl, CN, C1-6alkyleneX 3 C1-6alkyl and X 2 C1-6alkyleneX 3 C1-6alkyl, 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.
  • R13 is selected from H and C1-4alkyl, 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 13 is selected from H and C1-4alkyl, 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 deuterium.
  • R 13 is selected from H, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 chloroalkyl and C 1-4 deuteroalkyl.
  • R 13 is selected from H, C 1-2 alkyl, C 1-2 fluoroalkyl, C 1-4 chloroalkyl and C 1- 2deuteroalkyl.
  • R 13 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH(CH3)3, CD3, CDH2, CHD2, CH2CD2H, CH2CD3, CH2CDH2, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CCl3, CH2CClH2, CCl2H, CClH2, CH2CCl2H and CH 2 CCl 3 . In some embodiments, R 13 is selected from H, CH 3 , CF 3 , CFH 2 , CHF 2 , CCl 3 , CCl 2 H and CClH 2 .
  • R 13 is selected from is selected from H, CH3 and CF3. In some embodiments, R 13 is H. [00110] In some embodiments, R14 is selected from H and C1-4alkyl, 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. In some embodiments, R 14 is selected from H and C 1-4 alkyl, 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 deuterium.
  • R 14 is 31 Attorney Docket No.291.0024-WO00 selected from H, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 chloroalkyl and C 1-4 deuteroalkyl. In some embodiments, R 14 is selected from H, C1-2alkyl, C1-2fluoroalkyl, C1-4chloroalkyl and C1- 2deuteroalkyl.
  • R 14 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH(CH3)3, CD3, CDH2, CHD2, CH2CD2H, CH2CD3, CH2CDH2, CF 3 , CFH 2 , CHF 2 , CH 2 CF 2 H, CH 2 CF 3 , CH 2 CFH 2 , CCl 3 , CH 2 CClH 2 , CCl 2 H, CClH 2 , CH 2 CCl 2 H and CH 2 CCl 3 .
  • R 14 is selected from H, CH 3 , CF 3 , CFH 2 , CHF 2 , CCl 3 , CCl 2 H and CClH 2 . In some embodiments, R 14 is selected from H, CH 3 and CF 3 . In some embodiments, R 14 is H. [00111] In some embodiments, R15 is selected from H and C1-4alkyl, 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 15 is selected from H and C 1-4 alkyl, 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 deuterium.
  • R 15 is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl and C1-4deuteroalkyl.
  • R 15 is selected from H, C1-2alkyl, C1-2fluoroalkyl, C1-4chloroalkyl and C1- 2 deuteroalkyl.
  • R 15 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH(CH 3 ) 3 , CD 3 , CDH 2 , CHD 2 , CH 2 CD 2 H, CH 2 CD 3 , CH 2 CDH 2 , CF 3 , CFH 2 , CHF 2 , CH 2 CF 2 H, CH 2 CF 3 , CH 2 CFH 2 , CCl 3 , CH 2 CClH 2 , CCl 2 H, CClH 2 , CH 2 CCl 2 H and CH2CCl3.
  • R 15 is selected from H, CH3, CF3, CFH2, CHF2, CCl3, CCl2H and CClH2. In some embodiments, R 15 is selected from H, CH3 and CF3. In some embodiments, R 15 is H. [00112] In some embodiments, R13, R14, and R15 are all H. In some embodiments, R13, R 14 , and R 15 are all CH 3 .
  • the substituents on R12 are selected from one or more of halo, X 2 H, X 2 C1-4alkyl, CN, C1-4alkyleneX 3 C1-4alkyl and X 2 C1-4alkyleneX 3 C1-4alkyl, 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.
  • the substituents on R 12 are selected from one or more of Cl, F, Br, X 2 H, X 2 C1-4alkyl, CN, C1-4alkyleneX 3 C1-4alkyl and X 2 C1-4alkyleneX 3 C1-4alkyl, 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.
  • the substituents on R12 are selected from one or more of Cl, F, Br, X 2 H, X 2 C 1-4 alkyl, X 2 C 1-4 deuteroalkyl, X 2 C 1-4 fluoroalkyl, CN, C 1-4 alkyleneX 3 C 1- C 1- C1- Attorney Docket No.291.0024-WO00 4 alkyleneX 3 C 1-4 deuteroalkyl, C 1-4 fluoroalkyleneX 3 C 1-4 deuteroalkyl, C 1-4 deuteroalkyleneX 3 C 1- 4deuteroalkyl, X 2 C1-4alkyleneX 3 C1-4alkyl, X 2 C1-4fluoroalkyleneX 3 C1-4alkyl, X 2 C1- 4deuteroalkyleneX 3 C1-4alkyl, X 2 C1-4alkyleneX 3 C1-4deuteroroalkyl, X 2 C1-4fluoroalkyleneX 3 C1- 4deuteroroalkyl, X 2
  • the substituents on R 12 are selected from one or more of Cl, F, I, Br, X 2 H, X 2 C 1-4 alkyl, X 2 C 1-4 deuteroalkyl, X 2 C 1-4 fluoroalkyl, CN, C 1-4 alkyleneX 3 C 1-4 alkyl, C 1- 4alkyleneX 3 C1-4fluoroalkyl, C1-4alkyleneX 3 C1-4deuteroalkyl, X 2 C1-4alkyleneX 3 C1-4alkyl, X 2 C1- 4alkyleneX 3 C1-4deuteroroalkyl, X 2 C1-4fluoroalkyleneX 3 C1-4deuteroroalkyl, and X 2 C1- 4alkyleneX 3 C1-4fluoroalkyl.
  • the substituents on R 12 are selected from one or two of F, Br, I, Cl, X2H, X2CH3, X2CH2CH3, X2CH2CH2CH3, X2CH(CH3)2, X 2 CH(CH 3 )CH 2 CH 3 , X 2 CH(CH 3 ) 3 , X 2 CF 3 , X 2 CFH 2 , X 2 CHF 2 , X 2 CH 2 CF 2 H, X 2 CH 2 CF 3 , X 2 CH 2 CFH 2 , C 1-3 alkyleneX 3 CH 3 , C 1-3 alkyleneX 3 CH 2 CH 3 , C 1-3 alkyleneX 3 CH 2 CH 2 CH 3 , C 1- 3 alkyleneX 3 CH(CH 3 ) 2 , C 1-3 alkyleneX 3 CH(CH 3 )CH 2 CH 3 , C 1-3 alkyleneX 3 CH(CH 3 ) 3 , C 1- 2alkyleneX 3 CF3, C1-3alkyleneX 3 CH
  • the substituents on R12 are selected from one or two of F, Br, I, Cl, X2H, X2CH3, X2CH2CH3, X2CH2CH2CH3, X 2 CH(CH 3 ) 2 , X 2 CF 3 , X 2 CFH 2 , X 2 CHF 2 , X 2 CH 2 CF 2 H, X 2 CH 2 CF 3 , X 2 CH 2 CFH 2 , C 1- 3 alkyleneX 3 CH 3 , C 1-3 alkyleneX 3 CH 2 CH 3 , C 1-3 alkyleneX 3 CH 2 CH 2 CH 3 , C 1- 3alkyleneX 3 CH(CH3)3, C1-2alkyleneX 3 CF3, C1-3alkyleneX 3 CFH2, C1-3alkyleneX 3 CHF2, C1- 3alkyleneX 3 CH2CF2H, C1-3alkyleneX 3 CH2CF3 and C1-3alkyleneX 3 CH2CFH2.
  • X2 is selected from O, S, NH, NC1-4alkyl, C(X4) and C(X 4 )X 5 wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available hydrogen atoms are optionally replaced with deuterium.
  • X 2 is selected from O, S, NH, NC1-4alkyl, NC1- 4fluoroalkyl, NC1-4deuteroalkyl, C(X 4 ) and C(X 4 )X 5 wherein all available hydrogen atoms are optionally and independently replaced with a fluorine or chlorine atom and all available hydrogen atoms are optionally replaced with deuterium.
  • X 2 is selected from O, S, NH and NC 1-6 alkyl wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available hydrogen atoms are optionally replaced with deuterium.
  • X 2 is selected from O, S, NH and NC1-6alkyl, NC1-6fluoroalkyl and NC1-6deuteroalkyl.
  • X 2 is selected from O, S, NH, NCH2CH3, NCF3, NCD3, C(X 4 ) and C(X 4 )X 5 .
  • X 2 is selected from O, S, NH, NCH2CH3, NCH3 and NCD3.
  • X 2 is selected from O and S. In some embodiments, X 2 is S. In some embodiments, X 2 is O. 33 Attorney Docket No.291.0024-WO00 [00116]
  • X3 is selected from O, S, NH and NC1-6alkyl wherein all available hydrogen atoms are optionally and independently replaced with a fluorine or chlorine atom and all available hydrogen atoms are optionally replaced with deuterium. In some embodiments, X 3 is selected from O, S, NH, NC1-6alkyl, NC1-6fluoroalkyl and NC1- 6 deuteroalkyl.
  • X 3 is selected from O, S, NH and NC 1-4 alkyl wherein all available hydrogen atoms are optionally and independently replaced with a fluorine or chlorine atom and all available hydrogen atoms are optionally replaced with deuterium.
  • X 3 is selected from O, S, NH, NC1-4alkyl, NC1-4fluoroalkyl and NC1- 4deuteroalkyl.
  • X 3 is selected from O, S, NH, NCH2CH3, NCH3 and NCD3.
  • X 3 is selected from O and S.
  • X 3 is S.
  • X 3 is O.
  • X4 is selected from O, S, NH and NC1-6alkyl wherein all available hydrogen atoms are optionally and independently replaced with a fluorine or chlorine atom and all available hydrogen atoms are optionally replaced with deuterium.
  • X 4 is selected from O, S, NH and NC1-4alkyl.
  • X 4 is selected from O, S, NH, NC1-6alkyl, NC1-6fluoroalkyl and NC1-6deuteroalkyl.
  • X 4 is selected from O, S, NH, NC 1-4 alkyl, NC 1-4 fluoroalkyl and NC 1- 4 deuteroalkyl In some embodiments, X 4 is selected from O, S, NH, NCH 2 CH 3 , NCH 3 and NCD3. In some embodiments, X 4 is selected from O and S. In some embodiments, X 4 is S. In some embodiments, X 4 is O. [00118] In some embodiments, X5 is selected from O, S, NH and NC1-6alkyl wherein all available hydrogen atoms are optionally and independently replaced with a fluorine or chlorine atom and all available hydrogen atoms are optionally replaced with deuterium.
  • X 5 is selected from O, S, NH and NC1-4alkyl wherein all available hydrogen atoms are optionally and independently replaced with a fluorine or chlorine atom and all available hydrogen atoms are optionally replaced with deuterium.
  • X 5 is selected from O, S, NH, NC 1-6 alkyl, NC 1-6 fluoroalkyl and NC 1- 6 deuteroalkyl.
  • X 5 is selected from O, S, NH, NC 1-4 alkyl, NC 1- 4 fluoroalkyl and NC 1-4 deuteroalkyl
  • X 5 is selected from O, S, NH, NCH2CH3, NCH3 and NCD3.
  • X 4 is selected from O and S.
  • X 5 is S.
  • X 5 is O.
  • X2 is selected from O, S, NH and NC1-6alkyl and X3 is selected from O, S, NH and NC 1-6 alkyl, and the substituents on R 12 are selected from one to three of F, Br, Cl, I, OH, SH, NH 2 , N(C 1-6 alkyl)(C 1-6 alkyl), OC 1-6 alkyl, SC 1-6 alkyl, C 1- 6 alkyleneOC 1-6 alkyl, C 1-4 alkyleneSC 1-4 alkyl, OC 1-6 alkyleneOC 1-6 alkyl, OC 1-6 alkyleneSC 1- 6alkyl and SC1-4alkyleneSC1-4alkyl, wherein all available hydrogen atoms are optionally and 34 Attorney Docket No.291.0024-WO00 independently replaced with a fluorine or chlorine atom and all
  • X2 and X3 are both O, and the substituents on R12 are selected from one to three of F, Br, I, Cl, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCH(CH 3 )CH 2 CH 3 , OCH(CH 3 ) 3 , OCF 3 , OCFH 2 , OCHF 2 , OCH 2 CF 2 H, OCH 2 CF 3 , OCH 2 CFH 2 , C 1-2 alkyleneOCH 3 , C 1-3 alkyleneOCH 2 CH 3 , C 1-3 alkyleneOCH 2 CH 2 CH 3 , C 1- 3 alkyleneOCH(CH 3 ) 2 , C 1-3 alkyleneOCH(CH 3 )CH 2 CH 3 , C 1-3 alkyleneOCH(CH 3 ) 3 , C 1- 3alkyleneOCF3, C1-3alkyleneOCFH2, C1-3alkyleneOCHF2, C1-3alkyleneOCH
  • the substituents on R 12 are selected from one to three of F, OH, OCH3, OCF3, OCHF2, C1-3alkyleneOCH3, C1- 3alkyleneOCF3 and C1-3alkyleneOCHF2. In some embodiments, the substituents on R 12 are one or two of F, one C1-3alkyleneOCHF2 or one OCF2H.
  • R12 is selected from , wherein represents the point of attachment to the rest of the molecule; H, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2, OC 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, F, Cl, I, or Br; a is 0, 1, 2, 3 or 4; Z 2 is OH, SH, NH2, NH(C1-6alkyl), N(C1-6alkyl)2, OC1-6alkyl, OC1-6alkyl, SC1-6alkyl, F, Cl, I, or Br; b is 0, 1, 2, or 3; Z 3 is OH, SH, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2, OC 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, F, Cl, I, or Br; c is 1, 2, 3, 4 or 5; Z 4 is OH, SH, NH2, NH2, NH2, NH2,
  • R12 is selected from [00123] Within the R groups, described throughout the specification, all available hydrogen atoms are optionally and independently replaced with deuterium. [00124] In some embodiments, R12 is selected from Attorney Docket No.291.0024-WO00 .
  • X 1 is selected from O, NH, N(C1-4alkyl), S, S(O) and SO2;
  • R 1 is selected from R 12 and C1-4alkyleneR 12 , wherein the C1-4alkylene is optionally substituted with one or more of halo and C 1-4 alkyl;
  • R 2 is selected from H and halo;
  • R 3 is selected from H and halo;
  • R 4 is selected from H and halo;
  • R 5 is selected from H and halo;
  • R 6 is selected from H, halo and C1-4alkyl;
  • R 7 is selected from H, halo and C1-4alkyl;
  • R 8 is selected from H, halo and C 1-4 alkyl;
  • R 9 is selected from H, halo and C 1-4 alkyl;
  • R 10 is selected from H, C1-4alkyl, C1-4alkyleneOC1-4alkyl, C1-6alkyleneSC1-6alkyl, C1- 6alkyleneS(O
  • X 1 is selected from O, S, NH, NC 1-4 alkyl, NC 1-4 fluoroalkyl, NC 1-4 deuteroalkyl, S(O) and SO 2 ;
  • R 1 is selected from R 12 , C1-4alkyleneR 12 , wherein the C1-4alkylene is optionally substituted with one or more of Cl, F, C1-4alkyl, C1-4fluoroalkyl and C1-4deuteroalkyl;
  • R 2 is selected from H, D, Cl, I, Br, and F;
  • R 3 is from H, D, Cl, I, Br, and F;
  • R 4 is selected from H, D, Cl, I, Br, and F;
  • R 5 is selected from H, D, Cl, I, Br, and F;
  • R 6 is selected from H, Cl, F, I, Br, C 1-4
  • X 1 is selected from O, S, NH, NCH 3 , NCD 3 , NCF 3 , S(O) and SO 2 ;
  • R 1 is selected from R 12 and C1-4alkyleneR 12 , wherein the C1-4alkylene is optionally substituted with one or more of D, F, Cl, C1-2alkyl, C1-2fluoroalkyl and C1-2deuteroalkyl;
  • R 2 is selected from H, D, Cl, Br and F;
  • R 3 is selected from H, D, Cl, Br and F;
  • R 4 is selected from H, D, Cl, Br and F;
  • R 5 is selected from H, D, Cl, Br and F;
  • R 6 is selected from H, Cl, F, Br, C1-2alkyl, C1-2fluoroalkyl and C1-2deuteroalkyl;
  • R 7 is selected from H, Cl, F, Br, C1-2alkyl, C1-2fluoroalkyl and C1-2deuteroalkyl;
  • X 4 is selected from O, S, NH, NCH 3 , NCH 2 CH 3 , NCF 3 and NCD 3
  • X 5 is selected from O, S, NH, NCH 3 , NCH 2 CH 3 , NCF 3 and NCD 3 .
  • X 1 is selected from O, S, S(O) and SO2;
  • R 1 is selected from R 12 and C1-3alkyleneR 12 , wherein the C1-3alkylene is optionally substituted with one or more of D, F, I, Br, Cl, CH3, CF3, CHF2, CH2F, CD2H, CDH2, CD3, CH2CH3, CF 2 CF 3 , and CD 2 CD 3 ;
  • R 2 is selected from H, D, Cl, I, Br and F;
  • R 3 is selected from H, D, Cl, I, Br and F;
  • R 4 is selected from H, D, Cl, I, Br and F;
  • R 5 is selected from H, D, Cl, I, Br and F;
  • R 6 is selected from H, D, Cl, I, Br, F, CH3, CD2H, CDH2, CF2H, CFH2, CF3, CD3, CH2CH3, CH 2 CH 2 D, CH 2 CD 2 H and CD 3 ;
  • R 7 is selected from H, D,
  • C1-3alkylene in R1 is optionally substituted with one or more of D, F, CH 3 , CF 3 , CD 2 H, CDH 2 , CD 3, CH 2 CH 3 , CF 2 CF 3 , and CD 2 CD 3 .
  • C1-3alkylene in R 1 is optionally substituted with one or more of D, F, CH3, CF3, CD2H, CDH2, CD3, CH2CH3, CF2CF3, and CD2CD3.
  • R1 is selected from R 12 , CH2R 12 , CH(CH3)R 12 , CH2CH2R 12 , CH2CH2CH2R 12 , CD2R 12 , and CD 2 CD 2 R 12 .
  • X 1 is selected from O, S, S(O) and SO2;
  • R 1 is selected from CH2R 12 , CH(CH3)R 12 , CH2CH2R 12 , CH2CH2CH2R 12 , CD2R 12 , CH(CD3)R 12 , CD2CD2R 12 and CD2CD2CD2R 12 ;.
  • R 2 is selected from H, D, Cl, Br and F;
  • R 3 is selected from H, D, Cl, Br and F;
  • R 4 is selected from H, D, Cl, Br and F;
  • R 5 is selected from H, D, Cl, Br and F;
  • 42 Attorney Docket No.291.0024-WO00
  • R 6 is selected from H, D, Cl, F, CH 3 , CD 2 H, CDH 2 and CD 3 ;
  • R 7 is selected from H, D, Cl, F, CH3, CD2H, CDH2 and CD3;
  • R 8 is selected from H, D, Cl, F, CH3, CD2H, CDH2 and CD3;
  • R 9 is selected from H, D, Cl, F, CH3, CD2H, CDH2 and CD3;
  • R10 is selected from H, CH3, CD2H, CDH2, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF2H, CF3, C 1-3 alkyleneOCH 3 , C 1-3
  • X2 and X3 are both O, and R12 is optionally substituted with one or two substituents selected from F, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCH(CH3)CH2CH3, OCH(CH3)3, OCF3, OCFH2, OCHF2, OCH2CF2H, OCH2CF3, OCH2CFH2, C1-2alkyleneOCH3, C1-3alkyleneOCH2CH3, C1-3alkyleneOCH2CH2CH3, C1- 3alkyleneOCH(CH3)2, C1-3alkyleneOCH(CH3)CH2CH3, C1-3alkyleneOCH(CH3)3, C1- 43 Attorney Docket No.291.0024-WO00 3 alkyleneOCF 3 , C 1-3 alkyleneOCFH 2 , C 1-3 alkyleneOCHF 2 , C 1-3 alkyleneOCH 2 CF 2 H, C 1- 3alkyleneOCH2CF3 and C1-3alkyleneOCH
  • X 1 is selected from O, S, S(O) and SO2;
  • R 1 is selected from R 12 , CH 2 R 12 , CH(CH 3 )R 12 , CH 2 CH 2 R 12 , CH 2 CH 2 CH 2 R 12 , CD 2 R 12 , and CD2CD2R 12 .
  • R 2 is selected from H, D, Cl, Br and F
  • R 3 is selected from H, D, Cl, Br and F
  • R 4 is selected from H, D, Cl, Br and F
  • R 5 is selected from H, D, Cl, Br and F
  • R 6 is selected from H, D, Cl, F, CH 3 , CD 2 H, CDH 2 and CD 3
  • R 7 is selected from H, D, Cl, F, CH3, CD2H, CDH2 and CD3
  • R 8 is selected from H, D, Cl, F, CH3, CD2H, CDH2 and CD3
  • R 9 is selected from H, D, Cl, F, CH3, CD2H, CDH2 and CD3
  • R 10 is selected from H, CH 3 , CD 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C 1-2 alkyleneOCH 3 , C 1- 2 alkyleneOCF 3 and C 1-2 alkyleneOCHF 2
  • R 11 is selected from H, CH3, CD
  • R6, R7, R8 and R9 is F.
  • X 1 is selected from O, S, S(O) and SO2;
  • R 1 is selected from R 12 , CH 2 R 12 , CH(CH 3 )R 12 , CH 2 CH 2 R 12 , CH 2 CH 2 CH 2 R 12 , CD 2 R 12 and CD2CD2R 12 ;
  • R 2 is selected from H, D, Cl, Br and F;
  • R 3 is selected from H, D, Cl, Br and F;
  • R 4 is selected from H, D, Cl, Br and F;
  • R 5 is selected from H, D, Cl, Br and F;
  • R 6 is selected from H, D, F, CH3 and CD3;
  • R 7 is selected from H, D, F, CH3 and CD3;
  • R 8 is selected from H, D, F, CH3 and CD3;
  • R 9 is selected from H, D, F, CH 3 and CD 3 ;
  • R10 is selected from H, CH3, CD3, CF2H,
  • X 1 is selected from O, S, S(O) and SO2;
  • R 1 is selected from R 12 , CH2R 12 , CH(CH3)R 12 , CH2CH2R 12 and CH2CH2CH2R 12 ;
  • R 2 is selected from H and D;
  • R 3 is selected from H and D;
  • R 4 is selected from H and D;
  • R 5 is selected from H and D;
  • R 6 is selected from H and D;
  • R 7 is selected from H and D;
  • R 8 is selected from H and D;
  • R 9 is selected from H and D;
  • R10 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, C1- 3 alkyleneOCH 3 , C 1-3 alkyleneOCF 3 and C 1-3 alkyleneOCHF 2
  • R11 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2,
  • X 1 is selected from O, S, S(O) and SO 2 ;
  • R 1 is selected from R 12 , CH 2 R 12 , CH(CH 3 )R 12 , CH 2 CH 2 R 12 and CH 2 CH 2 CH 2 R 12 ;
  • 46 Attorney Docket No.291.0024-WO00
  • R 2 is selected from H and D;
  • R 3 is selected from H and D;
  • R 4 is selected from H and D;
  • R 5 is selected from H and D;
  • R 6 is selected from H and D;
  • R 7 is selected from H and D;
  • R 8 is selected from H and D;
  • R 9 is selected from H and D;
  • R10 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, C1- 3alkyleneOCH3, C1-3alkyleneOCF3 and C1-3alkyleneOCHF2, and
  • R11 is selected from H, CH3, CD3, CF2H, CF3, CH2
  • X 1 is selected from O, S, S(O) and SO2;
  • R 1 is selected from R 12 , CH2R 12 , CH(CH3)R 12 , CH2CH2R 12 and CH2CH2CH2R 12 ;
  • R 2 is selected from H and D;
  • R 3 is selected from H and D;
  • R 4 is selected from H and D;
  • R 5 is selected from H and D;
  • R 6 is selected from H and D;
  • R 7 is selected from H and D;
  • R 8 is selected from H and D;
  • R 9 is selected from H and D;
  • 47 Attorney Docket No.291.0024-WO00
  • R10 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, C1- 3alkyleneOCH3, C1-3alkyleneOCF3 and C1-3alkyleneOCHF2, and
  • R11 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH
  • R12 is phenyl substituted with one or two substituents selected from F, OCH3, OCF3, OCHF2, C1-3alkyleneOCH3, C1-3alkyleneOCF3 and C1- 3 alkyleneOCHF 2 .
  • R12 is unsubstituted or substituted or indanyl, and the substituents are selected from one or two of F, OCH3, OCF3, OCHF2, C1-3alkyleneOCH3, C1- 3alkyleneOCF3 and C1-3alkyleneOCHF2.
  • with the substituents on R12 are selected from one or two of F, one C 1-3 alkyleneOCHF 2 or one OCF 2 H.
  • X 1 is selected from O, S, S(O) and SO2;
  • R 1 is selected from R 12 , CH2R 12 , CH(CH3)R 12 , CH2CH2R 12 and CH2CH2CH2R 12 ;
  • R 2 is selected from H and D;
  • R 3 is selected from H and D;
  • R 4 is selected from H and D;
  • R 5 is selected from H and D;
  • R 6 is selected from H and D;
  • R 7 is selected from H and D;
  • R 8 is selected from H and D;
  • R 9 is selected from H and D;
  • R10 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, C1- 3 alkyleneOCH 3 , C 1-3 alkyleneOCF 3 and C 1-3 alkyleneOCHF 2
  • R11 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2,
  • 1 X is O;
  • R 1 is selected from R 12 , CH2R 12 , CH(CH3)R 12 , CH2CH2R 12 and CH2CH2CH2R 12 ;
  • R 2 is selected from H and D;
  • R 3 is selected from H and D;
  • R 4 is selected from H and D;
  • R 5 is selected from H and D;
  • R 6 is selected from H and D;
  • R 7 is selected from H and D;
  • R 8 is selected from H and D;
  • R 9 is selected from H and D;
  • R10 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, C1- 3alkyleneOCH3, C1-3alkyleneOCF3 and C1-3alkyleneOCHF2, and
  • R11 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, C1- 3alkyleneOCH3, C1-3alkyleneOCF3
  • R1 is selected from CH2R 12 , CH(CH3)R 12 , CH2CH2R 12 and CH2CH2CH2R 12 .
  • X 1 is selected from O, S, S(O) and SO 2 ;
  • R 1 is selected from Attorney Docket No.291.0024-WO00
  • R 2 is selecte
  • R 3 is selected from H and D;
  • R 4 is selected from H and D;
  • R 5 is selected from H and D;
  • R 6 is selected from H and D;
  • R 7 is selected from H and D;
  • R 8 is selected from H and D;
  • R 9 is selected from H and D;
  • R10 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, C1- 3 alkyleneOCH 3 , C 1-3 alkyleneOCF 3 and C 1-3 alkyleneOCHF 2
  • R11 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH
  • R1 comprises stereoisomers of the above structures.
  • X1 is O.
  • X1 is selected from S, S(O) and SO 2 .
  • X 1 is S.
  • X 1 is O; R 1 is selected from R 12 , CH2R 12 , CH(CH3)R 12 , CH2CH2R 12 and CH2CH2CH2R 12 ; R 2 is selected from H and D; R 3 is selected from H and D; R 4 is selected from H and D; R 5 is selected from H and D; R 6 is selected from H and D; R 7 is selected from H and D; R 8 is selected from H and D; R 9 is selected from H and D; R10 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, C1- 3 alkyleneOCH 3 , C 1-3 alkyleneOCF 3 and C 1-3 alkyleneOCHF 2 , and R11 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, C1- 3alkyleneOCH3, C1-3alkyleneOCF3 and C1-3alkyleneOCHF 2 , and R11 is selected
  • X 1 is O; R 1 is selected from R 12 , CH 2 R 12 , CH(CH 3 )R 12 , CH 2 CH 2 R 12 and CH 2 CH 2 CH 2 R 12 ; R 2 is H; R 3 is H; R 4 is H; R 5 is H; R 6 is selected from H and D; R 7 is selected from H and D; R 8 is selected from H and D; R 9 is selected from H and D; R10 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, C1- 3alkyleneOCH3, C1-3alkyleneOCF3 and C1-3alkyleneOCHF2, and R11 is selected from H, CH3, CD3, CF2H, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, C1- 3 alkyleneOCH 3 , C 1-3 alkyleneOCF 3 and C 1-3 alkyleneOCHF 2 ; or 56 Attorney Docket No.291.0024-WO00 R 10 and
  • R12 comprises stereoisomers of the above structures.
  • at least one of R2, R3, R4 and R5 is D.
  • all of R 2 , R 3 , R 4 and R 5 are D.
  • all of R 2 , R 3 , R 4 and R 5 are H.
  • at least one of R6 and R7 or R8 and R9 is D.
  • at least one of R6, R7, R8 and R9 is D.
  • at least one of R6, R7, R8 and R9 is D and the remaining of R6, R7, R8 and R9 are H.
  • R6 and R7 are both D and R8 and R9 are both H. In some embodiments, R6 and R7 are both H and R8 and R9 are both D. In some embodiments, R6, R7, R8 and R9 are all H. In some embodiments, R6, R7, R8 and R9 are all D. 60 Attorney Docket No.291.0024-WO00 [ 00156] In some embodiments, R2, R3, R4, R5 are all H and R6, R7, R8 and R9 are independently selected from H and D. In some embodiments, R 2 , R 3 , R 4 , R 5 are all H, and at l east one of R6 and R7 or R8 and R9 is D.
  • R10 and R11 are both CH(CH3)2, both CH3 or both CD3.
  • one of R 10 and R 11 is CH 3 or CD 3 and the other is CH(CH 3 ) 2 .
  • one of R 10 and R 11 is CH 3 and the other is CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C1-2alkyleneOCH3 or C1-2alkyleneOCHF2.
  • one of R 10 and R 11 is CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2 and the other is C1-2alkyleneOCH3 or C1-2alkyleneOCHF2.
  • R12 is selected from substituted or unsubstituted cyclopentyl, cyclohexyl and indanyl, and the substituents on R 12 are selected from one or two of F, OCH 3 , OCF 3 , OCHF 2 , C 1-3 alkyleneOCH 3 , C 1-3 alkyleneOCF 3 and C 1- 3alkyleneOCHF2.
  • R12 is selected from substituted or unsubstituted tetrahydropyranyl, thianyl, thianyl oxide and thianyl dioxide, and the substituents on R 12 are selected from one or two of F, OCH 3 , OCF 3 , OCHF 2 , C 1-3 alkyleneOCH 3 , C 1-3 alkyleneOCF 3 and C 1-3 alkyleneOCHF 2 .
  • R12 is selected from substituted or unsubstituted thiophenyl, thiazolyl, pyridinyl, furanyl and pyrrolyl, and the substituents on R 12 are selected from one or two of F, OCH3, OCF3, OCHF2, C1-3alkyleneOCH3, C1-3alkyleneOCF3 and C1- 3alkyleneOCHF2.
  • R12 is selected from substituted or unsubstituted cyclopentyl, cyclohexyl and indanyl, and the substituents on R 12 are selected from one or two of F, OCH3, OCF3, OCHF2, C1-3alkyleneOCH3, C1-3alkyleneOCF3 and C1- 3alkyleneOCHF2.
  • R2, R3, R4, R5 are all H and R10 and R11 are independently selected from CH 3 , CD 3 and CH(CH 3 ) 2 .
  • R10 and R11 together with the N atom to which they are bonded, form a pyrrolidinyl or a piperidinyl ring and optionally substituted with one OCHF2 or CH2CH2CH3.
  • the compounds of Formula I are selected from the compounds listed below in Table 1 or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof: Table 1 Compound C hemical Structure Chemical Name* Attorney Docket No.291.0024-WO00 I -1 2-(4-((4- (difluoromethoxy)benzyl)oxy)-1H- n- - n- - x ox ox ox n- Attorney Docket No.291.0024-WO00 I -10 2-(4-((4,4- difluorocyclohexyl)methoxy)-1H- n- )- )- )- )- 1- )- 1- H- - 1- - 1- - 63 Attorney Docket No.291.0024-WO00 I -19 N,N-bis(methyl-d3)-2-(4-(thiophen- 3-ylmethoxy)-1H-indol-3-yl)
  • the compounds of Formula I, or the compounds in Table 2 and pharmaceutically acceptable salts, solvates, zwitterions and/or prodrugs thereof are isotopically enriched with deuterium.
  • one or more of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , X 1 , X 2 , X 3 , X 4 and X 5 optionally comprise deuterium.
  • 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. 97 Attorney Docket No.291.0024-WO00 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 98 Attorney Docket No.291.0024-WO00 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-ethylpiper
  • 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, butyl 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
  • dicyclohexylamine, butyl amine, choline and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl and dibutyl sulfates), long chain halides (e.g., decyl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides) and others.
  • 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 organic ligands such as quaternary ammonium salts.
  • pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
  • zwitterions when a compound contains both a basic moiety, such as, but not limited to an aliphatic primary, secondary, tertiary or cyclic amine, an aromatic or heteroaryl amine, pyridine or imidazole and an acidic moiety, such as, but not limited to tetrazole or carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the terms “salt(s)” as used herein. It is understood that certain compounds may exist in zwitterionic form, having both anionic and cationic centers within the same compound and a net neutral charge. Such zwitterions are included within the application.
  • Solvates of compounds of the application include, for example, those made with solvents that are pharmaceutically acceptable. Examples of such solvents include water 99 Attorney Docket No.291.0024-WO00 (resulting solvate is called a hydrate) and ethanol and the like. Suitable solvents are physiologically tolerable at the dosage administered. [00173] It is understood and appreciated that in some embodiments, compounds of the application 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.
  • the stereochemistry of the compounds of Formula I and compounds in Table 2 may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the present application 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 the application can also include tautomeric forms, such as keto-enol tautomers and the like. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • any tautomeric forms which the compounds form, as well as mixtures thereof, are included within the scope of the present application.
  • the compounds of the application may further exist in varying polymorphic forms and it is contemplated that any polymorphs, or mixtures thereof, which form are included within the scope of the present application.
  • the compounds of the application may further be radiolabeled and accordingly all radiolabeled versions of the compounds of the application are included within the scope of the present application. Therefore, the compounds of Formula I and compounds in Table 2 also include those in which one or more radioactive atoms are incorporated within their structure. I II.
  • the compounds of the application are serotonergic binding agents that act as agonists, partial agonists or positive allosteric modulators at a serotonin receptor or subreceptor.
  • the present application includes a method for activating a serotonin receptor in and/or on a cell, either in a biological sample or in a subject, comprising administering an effective amount of one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, to the cell.
  • the application also includes a use of one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, 100 Attorney Docket No.291.0024-WO00 for activating a serotonin receptor in and/or on a cell as well as a use of one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, for the preparation of a medicament for activating a serotonin receptor in and/or on a cell.
  • the application further includes one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, for use in activating a serotonin receptor in and/or on a cell.
  • the activating a serotonin receptor is without a hallucinogenic effect in the subject or is with a reduced hallucinogenic effect in the subject compared to a hallucinogenic effect from administration of an equivalent dose of psilocybin.
  • the compounds of the application are capable of activating a serotonin receptor
  • the compounds of the application are useful for treating diseases, disorders or conditions by activating a serotonin receptor. Therefore, the compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, are useful as medicaments.
  • the compound of the application, and pharmaceutically acceptable salts, solvates, zwitterions and/or prodrugs thereof are non- hallucinogenic.
  • the compound of the application and pharmaceutically acceptable salts, solvates, zwitterions and/or prodrugs thereof, present a reduced hallucinogenic effect.
  • the application also includes one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, for use as a medicament, wherein the use is without a hallucinogenic effect or is with a reduced hallucinogenic effect compared to a hallucinogenic effect from use of an equivalent dose of psilocybin.
  • the present application also includes a method of treating a disease, disorder or condition treatable by activation of a serotonin receptor comprising administering a therapeutically effective amount of one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, to a subject in need thereof, wherein the treating a disease, disorder or condition treatable by activation of a serotonin receptor.
  • the treating is without a hallucinogenic effect in the subject or is with a reduced hallucinogenic effect in the subject compared to a hallucinogenic effect from administration of an equivalent dose of psilocybin.
  • the present application also includes a use of one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, for treatment of a disease, disorder or condition treatable by activation of a serotonin receptor, as well as a use of one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, for the preparation of a 101 Attorney Docket No.291.0024-WO00 medicament for treatment of a disease, disorder or condition treatable by activation of a serotonin receptor.
  • the application further includes one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, for use in treating a disease, disorder or condition treatable by activation of a serotonin receptor.
  • the use is without a hallucinogenic effect or is with a reduced hallucinogenic effect compared to a hallucinogenic effect from use of an equivalent dose of psilocybin.
  • the serotonin receptor is 5-HT2.
  • the serotonin receptor is selected from 5-HT2A, 5-HT2B and/or 5-HT2C.
  • the compounds of the application are useful for preventing, treating and/or reducing the severity of a mental illness disorder and/or condition in a subject. Therefore, in some embodiments, the disease, disorder or condition that is treated by activation of a serotonin receptor is a mental illness. Accordingly, the present application also includes methods and uses of treating a mental illness comprising administering a therapeutically effective amount of one or more compounds of the application or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, to a subject in need thereof. In some embodiments, the method of treating a mental illness is without a hallucinogenic effect in the subject.
  • the mental illness is selected from anxiety disorders such as generalized anxiety disorder, panic disorder, social anxiety disorder and specific phobias; depression such as, post-partum depression, 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; fact
  • 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 neurodegeneration.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is reduced brain- derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR) activation and/or inflammation.
  • BDNF brain- derived neurotrophic factor
  • mTOR mammalian target of rapamycin
  • the disease, disorder or condition that is treated by activation of a serotonin receptor comprises cognitive impairment; ischemia including stroke; neurodegeneration; refractory substance use disorders; sleep disorders; pain, such as social pain, acute pain, cancer pain, chronic pain, breakthrough pain, bone pain, soft tissue pain, nerve pain, referred pain, phantom pain, neuropathic pain, cluster headaches and migraine; obesity and eating disorders; epilepsies and seizure disorders; neuronal cell death; excitotoxic cell death; or a combination thereof.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is psychosis or psychotic symptoms.
  • the present application also includes methods and uses of treating psychosis or psychotic symptoms comprising administering a therapeutically effective amount of one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, to a subject in need thereof.
  • the method of treating psychosis or psychotic symptoms is without a hallucinogenic effect in the subject.
  • the method of treating psychosis or psychotic symptoms is without a reduced hallucinogenic effect in the subject.
  • administering to said subject in need thereof a therapeutically effective amount of the compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion 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 the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof results in an improvement of psychosis or psychotic symptoms such as, but not limited to, hallucinations and delusions.
  • the compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof are useful for treating a central nervous system (CNS) disease, disorder or condition and/or a neurological disease, disorder or condition in a subject in need thereof.
  • 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 the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, to a subject in need thereof.
  • the method of treating a CNS disease, disorder or condition and/or a neurological disease, disorder or condition is without a hallucinogenic effect in the subject.
  • the method of treating a CNS disease, disorder or condition and/or a neurological disease, disorder or condition is with a reduced hallucinogenic effect in the subject.
  • 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;
  • neurological diseases including neurodevelopmental diseases and
  • the “subject in need thereof” is a subject having the disease, disorder or condition to be treated.
  • 104 Attorney Docket No.291.0024-WO00
  • the subject is a mammal.
  • the subject is human.
  • the subject is a non-human animal.
  • the subject is canine.
  • the subject is feline. Accordingly, the compounds, methods and uses of the present application are directed to both human and veterinary diseases, disorders and conditions.
  • the compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion 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 non- human subjects, such as felines or canines.
  • 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 treatable by activation of a serotonin receptor comprising administering a therapeutically effective amount of one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, in combination with another known agent useful for treatment of a disease, disorder or condition treatable by activation of a serotonin receptor to a subject in need thereof.
  • the present application also includes a use of one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, in combination with another known agent useful for treatment of a disease, disorder or condition treatable by activation of a serotonin receptor for treatment of a disease, disorder or condition treatable by activation of a serotonin receptor, as well as a use of one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, in combination with another known agent useful for treatment of a disease, disorder or condition treatable by activation of a serotonin receptor for the preparation of a medicament for treatment of a disease, disorder or condition treatable by activation of a serotonin receptor.
  • the application further includes one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, in combination with another known agent useful for treatment of a disease, disorder or condition treatable by activation of a serotonin receptor for use in treating a disease, disorder or condition treatable by activation of a serotonin receptor.
  • 105 Attorney Docket No.291.0024-WO00 [00203]
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is a mental illness and the one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion 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), leviteracetam, brivaracetam, lamotrigine, gabapentin and topiramate.
  • antipsychotics including typical antipsychotics and atypical antipsychotics
  • antidepressants including selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is selected from attention deficit hyperactivity disorder and attention deficit disorder and a combination thereof.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is attention deficit hyperactivity disorder and/or attention deficit disorder and a combination thereof and the one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion 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 the application, or a pharmaceutically acceptable salt, solvate, zwitterion 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 nicotinic agonists.
  • the acetylcholinesterase inhibitors are selected from donepezil, galantamine, rivastigmine, and phenserine, and combinations thereof.
  • the NMDA antagonists are selected from MK-801, ketamine, phencyclidine, and memantine, and combinations thereof.
  • the nicotinic agonists is nicotine, nicotinic acid, nicotinic alpha7 agonists, or alpha2 beta4 agonists or a combination thereof.
  • the muscarinic agonists is a muscarinic M1 agonist, or a muscarinic M4 agonist, or a combination 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, zwitterion 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,
  • the atypical antipsychotics are selected from amoxapine, amisulpride, aripiprazole, asenapine, blonanserin, brexpiprazole, cariprazine, carpipramine, clocapramine, clorotepine, clotiapine, clozapine, iloperidone, levosulpiride, lurasidone, melperone, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpiride, sultopride, tiapride, veralipride, ziprasidone and zotepine, and combinations thereof.
  • effective amounts vary according to factors such as the disease state, age, sex and/or weight of the subject or species.
  • the amount of a given compound or compounds that will correspond to an effective amount will vary depending upon factors, such as the given drug(s) or compound(s), the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated and the like, but can nevertheless be routinely determined by one skilled in the art.
  • 107 Attorney Docket No.291.0024-WO00 [00215]
  • one or more compounds of the application are administered one, two, three or four times a year.
  • the one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof are administered at least once a week.
  • the one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof are administered to the subject from about one time per two weeks, three weeks or one month.
  • the one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof are administered about one time per week to about once daily.
  • 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 compound(s) and/or a combination thereof. It will also be appreciated that the effective dosage of the compound(s) 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 compound(s) are administered to the subject in an amount and for duration sufficient to treat the subject.
  • the one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof are administered at doses that are not hallucinogenic or psychotomimetic. In some embodiments, the one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, are administered at doses that have a reduced hallucinogenic effect.
  • the compound(s) are administered to the subject one to 4 times 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 have a reduced hallucinogenic effect or psychotomimetic.
  • the one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, are either used alone or in combination with other known agents useful for treating diseases, disorders or conditions by activation of a serotonin receptor.
  • ERTAIN 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 the one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, an additional therapeutic agent and a pharmaceutically acceptable carrier.
  • the dosage of the one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof varies depending on many factors such as the pharmacodynamic properties of the compound(s), 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(s) in the subject to be treated.
  • one or more compounds of the application are administered initially in a suitable dosage that is adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of the one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, from about 0.01 g /cc to about 1000 g/cc, or about 0.1 g/cc to about 100 g/cc.
  • oral dosages of one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof will range between about 10 g per day to about 1000 mg per day for an adult, suitably about 10 g per day to about 500 mg per day, more suitably about 10 g per day to about 200 mg per day.
  • a representative amount is from about 0.0001 mg/kg to about 10 mg/kg, about 0.0001 mg/kg to about 1 mg/kg, about 0.01 mg/kg to about 0.1 mg/kg or about 0.0001 mg/kg to about 0.01 mg/kg will be administered.
  • a representative amount is from about 0.001 g/kg to about 10 mg/kg, about 0.1 g/kg to about 10 mg/kg, about 0.01 g/kg to about 1 mg/kg or about 0.1 g/kg to about 1 mg/kg.
  • a representative amount is from about 0.1 mg/kg to about 10 mg/kg or about 0.1 mg/kg to about 1 mg/kg.
  • compositions are formulated for oral administration and the one or more compounds are suitably in the form of tablets containing 0.1, 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg of active ingredient (one or more compounds of the application) per tablet.
  • the one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion 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 one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion 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 hallucinogenic effects.
  • the compounds of the application are used or administered in an effective amount which comprises administration of doses or dosage regimens that provide clinical effects similar to those exhibited by a human plasma psilocin Cmax of 4 ng/mL or less and/or human 5-HT 2A human CNS receptor occupancy of 40% or less or those exhibited by a human plasma psilocin Cmax of 1 ng/mL or less and/or human 5-HT 2A human CNS receptor occupancy of 30% or less, but with reduced hallucinogenic effects compared to an equivalent dose of psilocybin.
  • the one or more compounds of the application are used or administered in an effective amount which comprises administration of doses or dosage regimens that provide clinical effects similar to those exhibited by a human plasma psilocin Tmax in excess of 60 minutes, in excess of 120 minutes or in excess of 180 minutes, but with reduced hallucinogenic effects compared to an equivalent dose of psilocybin.
  • reduced hallucinogenic effects it is meant that one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, when administered or used, show any detectable reduction in hallucinogenic effects compared to an equivalent dose of psilocybin.
  • the reduced hallucinogenic effects comprise a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% reduction in hallucinogenic effects compared to an equivalent dose of psilocybin.
  • administration or use of the one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof is devoid of a hallucinogenic effect.
  • the risk or propensity for a compound to 110 Attorney Docket No.291.0024-WO00 produce a hallucinogenic effect is measured or assessed using the Head Twitch Response (HTR) assay or Wet Dog Shake (WDS) assay performed in mice or rats, respectively.
  • HTR Head Twitch Response
  • WDS Wet Dog Shake
  • the present application also includes a composition comprising one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, and a carrier.
  • the compounds 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 comprising one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion 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 one or more compounds of the application are administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • a compound is administered by oral, inhalation, parenteral, buccal, sublingual, insufflation, epidurally, nasal, rectal, vaginal, patch, pump, minipump, micro-dosing, topical or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract and includes, for example intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, buccal, sublingual, 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.
  • GI gastrointestinal
  • Parenteral administration may be by continuous infusion over a selected period of time.
  • one or more compounds of the application is orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it is enclosed in hard or soft shell gelatin capsules, or it is compressed into tablets, or it is 111 Attorney Docket No.291.0024-WO00 incorporated directly with the food of the diet.
  • the compound is incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions and the like.
  • carriers that are used include lactose, com starch, sodium citrate and salts of phosphoric acid.
  • Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), or solvents (e.g. medium chain triglycerides, ethanol, water).
  • binding agents e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato starch or sodium star
  • Oral dosage forms also include modified release, for example immediate release and timed-release, formulations.
  • modified-release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet.
  • SR sustained-release
  • ER extended-release
  • CR controlled-release
  • Contin continuous-release
  • Timed-release compositions are formulated, for example as liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc.
  • Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • useful carriers, solvents or diluents include lactose, medium chain triglycerides, ethanol and dried com starch.
  • liquid preparations for oral administration take the form of, for example, solutions, syrups or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use.
  • aqueous suspensions and/or emulsions are administered orally, the compound 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, 112 Attorney Docket No.291.0024-WO00 methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., medium chain triglycerides, almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, 112 Attorney Docket No.291.0024-WO00 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
  • the one or more compounds of Formula I are administered parenterally.
  • solutions of one or more compounds 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.
  • these preparations Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • a person skilled in the art would know how to prepare suitable formulations.
  • sterile solutions of the compounds of the application are usually prepared and the pH's of the solutions are suitably adjusted and buffered.
  • 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.
  • diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.
  • one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof are 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.
  • the form must be sterile and must be fluid to the extent that easy syringability exists.
  • the compounds of the application are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders.
  • the one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion 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 one or more compounds in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which, for example, take the form of a cartridge or refill for use with an atomising device.
  • the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form comprises an aerosol dispenser, it will contain a propellant which is, for example, a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon.
  • Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas.
  • the dosage unit is suitably determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer contains a solution or suspension of the active compound.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator are, for example, formulated containing a powder mix of a compound of the application and a suitable powder base such as lactose or starch.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, are formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine.
  • Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • Suppository forms of the one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion 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 114 Attorney Docket No.291.0024-WO00 and fatty acid esters of polyethylene glycol.
  • the one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof are 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.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof are coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • the one or more compounds of the application are suitably used on their own but will generally be administered in the form of a pharmaceutical composition in which the one or more compounds (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 one or more compounds 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 one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, are used are administered in a composition comprising an additional therapeutic agent. Therefore the present application also includes a pharmaceutical composition comprising one or more compounds of the application, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug 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 treatable by activation of a serotonin receptor, for example those listed in the Methods and Uses section above.
  • the additional therapeutic agent is a psychoactive drug.
  • the application includes pharmaceutical compositions comprising one of more compounds of Formula I, or a pharmaceutically acceptable salt, solvate, zwitterion and/or prodrug thereof, and a pharmaceutically acceptable carrier.
  • a compound also includes embodiments wherein one or more compounds are referenced.
  • V. Preparation of Compounds Compounds of the application 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 is within the purview of the person of skill in the art.
  • a compound of Formula A is reacted with a compound B, wherein LG is a suitable leaving group such as halo (e.g. Br) in the presence of a suitable base, such as an inorganic or organic amine base, to provide compounds of Formula C.
  • a suitable base such as an inorganic or organic amine base
  • Compounds of Formula C are then reacted with oxalyl chloride (D) to provide compounds of Formula E.
  • Compounds of Formula D are then reacted with an amine of Formula F to provide compounds of Formula G which are then reduced using either lithium aluminum hydride or lithium aluminum deuteride to provide the corresponding non-deuterated and deuterated, respectively, compounds of Formula I.
  • compounds of Formula I wherein R1 is R12, R6, R7, R8 and R 9 are all H or are all D and R 12 , R 2 , R 3 , R 4 , R 5 , R 11 , R 12 and X 1 are as defined in Formula I are prepared using a similar method to that shown in Scheme 1, with the exception that compound B is replaced with, for example compound H: R 27 -B(OH) 2 (or the corresponding boronic acid ester) and the compound of Formula A is converted to, for example, a triflate (i.e.
  • the compounds of Formula I are also prepared by first protecting the “X 1 -H” group in the compounds of Formula A with a suitable protecting group, such as benzyl, followed by installation of the ethyl amine group using compounds of Formula D and F and the reduction steps as shown in Scheme 1.
  • a suitable protecting group such as benzyl
  • Salts of compounds of the application may be formed by methods known to those of ordinary skill in the art, for example, by reacting a neutral compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in aqueous medium followed by lyophilization.
  • a neutral compound such as an equivalent amount
  • a medium such as one in which the salt precipitates or in aqueous medium followed by lyophilization.
  • the formation of solvates will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.
  • Suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a "hydrate".
  • solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent.
  • the solvate is typically dried or azeotroped under ambient conditions.
  • suitable conditions to form a particular solvate can be made by a person skilled in the art.
  • Prodrugs of the compounds of the 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).
  • inert solvent e.g. an acid chloride in pyridine.
  • Isotopically-enriched compounds of the application and pharmaceutically acceptable salts, solvates, zwitterions and/or prodrugs thereof can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using suitable isotopically-enriched reagents and/or intermediates.
  • suitable protecting groups will be added to and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in “Protective Groups in Organic Synthesis”, T.W.
  • transformations are given herein and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations – A Guide to Functional Group Preparations” R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry”, March, 4th ed. McGraw Hill (1992) or, “Organic Synthesis”, Smith, McGraw Hill, (1994).
  • Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid- liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.
  • Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.
  • Example 5 Preparation of 1-(bromomethyl)-4-(2-(difluoromethoxy)ethyl)benzene rly, can be prepared from the corresponding starting 127 Attorney Docket No.291.0024-WO00
  • Example 6 Preparation of ((1r,4r)-4-(difluoromethoxy)cyclohexyl)methanol [ 00265]
  • General Scheme 2 can be adapted to obtaining compounds from Table 1, wherein R1 is a heterocycle or a cycloalkyl by replacing in Ste or h starting materials which bear heterocycles or cycloalkyls, instead of gs, as the ones enumerated previously and which are commercially available.
  • Step C the amine component can be replaced with commercially available amines such as the ones enumerated previously.
  • the compounds described in Table 1 can be obtained following the conditions in Scheme 2 by using the appropriate starting materials for Step A and the appropriate amine in Step C.
  • Example 6A Preparation of (R)-3-(2-(3-(Difluoromethoxy)pyrrolidin-1- yl)ethyl)-4-((4-fluorobenzyl)oxy)-1H-indole (R) I-15 [ ] yn ess o -(( - uoro enzy )oxy)- -n oe ( ): sou on o -n o- -o (0.5 g, 3.75 mmol) in dry acetone (10 mL) was treated with potassium carbonate (1.0 g, 7.51 mmol), followed by 1-(bromomethyl)-4-fluorobenzene (0.79 g, 4.20 mmol
  • the reaction was brought to room temperature, then refluxed for additional 2 h.
  • the reaction was cooled to 0 °C and quenched with the sequential addition of water (0.91 mL), 4 N NaOH solution (0.91 mL) and water (0.91 mL).
  • the reaction was brought to room temperature and stirred for additional 30 min.
  • the reaction was filtered through a pad of Na 2 SO 4 and washed with THF (2 x 25 mL).
  • Example 6B Preparation of N,N-Dimethyl-2-(4-((tetrahydro-2H-pyran-4-yl)methoxy)-1H- indol-3-yl)ethan-1-amine (I-77) Attorney Docket No.291.0024-WO00 Synthesis of 4-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-indole (5): A solution of 1H-indol-4- ol (0.5 g, 3.75 mmol) in dry acetone (10 mL) was treated with potassium carbonate (1.0 g, 7.51 mmol), followed by 4-(bromomethyl)tetrahydro-2H-pyran (0.75 g, 4.20 mmol) in a seal tube at room temperature.
  • reaction was stirred for over night (18 h) at 70 C.
  • the reaction was brought to room temperature, filtered through a pad of celite and washed with CH2Cl2 (2 x 15 mL). Solvent was evaporated and crude was purified by column chromatography (EtOAc: Hexanes, 8:92) on silica gel to obtain the title product (0.11 g, 12.6%) as an off- white solid with significant left-over starting material.
  • reaction was treated with dimethylamine solution (0.6 mL, 1.19 mmol, 2 M in THF) at 0 C over a period of 5 min.
  • the reaction was brought to room temperature and stirred for over night (18 h).
  • Reaction was quenched with water (25 mL) and product was extracted into ethyl acetate (2 x 25 mL).
  • Combined organic layer was washed with brine (25 mL), dried (Na2SO4) and solvent was evaporated to obtain crude title compound (0.2 g) as light brown glue.
  • reaction was cooled to 0 C and quenched with the sequential addition of water (0.2 mL), 4 N NaOH solution (0.2 mL) and water (0.2 mL). The reaction was brought to room temperature and stirred for additional 30 min. The reaction was filtered through a pad of Na 2 SO 4 and washed with THF (2 x 25 mL). Combined THF layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH: CH2Cl2, 5:95) on silica gel to obtain the title compound (0.035 g, 25% over two steps) as an off-white solid.
  • Example 8 Human 5-HT2A: Radioligand Binding Assay: Materials and Instruments: M aterials Vendor Cat# 133 Attorney Docket No.291.0024-WO00 Instrumentation and Consumables: I tem Supplier Cat# Microbeta2 Microplate Counter PerkinElmer 2450-0060 Experiment Procedure: [00281] i. Prepare the assay buffer following the table below; Reagent Concentration Tris 50 mM [00282] ii. Preparation of 8 doses of reference and exemplary test compounds starting from 10 mM stock solution as requested by 5-fold serial dilutions with 100%; [00283] iii. Prepare (v/v) DMSO: a.
  • Example 9 Human, Rat and Mouse Liver Microsomes Stability Objective [00292] The objective of this study is to estimate in vitro metabolic stability of exemplary compounds in pooled human, male rat and male mouse liver microsomes. The concentrations of exemplary compounds in reaction systems are evaluated by LC-MS/MS for estimating the stability in pooled human, male rat and male mouse liver microsomes. The in vitro intrinsic clearances of test compounds are determined as well. Protocol [00293] A master solution in the “Incubation Plate” containing phosphate buffer, ultra- pure H2O, MgCl2 solution and liver microsomes is made according to Table 3. The mixture is pre-warmed at 37 C water bath for 5 minutes.
  • Table 3 Preparation of master solution R eagent Stock Concentration Volume Final Concentration Phosphate buffer 200 mM 200 L 100 mM Ultra-pure H2O - 106 L - MgCl2 solution 50 mM 40 L 5 mM Microsomes 20 mg/mL 10 L 0.5 mg/mL 135 Attorney Docket No.291.0024-WO00 [00294] 40 L of 10 mM NADPH solution is added to each well. The final concentration of NADPH is 1 mM. The negative control samples are prepared by replacing NADPH with 40 L of ultra-pure H2O. Samples are prepared in duplicate. Negative controls are prepared in singlet.
  • the reaction is started with the addition of 4 L of 200 M exemplary test compounds or control compounds to each master solution to get the final concentration of 2 M. This study is performed in duplicate.
  • Aliquots of 50 ⁇ L are taken from the reaction solution at 0, 15, 30, 45 and 60 minutes.
  • the reaction solutions are stopped by the addition of 4 volumes of cold methanol with IS (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol and 2 M ketoprofen). Samples are centrifuged at 3,220 g for 40 minutes. Aliquot of 90 ⁇ L of the supernatant is mixed with 90 ⁇ L of ultra-pure H2O and then is used for LC-MS/MS analysis.
  • LC/MS analysis is performed for all samples from this study using a Shimadzu liquid chromatograph separation system equipped with degasser DGU-20A5R,; solvent delivery unit LC-30AD; system controller SIL-30AC; column oven CTO-30A; CTC Analytics HTC PAL System;. Mass spectrometric analysis is performed using a Triple QuadTM 5500 instrument.
  • All calculations are carried out using Microsoft Excel. Peak area ratios of test compound to internal standard (listed in the below table) are determined from extracted ion chromatograms.
  • All calculations are carried out using Microsoft Excel. Peak areas are determined from extracted ion chromatograms.
  • the slope value, k is determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve.
  • the in vitro half-life (in vitro t1/2) is determined from the slope value: [00301] Conversion of the in vitro t1/2 (min) into the in vitro intrinsic clearance (in vitro CLint, in ⁇ L/min/mg proteins) is done using the following equation (mean of duplicate determinations): 136 Attorney Docket No.291.0024-WO00 [00302] l compound that show an initial fast disappearance followed by a slow disappearance, only the time points that are within the initial rate are included in the calculation.
  • Dosing [00307] Formulations were administered intravenously (i.v.) via the tail vein or orally (p.o.) by gavage with disposable feeding needles.
  • Sample collection [00308] Serial blood samples are collected via tail snip. Terminal blood samples are collected under isoflurane anesthesia by cardiac puncture.
  • Sample processing/storage [00309] All blood samples are transferred into K2EDTA tubes on wet ice and centrifuged within 5 min (3200 x g for 5 min at 4oC) to obtain plasma. Plasma are stored at 80°C until analysis. Sample retention: [00310] Plasma samples are analyzed and any remaining samples are stored frozen at 80°C until the study is completed. IV. Bioanalytical method development and sample analysis Matrix: Mouse plasma.
  • Method qualification [00317] i. The determination of the quantification dynamic range using non-zero calibration standards (STDs) in singlet.
  • the STDs consist of a blank matrix sample (without IS), a zero sample (with IS), and at least 6 non-zero STDs covering the expected range and including the lower level of quantitation (LLOQ).
  • Method acceptance criteria [00319] i. At least 75% of non-zero STDs are included in the calibration curve with all back-calculated concentrations within ⁇ 20% deviation from nominal concentrations ( ⁇ 25% for the lower level of quantification, LLOQ).
  • Example 11 Psychedelic-Like Effect of Exemplary Compounds
  • the effect of different doses of exemplary compounds are evaluated on head- twitch response (HTR) as a behavior-based model of psychedelic activity.
  • Protocols Mouse head twitch [00331] Male, C57BL/6J mice (body weight range 20-30g) are dosed with the appropriate dose of test article, and following a 1-minute pre-treatment time, placed in individual observation chambers.
  • Head twitches are defined as a rapid jerk of the head which is not elicited by an external tactile stimulus (Corne and Pickering, 140 Attorney Docket No.291.0024-WO00 Psychopharmacologia, 1967, 11(1): 65-78).
  • Each head twitch is individually counted by a trained observer, and the data expressed as the mean+SEM of 6-10 mice per group. Mice are used in a single experiment only.
  • Rat behavioural test Male, Sprague-Dawley rats (body weight range 250-400g) are dosed with the appropriate dose of test article and following a 1-minute pre-treatment time, placed in locomotor activity boxes (dimensions 17” W x 17” L x 12” H) and are continuously monitored for a 1 hr period with data collected into 10 minute time bins. Animals are visually assessed for overt behavioural signs, including behaviours characteristic of 5-HT2A receptor activation (wet dog shakes, back muscle contractions), 5-HT2A receptor activation (yawning, penile grooming) and 5-HT1A behaviours (forepaw treading, hindlimb abduction) (Halberzettl et al, Behav Brain Res.
  • 5-HT2A receptor activation wet dog shakes, back muscle contractions
  • 5-HT2A receptor activation yawning, penile grooming
  • 5-HT1A behaviours forepaw treading, hindlimb abduction
  • the rats are trained to associate one lever to a psilocybin training dose of 1 mg/kg SC, and the second lever to a neutral stimulus (saline, SC) (Winter et al, Pharmacol Biochem Behav.87(4): 472-480, 2007). Training sessions last 30-min or until the delivery of 50 pellets and continue until the animals attain appropriate stimulus control (defined as six consecutive sessions where animals made no more than 16 lever presses before the delivery of the first reward, and at least 95% total responses on the appropriate lever). The rats continue to receive daily food ration in their home cage at day end. [00334] Once trained, tests of substitution are conducted.

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Abstract

La présente invention concerne des dérivés de psilocybine de formule générale (I), des procédés pour leur préparation, des compositions les comprenant et leur utilisation dans l'activation d'un récepteur de la sérotonine dans une cellule, ainsi que pour le traitement de maladies, de troubles ou d'affections par activation d'un récepteur de la sérotonine dans une cellule. L'invention concerne, par exemple, les méthodes de traitement de maladies, de troubles ou d'affections par activation d'un récepteur de la sérotonine dans une cellule. Parmi les maladies, troubles ou affections figurent, par exemple, la psychose, les maladies mentales et d'autres maladies, troubles et affections neurologiques.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH405312A (de) * 1961-10-20 1966-01-15 Sandoz Ag Verfahren zur Herstellung neuer heterocyclischer Verbindungen
WO2021155468A1 (fr) * 2020-02-04 2021-08-12 Mindset Pharma Inc. Dérivés de psilocine utilisés en tant qu'agents psychédéliques sérotoninergiques pour le traitement de troubles du système nerveux central
WO2021179091A1 (fr) * 2020-03-12 2021-09-16 Bright Minds Biosciences Inc. Dérivés de 3-(2-(aminoéthyl)-indol-4-ol, leurs procédés de préparation et leur utilisation en tant que modulateurs du récepteur 5-ht2
WO2022000091A1 (fr) * 2020-06-30 2022-01-06 Field Trip Psychedelics Inc. Promédicaments à base de tryptamine
WO2023173227A1 (fr) * 2022-03-18 2023-09-21 Enveric Biosciences Canada Inc. Dérivés de tryptamine substitués en c4 et procédés d'utilisation
WO2024013523A1 (fr) * 2022-07-15 2024-01-18 Beckley Psytech Limited Composés à base d'ergoline et de tryptamine et leurs utilisations
WO2024055106A1 (fr) * 2022-09-12 2024-03-21 Bionxt Solutions Inc. Dérivés de psilocine à base d'acides aminés et de glucides

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH405312A (de) * 1961-10-20 1966-01-15 Sandoz Ag Verfahren zur Herstellung neuer heterocyclischer Verbindungen
WO2021155468A1 (fr) * 2020-02-04 2021-08-12 Mindset Pharma Inc. Dérivés de psilocine utilisés en tant qu'agents psychédéliques sérotoninergiques pour le traitement de troubles du système nerveux central
WO2021179091A1 (fr) * 2020-03-12 2021-09-16 Bright Minds Biosciences Inc. Dérivés de 3-(2-(aminoéthyl)-indol-4-ol, leurs procédés de préparation et leur utilisation en tant que modulateurs du récepteur 5-ht2
WO2022000091A1 (fr) * 2020-06-30 2022-01-06 Field Trip Psychedelics Inc. Promédicaments à base de tryptamine
WO2023173227A1 (fr) * 2022-03-18 2023-09-21 Enveric Biosciences Canada Inc. Dérivés de tryptamine substitués en c4 et procédés d'utilisation
WO2024013523A1 (fr) * 2022-07-15 2024-01-18 Beckley Psytech Limited Composés à base d'ergoline et de tryptamine et leurs utilisations
WO2024055106A1 (fr) * 2022-09-12 2024-03-21 Bionxt Solutions Inc. Dérivés de psilocine à base d'acides aminés et de glucides

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