WO2022256554A1 - Fluorinated tryptamine compounds, analogues thereof, and methods using same - Google Patents

Fluorinated tryptamine compounds, analogues thereof, and methods using same Download PDF

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Publication number
WO2022256554A1
WO2022256554A1 PCT/US2022/032000 US2022032000W WO2022256554A1 WO 2022256554 A1 WO2022256554 A1 WO 2022256554A1 US 2022032000 W US2022032000 W US 2022032000W WO 2022256554 A1 WO2022256554 A1 WO 2022256554A1
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Prior art keywords
ethyl
indol
fluoro
amine
methyl
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French (fr)
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Jason WALLACH
Michael DYBEK
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University of the Sciences in Philadelphia
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University of the Sciences in Philadelphia
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Priority to CN202280039914.1A priority Critical patent/CN117957211A/zh
Priority to US18/565,565 priority patent/US20240286998A1/en
Priority to JP2023574858A priority patent/JP2024523822A/ja
Priority to MX2023014437A priority patent/MX2023014437A/es
Priority to BR112023025340A priority patent/BR112023025340A2/pt
Priority to KR1020237044652A priority patent/KR20240017363A/ko
Priority to EP22816868.8A priority patent/EP4347559A4/en
Priority to AU2022287013A priority patent/AU2022287013A1/en
Application filed by University of the Sciences in Philadelphia filed Critical University of the Sciences in Philadelphia
Priority to IL308944A priority patent/IL308944A/en
Priority to CA3220850A priority patent/CA3220850A1/en
Publication of WO2022256554A1 publication Critical patent/WO2022256554A1/en
Anticipated expiration legal-status Critical
Priority to CONC2023/0018652A priority patent/CO2023018652A2/es
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    • 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
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • C07D209/12—Radicals substituted by oxygen atoms
    • 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
    • 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
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • psychiatric diseases and/or disorders may vary, ranging from mild to severe impairment, i.e., severe mental illness, which substantially interferes with or limits one or more major life activities. It is estimated that there are 13.1 million U.S. adults (5.2%) with severe mental illness. There is thus a need in the art for compositions and methods of treating, preventing, and/or ameliorating a psychiatric disease and/or disorder in a subject. The present disclosure addresses this need.
  • the present disclosure provides certain compounds of formula (I), formula (II), and formula (III), or a salt, prodrug, solvate, isotopologue, or stereoisomer thereof, wherein the substituents in (I), (II), and (III) are defined elsewhere herein:
  • the present disclosure further provides pharmaceutical compositions comprising at least one compound of the present disclosure and a pharmaceutically acceptable carrier.
  • the present disclosure further provides methods of treating, preventing, and/or ameliorating a psychiatric disease or disorder in a subject in need thereof.
  • the method comprises administering to the subject a therapeutically effective amount of at least one compound of the present disclosure and/or at least one pharmaceutical composition of the present disclosure.
  • the psychiatric disease or disorder is selected from the group consisting of depressive disorder, anxiety disorder, and eating disorder.
  • the subject is further administered at least one additional agent useful for treating, preventing, and/or ameliorating the psychiatric disease or disorder.
  • the at least one additional agent is selected from the group consisting of a selective serotonin reuptake inhibitor, triple reuptake inhibitor, serotonin and norepinephrine reuptake inhibitor, tricyclic antidepressant, tetracyclic antidepressant, dopamine reuptake inhibitor, mood stabilizer, anticonvulsant, antipsychotic, anxiolytics, benzodiazepines, monoamine releasers, dopamine receptor agonist, cannabinoids, triptans, anti-migraine medications, analgesics, anti- inflammatory, immune modulator, 5-HT1A receptor antagonist, 5-HT2 receptor antagonist, 5-HT3 receptor antagonist, monoamine oxidase inhibitor, and noradrenergic antagonist.
  • a selective serotonin reuptake inhibitor is selected from the group consisting of a selective serotonin reuptake inhibitor, triple reuptake inhibitor, serotonin and norepinephrine reuptake inhibitor, tricyclic antide
  • FIG.1 shows the Head-Twitch Response (HTR) dose response curve of compound 4.
  • FIG.2 shows the Head-Twitch Response (HTR) dose response curve of compound 9.
  • FIG.3 shows the Head-Twitch Response (HTR) dose response curve for non-psychedelic 6-fluoro-N,N-diethyltryptamine (6-F-DET).
  • FIG.4 shows the predicted binding pose of compound 51 to 5-HT2A.
  • FIG.5 shows Head-Twitch Response (HTR) in mice as a function of time with administration of compound 88 at 2 mg/kg and 6 mg/kg as compared to a control (vehicle).
  • HTR Head-Twitch Response
  • values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.
  • a range of "about 0.1% to about 5%” or "about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range.
  • 5-HT1A agonism is being investigated in numerous therapeutic areas including pain, seizure, depression, etc.
  • 5-HT1A partial agonists like buspirone, are approved for the treatment of anxiety.
  • 5-HT1A agonism may counter 5-HT 2A activation reducing the intensity of 5-HT 2A signaling and psychedelic action.
  • 5-HT1A agonism may also contribute to the psychoactive subjective experience of a 5- HT 2A agonist in other ways.
  • the potent psychedelic tryptamine 5-methoxy- dimethyltryptamine (5-MeO-DMT) lacks a strong visual component, in contrast to many other psychedelic 5-HT2A agonists like DMT, but often leads to intense tactile effects and a near death like experience.
  • 5-HT1A agonism is responsible for at least some of the aforementioned differences.
  • 5-HT2C agonism is known to cause an anorectic effect (i.e., loss of appetite), as well as effects on mood including anxiety. With respect to psychedelic drug profile, such effects could be desirable or undesirable depending on indication.
  • it is desirable to minimize 5-HT 2C agonism potentially leading to a psychedelic experience with an attenuated or reduced chance of anxiety relative to existing compounds.
  • some degree of anxiety may actually raise the probability of having a transformative experience that could contribute to a desirable therapeutic outcome.
  • 5-HT 2C agonism may lead to long term (weeks to months) changes in 5-HT2C receptor expression following the administration of a 5-HT 2A /5-HT 2C agonist, which could confer or contribute to a lasting anxiolytic and antidepressant effect. It has been further hypothesized that changes in 5-HT2C expression (e.g., downregulation) that may follow agonist exposure could have unique benefits in anorexia.5-HT2C antagonism or knock down leads to weight gain in many models. Supporting this, chronic treatment with 5- HT2C agonists has led to significant rebound weight gain in animal models.
  • the compounds described herein may agonize one or more receptors selected from the group consisting of 5-HT 2A , 5-HT 2B , 5-HT 2C , and 5-HT 1A , or any mixtures thereof.
  • the compounds described herein are selective for 5-HT 2A over 5-HT 2B .
  • the compounds described herein are selective for 5-HT2A over 5-HT2C.
  • the compounds described herein are selective for 5-HT2A over 5-HT1A.
  • the compounds described herein are selective for 5-HT2A over 5-HT2B, 5-HT2C, and 5-HT 1A .
  • the compounds of the present disclosure selectively agonize 5-HT2A and 5-HT1A over 5-HT2B and 5-HT2C. In certain embodiments, the compounds of the present disclosure selective agonize 5-HT2A, 5-HT2C, and 5-HT1A over 5-HT2B. In certain embodiments, the compounds of the present disclosure selectively agonize 5-HT 1A over 5-HT 2A , 5-HT 2B , and 5-HT 2C . In certain embodiments, selectivity for 5-HT2A over 5-HT2B is desirable. In certain embodiments, selectivity for 5-HT 2A over 5-HT 2C is desirable. In certain embodiments, selectivity for 5-HT 2A over 5-HT 1A is desirable.
  • alkenyl refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms.
  • alkyl refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n- hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • alkyl encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl.
  • Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • alkynyl refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to among others.
  • acyl refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is bonded to a hydrogen forming a "formyl" group or is bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like.
  • An acyl group can include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group.
  • An acyl group can include double or triple bonds within the meaning herein.
  • An acryloyl group is an example of an acyl group.
  • An acyl group can also include heteroatoms within the meaning herein.
  • a nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein.
  • Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like.
  • the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen
  • the group is termed a "haloacyl” group.
  • An example is a trifluoroacetyl group.
  • alkoxy refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.
  • cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms.
  • an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.
  • the term "amine” as used herein refers to primary, secondary, and tertiary amines having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like.
  • Amines include but are not limited to R-NH 2 , for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like.
  • amine also includes ammonium ions as used herein.
  • aromatic refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized ⁇ (pi) electrons, where ‘n’ is an integer.
  • aryl refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
  • aryl groups contain about 6 to about 14 carbons in the ring portions of the groups.
  • Aryl groups can be unsubstituted or substituted, as defined herein.
  • aryl-(C 1 -C 6 )alkyl refers to a functional group wherein a one- to-six carbon alkylene chain is attached to an aryl group, e.g., -CH 2 CH 2 -phenyl or -CH 2 -phenyl (or benzyl).
  • aryl-CH 2 - and aryl-CH(CH 3 )- are aryl-CH 2 - and aryl-CH(CH 3 )-.
  • substituted aryl-(C 1 - C 6 )alkyl refers to an aryl-(C 1 -C 6 )alkyl functional group in which the aryl group is substituted.
  • substituted aryl(CH 2 )- is substituted.
  • heteroaryl-(C 1 -C 6 )alkyl refers to a functional group wherein a one-to-three carbon alkylene chain is attached to a heteroaryl group, e.g., -CH 2 CH 2 -pyridyl.
  • a specific example is heteroaryl-(CH 2 )-.
  • substituted heteroaryl-(C 1 -C 6 )alkyl refers to a heteroaryl-(C 1 -C 6 )alkyl functional group in which the heteroaryl group is substituted.
  • a specific example is substituted heteroaryl-(CH 2 )-.
  • co-administered and co-administration as relating to a subject refer to administering to the subject a compound and/or composition of the invention along with a compound and/or composition that may also treat or prevent a disease or disorder contemplated herein.
  • the co-administered compounds and/or compositions are administered separately, or in any kind of combination as part of a single therapeutic approach.
  • the co-administered compound and/or composition may be formulated in any kind of combinations as mixtures of solids and liquids under a variety of solid, gel, and liquid formulations, and as a solution.
  • cycloalkyl refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein.
  • Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri- substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • cycloalkenyl alone or in combination denotes a cyclic alkenyl group.
  • a "disease” is a state of health of a subject wherein the subject cannot maintain homeostasis, and wherein if the disease is not ameliorated then the subject’s health continues to deteriorate.
  • a “disorder” in a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the subject’s state of health.
  • half-maximal inhibitory concentration refers to the concentration of a compound or composition required to obtain a 50% decrease in a biological or biochemical process with administration of a compound and/or composition.
  • half-maximal effective concentration refers to the concentration of a compound or composition required to obtain a 50% increase in a biological or biochemical process with administration of a compound and/or composition.
  • halo means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • haloalkyl group includes mono-halo alkyl groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like.
  • heteroalkyl by itself or in combination with another term refers to, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group.
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 NH-OCH 3 , or -CH 2 CH 2 SSCH 3 .
  • heteroarylalkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein.
  • heteroaryl refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members.
  • a heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure.
  • a heteroaryl group designated as a C 2 -heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C4- heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.
  • Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein. Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl
  • heterocyclyl refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S.
  • a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof.
  • heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members.
  • a heterocyclyl group designated as a C 2 -heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms.
  • a heterocyclyl ring can also include one or more double bonds.
  • a heteroaryl ring is an embodiment of a heterocyclyl group.
  • the phrase "heterocyclyl group" includes fused ring species including those that include fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein.
  • Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridin
  • heterocyclylalkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein.
  • heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
  • hydrocarbon or “hydrocarbyl” as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups.
  • hydrocarbyl refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (Ca- C b )hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms.
  • (C 1 -C 4 )hydrocarbyl means the hydrocarbyl group can be methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ), or butyl (C4), and (C0-Cb)hydrocarbyl means in certain embodiments there is no hydrocarbyl group.
  • the term "independently selected from” as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise.
  • X 1 , X 2 , and X 3 are independently selected from noble gases” would include the scenario where, for example, X 1 , X 2 , and X 3 are all the same, where X 1 , X 2 , and X 3 are all different, where X 1 and X 2 are the same but X 3 is different, and other analogous permutations.
  • the term “median effective dose” or “ED 50 ” as used herein refers to the dose or concentration of a compound and/or composition that produces a therapeutic effect in 50% of the population administered the dose.
  • organic group as used herein refers to any carbon-containing functional group.
  • Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups.
  • an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group
  • a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester such as an alkyl and aryl sulfide group
  • sulfur-containing group such as an alkyl and aryl sulfide group
  • Non-limiting examples of organic groups include OR, OOR, OC(O)N(R) 2 , CN, CF 3 , OCF 3 , R, C(O), methylenedioxy, ethylenedioxy, N(R) 2 , SR, SOR, SO2R, SO2N(R) 2 , SO3R, C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R) 2 , OC(O)N(R) 2 , C(S)N(R) 2 , (CH 2 )0-2N(R)C(O)R, (CH 2 )0- 2 N(R)N(R) 2 , N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R) 2 , N(R)SO 2 R, N
  • the term “pharmaceutical composition” or “composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition facilitates administration of the compound to a subject.
  • pharmaceutically acceptable refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound useful within the invention, and is relatively non-toxic, i.e., the material may be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term "pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the subject such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the subject such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the subject.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline
  • pharmaceutically acceptable carrier also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the compositions.
  • the "pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention.
  • Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.
  • the language “pharmaceutically acceptable salt” refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids and/or bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates (including hydrates) and clathrates thereof.
  • a “pharmaceutically effective amount,” “therapeutically effective amount,” or “effective amount” of a compound is that amount of compound that is sufficient to provide a beneficial effect to the subject to which the compound is administered.
  • the term “prevent,” “preventing,” or “prevention” as used herein means avoiding or delaying the onset of symptoms associated with a disease or condition in a subject that has not developed such symptoms at the time the administering of an agent or compound commences.
  • prodrug refers to a biologically inactive compound which is metabolized to a biologically active compound in vivo.
  • metabolic reactions include hydrolysis and reduction.
  • a prodrug of a compound of the present invention may comprise substitution of any heteroatom with any of a number of unique prodrug moieties, including but not limited to an ester, amide, carbamate, carbonate ester, urea, imine, enamine, phosphate ester, thioester, sulfate, sulfonamide, acyloxyalkyl ester, disulfide, and N-sulfonyl imidate.
  • room temperature refers to a temperature of about 15 °C to 28 °C.
  • solvent refers to a liquid that can dissolve a solid, liquid, or gas.
  • Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.
  • subject and subject can be used interchangeably and may refer to a human or non-human mammal or a bird.
  • Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. In certain embodiments, the subject is human.
  • substantially refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%.
  • substantially free of can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less.
  • substantially free of can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%.
  • substituted as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms.
  • functional group or “substituent” as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group.
  • substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N- oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups.
  • a halogen e.g., F, Cl, Br, and I
  • an oxygen atom in groups such as hydroxy groups, alk
  • Non- limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R) 2 , CN, NO, NO 2 , ONO 2 , azido, CF 3 , OCF 3 , R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R) 2 , SR, SOR, SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R) 2 , OC(O)N(R) 2 , C(S)N(R) 2 , (CH 2 ) 0-2 N(R)C(O)R, (CH 2 )N(R)N(R) 2
  • treat means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a subject by virtue of administering an agent or compound to the subject.
  • the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the ring can be saturated or partially saturated, and can be optionally substituted.
  • the psychoactive experience (acute subjective effects) induced by 5-HT 2A agonists like Psilocybin (via its active metabolite psilocin) can be an intense psychological experience for patients. This duration risks limiting the access of this medication to patients and puts restrictions on the number of patients a clinician can treat. Furthermore, a longer duration is unlikely to be necessary for the clinical benefits in most therapeutic indications. For example, ketamine, an atypical rapid acting antidepressant, also induces potent psychoactive effects but with a one hour duration of action. Thus, a 5-8 hour experience is likely unnecessary for clinical outcome.
  • 5-HT2A agonists because the psychoactive effects of psilocybin and other 5-HT 2A agonists can be intense, patients need to be monitored by a physician or other caregiver during administration. Short duration 5-HT2A agonists that retain desired clinical activity can offer greater convenience for patients and their caregivers. Numerous previously studied fluorinated tryptamines have been shown to lack or reduce the classic psychoactivity associated with 5-HT2A agonists. The clearest and strongest example of this is with 6-fluoro-N,N-diethyltryptamine (6-F-DET), which has been tested in humans and found to lack the characteristic psychoactive effects of hallucinogenic 5-HT 2A agonists, such as psilocybin.
  • 6-F-DET 6-fluoro-N,N-diethyltryptamine
  • 6-F-DET has been used as an inactive control in clinical research since it induces some of the physiological effects but not the potent psychological effects seen with psychedelic 5-HT 2A agonists.
  • Others have described fluorinated dimethyl tryptamine (DMT) analogs as non-hallucinogenic synaptogenesis modulators.
  • DMT fluorinated dimethyl tryptamine
  • the duration of DMT analogs is generally short, under thirty minutes, which may be too brief for long term efficacy in disease states like major depressive disorder, post-traumatic stress disorder and substance use disorders. DMT and many of its analogs also lack oral activity.
  • the fluorinated compounds of the present invention act as 5-HT2A receptor agonists and induce psychoactive effects comparable to longer acting 5-HT 2A agonists like psilocybin, but with a reduced duration of action. Fluorine substitution at key sites of the indole ring can maintain high 5-HT2A efficacy and provide potent psychoactive effects.
  • the N-alkyl amine substituents discovered here uniquely modulate the pharmacokinetics of the compounds allowing tailoring of the desired pharmacological activities including binding profiles, bioavailability, half-life, and thus efficacy, side effect profile, and duration of the classic 5-HT2A mediated psychoactive effects.
  • asymmetric N,N-dialkyl amine substitutions completely novel to the 5- HT 2A tryptamine SAR, offer a unique strategy to optimize the balance between pharmacodynamic activity and desired pharmacokinetics, such as duration of action.
  • the compound of formula (I) is not N-ethyl-N-(2-(4-fluoro-1H- indol-3-yl)ethyl)propan-1-amine. In certain embodiments, the compound of formula (I) is not N- ethyl-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)propan-1-amine. In certain embodiments, the compound of formula (I) is not N-ethyl-N-(2-(6-fluoro-1H-indol-3-yl)ethyl)propan-1-amine.
  • the compound of formula (I) is not N-ethyl-N-(2-(7-fluoro-1H-indol-3- yl)ethyl)propan-1-amine. In certain embodiments, the compound of formula (I) is not N-ethyl-2- (4-fluoro-1H-indol-3-yl)-N-methylethan-1-amine. In certain embodiments, the compound of formula (I) is not N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine.
  • the compound of formula (I) is not N-ethyl-2-(6-fluoro-1H-indol-3-yl)-N- methylethan-1-amine. In certain embodiments, the compound of formula (I) is not N-ethyl-2-(7- fluoro-1H-indol-3-yl)-N-methylethan-1-amine. In certain embodiments, the compound of formula (I) is not (R)-4-fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H-indole.
  • the compound of formula (I) is not (R)-4-fluoro-3-((1-(methyl- d3)pyrrolidin-2-yl)methyl)-1H-indole. In certain embodiments, the compound of formula (I) is not (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl-d2)-1H-indole. In certain embodiments, the compound of formula (I) is not (S)-4-fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl-d2)-1H- indole.
  • R 1 is ethyl and R 2 is n-propyl
  • R 1 is n-propyl and R 2 is ethyl
  • R 1 is methyl and R 2 is ethyl
  • R 1 is ethyl and R 2 is methyl
  • no more than two of R 4 , R 5 , R 6 , and R 7 are H.
  • R 1 is n-butyl
  • R 2 is not 4-fluorobutyl.
  • R 1 is not 4-fluorobutyl.
  • R 1 is n- butyl
  • R 2 is not a C 4 fluoroalkyl.
  • R 1 is not a C 4 fluoroalkyl.
  • at least two of R 4 , R 5 , R 6 , and R 7 are F.
  • the compound of formula (I) is a compound of formula (I’’), or a salt, prodrug, solvate, isotopologue, or stereoisomer thereof: wherein: A is selected from the group consisting of , , , ,
  • R 3 is selected from the group consisting of H, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted benzyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 - C 8 alkenyl, and optionally substituted C 2 -C 8 alkynyl;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from the group consisting of H, F, Cl, Br, I, OR A , N(R A )(R B ), SR A , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C 2 -C 9 heteroaryl, wherein at least one of R 4 , R 5 , R 6 , and R 7 is F; each occurrence of R A
  • the compound of formula (I) is a compound of formula (I’’’), or a salt, prodrug, solvate, isotopologue, or stereoisomer thereof: wherein: A is selected from the group consisting R a1 and R a2 , if present, are each independently selected from the group consisting of H, halogen, C 1 -C 6 alkoxy, and C 1 -C 6 alkyl, R b1 and R b2 , if present, are each independently selected from the group consisting of H and C 1 -C 6 alkyl; R c1 , R c2 , R d1 , R d2 , R e1 , and R e2 , if present, are each independently selected from the group consisting of H, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; R 1 is selected from the group consisting of optionally substituted C 1 -C 8 alkyl, optionally substituted
  • R 1 is optionally substituted C 1 -C 3 alkyl and R 2 is optionally substituted, branched C 3 -C 8 alkyl.
  • R 1 is selected from the group consisting of methyl, allyl, and n-propyl and R 2 is optionally substituted, branched C 3 -C 8 alkyl.
  • R 1 is C 1 -C 3 alkyl and R 2 is selected from the group consisting of iso- propyl, sec-butyl, iso-butyl, 1,2-dimethylpropyl, methylallyl, and 2-methylallyl.
  • R 1 is selected from the group consisting of methyl, allyl, and n-propyl and R 2 is selected from the group consisting of iso-propyl, sec-butyl, iso-butyl, 1,2-dimethylpropyl, methylallyl, and 2-methylallyl.
  • R 1 is optionally substituted C 1 -C 3 alkyl and R 2 is optionally substituted C 3 -C 8 cycloalkyl.
  • R 1 is selected from the group consisting of methyl, allyl, and n-propyl and R 2 is optionally substituted C 3 -C 8 cycloalkyl.
  • R 1 is optionally substituted C 1 -C 3 alkyl
  • R 2 is selected from the group consisting of cyclopropyl and cyclobutyl.
  • R 1 is selected from the group consisting of methyl, allyl, and n-propyl and R 2 is selected from the group consisting of cyclopropyl and cyclobutyl.
  • R 1 is optionally substituted alkoxy.
  • R 1 is optionally substituted C 1 -C 8 haloalkyl.
  • R 1 is methyl.
  • R 1 is ethyl.
  • R 1 is n-propyl.
  • R 1 is iso-propyl. In certain embodiments, R 1 is sec-butyl. In certain embodiments, R 1 is iso-butyl. In certain embodiments, R 1 is n-butyl. In certain embodiments, R 1 is cyclopropyl. In certain embodiments, R 1 is cyclopropylmethyl. In certain embodiments, R 1 is methylcyclopropyl. In certain embodiments, R 1 is cyclopropylethyl. In certain embodiments, R 1 is 2-cyclopropyleth-2- yl. In certain embodiments, R 1 is cyclobutyl. In certain embodiments, R 1 is 2-thietanyl. In certain embodiments, R 1 is 3-thietanyl.
  • R 1 is allyl. In certain embodiments, R 1 is methylallyl. In certain embodiments, R 1 is 2-methylallyl. In certain embodiments, R 1 is 3- methylallyl. In certain embodiments, R 1 is allylmethyl. In certain embodiments, R 1 is propargyl. In certain embodiments, R 1 is cyanomethyl. In certain embodiments, R 1 is 2-hydroxyethyl. In certain embodiments, R 1 is and 2-methoxyethyl. In certain embodiments, R 1 is 1,2- dimethylpropyl. In certain embodiments, R 2 is optionally substituted alkoxy. In certain embodiments, R 2 is optionally substituted C 1 -C 8 haloalkyl. In certain embodiments, R 2 is methyl.
  • R 2 is ethyl. In certain embodiments, R 2 is n-propyl. In certain embodiments, R 2 is iso-propyl. In certain embodiments, R 2 is sec-butyl. In certain embodiments, R 2 is iso-butyl. In certain embodiments, R 2 is n-butyl. In certain embodiments, R 2 is cyclopropyl. In certain embodiments, R 2 is cyclopropylmethyl. In certain embodiments, R 2 is methylcyclopropyl. In certain embodiments, R 2 is cyclopropylethyl. In certain embodiments, R 1 is 2-cyclopropyleth-2- yl. In certain embodiments, R 2 is cyclobutyl.
  • R 1 is 2-thietanyl. In certain embodiments, R 1 is 3-thietanyl. In certain embodiments, R 2 is allyl. In certain embodiments, R 2 is methylallyl. In certain embodiments, R 2 is 2-methylallyl. In certain embodiments, R 2 is 3- methylallyl. In certain embodiments, R 2 is allylmethyl. In certain embodiments, R 2 is propargyl. In certain embodiments, R 2 is cyanomethyl. In certain embodiments, R 2 is 2-hydroxyethyl. In certain embodiments, R 2 is and 2-methoxyethyl. In certain embodiments, R 2 is 1,2- dimethylpropyl. In certain embodiments, R 3 is H. In certain embodiments, R 3 is methyl.
  • R 3 is phenyl. In certain embodiments, R 3 is benzyl. In certain embodiments, R 4 is selected from the group consisting of H, Cl, Br, I, OR A , N(R A )(R B ), SR A , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C 2 -C 9 heteroaryl, and R 5 , R 6 , and R 7 are each independently selected from the group consisting of H, F, Cl, Br, I, OR A , N(R A )(R B ), SR A , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted benzyl, optionally
  • R 4 is H
  • R 5 , R 6 , and R 7 are each independently selected from the group consisting of H, F, Cl, Br, I, OR A , N(R A )(R B ), SR A , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C 2 -C9 heteroaryl, wherein at least one of R 5 , R 6 , and R 7 is F.
  • R 4 is C 1 -C 6 haloalkyl.
  • R 4 is H.
  • R 4 is F. In certain embodiments, R 4 is OH. In certain embodiments, R 4 is OMe. In certain embodiments, R 4 is Cl. In certain embodiments, R 5 is C 1 -C 6 haloalkyl. In certain embodiments, R 5 is H. In certain embodiments, R 5 is F. In certain embodiments, R 5 is selected from the group consisting of OR A , N(R A )(R B ), and SR A . In certain embodiments, R 5 is OH. In certain embodiments, R 5 is OMe. In certain embodiments, R 5 is Cl. In certain embodiments, R 5 is Me. In certain embodiments, R 6 is C 1 -C 6 haloalkyl.
  • R 6 is H. In certain embodiments, R 6 is F. In certain embodiments, R 6 is OH. In certain embodiments, R 6 is OMe. In certain embodiments, R 6 is Cl. In certain embodiments, R 6 is Me. In certain embodiments, R 7 is C 1 -C 6 haloalkyl. In certain embodiments, R 7 is H. In certain embodiments, R 7 is F. In certain embodiments, R 7 is OH. In certain embodiments, R 7 is OMe. In certain embodiments, R 7 is Cl. In certain embodiments, R 7 is Br. In certain embodiments, R 7 is Me. In certain embodiments, R 4 is F, and each of R 5 , R 6 , and R 7 is H.
  • R 5 is F
  • each of R 4 , R 6 , and R 7 is H.
  • R 7 is F
  • each of R 4 , R 5 , and R 6 is H.
  • each of R 4 and R 5 is F
  • each of R 6 and R 7 is H.
  • each of R 4 and R 6 is F
  • each of R 5 and R 7 is H.
  • each of R 4 and R 7 is F
  • each of R 5 and R 6 is H.
  • each of R 5 and R 6 is F
  • each of R 4 and R 7 is H.
  • each of R 5 and R 6 is F
  • each of R 4 and R 7 is F
  • each of R 4 and R 6 is H.
  • each of R 6 and R 7 is F, and each of R 4 and R 5 is H.
  • R 5 is OMe
  • R 7 is F
  • each of R 4 and R 6 is H.
  • R 5 , R 6 , and R 7 are each F
  • R 4 is H.
  • each of R 4 and R 6 is H.
  • L is . In certain embodiments, L is .
  • A is selected from the group consisting of: , wherein: R c1 , R c2 , R d1 , R d2 , R e1 , and R e2 , if present, are each independently selected from the group consisting of H, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl. In certain embodiments, each of R a1 , R a2 , R b1 , R b2 , R c1 , R c2 , R d1 , R d2 , R e1 , R e2 , R f1 , and R f2 , if present, is H.
  • R 1 is iso-propyl and R 2 is ethyl. In certain embodiments, R 1 is iso-propyl and R 2 is methyl. In certain embodiments, R 1 is sec-butyl and R 2 is methyl. In certain embodiments, R 1 is iso-propyl and R 2 is n-propyl. In certain embodiments, R 1 is iso-propyl and R 2 is allyl. In certain embodiments, R 1 is methyl and R 2 is ethyl. In certain embodiments, R 1 is methyl and R 2 is n-propyl. In certain embodiments, R 1 is ethyl and R 2 is n-propyl. In certain embodiments, R 1 is ethyl and R 2 is n-propyl.
  • R 1 is ethyl and R 2 is sec-butyl. In certain embodiments, R 1 is n-propyl and R 2 is sec-butyl. In certain embodiments, R 1 is iso-propyl and R 2 is sec-butyl. In certain embodiments, R 1 is allyl and R 2 is sec-butyl. In certain embodiments, R 1 is allyl and R 2 is ethyl. In certain embodiments, R 1 is allyl and R 2 is n-propyl. In certain embodiments, R 1 is is isopropyl and R 2 is cyanomethyl. In certain embodiments, R 1 is iso-propyl and R 2 is propargyl.
  • R 1 is methyl and R 2 is 2-cyclopropyleth-2-yl. In certain embodiments, R 1 is methyl and R 2 is 3-thietanyl. In certain embodiments, R 1 is ethyl and R 2 is cyclobutyl. In certain embodiments, R 1 is n-propyl and R 2 is cyclobutyl. In certain embodiments, R 1 is iso-propyl and R 2 is cyclobutyl. In certain embodiments, R 1 is allyl and R 2 is cyclobutyl. In certain embodiments, R 1 is methyl and R 2 is iso-butyl. In certain embodiments, R 1 is cyclobutyl and R 2 is methyl.
  • R 1 is methyl and R 2 is allyl. In certain embodiments, R 1 is iso-propyl and R 2 is iso-butyl. In certain embodiments, R 1 is methyl and R 2 is cyclobutyl. In certain embodiments, R 1 is ethyl and R 2 is cyclobutyl. In certain embodiments, R 1 is propyl and R 2 is cyclobutyl. In certain embodiments, R 1 is is isopropyl and R 2 is cyclobutyl. In certain embodiments, R 1 is 1,2-dimethylpropyl and R 2 is cyclobutyl. In certain embodiments, R 1 is cyclopropyl and R 2 is cyclobutyl.
  • R 1 is 1-methylpropyl and R 2 is cyclobutyl. In certain embodiments, R 1 is isopropyl and R 2 is methylcyclobutyl. In certain embodiments, R 1 is methyl and R 2 is 1,2-dimethylpropyl. In certain embodiments, R 1 is methyl and R 2 is 1-methylallyl. In certain embodiments, R 1 is propargyl and R 2 is propyl. In certain embodiments, R 1 is propargyl and R 2 is 1-methylpropyl. In certain embodiments, R 1 is cyanomethyl and R 2 is propyl. In certain embodiments, R 1 is cyanomethyl and R 2 is 1- methylpropyl.
  • R 1 is methyl, and R 2 is cyclopropylmethyl. In certain embodiments, R 1 is methyl, and R 2 is cyanomethyl. In certain embodiments, R 1 is methyl, and R 2 is propargyl. In certain embodiments, R 1 is ethyl, and R 2 is propyl. In certain embodiments, R 1 is ethyl, and R 2 is iso-butyl. In certain embodiments, R 1 is ethyl, and R 2 is 3-thietanyl. In certain embodiments, R 1 is ethyl, and R 2 is cyclopropyleth-2-yl. In certain embodiments, R 1 is ethyl, and R 2 is cyclopropylmethyl.
  • R 1 is ethyl, and R 2 is 1,2- dimethylpropyl. In certain embodiments, R 1 is ethyl, and R 2 is cyanomethyl. In certain embodiments, R 1 is propyl, and R 2 is iso-butyl. In certain embodiments, R 1 is propyl, and R 2 is 3-thietanyl. In certain embodiments, R 1 is propyl, and R 2 is cyclopropyleth-2-yl. In certain embodiments, R 1 is propyl, and R 2 is cyclopropylmethyl. In certain embodiments, R 1 is propyl, and R 2 is 1,2-dimethylpropyl.
  • R 1 is iso-propyl, and R 2 is 3-thietanyl. In certain embodiments, R 1 is iso-propyl, and R 2 is cyclopropyleth-2-yl. In certain embodiments, R 1 is but-2-yl, and R 2 is cyclopropyl. In certain embodiments, R 1 is but-2-yl, and R 2 is iso-butyl. In certain embodiments, R 1 is but-2-yl, and R 2 is 3-thietanyl. In certain embodiments, R 1 is but- 2-yl, and R 2 is cyclopropyleth-2-yl. In certain embodiments, R 1 is but-2-yl, and R 2 is cyclopropylmethyl.
  • R 1 is but-2-yl, and R 2 is 1,2-dimethylpropyl. In certain embodiments, R 1 is but-2-yl, and R 2 is 1-methylallyl In certain embodiments, R 1 is cyclopropyl, and R 2 is allyl. In certain embodiments, R 1 is cyclopropyl, and R 2 is iso-butyl. In certain embodiments, R 1 is cyclopropyl, and R 2 is 3-thietanyl. In certain embodiments, R 1 is cyclopropyl, and R 2 is cyclopropylmethyl. In certain embodiments, R 1 is cyclopropyl, and R 2 is cyclopropyleth-2-yl.
  • R 1 is cyclopropyl, and R 2 is 1,2-dimethylpropyl. In certain embodiments, R 1 is cyclopropyl, and R 2 is 1-methylallyl. In certain embodiments, R 1 is cyclopropyl, and R 2 is cyanomethyl. In certain embodiments, R 1 is cyclopropyl, and R 2 is propargyl. In certain embodiments, R 1 is cyclobutyl, and R 2 is allyl. In certain embodiments, R 1 is cyclobutyl, and R 2 is iso-butyl. In certain embodiments, R 1 is cyclobutyl, and R 2 is 3- thietanyl.
  • R 1 is cyclobutyl, and R 2 is cyclopropylmethyl. In certain embodiments, R 1 is cyclobutyl, and R 2 is cyclopropyleth-2-yl. In certain embodiments, R 1 is cyclobutyl, and R 2 is 1,2-dimethylpropyl. In certain embodiments, R 1 is cyclobutyl, and R 2 is 1- methylallyl. In certain embodiments, R 1 is cyclobutyl, and R 2 is cyanomethyl. In certain embodiments, R 1 is cyclobutyl, and R 2 is propargyl. In certain embodiments, R 1 is iso-butyl, and R 2 is allyl.
  • R 1 is iso-butyl, and R 2 is 3-thietanyl. In certain embodiments, R 1 is iso-butyl, and R 2 is cyclopropylmethyl. In certain embodiments, R 1 is iso- butyl, and R 2 is cyclopropyleth-2-yl. In certain embodiments, R 1 is iso-butyl, and R 2 is 1,2- dimethylpropyl. In certain embodiments, R 1 is iso-butyl, and R 2 is 1-methylallyl. In certain embodiments, R 1 is iso-butyl, and R 2 is cyanomethyl. In certain embodiments, R 1 is iso-butyl, and R 2 is propargyl.
  • R 1 is allyl, and R 2 is iso-butyl. In certain embodiments, R 1 is allyl, and R 2 is 3-thietanyl. In certain embodiments, R 1 is allyl, and R 2 is cyclopropylmethyl. In certain embodiments, R 1 is allyl, and R 2 is cyclopropyleth-2-yl. In certain embodiments, R 1 is allyl, and R 2 is 1,2-dimethylpropyl. In certain embodiments, R 1 is allyl, and R 2 is 1-methylallyl. In certain embodiments, R 1 is allyl, and R 2 is cyanomethyl. In certain embodiments, R 1 is allyl, and R 2 is propargyl.
  • R 1 is 3-thietanyl, and R 2 is cyclopropylmethyl. In certain embodiments, R 1 is 3-thietanyl, and R 2 is cyclopropyleth-2-yl. In certain embodiments, R 1 is 3-thietanyl, and R 2 is 1,2-dimethylpropyl. In certain embodiments, R 1 is 3-thietanyl, and R 2 is 1-methylallyl. In certain embodiments, R 1 is 3- thietanyl, and R 2 is cyanomethyl. In certain embodiments, R 1 is 3-thietanyl, and R 2 is propargyl. In certain embodiments, R 1 is cyclopropyleth-2-yl, and R 2 is cyclopropylmethyl.
  • R 1 is cyclopropyleth-2-yl, and R 2 is 1,2-dimethylpropyl. In certain embodiments, R 1 is cyclopropyleth-2-yl, and R 2 is 1-methylallyl. In certain embodiments, R 1 is cyclopropyleth-2-yl, and R 2 is cyanomethyl. In certain embodiments, R 1 is cyclopropyleth-2-yl, and R 2 is propargyl. In certain embodiments, R 1 is cyclopropylemthyl, and R 2 is cyanomethyl. In certain embodiments, R 1 is cyclopropylmethyl, and R 2 is propargyl.
  • R 1 is 1,2-dimethylpropyl, and R 2 is 1-methylallyl. In certain embodiments, R 1 is 1,2- dimethylpropyl, and R 2 is propargyl. In certain embodiments, R 1 is 1,2-dimethylpropyl, and R 2 is cyanomethyl. In certain embodiments, R 1 is 1-methylallyl, and R 2 is cyanomethyl. In certain embodiments, R 1 is 1-methylallyl, and R 2 is propargyl. In certain embodiments, R 1 is propargyl, and R 2 is cyanomethyl. I certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is .
  • A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, certain embodiments, A is . In certain embodiments, embodiments, A is . In certain embodiments, embodiments, A is . In certain embodiments, embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments,
  • A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is In certain embodiments, A is In certain embodiments, certain embodiments, certain embodiments, certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiment
  • A is In certain embodiments, A is n certain embodiments, A is In certain embodiments, A is In certain embodiments, A . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, . In certain embodiments, A is In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments
  • A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, certain embodiments, certain embodiments, A is In certain embodiments, A is . In certain embodiments, certain embodiments, A is . In certain embodiments, certain embodiments, certain embodiments, A is . In certain embodiments, . In certain embodiments, certain embodiments, certain embodiments, A is In certain embodiments, A is . In certain embodiments, . certain embodiments, certain embodiments, certain embodiments, A is In certain embodiments, A is . In certain embodiments, . certain embodiments, A is . In certain embodiments, certain embodiments, certain embodiments, A is . In certain embodiments, certain embodiments, certain embodiments, certain embodiments, A is . In certain embodiments, certain embodiments, certain embodiments, certain embodiments, A is . In certain embodiments, certain embodiments, certain embodiments, certain embodiments, A is . In certain embodiments, certain embodiments, certain embodiments,
  • A is In certain embodiments, certain embodiments, A i In certain embodiments, A is In certain embodiments, certain embodiments, certain embodiments, A certain embodiments, certain embodiments, A embodiments, A is . In certain embodiments, A certain embodiments, certain embodiments, A certain embodiments, A certain embodiments, certain embodiments, certain embodiments, A is . In certain embodiment n certain embodiments, A is certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, certain embodiments, certain embodiments, certain embodiments, A is . In certain embodiments, A is . In certain embodiments, certain embodiments, certain S N embodiments, A is . In certain embodiments, A is In certain embodiments, certain embodiments, A is .
  • A is . In certain embodiments, A is . In certain embodiments, certain embodiments, certain embodiments, A i s . In certain embodiments, . In certain embodiments, A is In certain embodiments, certain embodiments, A is In certain embodiments, certain embodiments, certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embo diments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is .
  • A In certain embodiments, A is In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is In certain embodiments, A is In certain embodiments, A In certain embodiments, A is In certain embodiments, A In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments
  • A is In certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, . certain embodiments, A is . In certain embodiments, A is In certain embodiments, In certain embodiments, . certain embodiments, . certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, A is In certain embodiments, A is n certain embodiments, A is In certain embodiments, A is In certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is .
  • A is In certain embodiments, certain embodiments, A certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is n certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A i In certain embodiments, A is . In certain embodiments, certain embodiments, . certain embodiments, A is .
  • A is n certain embodiments, certain embodiments, A is In certain embodiments, A i In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, . certain embodiments, . certain embodiments, A is In certain embodiments, A is In certain embodiments, certain embodiments, certain embodiments, A is . In certain embodiments, A is In certain embodiments, A is In certain embodiments, certain embodiments, certain embodiments, certain embodiments, A is . In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is . In certain embodiments, . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is
  • A is . In certain embodiments, A is . In certain embodiments, In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is
  • A is .
  • the compound is selected from the group consisting of: N-ethyl-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)propan-2-amine; N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine; N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N-methylbutan-2-amine; N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N-isopropylpropan-1-amine; N-(2-(5,6-difluoro-1H-indol-3-yl)ethyl)-N-ethylpropan-1-amine; N-(2-(5-fluoro-1
  • the present disclosure provides a compound of formula (II), or a salt, prodrug, solvate, isotopologue, or stereoisomer thereof: wherein: R 3 is selected from the group consisting of H, optionally substituted C 1 -C 8 alkyl, optionally substituted benzyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 2 -C 8 alkynyl; R 4 , R 5 , R 6 , and R 7 are each independently selected from the group consisting of H, F, Cl, Br, I, OR A , N(R A )(R B ), SR A , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted benzyl, optional
  • R 3 is H. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is phenyl. In certain embodiments, R 3 is benzyl. In certain embodiments, R 4 is optionally substituted C 1 -C 8 haloalkyl. In certain embodiments, R 4 is H. In certain embodiments, R 4 is F. In certain embodiments, R 4 is OH. In certain embodiments, R 4 is OMe. In certain embodiments, R 5 is optionally substituted C 1 -C 8 haloalkyl. In certain embodiments, R 5 is H. In certain embodiments, R 5 is F. In certain embodiments, R 5 is OH. In certain embodiments, R 5 is OMe.
  • R 6 is optionally substituted C 1 -C 8 haloalkyl. In certain embodiments, R 6 is H. In certain embodiments, R 6 is F. In certain embodiments, R 6 is OH. In certain embodiments, R 6 is OMe. In certain embodiments, R 7 is optionally substituted C 1 -C 8 haloalkyl. In certain embodiments, R 7 is H. In certain embodiments, R 7 is F. In certain embodiments, R 7 is OH. In certain embodiments, R 7 is OMe. In certain embodiments, R 8 is methyl. In certain embodiments, R 8 is ethyl. In certain embodiments, R 8 is n-propyl. In certain embodiments, R 8 is iso-propyl.
  • R 8 is sec-butyl. In certain embodiments, R 8 is iso-butyl. In certain embodiments, R 8 is n-butyl. In certain embodiments, R 8 is cyclopropyl. In certain embodiments, R 8 is cyclopropylmethyl. In certain embodiments, R 8 is methylcyclopropyl. In certain embodiments, R 8 is cyclopropylethyl. In certain embodiments, R 8 is cyclobutyl. In certain embodiments, R 8 is allyl. In certain embodiments, R 8 is methylallyl. In certain embodiments, R 8 is 2-methylallyl. In certain embodiments, R 8 is 3-methylallyl. In certain embodiments, R 8 is allylmethyl.
  • R 8 is propargyl. In certain embodiments, R 8 is cyanomethyl. In certain embodiments, R 8 is 2-hydroxyethyl. In certain embodiments, R 8 is and 2-methoxyethyl. In certain embodiments, R 9 is methyl. In certain embodiments, R 9 is ethyl. In certain embodiments, R 9 is n-propyl. In certain embodiments, R 9 is iso-propyl. In certain embodiments, R 9 is sec-butyl. In certain embodiments, R 9 is iso-butyl. In certain embodiments, R 9 is n-butyl. In certain embodiments, R 9 is cyclopropyl. In certain embodiments, R 9 is cyclopropylmethyl.
  • R 9 is methylcyclopropyl. In certain embodiments, R 9 is cyclopropylethyl. In certain embodiments, R 9 is cyclobutyl. In certain embodiments, R 9 is allyl. In certain embodiments, R 9 is methylallyl. In certain embodiments, R 9 is 2-methylallyl. In certain embodiments, R 9 is 3-methylallyl. In certain embodiments, R 9 is allylmethyl. In certain embodiments, R 9 is propargyl. In certain embodiments, R 9 is cyanomethyl. In certain embodiments, R 9 is 2-hydroxyethyl. In certain embodiments, R 9 is and 2-methoxyethyl. In certain embodiments, R 8 and R 9 are different.
  • R 8 and R 9 are identical. In certain embodiments, R 8 and R 9 are methyl. In certain embodiments, R 8 is methyl and R 9 is ethyl. In certain embodiments, R 8 is ethyl and R 9 is n-propyl. In certain embodiments, R 10 is H. In certain embodiments, R 10 is methyl. In certain embodiments, R 10 is phenyl. In certain embodiments, R 10 is benzyl. In certain embodiments, R f1 is H. In certain embodiments, R f2 is H. In certain embodiments, R 4 is F, and each of R 5 , R 6 , and R 7 is H.
  • R 5 is F
  • each of R 4 , R 6 , and R 7 is H.
  • R 6 is F
  • each of R 4 , R 5 , and R 7 is H.
  • R 7 is F
  • each of R 4 , R 5 , and R 6 is H.
  • each of R 4 and R 5 is F
  • each of R 6 and R 7 is H.
  • each of R 4 and R 6 is F
  • each of R 5 and R 7 is H.
  • each of R 4 and R 7 is F
  • each of R 5 and R 6 is H.
  • each of R 5 and R 6 is F
  • each of R 4 and R 7 is H.
  • each of R 5 and R 7 is F, and each of R 4 and R 6 is H. In certain embodiment, each of R 6 and R 7 is F, and each of R 4 and R 5 is H. In certain embodiments, the compound is selected from the group consisting of: 2-(ethyl(propyl)amino)-1-(5-fluoro-1H-indol-3-yl)ethan-1-one; 2-(ethyl(methyl)amino)-1-(5-fluoro-1H-indol-3-yl)ethan-1-one; 2-(dimethylamino)-1-(4-fluoro-1H-indol-3-yl)ethan-1-one; 2-(dimethylamino)-1-(5-fluoro-1H-indol-3-yl)ethan-1-one; 2-(dimethylamino)-1-(6-fluoro-1H-indol-3-yl)ethan-1-one; 2-(dimethylamin
  • the present disclosure provides a compound of formula (III), or a salt, prodrug, solvate, isotopologue, or stereoisomer thereof: wherein: R 8 and R 9 are each independently selected from the group consisting of optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 2 -C 8 alkynyl; R 10 is selected from the group consisting of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C 2 -C9 heteroaryl; R 11 and R 12 are each independently selected from the group consisting of H, F, Cl, Br, I, OR A , N(R A )(R B ), optionally
  • R 3 is H. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is phenyl. In certain embodiments, R 3 is benzyl. In certain embodiments, R 8 is methyl. In certain embodiments, R 8 is ethyl. In certain embodiments, R 8 is n-propyl. In certain embodiments, R 8 is iso-propyl. In certain embodiments, R 8 is sec-butyl. In certain embodiments, R 8 is iso-butyl. In certain embodiments, R 8 is n-butyl. In certain embodiments, R 8 is cyclopropyl. In certain embodiments, R 8 is cyclopropylmethyl.
  • R 8 is methylcyclopropyl. In certain embodiments, R 8 is cyclopropylethyl. In certain embodiments, R 8 is cyclobutyl. In certain embodiments, R 8 is allyl. In certain embodiments, R 8 is methylallyl. In certain embodiments, R 8 is 2-methylallyl. In certain embodiments, R 8 is 3-methylallyl. In certain embodiments, R 8 is allylmethyl. In certain embodiments, R 8 is propargyl. In certain embodiments, R 8 is cyanomethyl. In certain embodiments, R 8 is 2-hydroxyethyl. In certain embodiments, R 8 is and 2-methoxyethyl. In certain embodiments, R 9 is methyl.
  • R 9 is ethyl. In certain embodiments, R 9 is n-propyl. In certain embodiments, R 9 is iso-propyl. In certain embodiments, R 9 is sec-butyl. In certain embodiments, R 9 is iso-butyl. In certain embodiments, R 9 is n-butyl. In certain embodiments, R 9 is cyclopropyl. In certain embodiments, R 9 is cyclopropylmethyl. In certain embodiments, R 9 is methylcyclopropyl. In certain embodiments, R 9 is cyclopropylethyl. In certain embodiments, R 9 is cyclobutyl. In certain embodiments, R 9 is allyl.
  • R 9 is methylallyl. In certain embodiments, R 9 is 2-methylallyl. In certain embodiments, R 9 is 3-methylallyl. In certain embodiments, R 9 is allylmethyl. In certain embodiments, R 9 is propargyl. In certain embodiments, R 9 is cyanomethyl. In certain embodiments, R 9 is 2-hydroxyethyl. In certain embodiments, R 9 is and 2-methoxyethyl. In certain embodiments, R 10 is H. In certain embodiments, R 10 is methyl. In certain embodiments, R 10 is phenyl. In certain embodiments, R 10 is benzyl. In certain embodiments, R 11 is optionally substituted C 1 -C 6 haloalkyl.
  • R 11 is H. In certain embodiments, R 11 is F. In certain embodiments, R 11 is OH. In certain embodiments, R 11 is OMe. In certain embodiments, R 12 is optionally substituted C 1 -C 6 haloalkyl. In certain embodiments, R 12 is H. In certain embodiments, R 12 is F. In certain embodiments, R 12 is OH. In certain embodiments, R 12 is OMe. In certain embodiments, R 13 is H. In certain embodiments, R 13 is methyl. In certain embodiments, R 13 is phenyl, optionally substituted with at least one halogen. In certain embodiments, R 13 is benzyl. In certain embodiments, R 13 is CF 3 .
  • R 13 is CHF2.
  • R f1 is H.
  • R f2 is H.
  • R g1 is H.
  • R g2 is H.
  • the compound is selected from the group consisting of: N-ethyl-N-(2-(7-fluoro-5-methoxy-1H-indol-3-yl)ethyl)propan-1-amine; 2-(7-fluoro-5-methoxy-1H-indol-3-yl)-N,N-dimethylethan-1-amine; N,N-diethyl-2-(7-fluoro-5-methoxy-1H-indol-3-yl)ethan-1-amine; N-(2-(7-fluoro-5-methoxy-1H-indol-3-yl)ethyl)-N-propylpropan-1-amine; 3-(2-(dimethylamino)ethy
  • the present disclosure provides a compound selected from the group consisting of: N-(2-(5-fluoro-1H-indol-3-yl)ethyl)prop-2-en-1-amine; 2-(5-fluoro-1H-indol-3-yl)-N,N-dimethylpropan-1-amine; N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N-propylpropan-1-amine; N,N-diethyl-2-(4-fluoro-1H-indol-3-yl)ethan-1-amine; N-(2-(4-fluoro-1H-indol-3-yl)ethyl)-N-propylpropan-1-amine; N-(2-(7-fluoro-1H-indol-3-yl)ethyl)-N-propylpropan-1-amine; N-(2-(5,6-difluoro-1H-in
  • the compounds of the invention may possess one or more stereocenters, and each stereocenter may exist independently in either the (R)- or (S)-configuration.
  • compounds described herein are present in optically active or racemic forms.
  • the compounds described herein encompass racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.
  • Preparation of optically active forms is achieved in any suitable manner, including, by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • a compound illustrated herein by the racemic formula further represents either of the two enantiomers or any mixtures thereof, or in the case where two or more chiral centers are present, all diastereomers or any mixtures thereof.
  • the compounds of the invention exist as tautomers. All tautomers are included within the scope of the compounds recited herein.
  • Compounds described herein also include isotopically labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S. In certain embodiments, substitution with heavier isotopes such as deuterium affords greater chemical stability. Isotopically labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • suitable optional substituents are not intended to limit the scope of the claimed invention.
  • the compounds of the invention may contain any of the substituents, or combinations of substituents, provided herein.
  • Salts The compounds described herein may form salts with acids or bases, and such salts are included in the present invention.
  • salts embraces addition salts of free acids or bases that are useful within the methods of the invention.
  • pharmaceutically acceptable salt refers to salts that possess toxicity profiles within a range that affords utility in pharmaceutical applications.
  • the salts are pharmaceutically acceptable salts.
  • Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds useful within the methods of the invention.
  • Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include sulfate, hydrogen sulfate, hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate).
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (or pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, sulfanilic, 2- hydroxyethanesulfonic, trifluoromethanesulfonic, p-toluenesulfonic, cyclohexylaminosulfonic, stearic, alginic, ⁇ -hydroxybutyric
  • Salts may be comprised of a fraction of one, one or more than one molar equivalent of acid or base with respect to any compound of the invention.
  • Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, ammonium salts and metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (or N-methylglucamine) and procaine.
  • All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
  • Synthesis The present invention further provides methods of preparing compounds of the present invention.
  • Compounds of the present teachings can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high- performance liquid chromatography (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high- performance liquid chromatography (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).
  • HPLC high- performance liquid chromatography
  • GC gas chromatography
  • GPC gel-permeation chromatography
  • TLC thin layer
  • the chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated by reference herein for all purposes.
  • the reactions or the processes described herein can be carried out in suitable solvents that can be readily selected by one skilled in the art of organic synthesis. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent’s freezing temperature to the solvent’s boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • a compound of formula (I), formula (II), or formula (III) can be prepared from commercially available or previously documented starting materials, for example, according to the synthetic methods outlined herein, or according to methods known in the art.
  • Fluorinated tryptamines (IV) can either be commercially acquired or synthesized according to procedures known to one of ordinary skill in the art.
  • R I and R II are each independently H or optionally substituted C 1 -C 8 hydrocarbyl
  • R III is optionally substituted C 1 -C 8 hydrocarbyl
  • X is Cl or Br
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L, R a1 , R b1 , R b2 , R c1 , R c2 , and R are defined within the scope of the present disclosure.
  • Reductive alkylation of IV using a suitable hydride source including but not limited to NaBH3CN, in the presence of carbonyl compound (V) provides VI (Scheme 1).
  • carbonyl compound (V) is an aldehyde or ketone.
  • Subsequent reductive alkylation of VI in non-limiting examples, using NaBH 3 CN in the presence of aldehyde (VII) provides the compound of formula (Ia).
  • compound (VI) is isolated as an intermediate.
  • compound (VI) is further reductively alkylated in situ to provide Ia without isolation of compound (VI).
  • a compound of formula (Ia) may be prepared in one step by reductive amination of IV, in non-limiting examples, using NaBH3CN in the presence of excess aldehyde (VII).
  • Scheme 1 Formylation of IV to provide IX is achieved using a suitable formylating reagent, non- limiting examples including compound (VIII) (e.g., ethyl formate), under conditions including but not limited to heating and/or microwave irradiation (Scheme 2).
  • a suitable formylating reagent including but not limited to Red-Al (i.e., sodium bis(2- methoxyethoxy)aluminium hydride)
  • VIa Reduction of VIa, in non-limiting examples using NaBH 3 CN in the presence of aldehyde (VII) provides a compound of formula (Ib).
  • Scheme 2 Reductive alkylation of VIa, in non-limiting examples using NaBH 3 CN in the presence of aldehyde (VII) provides a compound of formula (Ib).
  • alkylation of VI can be achieved in the presence of a suitable base, non- limiting examples including Et 3 N, and a suitable alkylating agent, non-limiting examples including alkyl, allyl, propargyl, and/or benzyl halides (X), to provide the compound of formula (Ic) (Scheme 3).
  • a suitable base non- limiting examples including Et 3 N
  • a suitable alkylating agent non-limiting examples including alkyl, allyl, propargyl, and/or benzyl halides (X)
  • X benzyl halides
  • XII electrophilic oxalic acid derivative
  • XIII nucleophilic amine
  • XIV Scheme 4
  • a suitable reducing agent non-limiting examples including LiAlH 4
  • the compound of formula (Id) is prepared from XI utilizing a Michael addition/reduction sequence (Scheme 5).
  • the compound of formula (I), which is the compound of formula (If), is prepared from XI utilizing a Friedel-Crafts acylation/SN2 reaction sequence (Scheme 6). Treatment of XI with ⁇ -halo-acyl halide (XV) in the presence of a base, including but not limited to pyridine, provides XVI.
  • a base including but not limited to pyridine
  • the acyl halide is an acyl chloride or acyl bromide.
  • the ⁇ -halo-acyl halide is an ⁇ -chloro-acyl halide or ⁇ -bromo- acyl halide.
  • the compound of formula (I) which is the compound of formula (Ig) is prepared from XVII in a sequence comprising installation of an ⁇ , ⁇ -unsaturated nitro group, with subsequent Michael addition, nitro-reduction, and reductive alkylation (Scheme 7).
  • the compound of formula (I), which is the compound of formula (Ih), is prepared from XI utilizing a [1,2]-carbonyl addition/reduction sequence (Scheme 8).
  • a suitable base non-limiting examples including KOH
  • a suitable solvent non-limiting examples including methanol
  • XXII N-protected heterocyclyl ketone
  • the XXIII may be prepared by alternative methods.
  • R is tert-butyl or benzyl.
  • Reduction of XXIII with a suitable reducing agent, non-limiting examples including LiAlH4 provides the compound of formula (Ih).
  • Scheme 8 Methods the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure and a pharmaceutically acceptable carrier.
  • the present disclosure provides a method of treating, preventing, and/or ameliorating a psychiatric disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure or a pharmaceutical composition of the present disclosure.
  • the psychiatric disease or disorder is selected from the group consisting of a depressive disorder, anxiety disorder, and eating disorder.
  • the psychiatric disease or disorder is selected from the group consisting of attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), treatment resistant depression, major depressive disorder (MDD), bipolar I disorder, bipolar II disorder, cyclothymic disorder, anti-social personality disorder, pain, sleep-wake disorders, disruptive mood dysregulation disorder, persistent depressive disorder (dysthymia) premenstrual dysphoric disorder, substance/medication-induced depressive disorder, post-partum depression, depressive disorder due to another medical condition, separation anxiety disorder, specific phobia, social anxiety disorder, panic disorder, panic attack, agoraphobia, generalized anxiety disorder, substance-medication induced anxiety disorder, anxiety disorder due to another medical condition, somatic symptom disorder, illness anxiety disorder, obsessive-compulsive disorder (OCD), obsessive-compulsive and related disorder (OCD), obsessive
  • the subject is further administered at least one additional agent useful for treating, preventing, and/or ameliorating the psychiatric disease or disorder.
  • the at least one additional agent is selected from the group consisting of a selective serotonin reuptake inhibitor, triple reuptake inhibitor, serotonin and norepinephrine reuptake inhibitor, tricyclic antidepressant, tetracyclic antidepressant, dopamine reuptake inhibitor, mood stabilizer, anticonvulsant, antipsychotic, anxiolytics, benzodiazepines, monoamine releasers, dopamine receptor agonist, cannabinoids, triptans, anti-migraine medications, analgesics, anti- inflammatory, immune modulator, 5-HT1A receptor antagonist, 5-HT2 receptor antagonist, 5-HT3 receptor antagonist, monoamine oxidase inhibitor, and noradrenergic antagonist.
  • the subject is co-administered the at least one compound and the at least one additional agent.
  • the at least one compound and the at least one additional agent are co-formulated.
  • the subject is a mammal.
  • the mammal is a human.
  • Pharmaceutical Compositions and Formulations The invention provides pharmaceutical compositions comprising at least one compound of the invention or a salt, prodrug, solvate, isotopologue, or stereoisomer thereof, which are useful to practice methods of the invention.
  • Such a pharmaceutical composition may consist of at least one compound of the invention or a salt or solvate thereof, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise at least one compound of the invention or a salt or solvate thereof, and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or any combinations of these.
  • At least one compound of the invention may be present in the pharmaceutical composition in the form of a physiologically acceptable salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.
  • the relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the compounds of the invention are useful within the methods of the invention in combination with one or more additional agents useful for treating a psychiatric disorder.
  • additional agents may comprise compounds or compositions identified herein, or compounds (e.g., commercially available compounds) known to treat, prevent, or reduce the symptoms of one or more psychiatric disorders described herein.
  • Administration/Dosing The regimen of administration may affect what constitutes an effective amount.
  • the therapeutic formulations may be administered to the patient either prior to or after the onset of a disease or disorder. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection.
  • the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • Administration of the compositions of the present invention to a patient, such as a mammal, such as a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a disease or disorder contemplated herein.
  • An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the activity of the particular compound employed; the time of administration; the rate of excretion of the compound; the duration of the treatment; other drugs, compounds or materials used in combination with the compound; the state of the disease or disorder, age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well-known in the medical arts. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • HPLC High Performance Liquid Chromatography
  • An Agilent 1260 Infinity system was used that includes a 1260 quaternary pump VL, a 1260 ALS autosampler, a 1260 Thermostatted Column Compartment, and a 1200 DAD Multiple Wavelength Detector (Agilent Technologies, Santa Clara, CA, USA). Detection wavelength was set at 220, and 254 nm. Separation for tryptamines was achieved using a Zorbax Eclipse Plus- C18 analytical column (5 ⁇ m, 4.6 x 150 mm) from Agilent (Agilent Technologies, Santa Clara, CA, USA).
  • Mobile phase A was 10 mM aqueous ammonium formate buffer titrated to pH 4.5 using 10 mM formic acid solution.
  • Mobile phase B was acetonitrile. The injection volume of samples was 40 ⁇ L, flow rate was 1.0 mL/min, and the column temperature was set at 25 °C. All samples were injected with a wash (30:70 A:B) between runs. Run times were 10 minutes using an isocratic mobile phase ratio (isocratic) of 70% A and 30% B. Chromatograms and peak areas were analyzed using the Agilent ChemStation Software (Agilent Technologies, Santa Clara, CA, USA).
  • HRMS High Resolution Mass Spectrometry
  • Measurement parameters Aux gas flow rate-8, Spray Voltage-3.50 kV, Capillary temperature- 275 °C, Capillary Voltage-25.00 V, Tube Lens Voltage-65.00 V, Skimmer Voltage-14.00 V, Heater Temperature-100 °C.
  • Gas Chromatography-Mass Spectrometry GC-MS
  • a Thermo Scientific TraceGold TG-5MS GC Column (30 m ⁇ 0.25 mm ⁇ 0.25 ⁇ m) was used for separation of any components.
  • NMR Nuclear Magnetic Resonance Spectroscopy
  • Example 1 N-ethyl-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)propan-2-amine
  • 5-fluorotryptamine hydrochloride 0.8 g, 3.73 mmol
  • MeOH 20 mL, dried over 3 ⁇ molecular sieves
  • glacial acetic acid 21.33 ⁇ L
  • NaCNBH3 0.26 g, 4.10 mmol
  • Acetone (0.82 mL, 11.2 mmol) was then added, and the reaction was allowed to stir at room temperature for 4 h.
  • acetaldehyde (0.63 mL, 11.2 mmol) was added, and the reaction was allowed to stir at room temperature for 1 h. Next, the reaction was poured into 300 mL of 0.2 M HCl and extracted with EtOAc (3 x 50 mL). These organic phases were pooled, extracted with 0.2 M aqueous HCl (3 x 75 mL), and the aqueous phases were combined with the original aqueous phase. This combined aqueous phases were basified by the addition of KOH flakes, and extracted with EtOAc (3 x 100 mL).
  • the organic phases were combined, the pooled organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, and the solvent removed in vacuo to provide the crude product (0.98 g) as an amber oil.
  • the crude product was purified by silica gel chromatography using a 50% EtOH/EtOAc (1% Et 3 N v/v) mobile phase to provide the title compound as an amber solid (0.83 g, 3.34 mmol, 89.54% yield).
  • the solid was dissolved in boiling cyclohexane and EtOAc (1 mL) and allowed to cool to room temperature. The solution was further cooled to 4 0C until thermodynamic equilibrium was attained, and subsequently placed at -20 0C for 72 h.
  • the pooled organic phases were then washed with brine (20 mL), dried over anhydrous Na2SO4, and the solvent removed in vacuo to provide the crude product as a yellow oil (0.92 g).
  • the crude product was purified by short path vacuum distillation (i.e., Kugelrohr distillation) at 170-195 °C under vacuum to provide the title compound as a yellow solid (0.91 g, 3.46 mmol, 92.9% yield).
  • the free base was converted to the HCl salt by titrating the free base with concentrated HCl solution in ethanol until the pH ⁇ 2. The solvent was then evaporated under a stream of warm air several times to yield crystalline material with the absence of excess acid or moisture.
  • a two-neck round bottom flask (RBF), addition funnel, rubber septa, and magnetic stir bar were dried in an oven overnight.
  • the reaction apparatus was assembled and subsequently purged with argon. Under a positive pressure of argon, Et 2 O (20 mL) was added to the flask through the addition funnel and the solvent was cooled to 0 °C in an ice-water bath. Oxalyl chloride (3.81 mL, 44.4 mmol) was added to the round bottom flask via a syringe. Next, a solution of 7-fluoroindole (5 g, 37.0 mmol) in Et 2 O (40 mL) was added dropwise over 30 mins.
  • the additional funnel was subsequently rinsed with THF (20 mL) and added to the reaction over a period of 10 min.
  • the reaction was then heated at reflux for 1.5 h, then cooled to 0 °C, and quenched with a THF/Et 2 O ( ⁇ 1:1) mixture and ice. Once quenched, brine and aqueous KOH were added to ensure basicity, followed by EtOAc (100 mL).
  • the inorganic solids were removed by gravity filtration over Whatman paper (24 cm diameter). The removed solids were then washed extensively with EtOAc.
  • the filtrate was extracted with 0.2 M HCl (aq.) (3 x 166 mL).
  • the aqueous phase was then basified by the addition of KOH pellets and extracted with EtOAc (3 x 100 mL).
  • the pooled organic phases were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , and concentrated in vacuo to provide the crude product as a brownish-red solid (3.98 g).
  • the crude product (free base) was recrystallized from boiling hexanes with a small amount of EtOAc and stored at -20 0C. The recrystallization was repeated three times to provide the title compound as light yellow transparent crystals (1.8 g, 7.25 mmol, 34.03% yield).
  • the purified material was converted to the HCl salt as a white crystalline solid (m.p.133.8-135 °C).
  • N-[2-(5-fluoro-1H-indol-3-yl)ethyl]propan-2-amine (0.7 g, 3.18 mmol) was dissolved in dry ACN (15 mL) in a heat dried 50 mL round bottom flask with stirring, under an argon atmosphere.
  • Triethylamine (2.66 mL, 19.1 mmol)
  • allyl iodide (1.45 mL, 15.9 mmol) were added to the reaction vessel, resulting in an exothermic reaction ( ⁇ 38 °C).
  • the flask was wrapped with aluminum foil and allowed to stir at room temperature for 44 h.
  • the reaction was poured into 200 mL of 0.2 M AcOH (aq.) and extracted with EtOAc (3 x 50 mL).
  • the organic phases were combined and extracted with 0.2 M AcOH (aq.) (3 x 50 mL), then the aqueous phases were combined with the original aqueous phases.
  • the combined aqueous phases were basified with NH4OH (28-30% NH3) and extracted with EtOAc (3 x 100 mL).
  • the pooled organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to provide the crude product as a viscous amber/brown oil (699 mg).
  • reaction was heated at reflux for 4 h. Upon completion, the reaction was cooled to 0 °C and cautiously quenched by the dropwise addition of THF/H2O (1:1, v/v) with ice. Once quenched a small amount of KOH (aq.), then 100 mL of EtOAc were added. The inorganic solids were then gravity filtered and washed with EtOAc. The filtrate was extracted with 0.2 M HCl (aq.) (3 x 166 mL). The pooled aqueous phases were then basified with KOH pellets and extracted with EtOAc (3 x 100 mL).
  • N-allyl-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)cyclobutanamine (14) N-allyl-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)cyclobutanamine (14) was synthesized in a similar manner as described above for N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N-isopropylprop-2- en-1-amine (11), starting from N-(2-(5-fluoro-1H-indol-3-yl)ethyl)cyclobutanamine (0.21 g, 0.000904 mol) and allyl iodide (0.77 g, 0.00461 mol) as the starting materials to give N-allyl-N- (2-(5-fluoro-1H-indol-3-yl)ethyl)cyclobutanamine (0.11
  • the reaction vessel was heated to 90 °C at 150 W in a microwave reactor, with stirring, for 24 h. Upon completion, the solvent was removed in vacuo to provide a crude oil.
  • the crude oil was dissolved in EtOAc, washed with water (3 x 100 mL) and brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to provide the crude product.
  • the crude product was recrystallized from boiling EtOAc to provide 3-(5-fluoro-1H-indol-3-yl)-1-methylpyrrolidine-2,5-dione as a yellow solid (2.4 g, 9.75 mmol, 87.8% yield).
  • the inorganic solids were removed by gravity filtration over Whatman paper (24 cm diameter). The removed solids were then washed with EtOAc, and the filtrate was extracted with 0.2 M HCl (aq.) (3 x 166 mL) of a 0.2 M aqueous HCl solution. The aqueous phases were pooled and was basified by the addition of KOH flakes, then extracted with EtOAc (3 x 100 mL). The organic phases were pooled, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to provide the crude product as a tannish-brown solid (1.53 g).
  • N-(2-(5-fluoro-1H-indol-3-yl)ethyl)prop-2-en-1-amine (18) N-(2-(5-fluoro-1H-indol-3-yl)ethyl)prop-2-en-1-amine was synthesized in a similar manner as described above for N-ethyl-2-(7-fluoro-1H-indol-3-yl)-N-methylene-1-amine (7), starting from 2-(5-fluoro-1H-indol-3-yl)-2-oxo-N-(prop-2-en-1-yl)acetamide (9.11 g, 0.0370 mol) as starting material to give N-(2-(5-fluoro-1H-indol-3-yl)ethyl)prop-2-en-1-amine as an orange oil (1.5 g, 0.00687 mol, 18.57% yield).
  • N-(2-(4,5-difluoro-1H-indol-3-yl)ethyl)-N-ethylpropan-1-amine was synthesized in a similar manner as described above for N-ethyl-2-(7-fluoro-1H-indol-3-yl)-N-methylene-1-amine (7), starting from 2-(4,5-difluoro-1H-indol-3-yl)-N-ethyl-2-oxo-N-propylacetamide (6.9 g, 0.0234 mol) as the starting material to give provide the fumarate salt of the title compound as a white crystalline solid (2.1 g, 0.00549 mol, 23.5% yield) (m.p.182.1-183.3 °C).
  • Example 22 N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N-propylbutan-2-amine (22) N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N-propylbutan-2-amine was synthesized in a similar manner as described above for N-ethyl-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)propan-2-amine (1), starting from 5-fluorotryptamine hydrochloride 5-fluoro-tryptamine hydrochloride (0.5 g, 0.00233 mol), methyl ethyl ketone (0.51 g, 0.00699 mol), and propionaldehyde (0.41 g, 0.0699 mol) as the starting materials to provide the title compound as a yellow oil (0.34 g, 0.00110 mol, 47.2 % yield).
  • the reaction mixture was taken and dissolved in 250 mL of 0.174 M acetic acid solution.
  • Two extractions were performed with EtOAc utilizing 50 mL each time.
  • the extractions were pooled and were extracted 3 x 250 mL of 0.174 M acetic acid solution to extract any product that may have partitioned into the organic phase.
  • the acetic acid washes were pooled with the initial acetic acid solution to form a total of 500 mL of 0.174 M acetic acid solution. This was basified with KOH until pH > 12 and the precipitate was extracted three times with 100 mL of EtOAc each time (3 x 100 mL). Once the EtOAc extractions were complete, they were combined and washed with 60 mL of brine solution.
  • the organic phase was dried utilizing sodium sulfate and was decanted, and removed under reduced pressure to yield 635 mg as a yellow solid.
  • the freebase was converted to the HCl salt by dissolving the freebase in 20 mL of EtOH and then adding 206 ⁇ L of 36.5% HCl directly to the solution. The solvent was then evaporated under a stream of warm air several times to yield crystalline material with the absence of excess acid or moisture. The resulting solids were washed with EtOAc (2 x 5 mL) and Et 2 O (10 mL). Crystallization was performed by dissolving the solids into 7 mL of boiling EtOH and then slowly adding 25 mL Et 2 O until the solution was milky white and opaque.
  • nitromethane 40 mL was added to the round bottom flask, along with ammonium acetate (1.34 g, 0.0174 mol) and reflux was initiated under a heat mantle. This reflux was maintained for 3 h. After 3 h, the reaction was terminated by removing the nitromethane under reduced pressure to yield a red-orange crystalline material. This material was recrystallized in the same round bottom flask by dissolving the crystalline material in 60 mL of boiling Isopropanol (IPA) and allowed to cool to room temperature. After cooling down to RT, the round bottom flask with a septum was placed at -20 °C and allowed to recrystallize overnight.
  • IPA Isopropanol
  • reaction was then worked up by mixing the reaction solution in 700 mL of saturated ammonium chloride solution and was extracted five times with 110 mL of EtOAc (5 x 110 mL). Once extracted the EtOAc extractions were pooled and washed with 60 mL of brine (1 x 60 mL). Then the EtOAc was dried with sodium sulfate and decanted to remove the solvent under pressure.
  • the methanol was removed under reduced pressure and the material was dissolved in 100 mL of EtOAc. This was then extracted five times with 100 mL of 0.285 M HCl each time (5 x 100 mL). The extractions were pooled and basified with KOH to obtain a pH > 12. Then following basified the product was extracted from the aqueous phase three times with 100 mL of EtOAc each time (3 x 100 mL). Once the final extraction was performed, they were pooled and washed with 60 mL of brine once (1 x 60 mL). The organic phase was dried with sodium sulfate, decanted, and removed under reduced pressure to obtain 2.24 g of crude oil.
  • Crystallization was performed by dissolving the solids into 7 mL of boiling EtOH and then slowly adding 25 mL Et 2 O until the solution was milky white and opaque. The solution was allowed to recover to room temperature and allowed to sit for 1 h, before placing at 4 °C until thermodynamic equilibrium was attained and then stored at -20 °C overnight. The resulting crystals were collected by decanting the supernatant and the recrystallization was repeated a total of three time to yield a white crystalline solid (m.p. 193.3-194.0 °C).
  • N-benzyloxylcarbonyl-L-proline (5 g, 0.0200 mol) was dissolved in dichloromethane (50 mL) in a separate round bottom flask along with oxalyl chloride (3.8 g, 0.0300 mol) and allowed to react for 2 h. After 2 h, the dichloromethane and excess oxalyl chloride was removed under reduced pressure. To ensure all oxalyl chloride was removed, 4 ⁇ dried hexanes was added after all the dichloromethane was removed and the hexanes and residual oxalyl chloride was removed under reduced pressure.
  • LiAlH4 (1.04 g, 0.0273 mol) was added to the reaction. LiAlH 4 that was stuck to the walls of the round bottom flask was rinsed with ⁇ 20 mL THF. Following LiAlH 4 addition, benzyl (2S)-2-(5-fluoro-1H-indole-3-carbonyl)pyrrolidine-1- carboxylate (2 g, 0.00546 mol) was added to the addition funnel and dissolved in 80 mL of THF, which was added dropwise over 30 minutes. Once the addition was complete, a heating mantle was utilized to heat the reaction to a moderate reflux. Once the reflux was obtained the reaction was allowed to continue for 2 h.
  • the reaction was placed in an ice bath to cool to ⁇ 10 °C.
  • the reaction was then quenched with ⁇ 10 °C 50% THF in H 2 O with 60 mL total volume. Upon quenching a small amount of KOH was added to the quenched reaction and was then filled with ⁇ 200 mL of EtOAc and allowed to stir for a couple minutes. After stirring the solution, the solids in the reaction mixture were gravity filtered, and wash excessive with EtOAc. Washing was done until no more oil was eluting out of the washes. The organic phase was then extracted from with 0.3 M HCl three times (3 x 166 mL).
  • N-Boc-3-azetidinone (1.39 g, 0.00814 mol) was added all at once and heated via a water bath at 50 °C for 15 h over two days. After two days, the reaction was worked up by removing the MeOH under reduced pressure and then re-dissolved in EtOAc (150 mL). The organic phase was washed with 50 mL of H 2 O (3 x 50 mL), brine (1 x 60 mL), and the organic phase separated, dried with anhydrous sodium sulfate, decanted and removed under reduced pressure to provide the title compound as an orange oil (1.78 g, 0.00581 mol, 78.5% yield). The product was used without further purification.
  • tert-butyl 3-(5-fluoro-1H-indol-3-yl)-3- hydroxyazetidine-1-carboxylate (1.7 g, 0.00555 mol) was added to the addition funnel and dissolved in 80 mL of THF. This was added dropwise over 30 minutes. Once the addition was complete, a heating mantle was utilized to heat the reaction to a moderate reflux. Once the reflux was obtained the reaction was allowed to continue for 2 h. Following the 2 h period, the reaction was then placed in an ice bath to cool to ⁇ 10 °C. The reaction was then quenched with ⁇ 10 °C 50% THF in H 2 O with 60 mL total volume.
  • Example 35 N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N-propylprop-2-en-1-amine (35) N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N-propylprop-2-en-1-amine was synthesized in a similar manner as described above for N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N-propylpropan-1- amine (5), starting from N-(2-(5-fluoro-1H-indol-3-yl)ethyl)prop-2-en-1-amine (0.5 g, 0.00229 mol) and propionaldehyde (495 ⁇ L, 0.00687 mol) as starting materials to provide the title compound as a pale-yellow odorless oil (0.48 g, 0.00198 mol, 80.5 % yield).
  • the hydrochloride salt was collected as a white crystalline material (m.p.123.7-128.5 °C). Variations from the method used to prepare compound (5) include the use of 1.1 molar eq. of acetic acid, 0.65 mol. eq. of NaBH3CN and direct work-up with base. The product was purified by flash column chromatography using silica gel as the stationary phase with gradient elution by EtOAc (0.5% Et 3 N) to 10% EtOH in EtOAc (0.5% Et 3 N).
  • Lithium aluminum hydride (LiAlH4) (2.95 g, 0.0777 mol) was added slowly to the round bottom flask while stirring and under argon atmosphere. Meanwhile, 100 mL of dry THF was added to an oven-dried Erlenmeyer flask, placed into an ice-water bath ( ⁇ 0 °C) and allowed to cool. Once cool, AlCl3 (3.55 g, 0.02663 mol) was added portion-wise with swirling. The solution was transferred into the addition funnel and added dropwise to the stirred, cooled LiAlH 4 suspension over 30 min at ⁇ 12-17 °C. An additional 3 x 25 mL of THF was added to the addition funnel to wash any remaining material.
  • LiAlH4 LiAlH4
  • the reaction was then placed back on an ice-water bath and quenched by the cautious addition of ⁇ 1:1 THF/H 2 O with ice added. Once quenched, a few mL of brine, and aqueous KOH solution were added to ensure basicity, followed by 100 mL of EtOAc. The inorganic solids were removed by gravity filtration over Whatman paper (24 cm diameter). The removed solids were then washed extensively with EtOAc. After washing the solids, the mother liquor was taken and extracted 4 x 125 mL of a 0.2 M aqueous HCl solution. The aqueous phase was then basified with KOH pellets and extracted with 3 x 100 mL EtOAc.
  • the hydrochloride salt of the title compound was collected as white round pearl-shaped solids. Variations from the method used for the synthesis of compound (1) are as follows: the reaction mixture was heated to reflux to form the secondary amine intermediate, cooled to RT, then fresh NaBH 3 CN (0.114 g, 0.00181 mol) and formaldehyde were added; and the reaction was worked up directly with base. The product was purified by flash column chromatography using silica gel as the stationary phase with gradient elution by EtOAc (0.5% TEA) to 35% EtOH in EtOAc (0.5 % TEA).
  • the hydrochloride salt was collected as a white crystalline powder, m.p.191.6-193.0 °C. Variations from the method B include: removal of the solvent was performed under reduced pressure with continued additions of MeOH once full conversion was observed; the residue was re-dissolved in dry MeOH, followed by the addition of acetic acid (16 ⁇ L), NaBH 3 CN (0.114 g, 0.00181 mol) and cyclobutanone (0.83 mL, 0.01116 mol) and reaction was set to reflux.
  • the hydrochloride salt was collected as a white crystalline solid.
  • the conditions employed differ from that which is described for compound (1) the material was purified in 80% EtOAc in hexanes with 0.5% triethylamine. Also, after addition of the cyclobutanone the reaction was held at reflux for 7.5 h.
  • High-resolution atmospheric solid analysis probe mass spectrometry (HR-ASAP-MS): m/z 289.2061 (theory [M + H] + C 18 H 26 FN 2 + , m/z 289.2075, ⁇ - 4.84 ppm).
  • the hydrochloride salt was collected as a white crystalline solid (m.p.191.0- 192.5 °C).
  • the conditions employed differ from that which is described for compound (1) the material was purified with a gradient starting with pure ethyl acetate and 0.5% TEA to 5% EtOH in EtOAc with 0.5% TEA.
  • Example 54 N-ethyl-N-[2-(5,6,7-trifluoro-1H-indol-3-yl)ethyl]propan-1-amine (165) Synthesis of N-ethyl-2-oxo-N-propyl-2-(5,6,7-trifluoro-1H-indol-3-yl)acetamide N-ethyl-2-oxo-N-propyl-2-(5,6,7-trifluoro-1H-indol-3-yl)acetamide was synthesized in a similar manner as described above for N-ethyl-2-(7-fluoro-1H-indol-3-yl)-N-methylene-1-amine (7), starting from 5,6,7-TriF-indole (1.0 g, 0.00584 mol), oxalyl chloride (0.96 g, 0.00760 mol), and N-ethylpropylamine (0.89 mL, 0.00760 mol),
  • Example 55 N-ethyl-N-(2-(7-fluoro-5-methyl-1H-indol-3-yl)ethyl)propan-1-amine (166) Synthesis of N-ethyl-2-(7-fluoro-5-methyl-1H-indol-3-yl)-2-oxo-N-propylacetamide N-ethyl-2-(7-fluoro-5-methyl-1H-indol-3-yl)-2-oxo-N-propylacetamide was synthesized in a similar manner as described above for N-ethyl-2-(7-fluoro-1H-indol-3-yl)-N-methylene-1- amine (7), starting from 5-Me-7-F-indole (1.0 g, 0.00670 mol), oxalyl chloride (0.74 g, 0.00872 mol), and N-ethylpropylamine (2.0 mL, 0.0172 mol), and
  • N-[2-(6,7-difluoro-1H-indol-3-yl)ethyl]-N-ethylpropan-1-amine was synthesized in a similar manner as described above for N-ethyl-2-(7-fluoro-1H-indol-3-yl)-N-methylene-1-amine (7), starting from 2-(6,7-difluoro-1H-indol-3-yl)-N-ethyl-2-oxo-N-propylacetamide (1.22 g, 0.00415 mol) as the starting materials to provide the title compound.
  • N-ethyl-2-(5-fluoro-7-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide was synthesized in a similar manner as described above for N-ethyl-2-(7-fluoro-1H-indol-3-yl)-N-methylene-1- amine (7), starting from 5-F-7-Me -Indole (0.95 g, 0.00637 mol), oxalyl chloride (0.97 g, 0.00764 mol), and N-methylethylamine (0.54 g, 0.00917 mol), and TEA (3.1 g, 0.0306 mol) as starting material, yielding crude material as orange solids (1.20 g, 0.00457 mol, 59.89% yield).
  • the title compound was prepared from reduction of the glyoxylamide to yield the title compound as a slightly yellow solid (0.72, 0.00241 mol, 77.5% Yield).
  • the hydrochloride salt was collected a yellow tinted crystalline solid (m.p 228.3-230.5 °C).
  • Example 78 Molecular Docking Studies Rigid docking using UCSD Autodock 4.2.6 was utilized. The receptor used was 6WGT (Kim et al.2020). Receptor and ligand structures were prepared using Discovery Studio Visualizer. Docking was performed using AutodockTools 1.5.6. Receptor preparation included removing ligand, adding polar hydrogen atoms, merging non-polar hydrogen atoms, and adding Gasteiger charges. The grid was centered around the orthosteric LSD binding site. Genetic algorithm was used for search parameters and output was Lamarckian genetic algorithm. Docking results (top 10 poses per compound) were ranked by energy and exported (as .pdb files), then individually viewed in PyMol.
  • FIG.4 shows binding of compound 51 to the 5-HT 2A receptor.
  • Compound 51 shows close intermolecular interactions with several key residues of the orthosteric 5-HT2A binding site. Docking was also performed on the endogenous ligand 5- hydroxytryptamine (5-HT or serotonin). Compound 51 shows a similar binding mode as serotonin, suggesting that the fluorine atom confers desirable interactions which underlie its ability to modulate the activity off the tryptamine scaffold.
  • the predicted hydrogen bonding interaction between 52 and Asn343 6.55 suggests that the 5-fluoro-substituent can act as a hydrogen bonding acceptor comparable to a hydroxy or methoxy substituent, which are common in many reported tryptamine derivatives, including 5-methoxy-dimethyltryptamine (5-MeO- DMT) and 5-hydroxy-dimethyltryptamine (5-OH-DMT).
  • 5-MeO- DMT 5-methoxy-dimethyltryptamine
  • 5-OH-DMT 5-hydroxy-dimethyltryptamine
  • N-alkyl substituents Close interactions involving N-alkyl substituents with Ile152 3.29 , Trp151 3.28 , Phe339 6.51 , and Tyr370 7.43 , were also observed, suggesting the importance of these substituents on binding affinity and functional activity.
  • the N-alkyl substituents were also in close proximity to the important toggle switch Trp336 6.48 . It is proposed herein that the functional selectivity observed in a number of cases may be due to differential interactions between these residues of TM3, TM5, TM6, and TM7 of the orthosteric site.
  • Non-symmetrical N,N-dialkyl substitution of the 5- fluorotryptamine scaffold thus represents one approach to modulate binding affinities and functional activities of the 5-HT2A receptor, as well as similar receptors including, but not limited to 5-HT 2B , 5-HT 2C , and 5-HT 1A , while simultaneously optimizing pharmacokinetic and physiochemical properties (e.g., absorption, distribution, metabolism, and excretion). Additionally, close contact between compound 6 and Val235 5.39 and Leu229 ECL2 were observed, suggesting Van der Waals interactions (i.e., hydrophobic interactions). Leu229 ECL2 is implicated in the high binding affinity of prototypical hallucinogenic LSD at the 5-HT 2 receptors.
  • the compounds of the present invention provided binding energy scores between -6 to -7 kcal/mol, which is consistent with the endogenous agonist 5-HT and known biologically active tryptamine derivatives (e.g., 5-MeO-DMT), suggesting favorable binding interactions. Similar binding modes and scores were also observed with the disubstituted 5-fluoro containing compounds 61 and 164. This was in contrast to the binding modes predicted for the non-psychedelic 5-HT2A agonist 6-F-DET.
  • the fluorinated tryptamine derivatives of the present invention provide favorable interactions with the 5-HT2A receptor, non-limiting examples including hydrogen-bonding, ⁇ -stacking, and Van der Waals interactions.
  • the favorable interactions are a result of modified electronic properties of the compounds due to fluorine substitution (e.g., ⁇ -withdrawing, ⁇ -donating, hydrogen bonding accepting).
  • the favorable interactions are a result of the N,N-dialkyl substitution pattern.
  • the favorable interactions are a result of synergistic properties of both the fluorine substitution and N,N-dialkyl substitution pattern.
  • substituents at any position of the compound of the present invention may contribute to the favorable properties of the compounds of the present invention.
  • the compounds of the present invention possess desirable pharmacokinetic and pharmacodynamic properties, non- limiting examples including absorption, metabolic stability, bioavailability, solubility, and half- life.
  • Example 79 5-HT 2A Receptor Binding Studies ValiScreen Serotonin 5-HT2A (human) cell line (product No: ES-313-C) grown in DMEM/F12 media augmented with 10% FBS, 4 mM GlutaMAX, 0.4 mg/mL Geneticin, 1% Penicillin-Streptomycin were utilized to prepare 5-HT2A membrane fractions.
  • Cells were grown in a 150 mm culture dishes and were harvested at between 70-90% confluency between passages 5-15. Cells were detached and lysed at room temperature with 1 mM HEPES buffer containing 2 mM EDTA at pH 7.4 and homogenized with a hand-held homogenizer.
  • the lysate was then centrifuged (30 minutes at 30,000 x G at 4°C).
  • the resultant pellet was resuspended in a storage buffer (20 mM HEPES, 10 mM MgCl 2 , 0.1 mM EDTA, pH 7.4 at room temperature) and the suspension frozen and stored at -80°C until use.
  • Protein concentration was determined via the Bradford method using Coomassie protein assay reagent (Sigma, USA) with Bovine Serum albumin (Sigma, USA) as standard. Aliquots were resuspended in 10 mM HEPES immediately before the experiment.
  • 5-HT was included as a positive control for each plate.
  • 5-HT2 subtypes 5-HT2A, 5- HT2B, and 5-HT2C
  • Gq-mediated calcium flux function HEK Flp-In 293 T-Rex stable cell lines (Invitrogen) were loaded with Fluo-4 dye for 1 h, stimulated with desired concentration of compound and read for baseline (0–10 sec), and drug-induced effect (120 sec). Peak fold-over- basal fluorescence at 25 °C was then calculated using a FLIPRTETRA.
  • Example 81 Head-Twitch Response (HTR) studies Male C57BL/6J mice (6 ⁇ 8 weeks old) were obtained from Jackson Laboratories (Bar Harbor, ME) and housed in a vivarium at the University of California San Diego, an AAALAC- approved animal facility that meets all federal and state requirements for care and treatment of laboratory animals. All animal experiments were carried out in accordance with NIH guidelines and were approved by the UCSD Institutional Animal Care and Use Committee. Mice were housed up to four per cage in a climate-controlled room on a reverse-light cycle (lights on at 1900 h, off at 0700 h).
  • mice were provided with ad libitum access to food and water, with the exception of during behavioral testing. Testing was conducted between 1000 and 1800 h. Head movements were recorded using a head-mounted magnet and a magnetometer coil as described in Halberstadt et al. (Psychopharmacology, 2013, 227(4):727-739). For the head mounted magnet, mice were anesthetized, an incision was made in the scalp, and a neodymium magnet was attached to the dorsal surface of the cranium using dental cement. Following a 2-week recovery period, behavioral experiments were conducted in a well-lit room. At least 7 days occurred between sessions to avoid any carryover effects.
  • Test substances i.e., dimethyltryptamine (DMT), diethyltryptamine (DET), psilocybin, 6-fluoro-diethyltryptamine (6-F-DET), compounds 3-4, 6, 9, 12-13, 22, 33, 41, 69, 88, 166, and 178) were administered intraperitoneally (IP) at a volume of 5 mL/kg. Mice were treated with vehicle (saline) or 6 doses of the test compound and then placed in a glass cylinder surrounded by a magnetometer coil and tested for 30 min.
  • DMT dimethyltryptamine
  • DET diethyltryptamine
  • 6-F-DET 6-fluoro-diethyltryptamine
  • Coil voltage was filtered (1 kHz lowpass), digitized (20 kHz sampling rate) and saved to disk using a Powerlab/8SP with LabChart v 7.3.2 (ADInstruments, Colorado Springs, CO). The entire 30 min recordings were examined for head twitches. Established procedures based on artificial intelligence were used to identify head twitches in the recordings (Scientific Reports, 2020, 10(1):1-12). HTR counts were analyzed using one-way analyses of variance (ANOVA), followed by post hoc pairwise comparisons between individual groups and vehicle using Dunnett's multiple comparisons test. Significance was demonstrated when an ⁇ -level of 0.05 was surpassed.
  • ANOVA one-way analyses of variance
  • HTR Median effective doses (ED50 values) and 95% confidence intervals (95% CI) were calculated using nonlinear regression (Prism 9.0.2, GraphPad Software, San Diego, CA) (Table 4 and FIGs.1-3). Results of the studies described herein indicate that the compounds of the present disclosure induce HTR in mice with a comparable and/or reduced ED50, as compared to reported values of known 5HT 2A agonists run under comparable conditions (e.g., DMT, DET, psilocybin, and 6-F-DET) (Table 4) (Halberstadt et al. Neuropharmacology 2020, 167:107933). HTR has predictive validity for classical hallucinogen induced psychedelic activity in humans, as well as potency for inducing such effects.
  • the 5-HT 2A agonist 6-F-DET lacks psychedelic effects in humans and was similarly inactive in the HTR study. A significant increase in HTR counts, over baseline, was observed with administration of each of compounds 4 and 9, as compared to inactive compound 6-F-DET, as shown in the ED 50 plots of each respective compound (FIGs.1-3). Compound 8 (4-F-DET) was also inactive in inducing HTR as compared to a control (i.e., vehicle). The lack of HTR with compound 8 and 6- F-DET are consistent with the literature regarding fluorinated derivatives of known psychedelics with reduced or attenuated psychedelic activity in rodents and humans.
  • Duration of the HTR was also assessed using an ascending and descending arm dose relative to several psychedelic tryptamines of known durations of action in humans, including DMT, psilocin, 5-methoxy- ⁇ -methyltryptamine (5-MeO-AMT), and ⁇ -methyltryptamine (AMT).
  • the compounds of the present disclosure typically had a duration of HTR above baseline that was longer than the short acting DMT (i.e., about 10 minutes), but shorter or comparable to psilocin (i.e., about 35 minutes), and substantially shorter than long acting compounds 5-MeO- AMT and AMT, in C57BL/6J mice.
  • a time course group is provided for compound 88 (FIG.5).
  • Table 4 Table 4.
  • Test Compound stock solutions (10 mM) were diluted 1 in 100 (2 ⁇ L 10 mM DMSO stock + 198 ⁇ L 50:50 acetonitrile:water) to provide a 100 ⁇ M working solution.
  • samples were pre-incubated at 37 °C for 5 minutes prior to initiating the incubation by the addition of test compounds to hepatocytes (these were held at 37 °C during pre-incubation period).
  • Aliquots were sampled at 0, 5, 10, 20, 40 and 60 min and added to ice cold acetonitrile to terminate the reaction and precipitate proteins.
  • Embodiment 2 provides the compound of Embodiment 1, wherein R 1 is optionally substituted C 1 -C 3 alkyl and R 2 is selected from the group consisting of optionally substituted, branched C 3 -C 8 alkyl and optionally substituted C 3 -C 8 cycloalkyl.
  • Embodiment 3 provides the compound of Embodiment 1 or 2, wherein R 1 is selected from the group consisting of methyl, allyl, and n-propyl.
  • Embodiment 4 provides the compound of any one of Embodiments 1-3, wherein R 2 is optionally substituted, branched C 3 -C 8 alkyl.
  • Embodiment 5 provides the compound of any one of Embodiments 1-4, wherein R 2 is selected from the group consisting of iso-propyl, sec-butyl, iso-butyl, 1,2-dimethylpropyl, methylallyl, and 2-methylallyl.
  • Embodiment 6 provides the compound of any one of Embodiments 1-3, wherein R 2 is optionally substituted C 3 -C 8 cycloalkyl.
  • Embodiment 7 provides the compound of any one of Embodiments 1-3 and 6, wherein R 2 is selected from the group consisting of cyclopropyl and cyclobutyl.
  • Embodiment 8 provides the compound of Embodiment 1, wherein each of R 1 and R 2 are independently selected from the group consisting of methyl, ethyl, n-propyl, 1,2-dimethylpropyl, iso-propyl, sec-butyl, iso-butyl, n-butyl, cyclopropyl, cyclopropylmethyl, methylcyclopropyl, cyclopropylethyl, 2-cyclopropyleth-2-yl, cyclobutyl, 2-thietanyl, 3-thietanyl, allyl, methylallyl, 2-methylallyl, 3-methylallyl, propargyl, cyanomethyl, 2-hydroxyethyl, and 2-methoxyethyl.
  • Embodiment 9 provides the compound of any one of Embodiments 1-8, wherein R 3 is H.
  • Embodiment 10 provides the compound of any one of Embodiments 1-9, wherein R 4 is F and each of R 5 , R 6 , and R 7 is H.
  • Embodiment 11 provides the compound of any one of Embodiments 1-9, wherein R 5 is F, and each of R 4 , R 6 , and R 7 is H.
  • Embodiment 12 provides the compound of any one of Embodiments 1-9, wherein R 7 is F, and each of R 4 , R 5 , and R 6 is H.
  • Embodiment 13 provides the compound of any one of Embodiments 1-9, wherein each of R 4 and R 5 is F, and each of R 6 and R 7 is H.
  • Embodiment 14 provides the compound of any one of Embodiments 1-9, wherein each of R 4 and R 6 is F, and each of R 5 and R 7 is H.
  • Embodiment 15 provides the compound of any one of Embodiments 1-9, wherein each of R 4 and R 7 is F, and each of R 5 and R 6 is H.
  • Embodiment 16 provides the compound of any one of Embodiments 1-9, wherein each of R 5 and R 6 is F, and each of R 4 and R 7 is H.
  • Embodiment 17 provides the compound of any one of Embodiments 1-9, wherein each of R 5 and R 7 is F, and each of R 4 and R 6 is H.
  • Embodiment 18 provides the compound of any one of Embodiments 1-9, wherein each of R 6 and R 7 is F, and each of R 4 and R 5 is H.
  • Embodiment 19 provides the compound of any one of Embodiments 1-9, wherein R 5 is OMe, R 7 is F, and each of R 4 and R 6 is H.
  • Embodiment 20 provides the compound of any one of Embodiments 1-9, wherein each of R 5 , R 6 , and R 7 are F, and R 4 is H.
  • Embodiment 21 provides the compound of any one of Embodiments 1-9, wherein R 5 is selected from the group consisting of OR A , N(R A )(R B ), and SR A .
  • Embodiment 22 provides the compound of any one of Embodiments 1-9, wherein R 5 is selected from the group consisting of H, F, Cl, OMe, OH, and Me.
  • Embodiment 23 provides the compound of Embodiment 22, wherein R 5 is OMe.
  • Embodiment 24 provides the compound of Embodiment 22, wherein R 5 is F.
  • Embodiment 25 provides the compound of any one of Embodiments 1-9 and 21-24, wherein R 6 is selected from the group consisting of H, F, Me, Cl.
  • Embodiment 26 provides the compound of any one of Embodiments 1-9 and 21-25, wherein R 7 is selected from the group consisting of H, F, Cl, Br, and Me.
  • Embodiment 27 provides the compound of any one of Embodiments 1-9 and 21-26, wherein each of R 4 and R 6 is H.
  • Embodiment 28 provides the compound of any one of Embodiments 1-27, wherein L is selected from the group consisting of .
  • Embodiment 29 provides the compound of Embodiment 28, wherein L is .
  • Embodiment 30 provides the compound of any one of Embodiments 1-27, wherein A is selected from the group consisting of: wherein: R c1 , R c2 , R d1 , R d2 , R e1 , and R e2 , if present, are each independently selected from the group consisting of H, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
  • Embodiment 31 provides the compound of any one of Embodiments 1-27 and 30, wherein each of R a1 , R a2 , R b1 , R b2 , R c1 , R c2 , R d1 , R d2 , R e1 , R e2 , R f1 , and R f2 , if present, is H.
  • Embodiment 32 provides the compound of any one of Embodiments 1-31, wherein A is selected from the group consisting of:
  • Embodiment 33 provides the compound of any one of Embodiments 1-32, which is selected from the group consisting of: N-ethyl-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)propan-2-amine; N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine; N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N-methylbutan-2-amine; N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N-isopropylpropan-1-amine; N-(2-(5,6-difluoro-1H-indol-3-yl)ethyl)-N-ethylpropan-1-amine; N-(2-(5-fluoro-1H-indol-3-yl)ethyl)
  • Embodiment 34 provides a compound of formula (II), or a salt, prodrug, solvate, isotopologue, or stereoisomer thereof: wherein: R 3 is selected from the group consisting of H, optionally substituted C 1 -C 8 alkyl, optionally substituted benzyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 2 -C 8 alkynyl; R 4 , R 5 , R 6 , and R 7 are each independently selected from the group consisting of H, F, Cl, Br, I, OR A , N(R A )(R B ), SR A , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted benzyl, optionally
  • Embodiment 35 provides the compound of Embodiment 34, wherein R 3 is H.
  • Embodiment 36 provides the compound of Embodiment 34 or 35, wherein R 8 and R 9 are each independently selected from the group consisting of methyl, ethyl, and n-propyl.
  • Embodiment 37 provides the compound of any one of Embodiments 34-36, wherein R 10 is H.
  • Embodiment 38 provides the compound of any one of Embodiments 34-37, wherein R f1 and R f2 are H.
  • Embodiment 39 provides the compound of any one of Embodiments 34-38, wherein: (a) R 4 is F, and each of R 5 , R 6 , and R 7 is H; (b) R 5 is F, and each of R 4 , R 6 , and R 7 is H; (c) R 6 is F, and each of R 4 , R 5 , and R 7 is H; (d) R 7 is F, and each of R 4 , R 5 , and R 6 is H; (e) each of R 4 and R 5 is F, and each of R 6 and R 7 is H; (f) each of R 4 and R 6 is F, and each of R 5 and R 7 is H; (g) each of R 4 and R 7 is F, and each of R 5 and R 6 is H; (h) each of R 5 and R 6 is F, and each of R 4 and R 7 is H; (i) each of R 5 and R 7 is F, and each of R 4 and R 6 is H; or (j) each of R 6 and R 7
  • Embodiment 40 provides the compound of any one of Embodiments 34-39, which is selected from the group consisting of: 2-(ethyl(propyl)amino)-1-(5-fluoro-1H-indol-3-yl)ethan-1-one; 2-(ethyl(methyl)amino)-1-(5-fluoro-1H-indol-3-yl)ethan-1-one; 2-(dimethylamino)-1-(4-fluoro-1H-indol-3-yl)ethan-1-one; 2-(dimethylamino)-1-(5-fluoro-1H-indol-3-yl)ethan-1-one; 2-(dimethylamino)-1-(6-fluoro-1H-indol-3-yl)ethan-1-one; 2-(dimethylamino)-1-(7-fluoro-1H-indol-3-yl)ethan-1-one; 1-(4,5-
  • Embodiment 41 provides a compound of formula (III), or a salt, prodrug, solvate, isotopologue, or stereoisomer thereof: wherein: R 8 and R 9 are each independently selected from the group consisting of optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 2 -C 8 alkynyl; R 10 is selected from the group consisting of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C 2 -C9 heteroaryl; R 11 and R 12 are each independently selected from the group consisting of H, F, Cl, Br, I, OR A , N(R A )(R B ), optionally substitute
  • Embodiment 42 provides the compound of Embodiment 41, wherein R 3 is H.
  • Embodiment 43 provides the compound of Embodiment 41 or 42, wherein each of R 8 and R 9 are independently selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, sec-butyl, iso-butyl, n-butyl, cyclopropyl, cyclopropylmethyl, methylcyclopropyl, cyclopropylethyl, cyclobutyl, allyl, methylallyl, 2-methylallyl, 3-methylallyl, allylmethyl, propargyl, cyanomethyl, 2-hydroxyethyl, and 2-methoxyethyl.
  • Embodiment 44 provides the compound of any one of Embodiments 41-43, wherein R 10 is H.
  • Embodiment 45 provides the compound of any one of Embodiments 41-44, wherein each of R 11 and R 12 is H.
  • Embodiment 46 provides the compound of any one of Embodiments 41-45, wherein R 13 is H or methyl.
  • Embodiment 47 provides the compound of any one of Embodiments 41-46, wherein each of R f1 , R f2 , R g1 , and R g2 is H.
  • Embodiment 48 provides the compound of any one of Embodiments 41-47, which is selected from the group consisting of: N-ethyl-N-(2-(7-fluoro-5-methoxy-1H-indol-3-yl)ethyl)propan-1-amine; 2-(7-fluoro-5-methoxy-1H-indol-3-yl)-N,N-dimethylethan-1-amine; N,N-diethyl-2-(7-fluoro-5-methoxy-1H-indol-3-yl)ethan-1-amine; N-(2-(7-fluoro-5-methoxy-1H-indol-3-yl)ethyl)-N-propylpropan-1-amine; 3-(2-(dimethylamino)ethyl)-7-fluoro-1H-indol-5-ol; 3-(2-(diethylamino)ethyl)-7-fluoro-1H-in
  • Embodiment 51 provides a compound selected from the group consisting of: N-(2-(5-fluoro-1H-indol-3-yl)ethyl)prop-2-en-1-amine; 2-(5-fluoro-1H-indol-3-yl)-N,N-dimethylpropan-1-amine; N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N-propylpropan-1-amine; N,N-diethyl-2-(4-fluoro-1H-indol-3-yl)ethan-1-amine; N-(2-(4-fluoro-1H-indol-3-yl)ethyl)-N-propylpropan-1-amine; N-(2-(7-fluoro-1H-indol-3-yl)ethyl)-N-propylpropan-1-amine; N-(2-(5,6-difluoro-1H-ind
  • Embodiment 52 provides a pharmaceutical composition comprising at least one compound of any one of Embodiments 1-51 and a pharmaceutically acceptable carrier.
  • Embodiment 53 provides a method of treating, preventing, and/or ameliorating a psychiatric disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one compound of any of Embodiments 1-51, at least one compound of any of compounds 1-218, or the pharmaceutical composition of Embodiment 52.
  • Embodiment 54 provides the method of Embodiment 53, wherein the psychiatric disease or disorder is selected from the group consisting of a depressive disorder, anxiety disorder, and eating disorder.
  • Embodiment 55 provides the method of Embodiment 53 or 54, wherein the psychiatric disease or disorder is selected from the group consisting of attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), treatment resistant depression, major depressive disorder (MDD), bipolar I disorder, bipolar II disorder, cyclothymic disorder, anti-social personality disorder, pain, sleep-wake disorders, disruptive mood dysregulation disorder, persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance/medication-induced depressive disorder, post-partum depression, depressive disorder due to another medical condition, separation anxiety disorder, specific phobia, social anxiety disorder, panic disorder, panic attack, agoraphobia, generalized anxiety disorder, substance- medication induced anxiety disorder, anxiety disorder due to another medical condition, somatic symptom disorder, illness anxiety disorder, obsessive-compulsive disorder (OCD), obsessive- compulsive and related disorder (OCRD), OCRD due to another medical condition, substance- related disorders, alcohol-related disorders,
  • Embodiment 56 provides the method of any one of Embodiments 53-55, wherein the subject is further administered at least one additional agent useful for treating, preventing, and/or ameliorating the psychiatric disease or disorder.
  • Embodiment 57 provides the method of Embodiment 56, wherein the at least one additional agent is selected from the group consisting of a selective serotonin reuptake inhibitor, triple reuptake inhibitor, serotonin and norepinephrine reuptake inhibitor, tricyclic antidepressant, tetracyclic antidepressant, dopamine reuptake inhibitor, mood stabilizer, anticonvulsant, antipsychotic, anxiolytics, benzodiazepines, monoamine releasers, dopamine receptor agonist, cannabinoids, triptans, anti-migraine medications, analgesics, anti- inflammatory, immune modulator, 5-HT 1A receptor antagonist, 5-HT 2 receptor antagonist, 5-HT 3 receptor antagonist, monoamine oxidase inhibitor
  • Embodiment 58 provides the method of Embodiment 56 or 57, wherein the subject is co- administered the at least one compound and the at least one additional agent.
  • Embodiment 59 provides the method of any one of Embodiments 56-58, wherein the at least one compound and the at least one additional agent are co-formulated.
  • Embodiment 60 provides the method of any one of Embodiments 53-59, wherein the subject is a mammal.
  • Embodiment 61 provides the method of Embodiment 60, wherein the mammal is a human.

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EP22816868.8A EP4347559A4 (en) 2021-06-02 2022-06-02 FLUORINATED TRYPTAMINE COMPOUNDS, RELATED ANALOGUES AND METHODS USING THEM
JP2023574858A JP2024523822A (ja) 2021-06-02 2022-06-02 フッ素化トリプタミン化合物、その類似体、及びそれを使用する方法
MX2023014437A MX2023014437A (es) 2021-06-02 2022-06-02 Compuestos de triptamina fluorada, análogos de estos y métodos de uso estos.
BR112023025340A BR112023025340A2 (pt) 2021-06-02 2022-06-02 Compostos de triptamina fluorada, análogos dos mesmos e métodos usando os mesmos
KR1020237044652A KR20240017363A (ko) 2021-06-02 2022-06-02 플루오린화 트립타민 화합물, 이의 유사체 및 이를 사용하는 방법
CN202280039914.1A CN117957211A (zh) 2021-06-02 2022-06-02 氟化色胺化合物、其类似物及其使用方法
CA3220850A CA3220850A1 (en) 2021-06-02 2022-06-02 Fluorinated tryptamine compounds, analogues thereof, and methods using same
AU2022287013A AU2022287013A1 (en) 2021-06-02 2022-06-02 Fluorinated tryptamine compounds, analogues thereof, and methods using same
IL308944A IL308944A (en) 2021-06-02 2022-06-02 Fluorinated tryptamine compounds, their analogs, and methods of using them
US18/565,565 US20240286998A1 (en) 2021-06-02 2022-06-02 Fluorinated tryptamine compounds, analogues thereof, and methods using same
CONC2023/0018652A CO2023018652A2 (es) 2021-06-02 2023-12-29 Compuestos de triptamina fluorada, análogos de estos y métodos de uso de estos

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