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WO2025080608A9 - Desamide isotryptamine tetracycles for treating brain disorders - Google Patents

Desamide isotryptamine tetracycles for treating brain disorders

Info

Publication number
WO2025080608A9
WO2025080608A9 PCT/US2024/050417 US2024050417W WO2025080608A9 WO 2025080608 A9 WO2025080608 A9 WO 2025080608A9 US 2024050417 W US2024050417 W US 2024050417W WO 2025080608 A9 WO2025080608 A9 WO 2025080608A9
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
disease
disorder
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/050417
Other languages
French (fr)
Other versions
WO2025080608A1 (en
Inventor
Jeremy R. TUCK
David E. Olson
Andrian G. BASARGIN
Lee Dunlap
Noel Aaron Powell
Milan Chytil
Manuka Ghosh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Delix Therapeutics Inc
University of California Berkeley
University of California San Diego UCSD
Original Assignee
Delix Therapeutics Inc
University of California Berkeley
University of California San Diego UCSD
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Delix Therapeutics Inc, University of California Berkeley, University of California San Diego UCSD filed Critical Delix Therapeutics Inc
Publication of WO2025080608A1 publication Critical patent/WO2025080608A1/en
Publication of WO2025080608A9 publication Critical patent/WO2025080608A9/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • Such structural alterations include, for example, the loss of dendritic spines and synapses in the prefrontal cortex (PFC) as well as reductions in dendritic arbor complexify.
  • pyramidal neurons in the PFC exhibit top-down control over areas of the brain controlling motivation, fear, rew ard, and cognition.
  • Hallucinogenic psychoplastogens have demonstrated antidepressant, anxiolytic, and anti-addictive effects in the clinic. However, their subjective effects have limited their clinical utility.
  • hallucinogenic compounds are contraindicated for psychotic illnesses like schizophrenia, w hich are well known to involve the loss of dendritic spines in the PFC.
  • non- hallucinogenic psychoplastogens may have distinct advantages over their hallucinogenic counterparts.
  • compounds with clinically relevant therapeutic efficacy that have improved physicochemical properties, and possess reduced hallucinogenic (e.g., non- hallucinogenic) properties as compared to their hallucinogenic (e.g., ergoline) counterparts.
  • each R la , R lb , R lc , and R ld is independently Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxy alkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, -NO2, or - CN; alternatively, two R la groups on adjacent ring atoms are combined to form a C4-8 cycloalkyl or 4 to 8 membered heterocycloalkyl having 1 to 2 heteroatoms, each independently N, O, or S;
  • R 3 is absent, H, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, Ci-6 haloalkyl, or C1-6 haloalkoxy;
  • R 3a is absent or C 1-6 alkyl; alternatively, R 3 and R 3a are combined to form a 3 to 8 membered heterocycloalkyl having 1 to 2 heteroatoms, each independently N, O, or S; dashed bond a, b and c are each independently absent or a bond; subscripts m and p are each independently 0, 1 or 2; and subscripts n and r are each independently 0, 1, 2 or 3.
  • R 2 is H, C1-6 alkyl, C3-6 cycloalkyl. C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, or C1-6 haloalkoxy;
  • R 3 is absent, H, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy alkyl. Ci-6 haloalkyl, or C1-6 haloalkoxy;
  • R 3a is absent or C1-6 alkyl; alternatively, R 3 and R 3a are combined to form a 3 to 8 membered heterocycloalkyl having 1 to 2 heteroatoms, each independently N, O, or S; dashed bond a, b and c are each independently absent or a bond; wherein when dashed bond b is a bond then R 3a is absent; subscripts m and p are each independently 0, 1 or 2; and subscripts n and r are each independently 0, 1, 2 or 3.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • a method of treating a disease comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, thereby treating the disease.
  • a method for increasing neural pl asti ci ty comprising contacting a neuronal cell with a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount sufficient to increase neural plasticity of the neuronal cell, wherein the compound produces a maximum number of dendritic crossings with an increase of greater than 1.0 fold by a Sholl Analysis.
  • a method for increasing neural plasticity and increasing dendritic spine density comprising contacting a neuronal cell with a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount sufficient to increase neural plasticity and increase dendritic spine density of the neuronal cell.
  • FIG. 2 shows the synthesis of compounds 31 and 32 (Example 3).
  • FIG. 3 shows the synthesis of haloindole derivatives of isotryptoline.
  • the compounds of the present invention are useful for treatment of diseases, such as brain disorders, neuropsychiatric diseases, and other neurological diseases.
  • the compounds of the present invention are also useful for increasing neural plasticity, increasing dendritic spine density, or both.
  • Alkyl refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated. Disclosures provided herein of an “alkyl” are intended to include independent recitations of a saturated alkyl, unless otherwise stated. Alkyd groups described herein are generally monovalent, but may also be divalent which may also be described herein as “alkylene” or “alkylenyl” groups. Alkyl can include any number of carbons, such as C1-2, C1-3, C1-4, C1-5, C1-6, C1-7, C1-8, C1-9, Cuo, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6.
  • C1-6 alky l includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc.
  • Alkyl can also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to hepty l, octyd, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.
  • Alkenyl refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond.
  • Alkenyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and Ce.
  • Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more.
  • alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl. 2-pentenyl, isopentenyl. 1,3 -pentadienyl, 1.4-pentadienyl, 1 -hexenyl. 2-hexenyL 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.
  • Alkyn 1 refers to either a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond. Alkyny 1 can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and Ce.
  • alkynyl groups include, but are not limited to, acety lenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1 -pentynyl, 2-pentynyl, isopenty nyl, 1,3-pentadiynyl,
  • Alkoxy refers to an alkyl group having an oxygen atom that connects the alkyd group to the point of attachment: alkyl-O-.
  • alkyl group alkoxy groups can have any suitable number of carbon atoms, such as C1-6.
  • Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy. hexoxy, etc.
  • the alkoxy groups can be further substituted with a variety of substituents described within. Alkoxy groups can be substituted or unsubstituted.
  • Alkoxyalkyl refers to a radical having an alkyl component and an alkoxy component, where the alkyl component links the alkoxy component to the point of attachment.
  • the alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the alkoxy component and to the point of attachment.
  • the alkyl component can include any number of carbons, such as Co-6, C1-2, C1-3. C1-4. C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some instances, the alkyl component can be absent.
  • the alkoxy component is as defined above. Examples of the alkoxyalkyl group include, but are not limited to, 2-ethoxy-ethyl and methoxymethyl.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Haloalkyl refers to alkyl, as defined above, where some or all of the hydrogen atoms are replaced with halogen atoms.
  • alky l group haloalkyl groups can have any suitable number of carbon atoms, such as C1-6.
  • haloalkyl includes trifluoromethyl, flouromethyl, etc.
  • perfluoro can be used to define a compound or radical where all the hydrogens are replaced with fluorine.
  • perfluoromethyl refers to 1,1,1 -trifluoromethyl.
  • Haloalkoxy refers to an alkoxy group where some or all of the hydrogen atoms are substituted with halogen atoms.
  • haloalkoxy groups can have any suitable number of carbon atoms, such as C1-6.
  • the alkoxy groups can be substituted with 1. 2, 3, or more halogens.
  • the compounds are per-substituted, for example, perfluorinated.
  • Haloalkoxy includes, but is not limited to, trifluoromethoxy. 2, 2, 2, -trifluoroethoxy, perfluoroethoxy, etc.
  • Cycloalkyl refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyd can include any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, Ce-8, C3-9, C3-10, C3-11, and C3-12. In some embodiments, cycloalky ls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom.
  • Saturated monocyclic cycloalkyl rings include, for example, cyclopropy l, cyclobutyl, cyclopenty l, cyclohexy l, and cyclooctyl.
  • Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbomane, [2.2.2] bi cyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring.
  • Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1.3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbomene, and norbomadiene.
  • exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopent l, cyclohexyl, cycloheptyl and cycloocty l.
  • exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Cycloalkyl groups can be substituted or unsubstituted. Cycloalkyl groups can contain one or more double bonds in the ring.
  • Heterocycloalkyl refers to a saturated ring system having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S.
  • the heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-
  • Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members.
  • Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3. or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4.
  • heterocycloalkyls are spirocyclic or bridged compounds. In some embodiments, heterocycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon or heteroatom (e.g., nitrogen atom) that is not an aromatic ring carbon atom.
  • a carbon or heteroatom e.g., nitrogen atom
  • the heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane.
  • groups such as aziridine, azetidine, pyrrolidine, piperidine, a
  • heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline.
  • Heterocycloalkyl groups can be unsubstituted or substituted.
  • the heterocycloalkyl groups can be linked via any position on the ring.
  • aziridine can be 1- or 2-aziridine
  • azetidine can be 1- or 2- azetidine
  • pyrrolidine can be 1-, 2- or 3 -pyrrolidine
  • piperidine can be 1-, 2-, 3- or 4-piperidine
  • pyrazolidine can be 1-, 2-, 3-, or 4-pyrazolidine
  • imidazolidine can be 1-, 2-, 3- or 4-imidazolidine.
  • piperazine can be
  • isoxazolidine can be 2-, 3-, 4- or 5-oxazolidine
  • isoxazolidine can be 2-, 3-, 4- or 5-isoxazolidine
  • thiazolidine can be 2-, 3-, 4- or 5-thiazolidine
  • isothiazolidine can be 2-, 3-, 4- or 5- isothiazolidine
  • morpholine can be 2-, 3- or 4-morpholine.
  • heterocycloalkyl includes 3 to 8 ring members and 1 to 3 heteroatoms
  • representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxzoalidine.
  • thiazolidine isothiazolidine.
  • Heterocycloalkyl can also form a nng having 5 to 6 ring members and 1 to 2 heteroatoms, with representative members including, but not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine. thiazolidine, isothiazolidine. and morpholine.
  • Aryl refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings.
  • Aryl groups can include any suitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ring members.
  • Ar l groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group.
  • Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, having a methylene linking group.
  • aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as. but not limited to, -S(O)- and -S(O)2-. Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 5 to 8, 6 to 8, 5 to 9, 5 to 10, 5 to 11, or 5 to 12 ring members.
  • heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms.
  • the heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole. triazole, tetrazole, py razine, pyrimidine.
  • pyridazine triazine (1.2.3-, 1,2,4- and 1.3.5-isomers).
  • the heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline.
  • benzopyrazine quinoxaline
  • benzopyrimidine quinazoline
  • benzopyridazines such as phthalazine and cinnoline
  • benzothiophene benzofuran
  • Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.
  • the heteroaryl groups can be linked via any position on the ring.
  • pyrrole includes 1-, 2- and 3-pyrrole
  • pyridine includes 2-, 3- and 4-pyridine.
  • imidazole includes 1-, 2-, 4- and 5-imidazole
  • pyrazole includes 1-, 3-, 4- and 5-pyrazole
  • triazole includes 1-, 4- and 5-triazole
  • tetrazole includes 1- and 5-tetrazole
  • pyrimidine includes 2-, 4-, 5- and 6- pyrimidine
  • pyridazine includes 3- and 4-pyridazine
  • 1,2,3-triazine includes 4- and 5-triazine
  • 1,2,4-triazine includes 3-.
  • heteroaryl groups include those having from 5 to 10 ring members and from 1 to 3 ring atoms including N, O or S. such as pyrrole, pyridine, imidazole, pyrazole. triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran.
  • heteroaryl groups include those having from 5 to 8 ring members and from 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • Some other heteroaryl groups include those having from 9 to 12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline.
  • heteroaryl groups include those having from 5 to 6 ring members and from 1 to 2 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • heteroaryl groups include from 5 to 10 ring members and only nitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3, 5 -isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline.
  • Other heteroaryl groups include from 5 to 10 ring members and only oxygen heteroatoms, such as furan and benzofuran.
  • optional substituents are independently selected from halogen.
  • optional substituents are independently selected from halogen, -CN. - NH 2 , -OH, -NH(CHS), -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CF 3 , -OCHS, and -OCF 3
  • substituted groups are substituted with one or two of the preceding groups.
  • Salt refers to acid or base salts of the compounds used in the methods of the present invention.
  • Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed.. Mack Publishing Company, Easton. Pa., 1985, which is incorporated herein by reference.
  • salts of the acidic compounds of the present invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.
  • bases namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.
  • acid addition salts such as of mineral acids, organic carboxylic and organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • '‘Therapeutically effective amount or dose’ or “therapeutically sufficient amount or dose” or “effective or sufficient amount or dose” refer to a dose that produces therapeutic effects for which it is administered.
  • the exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). In sensitized cells, the therapeutically effective dose can often be lower than the conventional therapeutically effective dose for non-sensitized cells.
  • Treating”, “treating” and “treatment” refers to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom.
  • the treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination.
  • Disease refers abnormal cellular function in an organism, which is not due to a direct result of a physical or external injury.
  • Diseases can refer to any condition that causes distress, dysfunction, disabilities, disorders, infections, pain, or even death.
  • Diseases include, but are not limited to hereditary diseases such as genetic and non-genetic diseases, infectious diseases, non-infectious diseases such as cancer, deficiency diseases, neurological diseases, and physiological diseases.
  • administering refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject.
  • a slow-release device e.g., a mini-osmotic pump
  • Subject refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.
  • Neuroplasticity' refers to the ability of the brain to change its structure and/or function continuously throughout a subject’s life. Examples of the changes to the brain include, but are not limited to, the ability' to adapt or respond to internal and/or external stimuli, such as due to an injury, and the ability to produce new neurites, dendritic spines, and synapses.
  • Dendritic spine refers to the small membrane protruding from a dendrite which can receive electric signal from an axon at the synapse. Dendritic spines are useful for transmitting electric signals to the neuron’s cell body. Dendrites of a single neuron can comprise hundreds to thousands of spines. Dendritic spine density' refers to the number of spines within the length of a dendrite. As an illustrative example, a dendritic spine density of 5pm’ 1 indicates 5 spines per 1 pm stretch of a dendrite.
  • Modulate or “modulating” or “modulation” refers to an increase or decrease in the amount, quality', or effect of a particular activity 7 , function or molecule.
  • agonists, partial agonists, antagonists, and allosteric modulators e.g., a positive allosteric modulator
  • a G protein-coupled receptor e.g.. 5HT2 or 5HT2c
  • Agonism refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response.
  • “Agonist” refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response.
  • “5HT2A agonist” can be used to refer to a compound that exhibits an EC so with respect to 5HT2A activity of no more than about 100 pM.
  • the term “agonist” includes full agonists or partial agonists.
  • “Full agonist” refers to a modulator that binds to and activates a receptor with the maximum response that an agonist can elicit at the receptor.
  • Partial agonist refers to a modulator that binds to and activates a given receptor, but has partial efficacy, that is, less than the maximal response, at the receptor relative to a full agonist.
  • Fully selective agonisf ' refers to a modulator that produces one or a subset of biological responses that are possible from activation of a receptor. For example, activation of 5HT2A receptors is known to cause many downstream effects including increased neural plasticity, increased intracellular calcium concentrations, and hallucinations, among many other biological responses. A functionally selective agonist would produce only a subset of the biological responses possible from activation of the 5HT2A receptor.
  • “Positive allosteric modulator” refers to a modulator that binds to a site distinct from the orthosteric binding site and enhances or amplifies the effect of an agonist.
  • Antagonist refers to the inactivation of a receptor or enzy me by a modulator, or antagonist.
  • Antagonism of a receptor for example, is when a molecule binds to the receptor and does not allow activity to occur.
  • “Functionally selective antagonists” block one signaling pathway while leaving others intact.
  • Antagonist or “neutral antagonist” refers to a modulator that binds to a receptor or enzyme and blocks a biological response.
  • An antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response.
  • a bold and not wedged bond in chemical structures in the present application is used to indicate a stereocenter of unknown stereochemistry.
  • Chemical structures with a bold and not wedged bond can represent a mixture of multiple stereoisomers.
  • the present invention provides tetracyclic heterocyclic compounds of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), useful for the treatment of a variety of neurological diseases and disorders as well as increasing neuronal plasticity.
  • the compounds of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) have improved physiochemical properties compared to ergoline-based compounds as a result of the loss of a hydrogen bond donor, decreasing total polar surface area and improving central nervous system multi parameter optimization (MPO) scores.
  • MPO central nervous system multi parameter optimization
  • Described herein in some embodiments are non- hallucinogenic compounds that unexpectedly demonstrate similar therapeutic potential as hallucinogenic 5-HT modulators (e.g., 5HT2A and/or 5HT2C modulators).
  • the non-hallucinogenic compounds described herein provide better therapeutic potential than hallucinogenic 5-HT modulators (e.g., 5HT2A and/or 5HT2C modulators) for neurological diseases.
  • heterocyclic compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja- 1b), (Ja-lc), (Ja-ld), (Jb), (Jb-1 ), (Jb-2), (Jb-3), (Jb-4), (II), or (III) useful for the treatment of a variety of diseases such as brain disorders and other conditions.
  • the heterocyclic compounds provided herein are 5-HT2 modulators and promote neural plasticity (e.g.. cortical structural plasticity).
  • each R la , R lb , R lc , and R ld is independently Ci-6 alkyl.
  • R 3 is absent, H, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy alkyd, Ci-6 haloalkyl, or C1-6 haloalkoxy;
  • R 3a is absent or C1-6 alkyl; alternatively, R 3 and R ’ a are combined to form a 3 to 8 membered heterocycloalkyl having 1 to 2 heteroatoms, each independently N, O, or S; dashed bond a, b and c are each independently absent or a bond; subscripts m and p are each independently 0, 1 or 2; and subscripts n and r are each independently 0, 1, 2 or 3.
  • each R la , R lb , R lc , and R ld is independently Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxyalkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, -NO2, or - CN; alternatively, two R la groups on adjacent ring atoms are combined to form a C4-8 cycloalkyl or 4 to 8 membered heterocycloalkyl having 1 to 2 heteroatoms, each independently N, O, or S;
  • R 2 is H, C1-6 alkyl, C3-6 cycloalkyd, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxy alkyl, C1-6 haloalkyl, or C1-6 haloalkoxy;
  • R 3 is absent, H. C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy alkyl, Ci-6 haloalkyl. or C1-6 haloalkoxy;
  • R 3a is absent or C 1-6 alkyl; alternatively, R 3 and R 3a are combined to form a 3 to 8 membered heterocycloalkyl having 1 to 2 heteroatoms, each independently N, O, or S; dashed bond a, b and c are each independently absent or a bond; wherein when dashed bond b is a bond then R 3a is absent; subscripts m and p are each independently 0, 1 or 2; and subscripts n and r are each independently 0, 1, 2 or 3.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1 ), (Ja-1 a), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 2 is H, Ci-6 alkyl, Ci-6 alkoxyalkyl, or Ci-6 hydroxyalkyl.
  • R 2 is H, Ci-6 alkyl, Ci-6 alkoxyalkyl, or Ci-6 hydroxyalkyl.
  • R 2 is H, methyl, ethyl, n-propyl, iso-propyl, -CH2OCH3, CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2OH, or -CH2CH2OH.
  • R 2 is H, methyl, ethyl, n-propyl, iso-propyl, -CH2OCH3, CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2OH, or -CH2CH2OH.
  • R 2 is H.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja- lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 2 is CH2OH.
  • provided herein is a compound of Formula (J), (Ja), or (Ja-
  • a compound of Formula (J), (Ja), or (Ja- 1) or a pharmaceutically acceptable salt thereof, having a structure of Formula (Ja-1 a): (Ja-1 a).
  • provided herein is a compound of Formula (J), (Ja), or (Ja- I), or a pharmaceutically acceptable salt thereof, having a structure of Formula (Ja-lb): (Ja-lb). [0067] In some embodiments, provided herein is a compound of Formula (J), (Ja), or (Ja-
  • each R la is independently Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxyalkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy. - NO2, or -CN.
  • a compound of Formula (J). (Ja), (Ja-1). (Ja-la), (Ja-lb), (Ja-lc). (Ja-ld). (Jb).
  • each R la is independently C1-6 alkyl, C1-6 alkoxy, or halogen.
  • Jb is independently C1-3 alkyl, C1-3 alkoxy, or halogen.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each R la is independently Me, MeO, fluoro, or chloro.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each R la is independently C1-6 alkoxy.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2). (Jb-3), (Jb-4),
  • each R la is independently methoxy, fluoro, or chloro.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each R la is independently halogen. In some embodiments, each R la is independently fluoro or chloro.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript n is 0.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript n is 1.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript n is 2.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc). (Ja-ld), (Jb). (Jb-1), (Jb-2), (Jb-3), (Jb-4). (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript n is 1 or 2.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each R lb is independently C1-6 alkyl. C1-6 alkoxy, or halogen.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1). (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld).
  • each R lb is independently C1-3 alkyl, C1-3 alkoxy, or halogen.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each R lb is independently C1-6 alkoxy.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1). (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld). (Jb), (Jb-1), (Jb-2).
  • each R lb is independently Ci-6 alkoxy, or halogen.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4),
  • each R lb is independently halogen.
  • each R lb is independently fluoro or chloro.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript m is 0, 1, or 2.
  • a compound of Formula (J) provided herein is a compound of Formula (J).
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Jb), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript m is 0 or 1.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript m is 2.
  • provided herein is a compound of Formula (J). (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc). (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3). (Jb-4), (II), or
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja- lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R lc is C1-6 alkyl, Ci-6 alkoxy, or halogen.
  • provided herein is a compound of Formula (J). (Ja), (Ja-1).
  • R lb is methoxy, fluoro, or chloro.
  • R lc is fluoro or chloro.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript p is 1 or 2.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1). (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb- 2), (Jb-3), (Jb-4).
  • a pharmaceutically acceptable salt thereof wherein subscript p is 0 or 1.
  • provided herein is a compound of Formula (J), (Ja). (Ja-1), (Ja-la), (Ja-lb). (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript p is 1.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja- lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R ld is C1-6 alkyl, C1-6 alkoxy, or halogen.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc). (Ja-ld), (Jb).
  • R ld is Ci-6 alkoxy, or halogen.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3). (Jb-4), (II), or (111), or a pharmaceutically acceptable salt thereof, wherein R ld is Ci-6 alkyl.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R ld is halogen.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1). (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld).
  • R ld is methoxy, fluoro, or chloro. In some embodiments, R ld is fluoro or chloro.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript r is 1, 2. or 3.
  • provided herein is a compound of Formula (J), (Ja). (Ja-1), (Ja-la).
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript r is 1.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1 ), (Jb-2). (Jb-3), (Jb-4), or (II), or a pharmaceutically acceptable salt thereof, wherein R 3 is H or Ci-6 alkyl.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), or (II), or a pharmaceutically acceptable salt thereof, wherein R 3 is Ci-6 alky l.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc). (Ja-ld), (Jb). (Jb-1). (Jb-2), (Jb-3), (Jb-4).
  • R 3 is methyl, ethyl, n-propyl, or iso-propyl.
  • provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein R 3a can be absent or Ci-6 alkyl. In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein R 3a is Ci-6 alkyl. In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein R 3a is methyl, ethyl, n-propyl, or iso-propyl. In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein R 3a is methyl. In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein R 3a is absent.
  • provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond a and b are each a bond, and dashed bond c is absent.
  • a compound of Formula (J), or a pharmaceutically acceptable salt thereof wherein dashed bond a and c are each a bond, and dashed bond b is absent.
  • a compound of Formula (J), or a pharmaceutically acceptable salt thereof wherein dashed bond b and c are each a bond, and dashed bond a is absent.
  • provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond a is a bond, and dashed bond b and c are each independently absent or a bond.
  • provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond b is a bond, and dashed bond a and c are each independently absent or a bond.
  • a compound of Formula (J), or a pharmaceutically acceptable salt thereof wherein dashed bond b is a bond, and dashed bond a and c are each absent.
  • provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond c is a bond, and dashed bond a and b are each independently absent or a bond.
  • a compound of Formula (J), or a pharmaceutically acceptable salt thereof wherein dashed bond c is a bond, and dashed bond a and b are each absent.
  • provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond a is absent, and dashed bond b and c are each independently absent or a bond. In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond a, b and c are each absent.
  • a compound of Formula (J), or a pharmaceutically acceptable salt thereof wherein dashed bond a, b and c are each a bond.
  • provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2). (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, having a structure of: pharmaceutically acceptable salt thereof.
  • the compounds of the present invention can also be in the salt forms, such as acid or base salts of the compounds of the present invention.
  • pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (fumaric acid, acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non- toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed.. Mack Publishing Company, Easton. Pa., 1985, which is incorporated herein by reference.
  • Isotopically - labeled compounds of the present invention are useful in assays of the tissue distribution of the compounds and their prodrugs and metabolites; preferred isotopes for such assays include 3 H and 14 C.
  • substitution with heavier isotopes, such as deuterium ( 2 H) can provide increased metabolic stability, which offers therapeutic advantages such as increased in vivo half-life or reduced dosage requirements.
  • Isotopically - labeled compounds of this invention can generally be prepared according to the methods known by one of skill in the art by substituting an isotopically-labeled reagent for a non- isotopically labeled reagent.
  • Compounds of the present invention can be isotopically labeled at positions adjacent to the basic amine, in aromatic rings, and the methyl groups of methoxy substituents.
  • the present invention includes all tautomers and stereoisomers of compounds of the present invention, either in admixture or in pure or substantially pure form.
  • the compounds of the present invention can have asymmetric centers at the carbon atoms, and therefore the compounds of the present invention can exist in diastereomeric or enantiomeric forms or mixtures thereof. All conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs and tautomers are within the scope of the present invention.
  • a compound of Formula (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), or (Jb-4) may be synthesized according to the following process:
  • compound 1 undergoes a reduction reaction to yield compound 2.
  • compound 3 undergoes an alkylation to yield compound 3.
  • compound 3 undergoes a reduction to yield compound 4.
  • compound 4 undergoes a cross coupling reaction with compound la to yield compound 5.
  • compound 5 undergoes a substitution reaction to yield compound 6.
  • racemic compound 6 is separated into enantiomers compound 7 and compound 8.
  • R 2 is methyl and R 3 is methyl.
  • R la is Me, MeO, fluoro, or chloro.
  • R lb is Me, MeO, fluoro, chloro, or CN.
  • n is 0, 1, or 2.
  • m is 0 or 1.
  • 5-HT2 agonism has been correlated with the promotion of neural plasticity (Ly et al., 2018).
  • 5-HT2 antagonists abrogate the neuritogenesis and spinogenesis effects of hallucinogenic compounds with 5-HT2 agonist activity, e.g., DMT, LSD, and DOI.
  • DMT and other psychedelic compounds promote increased dendritic arbor complexity, dendritic spine density, and synaptogenesis through a 5-HT2-dependent process.
  • the psychoplastogenic effects of compounds provided herein are also blocked under these conditions, implicating the 5-HT2 receptor in their mechanism of action.
  • modulation of the 5-HT2 receptor appears to be important in neuroplasticity as well as various psychological conditions, such as, for example, anxiety, depression, post-traumatic stress disorder (PTSD), and schizophrenia.
  • non-hallucinogenic compounds e.g., lisuride and 6-MeO-DMT
  • compounds such as, for example, 6-F-DET and Ketanserin, which are non-hallucinogenic in animals (e.g., humans)
  • a compound provided herein prevents binding of 5-HT to 5HT2A.
  • the 5HT2A sensor assay is in an antagonist mode.
  • a compound provided herein prevents binding of 5-HT to 5HT2A and has non- hallucinogenic potential.
  • a compound provided herein prevents binding of 5-HT to 5HT2A and is non-hallucinogenic. In some embodiments, a compound provided herein prevents binding of 5-HT to 5HT2A in antagonist mode has non- hallucinogenic potential. In some embodiments, a compound provided herein prevents binding of 5-HT in antagonist mode is anon-hallucinogenic compound. In some embodiments, a compound provided herein inhibits the response of a sensor assay in antagonist mode has non-hallucinogenic potential. In some embodiments, a compound provided herein inhibits the response of a sensor assay in antagonist mode is a non- hallucinogenic compound.
  • the effect of a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) on an agonist mode sensor assay suggests the compound is a non-hallucinogenic ligand of the 5-HT2A receptor and/or the 5-HT2C receptor.
  • the effect of a compound provided herein on an antagonist mode sensor assay suggests the compound is a non-hallucinogenic ligand of the 5-HT2A receptor and/or the 5-HT2C receptor.
  • effect of a compound provided herein on an agonist mode and an antagonist mode sensor assay together suggest the compound is anon-hallucinogenic ligand of the 5-HT2A receptor and/or the 5-HT2C receptor.
  • Described herein in some embodiments are non-hallucinogenic compounds of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) that demonstrate similar therapeutic potential as hallucinogenic 5-HT2 agonists.
  • the non-hallucinogenic compounds described herein provide better therapeutic potential than hallucinogenic 5-HT2 agonists for neurological diseases.
  • the compounds of the present invention are modulators of the 5-HT2A receptor and/or the 5-HT2C receptor and promote neural plasticity (e g., cortical structural plasticity).
  • the compounds of Formula (J). (Ja), (Ja-1 ), (Ja-la), (Ja-lb), (Ja-lc). (Ja-ld), (Jb). (Jb-1), (Jb-2), (Jb-3), (Jb-4). (II), or (III) have activity at the 5-HT2A receptor and/or the 5-HT2C receptor.
  • the compounds provided herein elicit a biological response by activating the 5-HT2A receptor and/or the 5-HT2C receptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT2A receptor and/or the 5-HT2C receptor).
  • the compounds provided herein are selective 5-HT2A modulators and promote neural plasticity (e.g., cortical structural plasticity).
  • the compounds provided herein are selective 5-HT2C modulators and promote neural plasticity (e.g., cortical structural plasticity ).
  • promotion of neural plasticity includes, for example, increased dendritic spine growth, increased synthesis of synaptic proteins, strengthened synaptic responses, increased dendritic arbor complexity, increased dendritic branch content, increased spinogenesis, increased neuritogenesis, or any combination thereof.
  • increased neural plasticity' includes, for example, increased cortical structural plasticity in the anterior parts of the brain.
  • 5-HT2C agonists have been suggested as treatments for multiple symptom domains of schizophrenia including positive, negative, cognitive, and depressive symptoms without the adverse events or tolerability issues associated with existing agents.
  • the 5-HT2C receptor is a highly complex, highly regulated receptor which is widely distributed throughout the brain.
  • the 5-HT2C receptor couples to multiple signal transduction pathways leading to engagement of a number of intracellular signaling molecules.
  • the preclinical profile of 5-HT2C agonists from a neurochemical, electrophysiological, and a behavioral perspective is indicative of antipsychotic-like efficacy.
  • disclosed herein are compounds having dual 5-HT2a antagonist and 5-HT2 C agonist activity'.
  • a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja- lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) is non-hallucinogenic.
  • a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) is used to treat neurological diseases, which modulators do not elicit dissociative side-effects.
  • the hallucinogenic potential of the compounds described herein is assessed in vitro.
  • the hallucinogenic potential assessed in vitro of the compounds described herein is compared to the hallucinogenic potential assessed in vitro of hallucinogenic homologs.
  • the compounds of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) elicit less hallucinogenic potential in vitro than the hallucinogenic homologs.
  • the neurological diseases comprise decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT2A receptor content, increased 5-HT2C receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof.
  • (II), or (III) e.g., a 5-HT2A modulator and/or a 5-HT2C modulator is used for increasing neuronal plasticity.
  • a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) is used for treating a brain disorder.
  • a compound of Formula (J), (Ja), (Ja-1), (Ja- la), (Ja-lb), (Ja-lc), (Ja-ld). (Jb), (Jb-1), (Jb-2). (Jb-3). (Jb-4), (II). or (III) is used for increasing at least one of translation, transcription, or secretion of neurotrophic factors.
  • a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja- lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4). (II), or (III), including pharmaceutically acceptable salts and solvates thereof, is a non-hallucinogenic psychoplastogen.
  • the non-hallucinogenic psychoplastogen promotes neuronal grow th, improves neuronal structure, or a combination thereof.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof.
  • compositions of the present invention can be prepared in a wide variety of oral, parenteral and topical dosage forms.
  • Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient.
  • the compositions of the present invention can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compositions described herein can be administered by inhalation, for example, intranasally. Additionally, the compositions of the present invention can be administered transdermally.
  • compositions of this invention can also be administered by intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy’ Asthma Immunol. 75:107-111, 1995).
  • the present invention also provides pharmaceutical compositions including a pharmaceutically acceptable carrier or excipient and the compound of the present invention.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences. Maack Publishing Co. Easton PA ("Remington's").
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5% or 10% to 70% of the compound the present invention.
  • Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; a low melting wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starch from com, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins including, but not limited to, gelatin and collagen.
  • disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.
  • Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage).
  • compositions of the invention can also be used orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol.
  • Push-fit capsules can contain the compound of the present invention mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the compound of the present invention may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol wi th or without stabilizers.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the compound of the present invention is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the compound of the present invention in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a
  • the aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate.
  • Formulations can be adjusted for osmolarity.
  • Oil suspensions can be formulated by suspending the compound of the present invention in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these.
  • the oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose.
  • These formulations can be preserved by the addition of an antioxidant such as ascorbic acid.
  • an injectable oil vehicle see Minto, J. Pharmacol. Exp. Ther. 281 :93-102, 1997.
  • the compositions of the present invention can be formulated for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ.
  • parenteral administration such as intravenous (IV) administration or administration into a body cavity or lumen of an organ.
  • the formulations for administration will commonly comprise a solution of the compositions of the present invention dissolved in a pharmaceutically acceptable carrier.
  • acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride.
  • sterile fixed oils can conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are stenle and generally free of undesirable matter.
  • the formulations of the compositions of the present invention can be delivered by the use of liposomes w hich fuse with the cellular membrane or are endocytosed, i.e., by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis.
  • liposomes particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery' of the compositions of the present invention into the target cells in vivo.
  • the compound of the present invention can be present in any suitable amount, and can depend on various factors including, but not limited to, weight and age of the subject, state of the disease, etc.
  • Suitable dosage ranges for the compound of the present invention include from about 0.1 mg to about 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about 750 mg. or about 25 mg to about 500 mg, or about 50 mg to about 250 mg.
  • Suitable dosages for the compound of the present invention include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg.
  • the compounds of the present invention can be administered at any suitable frequency, interval and duration.
  • the compound of the present invention can be administered once an hour, or two, three or more times an hour, once a day, or two, three, or more times per day, or once every 2, 3, 4, 5, 6, or 7 days, so as to provide the preferred dosage level.
  • representative interv als include 5, 10. 15. 20, 30, 45 and 60 minutes, as well as 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours.
  • the compound of the present invention can be administered once, twice, or three or more times, for an hour, for 1 to 6 hours, for 1 to 12 hours, for 1 to 24 hours, for 6 to 12 hours, for 12 to 24 hours, for a single day, for 1 to 7 days, for a single week, for 1 to 4 weeks, for a month, for 1 to 12 months, for a year or more, or even indefinitely.
  • composition can also contain other compatible therapeutic agents.
  • the compounds described herein can be used in combination with one another, with other active agents known to be useful in modulating a glucocorticoid receptor, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.
  • the compounds of the present invention can be co-administered with another active agent.
  • Co-administration includes administering the compound of the present invention and active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of each other.
  • Co- administration also includes administering the compound of the present invention and active agent simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order.
  • the compound of the present invention and the active agent can each be administered once a day, or two, three, or more times per day so as to provide the preferred dosage level per day.
  • co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both the compound of the present invention and the active agent.
  • the compound of the present invention and the active agent can be formulated separately.
  • the compound of the present invention and the active agent can be present in the compositions of the present invention in any suitable weight ratio, such as from about 1 : 100 to about 100:1 (w/w), or about 1:50 to about 50:1, or about 1 :25 to about 25: 1, or about 1: 10 to about 10: 1, or about 1 :5 to about 5: 1 (w/w).
  • the compound of the present invention and the other active agent can be present in any suitable weight ratio, such as about 1: 100 (w/w). 1 :50, 1 :25, 1 :10, 1:5, 1:4, 1 :3, 1:2, 1 : 1, 2: 1, 3: 1, 4:1, 5: 1, 10: 1, 25: 1, 50: 1 or 100: 1 (w/w).
  • Other dosages and dosage ratios of the compound of the present invention and the active agent are suitable in the compositions and methods of the present invention.
  • a method of treating a disease or disorder comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, thereby treating the disease or disorder.
  • provided herein is a method of treating a disease, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, thereby treating the disease.
  • Neuronal plasticity and changes thereof, have been attributed to many neurological diseases and disorders. For example, during development and in adulthood, changes in dendritic spine number and morphology (e.g., lengths, crossings, density) accompany synapse formation, maintenance and elimination; these changes are thought to establish and remodel connectivity' within neuronal circuits. Furthermore, dendritic spine structural plasticity is coordinated with synaptic function and plasticity. For example, spine enlargement is coordinated with long-term potentiation in neuronal circuits, whereas long- term depression is associated with spine shrinkage.
  • dendritic spine number and morphology e.g., lengths, crossings, density
  • dendritic spine structural plasticity is coordinated with synaptic function and plasticity. For example, spine enlargement is coordinated with long-term potentiation in neuronal circuits, whereas long- term depression is associated with spine shrinkage.
  • dendritic spines undergo experience-dependent morphological changes in live animals, and even subtle changes in dendritic spines can affect synaptic function, synaptic plasticity, and patterns of connectivity in neuronal circuits.
  • disease-specific disruptions in dendritic spine shape, size, and/or number accompany neurological diseases and disorders, such as, for example, neurodegenerative (e.g., Alzheimer’s disease or Parkinson's disease) and neuropsychiatric (e.g., depression or schizophrenia) diseases and disorders, suggesting that dendritic spines may serve as a common substrate in diseases that involve deficits in information processing.
  • neurodegenerative e.g., Alzheimer’s disease or Parkinson's disease
  • neuropsychiatric e.g., depression or schizophrenia
  • a neurological disease or disorder generally refers to a disease or disorder of the central nervous system (CNS) (e.g., brain, spine, and/or nerves) of an individual.
  • CNS central nervous system
  • a method of treating a neurological disease or disorder with a compound provided herein (e.g., a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1 ), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof).
  • a compound provided herein e.g., a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1 ), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof).
  • a compound useful for the treatment of a variety of brain disorders and other conditions is a compound useful for the treatment of a variety of brain disorders and other conditions.
  • a 5-HT2A modulator and promotes neural plasticity (e.g., cortical structural plasticity).
  • the 5-HT2A modulator e.g., 5-HT2A agonists
  • a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) is a 5-HT2C modulator and promotes neural plasticity (e.g., cortical structural plasticity).
  • the 5-HT2C modulator is used to treat a brain disorder.
  • the brain disorder comprises decreased neural plasticity, decreased cortical structural plasticity, decreased 5- HT 2A receptor content, increased 5-HT2C receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites. or any combination thereof.
  • a compound provided herein e.g., a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or
  • the neurological disease is a migraine, headaches (e.g., cluster headache), post- traumatic stress disorder (PTSD), anxiety 7 , depression, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury 7 , and addiction (e g., substance use disorder).
  • headaches e.g., cluster headache
  • PTSD post- traumatic stress disorder
  • anxiety 7 e.g., cluster headache
  • depression e.g., cluster headache
  • neurodegenerative disease e.g., Alzheimer's disease, Parkinson's disease
  • psychological disorder e.g., treatment resistant depression
  • suicidal ideation e.g., major depressive disorder
  • bipolar disorder e., schizophrenia
  • schizophrenia stroke
  • traumatic brain injury 7 e.g., substance use disorder
  • the disease is headache disorders. In some embodiments, the disease is a migraine or cluster headache. In some embodiments, the disease is migraines. In some embodiments, the disease is cluster headaches. In some embodiments, the disease is addiction. In some embodiments, the disease is substance use disorder. In some embodiments, the disease is alcohol use disorder.
  • the neurological disease is a neurodegenerative disease, Alzheimer’s disease, or Parkinson’s disease.
  • the neurological disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety 7 .
  • the neuropsychiatric disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety.
  • the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety.
  • the neuropsychiatric disease or neurological disease is addiction (e g., substance use disorder).
  • the neuropsychiatric disease or neurological disease is depression.
  • the neuropsychiatric disease or neurological disease is anxiety.
  • the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD).
  • the neurological disease is stroke or traumatic brain injury.
  • the neuropsychiatric disease or neurological disease is schizophrenia.
  • a compound of the present invention is used to treat a neuropsychiatric disease.
  • the neuropsychiatric disease is major depressive disorder, treatment resistant depression, generalized anxiety disorder, post- traumatic stress disorder, obsessive compulsive disorder, substance use disorders, or a psychosis.
  • the psychosis is schizophrenia, bipolar disorder, or psychosis in Alzheimer’s disease (AD-P).
  • a compound of the present invention is used to treat pain. In some embodiments, a compound of the present invention is used to treat migraine.
  • a compound of the present invention is used to treat a neurodegenerative disease.
  • the neurodegenerative disease is a dementia, traumatic brain injury, or Parkinson’s disease.
  • the dementia is Alzheimer’s disease, vascular dementia, Lewy body dementia, frontotemporal dementia. Huntington’s disease, or mixed dementia.
  • the compound of the present invention is used to treat behavioral and/or psychological symptoms in dementia.
  • the compound of the present invention is used to treat motor symptoms, behavioral symptoms, and/or psychological symptoms in Parkinson’s disease.
  • the disease is a neuropsychiatric disease. In some embodiments, the diseases is a neurodegenerative disease.
  • a compound of the present invention is used to treat a neurodegenerative, a neuropsychiatric, or substance use disease or disorder.
  • the neurological disease or disorder is an injury.
  • the disease or disorder is an anxiety disorder, a mood disorder, a psychotic disorder, a personality 7 disorder, an eating disorder, a sleep disorder, a sexuality 7 disorder, an impulse control disorder, a substance use disorder, a dissociative disorder, a cognitive disorder, a developmental disorder, or a factitious disorder.
  • the disease or disorder is a psychotic disorder.
  • the psychotic disorder is selected from schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, delusional disorder, shared psychotic disorder, substance-induced psychotic disorder, paraphrenia, psychotic depression, bipolar disorder, schizotypal personality disorder, paranoid personality disorder, schizoid personality 7 disorder, borderline personality 7 disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and dissociative disorders, or psychosis associated with a neurodegenerative disease.
  • the neurodegenerative disease is selected from Huntington’s disease, Alzheimer’s disease, Lewy 7 body 7 dementia, and Parkinson’s disease.
  • the psychotic disorder is schizophrenia or bipolar disorder.
  • a compound of the present invention is used to treat brain disorders.
  • the compounds have, for example, anti-addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof.
  • the brain disorder is a neuropsychiatric disease.
  • the neuropsychiatric disease is a mood or anxiety disorder.
  • brain disorders include, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), anxiety, depression, schizophrenia, and addiction (e.g., substance abuse disorder).
  • brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety.
  • a method for increasing neural plasticity comprising contacting a neuronal cell with a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount sufficient to increase neural plasticity 7 of the neuronal cell, wherein the compound produces a maximum number of dendritic crossings with an increase of greater than 1.0 fold by a Sholl Analysis.
  • Neural plasticity refers to the ability of the brain to change structure and/or function throughout a subject’s life. New neurons can be produced and integrated into the central nervous system throughout the subject’s life. Increasing neural plasticity includes, but is not limited to, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain. In some embodiments, increasing neural plasticity comprises promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and increasing dendritic spine density.
  • increasing neural plasticity can treat neurodegenerative disease, Alzheimer’s, Parkinson’s disease, psychological disorder, depression, addiction, anxiety 7 , post-traumatic stress disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury 7 , or substance use disorder.
  • the neuropsychiatric disease is bipolar disorder.
  • the disease is depression.
  • the disease is post-traumatic stress syndrome (PTSD).
  • the disease is anxiety.
  • the disease is a neurodegenerative disease.
  • the disease is Alzheimer’s disease or Parkinson’s disease.
  • the disease is Alzheimer’s disease.
  • the disease is Parkinson’s disease.
  • a compound of the present invention is used to increase neural plasticity.
  • the compounds used to increase neural plasticity have, for example, anti-addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof.
  • decreased neural plasticity is associated with a neuropsychiatric disease.
  • the neuropsychiatric disease is a mood or anxiety disorder.
  • the neuropsychiatric disease includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., substance abuse disorder).
  • brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety.
  • the disease is a neuropsychiatric disease.
  • the experiment or assay to determine increased neural plasticity of any compound of the present invention is a phenotypic assay, a dendritogenesis assay, a spinogenesis assay, a synaptogenesis assay, a Sholl analysis, a concentration- response experiment, a 5-HT2A agonist assay, a 5-HT2A antagonist assay, a 5-HT2A binding assay, or a 5-HT2A blocking experiment (e.g., ketanserin blocking experiments).
  • the experiment or assay to determine the hallucinogenic potential of any compounds of the present invention is a mouse head-twitch response (HTR) assay.
  • HTR mouse head-twitch response
  • Compounds of the present invention may have activity' as 5-HT2A modulators.
  • the compounds of the present invention have activity as 5-HT2A modulators.
  • the compounds of the present invention elicit a biological response by activating the 5-HT2A receptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT2A receptor).
  • 5-HT2A agonism has been correlated with the promotion of neural plasticity.
  • the 5HT2A sensor assay is in an agonist mode or an antagonist mode. In some embodiments, the 5HT2A sensor assay is in an agonist mode.
  • the compounds described herein are selective 5-HT2A modulators.
  • the compounds described herein are 5-HT2A modulators and promote neural plasticity’ (e.g., cortical structural plasticity).
  • the compounds described herein are selective 5-HT2A modulators and promote neural plasticity (e.g., cortical structural plasticity).
  • promotion of neural plasticity includes, for example, increased dendritic spine growth, increased synthesis of synaptic proteins, strengthened synaptic responses, increased dendritic arbor complexity, increased dendritic branch content, increased spinogenesis, increased neuritogenesis. or any combination thereof.
  • increased neural plasticity includes, for example, increased cortical structural plasticity in the anterior parts of the brain.
  • non-hallucinogenic 5-HT2A modulators are used for treating a disease.
  • non-hallucinogenic 5-HT2A modulators e.g., 5-HT2A agonists
  • non-hallucinogenic 5-HT2A modulators e.g.. 5-HT2A agonists
  • the experiment or assay to determine increased neural plasticity of any compound of the present invention is a phenotypic assay, a dendritogenesis assay, a spinogenesis assay, a synaptogenesis assay, a Sholl analysis, a concentration- response experiment, a 5-HT2C agonist assay, a 5-HT2C antagonist assay, a 5-HT2C binding assay, or a 5-HT2C blocking experiment (e.g., ketanserin blocking experiments).
  • the experiment or assay to determine the hallucinogenic potential of any compounds of the present invention is a mouse head-twitch response (HTR) assay.
  • Compounds of the present invention may have activity as 5-HT2C modulators.
  • the compounds of the present invention have activity' as 5-HT2C modulators.
  • the compounds of the present invention elicit a biological response by activating the 5-HT2C receptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT2C receptor).
  • 5-HT2C agonism has been correlated with the promotion of neural plasticity.
  • the 5HT2C sensor assay is in an agonist mode or an antagonist mode. In some embodiments, the 5HT2C sensor assay is in an agonist mode.
  • non-hallucinogenic 5-HT2C modulators are used for treating a disease.
  • non-hallucinogenic 5-HT2C modulators e.g., 5-HT2C agonists
  • non-hallucinogenic 5-HT2C modulators e.g.. 5-HT2C agonists
  • a method for increasing neural plasticity and increasing dendritic spine density comprising contacting a neuronal cell with a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount sufficient to increase neural plasticity and increase dendritic spine density of the neuronal cell.
  • Dendritic spines are dynamic and can have significant changes in density 7 , shape, and volume over time.
  • the growth or loss of dendritic spines, w hich contribute to the dendritic spine density, can be important for reinforcing neural pathways for learning, memory, and general cognitive function.
  • Increasing dendritic spine density can be useful for treatment of neurological diseases, such as, but not limited to, neurodegenerative diseases and neuropsychiatric diseases.
  • Increasing dendritic spine density can be measured by staining and immunocytochemical methods known by one of skill in the art.
  • Staining methods include, but are not limited to electron microscopy, Golgi staining, crystal violet staining, DAPI staining, and eosin staining.
  • Golgi staining can be used to measure dendritic spine density.
  • a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja- 1c), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4). (II), or (III), or pharmaceutically acceptable salts thereof, is anon-hallucinogenic psychoplastogens useful for treating one or more diseases or disorders associated with loss of synaptic connectivity and/or plasticity 7 .
  • a modulator of 5-hydroxytryptamine receptor 2A that is useful for treating one or more diseases or disorders associated with 5-HT2A activity.
  • a modulator of 5- hydroxy tryptamine receptor 2C (5-HT2c) that is useful for treating one or more diseases or disorders associated with 5-HT2C activity.
  • (II), or (III), or a pharmaceutically acceptable salt thereof is used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from promoting neuronal growth and/or improving neuronal structure.
  • compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a mammal already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the mammal’s health status, weight, and response to the drugs, and the judgment of a healthcare practitioner.
  • Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • compositions containing the compounds described herein are administered to a mammal susceptible to or otherw ise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use. the precise amounts also depend on the mammal's state of health, weight, and the like. When used in mammals, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the mammal’s health status and response to the drugs, and the judgment of a healthcare professional.
  • prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
  • the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the mammal’s life in order to ameliorate or otherwise control or limit the symptoms of the mammal's disease or condition.
  • the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (/. ⁇ ?., a “drug holiday”).
  • the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days. 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days.
  • the dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In some embodiments, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In some embodiments, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In some embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50.
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50.
  • the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
  • the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
  • any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non- systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
  • any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose;
  • the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
  • the length of the drug holiday varies from 2 days to 1 year.
  • the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e.. by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • an adjuvant i.e.. by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced.
  • the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like.
  • additional agent such as an additional therapeutically effective drug, an adjuvant or the like.
  • Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens is optionally determined by means similar to those set forth hereinabove for the actives themselves.
  • the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e.. providing more frequent, lower doses in order to minimize toxic side effects.
  • a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, is initiated prior to. during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
  • the dosage regimen to treat, prevent, or ameliorate the disease(s) for which relief is sought is modified in accordance with a variety of factors (e.g. the disease or disorder from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject).
  • the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
  • Nuclear magnetic resonance (NMR) spectra were acquired on a Bruker 400 operating at 400 and 100 MHz for 'H and 13 C. respectively, and are referenced internally according to residual solvent signals. Data for 1 H NMR are recorded as follows: chemical shift (5, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m, multiplet), coupling constant (Hz), and integration. Data for 13 C NMR are reported in terms of chemical shift (6, ppm). Liquid chromatography -mass spectrometry (LC-MS) was performed using a Waters Alliance 2695 HPLC with a Waters Micromass ZQ Detector.
  • LC-MS Liquid chromatography -mass spectrometry
  • 6-fluoroindole was used to prepare 6-fluoro-7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lF7-indole (1.30 g, 83%) as light purple solid.
  • Example 3 (8-methyl-7a.,8.,9,10-tetrahvdro-7H-indolo[7,l-fgl[l.,7]naphthyridin-10- vDmethanol (major) (8-nietliyl-7a.8.9.10-tetralivdro-711-iiid()lol7.1- fgl [ 1.7 lnaphthyridin-10-yljmethanol (minor) ethyl 6-(hydroxymethyl)-5-(lH-indol-7-yl)nicotinate
  • Racemic (8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7, L/g][l,7]naphthyridin-10- yljmethanol (minor) was separated into its enantiomers by preparatory chiral SFC (Chiralpak-AD-H 25 cm x 3 cm; Isocratic method: 40% EtOH (0.1% diethylamine)/CO 2 ; 100 bar, 85 mL/min; injection volume 1 mL. 1 mg/mL in MeOH).
  • Example 13 3-fluoro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo
  • Racemic 2-fluoro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,l- fg][1,7]naphthyridine was separated into its enantiomers by preparatory chiral SFC (Chiralpak-IG 25 cm x 2 cm; Isocratic method: 25% MeOH (0.1% diethylamine)/CO2: 100 bar, 60 mL/min; injection volume 0.75 mL, 5 mg/mL in methanol).
  • Example 15 l-fluoro-8-methyl-7a,8,9,10-tetrahvdro-7H-indolo[7,l- fg] [ 1.71naphthyridine
  • Racemic l-fluoro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1- fg][1,7]naphthyridine was separated into its enantiomers by preparatory chiral SFC (Chiralpak-IG 25 cm x 2 cm; Isocratic method: 25% MeOH (0.1% diethylamine)/CO 2 ; 100 bar, 60 mL/min; injection volume 0.75 mL, 5 mg/mL in MeOH).
  • Racemic 3-chloro-8-methyl-7a, 8,9,10-tetrahyd ro-7H-indolo [7,1- fg][1,7]naphthyridine was separated into its enantiomers by preparatory chiral SFC (Chiralpak-IG 25 cm x 2 cm; Isocratic method: 30% MeOH (0.1% diethylamine)/CO2; 100 bar, 60 mL/min; injection volume 0.75 mL, 6 mg/mL in MeOH).
  • Example 17 2-chloro-8-methyl-7a,8,9,10-tetrahydro-7/Z-indolo[7,l- fg] [ l,7]naphthyridine
  • Racemic 2-chloro-8-methyl-7a, 8, 9,10-tetrahy dro-7H-indolo [7,1- fg][1,7]naphthyridine was separated into its enantiomers by preparatory chiral SFC (Chiralpak-IG 25 cm x 2 cm; Isocratic method: 32% MeOH (0.1% diethylamine)/CO2: 100 bar, 60 mL/min; injection volume 0.75 mL, 6 mg/rnL in MeOH).
  • Racemic l-chloro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo [7,1- fg][1,7]naphthyridine was separated into its enantiomers by preparatory chiral SFC (Chiralpak-IG 25 cm x 2 cm; Isocratic method: 30% MeOH (0.1% diethylamine)/CO2; 100 bar, 60 mL/min; injection volume 0.75 mL, 5 mg/mL in MeOH).
  • Example 20 Synthesis of 7a & 8a: [0309] 80 mg of racemic 6a was purified by Chiral Pak AD-H (20mmX250 mm
  • Racemic 6b 25 mg was purified Column AD-H (20 X250*mm,5pm) Mobile phase A hexane Mobile phase B EtOH Eluent A: B:90: 10 Total Flow rate (mL/min) 20 ml/min was assigned as 7b, and the more slowly eluting peak was assigned as 8b.
  • racemic 6f was purified by Column: Chiral Pak-IG (30mmX250 mm, 5p), Mobile Phase-A: n-Hexane. Mobile Phase-B: ETOH: MeOH (1: 1), Mobile Phase-A: B- 80:20, Flow: 42 mL/min. The faster eluting peak was assigned as 7f, and the more slowly eluting peak was assigned as 8f.
  • racemic 6g 50 mg was purified by Column IG (30 X250*mm, 5pm) Mobile phase A n-HEXANE Mobile phase B ETOH-MEOH Eluent A: B: 60:40 Total Flow rate (mL/min) 42 ml/min. The faster eluting peak was assigned as 7g, and the more slowly eluting peak was assigned as 8g.
  • racemic 6h was purified by Column IG (30 X250*mm,5pm) Mobile phase A 0.1 % of IPamine in n-HEXANE Mobile phase B ETOH-MEOH (1-1) Eluent A: B: 80:20 Total Flow rate (mL/min) 42 ml/min. The faster eluting peak was assigned as 7h, and the more slowly eluting peak was assigned as 8h.
  • racemic 6k was purified by Column CHIARALPAK-IC (30X250mm,5pm) MP(A)C02 63 g/min MP(B)Co-Solvent 37 ml/min (0.1% MeONH2 in EtOH) Total Flow rate (mL/min) 90g-30%- lOObar Diluent EtOH+MeOH+3 Drops Of THF. The faster eluting peak was assigned as 7k, and the more slowly eluting peak was assigned as 8k
  • racemic 61 45 mg was purified by chiral CHIRALPAK AD-H (250 X4.6mm, 5pm) Mobile phase A: 0.1% IP AMINE in n-HEXANE Mobile phase B: ETOH A:B : 80:20 FLOW : 1.0 ml/min PDA : AD-H_013. The faster eluting peak was assigned as 71, and the more slowly eluting peak was assigned as 81.
  • racemic 6n was purified by Column IG (30 X250*mm,5u) Mobile phase A IP AMINE IN n-HEX Mobile phase B DCM-IPA Eluent A: B: 95-05 Total Flow rate (mL/min) 42 ml/min The faster eluting peak was assigned as 7n, and the more slowly eluting peak was assigned as 8n.
  • Example 54 Synthesis of 8r ((7aS,10R)-N,N-diethyl-7a,8,9,10-tetrahvdro-7H- indolo[7.1-fg][l,71naphthyridine-10-carboxamide):
  • racemic 8r was purified by chiral CHIRALPAK AD-H (250 X4.6mm.5pm) Mobile phase A :0. 1% IP AMINE in n-HEXANE Mobile phase B: ETOH A:B : 80:20 FLOW : 1 .0 ml/min PDA : AD-H 013.
  • the faster eluting peak was assigned as 9r-a, and the more slowly eluting peak was assigned as 9r-b.
  • Radioligand Binding Assays (5-HT2AR and 5-HT2CR).
  • the 5-HT2AR and 5- HT2CR competitive radioligand binding assays were performed at Epics Therapeutics S.A. (Belgium, FAST-0505B. FAST-0507B) using conventional methods. Experiments were performed using the free bases of all compounds, except for 5.35 which was used as the hydrochloride salt. Briefly, competition binding was performed in duplicate in the wells of a 96-well plate (Master Block, Greiner, 786201) containing binding buffer, membrane extracts, radiotracer [ 3 H]-DOI and test compound. Nonspecific binding was determined by co- incubation with 200-fold excess of cold competitor DOI.
  • the samples were incubated in a final volume of 0. 1 mL at a temperature and for a duration optimized for either the 5-HT2AR or 5-HT2CR and then filtered over filter plates. Filters were washed six times with 0.5 mL of ice-cold washing buffer (optimized for 5-HT2AR) and 50 pL of Microscint 20 (Packard) were added in each well. The plates were incubated for 15 min on an orbital shaker and then counted with a TopCountTM for 1 min/well.
  • Radioligand Binding Assays 5-HT2BR.
  • the 5-HT2BR competitive radioligand binding assays were performed at Eurofms Cerep SA (Celle 1’Evescault, France) using conventional methods (Catalog #1333). Experiments were performed using the free bases of all compounds, except for 5.35 which was used as the hydrochloride salt.
  • Cell membrane homogenates (10 pg protein) are incubated for 60 min at room temperature with 0.2 nM [125I]( ⁇ )DOI in the absence or presence of the test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MgC12, 10 pM pargyline and 0.1% ascorbic acid.
  • Nonspecific binding is determined in the presence of 1 pM ( ⁇ )DOI. Following incubation, the samples are filtered rapidly under vacuum through glass fiber filters (GF/B. Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). The filters are dried then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as a percent inhibition of the control radioligand specific binding.
  • the standard reference compound is ( ⁇ )DOI, which is tested in each experiment at several concentrations to obtain a competition curve from which its IC50 is calculated.
  • IP1 Assays 5-HT2AR and 5-HT2CR.
  • the 5-HT2AR and 5-HT2CR IPOne HTRF assays were performed at Epics Therapeutics S.A. (Belgium, FAST-05051, FAST- 05071) using conventional methods. Experiments were performed using the free bases of all compounds, except 5.35 which was used as the hydrochloride salt . Briefly, CHO-K1 cells expressing human recombinant 5-HT2AR or 5-HT2CR grown to mid-log phase in culture media without antibiotics were detached with PBS-EDTA, centrifuged, and resuspended in stimulation buffer.
  • test compounds or reference agonist diluted in stimulation buffer are dispensed in the wells of a 384-well plate.
  • 5 pl of cells suspension (20,000 cells) are added and the plate is incubated 60 min at 37°C with 5% CO2.
  • lysis buffer containing IPl-d2 and anti-IPl cryptate detection reagents 5 pl each
  • plates are incubated for 1 h at room temperature and fluorescence ratios are measured according to the manufacturer’s specifications using the HTRF kit.
  • test compounds or reference antagonist Ketanserin for 5-HT2AR and Methysergide for 5-HT2CR
  • stimulation buffer with reference agonist oc-Me-5-HT for a final concentration corresponding to its EC so
  • reference agonist oc-Me-5-HT for a final concentration corresponding to its EC so
  • IP1 Assays 5-HT2BR.
  • the 5-HT2BR IP1 assays were performed at Eurofins Cerep SA (Celle 1’Evescault, France) using conventional methods (Catalog #3344). Experiments were performed using the free bases except for 5.35 which was used as the hydrochloride salt.
  • the cells are suspended in a buffer containing 10 mM Hepes/NaOH (pH 7.4), 4.2 mM KC1, 146 mM NaCl, 1 mM CaC12, 0.5 mM MgC12, 5.5 mM glucose and 50 mM LiCl, then distributed in microplates at a density of about 20,000 cells/well.
  • the IP1 concentration is determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio). The results are expressed as a percent inhibition of the control response to 30 nM 5-HT.
  • the standard reference antagonist is SB 206553, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its IC50 value is calculated.

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Abstract

Provided herein are tetracyclic heterocyclic compounds which can be useful for methods of treating a disease or for increasing neural plasticity. The compounds can also be useful for increasing dendritic spine density.

Description

DESAMIDE ISOTRYPTAMINE TETRACYCLES FOR TREATING BRAIN DISORDERS CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63/588,936, filed on October 9, 2023, which is incorporated herein by reference in its entirety.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
[0002] This invention was made with Government support under Grant No. R01GM128997 aw arded by the National Institutes of Health. The Government has certain rights in this invention.
BACKGROUND
[0003] Altered synaptic connectivity’ and plasticity has been observed in the brains of individuals with neuropsychiatric and neurological diseases/disorders. Psychoplastogens promote neuronal growth and improve neuronal architecture through mechanisms that may involve the activation of the serotonin 5-HT2 receptors. Modulators of these biological targets, such as, for example, N,N-dimethyltryptamine (DMT), ibogaine, and lysergic acid diethylamide (LSD) have demonstrated psychoplastogenic properties. For example, LSD and other analogs of the ergoline scaffold are capable of rectifying deleterious changes in neuronal structure that are associated with neuropsychiatric and neurological diseases/disorders. Such structural alterations include, for example, the loss of dendritic spines and synapses in the prefrontal cortex (PFC) as well as reductions in dendritic arbor complexify. Furthermore, pyramidal neurons in the PFC exhibit top-down control over areas of the brain controlling motivation, fear, rew ard, and cognition. Hallucinogenic psychoplastogens have demonstrated antidepressant, anxiolytic, and anti-addictive effects in the clinic. However, their subjective effects have limited their clinical utility. Moreover, hallucinogenic compounds are contraindicated for psychotic illnesses like schizophrenia, w hich are well known to involve the loss of dendritic spines in the PFC. Thus, non- hallucinogenic psychoplastogens may have distinct advantages over their hallucinogenic counterparts. [0004] Provided herein are compounds with clinically relevant therapeutic efficacy that have improved physicochemical properties, and possess reduced hallucinogenic (e.g., non- hallucinogenic) properties as compared to their hallucinogenic (e.g., ergoline) counterparts.
BRIEF SUMMARY OF THE INVENTION
[0005] In one embodiment, provided herein is a compound, or a pharmaceutically acceptable salt thereof, having a structure of Formula (J): wherein: each Rla, Rlb, Rlc, and Rld is independently Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxy alkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, -NO2, or - CN; alternatively, two Rla groups on adjacent ring atoms are combined to form a C4-8 cycloalkyl or 4 to 8 membered heterocycloalkyl having 1 to 2 heteroatoms, each independently N, O, or S;
R2 is H, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, or C1-6 haloalkoxy;
R3 is absent, H, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, Ci-6 haloalkyl, or C1-6 haloalkoxy;
R3a is absent or C 1-6 alkyl; alternatively, R3 and R3a are combined to form a 3 to 8 membered heterocycloalkyl having 1 to 2 heteroatoms, each independently N, O, or S; dashed bond a, b and c are each independently absent or a bond; subscripts m and p are each independently 0, 1 or 2; and subscripts n and r are each independently 0, 1, 2 or 3.
[0006] In one embodiment, provided herein is a compound, or a pharmaceutically acceptable salt thereof, having a structure of Formula (J):
wherein: each Rla, Rlb, Rlc, and Rld is independently Ci-6 alky l. C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxyalkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, -NO2, or - CN; alternatively, two Rla groups on adjacent ring atoms are combined to form a C4-8 cy cloalkyl or 4 to 8 membered heterocycloalkyl having 1 to 2 heteroatoms, each independently N, O, or S;
R2 is H, C1-6 alkyl, C3-6 cycloalkyl. C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, or C1-6 haloalkoxy;
R3 is absent, H, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy alkyl. Ci-6 haloalkyl, or C1-6 haloalkoxy;
R3a is absent or C1-6 alkyl; alternatively, R3 and R3a are combined to form a 3 to 8 membered heterocycloalkyl having 1 to 2 heteroatoms, each independently N, O, or S; dashed bond a, b and c are each independently absent or a bond; wherein when dashed bond b is a bond then R3a is absent; subscripts m and p are each independently 0, 1 or 2; and subscripts n and r are each independently 0, 1, 2 or 3.
[0007] In another embodiment, provided herein is a pharmaceutical composition, comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
[0008] In another embodiment, provided herein is a method of treating a disease, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, thereby treating the disease.
[0009] In another embodiment, provided herein is a method for increasing neural pl asti ci ty, the method comprising contacting a neuronal cell with a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount sufficient to increase neural plasticity of the neuronal cell, wherein the compound produces a maximum number of dendritic crossings with an increase of greater than 1.0 fold by a Sholl Analysis.
[0010] In another embodiment, provided herein is a method for increasing neural plasticity and increasing dendritic spine density, the method comprising contacting a neuronal cell with a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount sufficient to increase neural plasticity and increase dendritic spine density of the neuronal cell.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1A shows synthesis of isotryptoline (13, Example 1), the isotryptamine isostere of didehydro-N-methyl-ergoline.
[0012] FIG. IB shows synthesis of isotryptine (20, Example 2), the isotryptamine isostere of lysergine.
[0013] FIG. 2 shows the synthesis of compounds 31 and 32 (Example 3).
[0014] FIG. 3 shows the synthesis of haloindole derivatives of isotryptoline.
DETAILED DESCRIPTION OF THE INVENTION
I. GENERAL
[0015] Provided herein are tetracyclic ergoline analogs of heterocyclic compounds of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof. The compounds of the present invention are useful for treatment of diseases, such as brain disorders, neuropsychiatric diseases, and other neurological diseases. The compounds of the present invention are also useful for increasing neural plasticity, increasing dendritic spine density, or both.
II. DEFINITIONS
[0016] Unless specifically indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this invention belongs. In addition, any method or material similar or equivalent to a method or material described herein can be used in the practice of the present invention. For purposes of the present invention, the following terms are defined.
[0017] “A,” ‘"an/’ or "‘the” not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a celf’ includes a plurality of such cells and reference to "the agent" includes reference to one or more agents known to those skilled in the art, and so forth.
[0018] “Alkyl” refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated. Disclosures provided herein of an “alkyl” are intended to include independent recitations of a saturated alkyl, unless otherwise stated. Alkyd groups described herein are generally monovalent, but may also be divalent which may also be described herein as “alkylene” or “alkylenyl” groups. Alkyl can include any number of carbons, such as C1-2, C1-3, C1-4, C1-5, C1-6, C1-7, C1-8, C1-9, Cuo, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. For example, C1-6 alky l includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to hepty l, octyd, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.
[0019] “Alkenyl” refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and Ce. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl. 2-pentenyl, isopentenyl. 1,3 -pentadienyl, 1.4-pentadienyl, 1 -hexenyl. 2-hexenyL 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.
[0020] “Alkyn 1” refers to either a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond. Alkyny 1 can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and Ce. Examples of alkynyl groups include, but are not limited to, acety lenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1 -pentynyl, 2-pentynyl, isopenty nyl, 1,3-pentadiynyl,
1.4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1.4-hexadiynyl,
1.5-hexadiynyl, 2, 4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can be substituted or unsubstituted.
[0021] “Alkoxy” refers to an alkyl group having an oxygen atom that connects the alkyd group to the point of attachment: alkyl-O-. As for alkyl group, alkoxy groups can have any suitable number of carbon atoms, such as C1-6. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy. hexoxy, etc. The alkoxy groups can be further substituted with a variety of substituents described within. Alkoxy groups can be substituted or unsubstituted. [0022] “Alkoxyalkyl” refers to a radical having an alkyl component and an alkoxy component, where the alkyl component links the alkoxy component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the alkoxy component and to the point of attachment. The alkyl component can include any number of carbons, such as Co-6, C1-2, C1-3. C1-4. C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some instances, the alkyl component can be absent. The alkoxy component is as defined above. Examples of the alkoxyalkyl group include, but are not limited to, 2-ethoxy-ethyl and methoxymethyl.
[0023] "Halogen" refers to fluorine, chlorine, bromine and iodine.
[0024] ■‘Haloalkyl” refers to alkyl, as defined above, where some or all of the hydrogen atoms are replaced with halogen atoms. As for alky l group, haloalkyl groups can have any suitable number of carbon atoms, such as C1-6. For example, haloalkyl includes trifluoromethyl, flouromethyl, etc. In some instances, the term “perfluoro” can be used to define a compound or radical where all the hydrogens are replaced with fluorine. For example, perfluoromethyl refers to 1,1,1 -trifluoromethyl.
[0025] “Haloalkoxy” refers to an alkoxy group where some or all of the hydrogen atoms are substituted with halogen atoms. As for an alkyl group, haloalkoxy groups can have any suitable number of carbon atoms, such as C1-6. The alkoxy groups can be substituted with 1. 2, 3, or more halogens. When all the hydrogens are replaced with a halogen, for example by' fluorine, the compounds are per-substituted, for example, perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy. 2, 2, 2, -trifluoroethoxy, perfluoroethoxy, etc. [0026] “Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyd can include any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, Ce-8, C3-9, C3-10, C3-11, and C3-12. In some embodiments, cycloalky ls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Saturated monocyclic cycloalkyl rings include, for example, cyclopropy l, cyclobutyl, cyclopenty l, cyclohexy l, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbomane, [2.2.2] bi cyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1.3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbomene, and norbomadiene. When cycloalkyl is a saturated monocyclic C3-8 cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopent l, cyclohexyl, cycloheptyl and cycloocty l. When cycloalkyl is a saturated monocyclic C3-6 cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted. Cycloalkyl groups can contain one or more double bonds in the ring.
[0027] “Heterocycloalkyl” refers to a saturated ring system having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2- Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3. or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. In some embodiments, heterocycloalkyls are spirocyclic or bridged compounds. In some embodiments, heterocycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon or heteroatom (e.g., nitrogen atom) that is not an aromatic ring carbon atom. The heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. The heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups can be substituted with C 1-6 alkyl or oxo (=0), among many others.
[0028] The heterocycloalkyl groups can be linked via any position on the ring. For example, aziridine can be 1- or 2-aziridine, azetidine can be 1- or 2- azetidine, pyrrolidine can be 1-, 2- or 3 -pyrrolidine, piperidine can be 1-, 2-, 3- or 4-piperidine, pyrazolidine can be 1-, 2-, 3-, or 4-pyrazolidine, imidazolidine can be 1-, 2-, 3- or 4-imidazolidine. piperazine can be
1-, 2-, 3- or 4-piperazine, tetrahydrofuran can be 1- or 2-tetrahydrofuran. oxazolidine can be
2-, 3-, 4- or 5-oxazolidine, isoxazolidine can be 2-, 3-, 4- or 5-isoxazolidine, thiazolidine can be 2-, 3-, 4- or 5-thiazolidine, isothiazolidine can be 2-, 3-, 4- or 5- isothiazolidine, and morpholine can be 2-, 3- or 4-morpholine.
[0029] When heterocycloalkyl includes 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxzoalidine. thiazolidine, isothiazolidine. morpholine, thiomorpholine, dioxane and dithiane. Heterocycloalkyl can also form a nng having 5 to 6 ring members and 1 to 2 heteroatoms, with representative members including, but not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine. thiazolidine, isothiazolidine. and morpholine.
[0030] “Aryl” refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can include any suitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ring members. Ar l groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, having a methylene linking group. Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. Aryl groups can be substituted or unsubstituted.
[0031] “Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as. but not limited to, -S(O)- and -S(O)2-. Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 5 to 8, 6 to 8, 5 to 9, 5 to 10, 5 to 11, or 5 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5. 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms. The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole. triazole, tetrazole, py razine, pyrimidine. pyridazine, triazine (1.2.3-, 1,2,4- and 1.3.5-isomers). thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline. benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.
[0032] The heteroaryl groups can be linked via any position on the ring. For example, pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-, 3- and 4-pyridine. imidazole includes 1-, 2-, 4- and 5-imidazole, pyrazole includes 1-, 3-, 4- and 5-pyrazole, triazole includes 1-, 4- and 5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes 2-, 4-, 5- and 6- pyrimidine, pyridazine includes 3- and 4-pyridazine, 1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-. 5- and 6-triazine, 1,3,5-triazine includes 2-triazine, thiophene includes 2- and 3-thiophene, furan includes 2- and 3-furan, thiazole includes 2-, 4- and 5-thiazole, isothiazole includes 3-, 4- and 5-isothiazole, oxazole includes 2-, 4- and 5- oxazole, isoxazole includes 3-, 4- and 5-isoxazole, indole includes 1-, 2- and 3-indole, isoindole includes 1- and 2-isoindole, quinoline includes 2-, 3- and 4-quinoline, isoquinoline includes 1-, 3- and 4-isoquinoline, quinazoline includes 2- and 4-quinoazoline, cinnoline includes 3- and 4-cinnoline, benzothiophene includes 2- and 3-benzothiophene, and benzofuran includes 2- and 3-benzofuran.
[0033] Some heteroaryl groups include those having from 5 to 10 ring members and from 1 to 3 ring atoms including N, O or S. such as pyrrole, pyridine, imidazole, pyrazole. triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include those having from 5 to 8 ring members and from 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other heteroaryl groups include those having from 9 to 12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline. quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran and bi pyridine. Still other heteroaryl groups include those having from 5 to 6 ring members and from 1 to 2 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
[0034] Some heteroaryl groups include from 5 to 10 ring members and only nitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3, 5 -isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline. Other heteroaryl groups include from 5 to 10 ring members and only oxygen heteroatoms, such as furan and benzofuran. Some other heteroaryl groups include from 5 to 10 ring members and only sulfur heteroatoms, such as thiophene and benzothiophene. Still other heteroaryl groups include from 5 to 10 ring members and at least two heteroatoms, such as imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine. triazine (1.2.3-, 1,2,4- and 1.3.5-isomers). thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and cinnoline.
[0035] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from halogen. -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, - C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), - S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalky 1, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from halogen. - CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(Ci-C4alkyl), -C(=O)NH2, - C(=O)NH(Ci-C4alkyl), -C(=O)N(Ci-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(Ci-C4alkyl), - S(=O)2N(Ci-C4alkyl)2, Ci-C4alkyl, C3-C6cycloalkyl, Ci-C4fluoroalkyl, Ci-C4heteroalkyl, Ci- C4alkoxy, Ci-C4fluoroalkoxy, -SCi-C4alkyl. -S(=O)Ci-C4alkyl, and -S(=O)2Ci-C4alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN. - NH2, -OH, -NH(CHS), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCHS, and -OCF3 In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0).
[0036] “Salt” refers to acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed.. Mack Publishing Company, Easton. Pa., 1985, which is incorporated herein by reference. [0037] Pharmaceutically acceptable salts of the acidic compounds of the present invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.
[0038] Similarly acid addition salts, such as of mineral acids, organic carboxylic and organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure.
[0039] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
[0040] '‘Therapeutically effective amount or dose’’ or “therapeutically sufficient amount or dose” or “effective or sufficient amount or dose” refer to a dose that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). In sensitized cells, the therapeutically effective dose can often be lower than the conventional therapeutically effective dose for non-sensitized cells.
[0041] “Treat”, “treating” and “treatment” refers to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom. The treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination.
[0042] '‘Disease” refers abnormal cellular function in an organism, which is not due to a direct result of a physical or external injury. Diseases can refer to any condition that causes distress, dysfunction, disabilities, disorders, infections, pain, or even death. Diseases include, but are not limited to hereditary diseases such as genetic and non-genetic diseases, infectious diseases, non-infectious diseases such as cancer, deficiency diseases, neurological diseases, and physiological diseases. [0043] “Administering” refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject.
[0044] “Subject” refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.
[0045] “Neural plasticity'” refers to the ability of the brain to change its structure and/or function continuously throughout a subject’s life. Examples of the changes to the brain include, but are not limited to, the ability' to adapt or respond to internal and/or external stimuli, such as due to an injury, and the ability to produce new neurites, dendritic spines, and synapses.
[0046] “Dendritic crossing” refers to dendritic branches which overlap each other or form a cluster. Dendritic crossing can be measured by Sholl Analysis.
[0047] “Dendritic spine” refers to the small membrane protruding from a dendrite which can receive electric signal from an axon at the synapse. Dendritic spines are useful for transmitting electric signals to the neuron’s cell body. Dendrites of a single neuron can comprise hundreds to thousands of spines. Dendritic spine density' refers to the number of spines within the length of a dendrite. As an illustrative example, a dendritic spine density of 5pm’1 indicates 5 spines per 1 pm stretch of a dendrite.
[0048] “Modulate” or “modulating” or “modulation” refers to an increase or decrease in the amount, quality', or effect of a particular activity7, function or molecule. By way of illustration and not limitation, agonists, partial agonists, antagonists, and allosteric modulators (e.g., a positive allosteric modulator) of a G protein-coupled receptor (e.g.. 5HT2 or 5HT2c) are modulators of the receptor.
[0049] “Agonism” refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response.
[0050] “Agonist” refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response. By way of example only, “5HT2A agonist” can be used to refer to a compound that exhibits an EC so with respect to 5HT2A activity of no more than about 100 pM. In some embodiments, the term “agonist” includes full agonists or partial agonists. “Full agonist” refers to a modulator that binds to and activates a receptor with the maximum response that an agonist can elicit at the receptor. “Partial agonist” refers to a modulator that binds to and activates a given receptor, but has partial efficacy, that is, less than the maximal response, at the receptor relative to a full agonist. "Functionally selective agonisf ' refers to a modulator that produces one or a subset of biological responses that are possible from activation of a receptor. For example, activation of 5HT2A receptors is known to cause many downstream effects including increased neural plasticity, increased intracellular calcium concentrations, and hallucinations, among many other biological responses. A functionally selective agonist would produce only a subset of the biological responses possible from activation of the 5HT2A receptor.
[0051] “Positive allosteric modulator" refers to a modulator that binds to a site distinct from the orthosteric binding site and enhances or amplifies the effect of an agonist.
[0052] “Antagonism” refers to the inactivation of a receptor or enzy me by a modulator, or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor and does not allow activity to occur. “Functionally selective antagonists” block one signaling pathway while leaving others intact.
[0053] “Antagonist” or “neutral antagonist” refers to a modulator that binds to a receptor or enzyme and blocks a biological response. An antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response.
[0054] A bold and not wedged bond in chemical structures in the present application is used to indicate a stereocenter of unknown stereochemistry. Chemical structures with a bold and not wedged bond can represent a mixture of multiple stereoisomers.
III. COMPOUNDS
[0055] The present invention provides tetracyclic heterocyclic compounds of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), useful for the treatment of a variety of neurological diseases and disorders as well as increasing neuronal plasticity.
[0056] In some embodiments, the compounds of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) have improved physiochemical properties compared to ergoline-based compounds as a result of the loss of a hydrogen bond donor, decreasing total polar surface area and improving central nervous system multi parameter optimization (MPO) scores. Described herein in some embodiments are non- hallucinogenic compounds that unexpectedly demonstrate similar therapeutic potential as hallucinogenic 5-HT modulators (e.g., 5HT2A and/or 5HT2C modulators). In some embodiments, the non-hallucinogenic compounds described herein provide better therapeutic potential than hallucinogenic 5-HT modulators (e.g., 5HT2A and/or 5HT2C modulators) for neurological diseases.
[0057] Provided herein is a heterocyclic compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja- 1b), (Ja-lc), (Ja-ld), (Jb), (Jb-1 ), (Jb-2), (Jb-3), (Jb-4), (II), or (III) useful for the treatment of a variety of diseases such as brain disorders and other conditions. In some embodiments, the heterocyclic compounds provided herein are 5-HT2 modulators and promote neural plasticity (e.g.. cortical structural plasticity).
[0058] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, having a structure of Formula (J): wherein: each Rla, Rlb, Rlc, and Rld is independently Ci-6 alkyl. C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxyalkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, -NO2, or - CN; alternatively, two Rla groups on adjacent ring atoms are combined to form a C4-8 cy cloalkyl or 4 to 8 membered heterocycloalkyl having 1 to 2 heteroatoms, each independently N, O, or S;
R2 is H, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, or C 1-6 haloalkoxy;
R3 is absent, H, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy alkyd, Ci-6 haloalkyl, or C1-6 haloalkoxy;
R3a is absent or C1-6 alkyl; alternatively, R3 and R ’a are combined to form a 3 to 8 membered heterocycloalkyl having 1 to 2 heteroatoms, each independently N, O, or S; dashed bond a, b and c are each independently absent or a bond; subscripts m and p are each independently 0, 1 or 2; and subscripts n and r are each independently 0, 1, 2 or 3. [0059] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, having a structure of Formula (J): wherein: each Rla, Rlb, Rlc, and Rld is independently Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxyalkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, -NO2, or - CN; alternatively, two Rla groups on adjacent ring atoms are combined to form a C4-8 cycloalkyl or 4 to 8 membered heterocycloalkyl having 1 to 2 heteroatoms, each independently N, O, or S;
R2 is H, C1-6 alkyl, C3-6 cycloalkyd, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxy alkyl, C1-6 haloalkyl, or C1-6 haloalkoxy;
R3 is absent, H. C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy alkyl, Ci-6 haloalkyl. or C1-6 haloalkoxy;
R3a is absent or C 1-6 alkyl; alternatively, R3 and R3a are combined to form a 3 to 8 membered heterocycloalkyl having 1 to 2 heteroatoms, each independently N, O, or S; dashed bond a, b and c are each independently absent or a bond; wherein when dashed bond b is a bond then R3a is absent; subscripts m and p are each independently 0, 1 or 2; and subscripts n and r are each independently 0, 1, 2 or 3.
[0060] In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, having the structure of Formula (Ja): [0061] In some embodiments, provided herein is a compound of Formula (J) or (Ja), or a pharmaceutically acceptable salt thereof, having the structure of Formula (Ja- 1):
In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja- 1), or a pharmaceutically acceptable salt thereof, having the structure of Formula (Jb):
[0062] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R2 is H, Ci-6 alkyl, C3-6 cycloalkyl. C1-6 alkoxy. C1-6 alkoxyalkyl, C1-6 hydroxyalkyl. C1-6 haloalkyl, or Ci-6 haloalkoxy. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1 ), (Ja-1 a), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R2 is H, Ci-6 alkyl, Ci-6 alkoxyalkyl, or Ci-6 hydroxyalkyl. In some embodiments, provided herein is a compound of Formula (J). (Ja), (Ja-1), (Ja-la), (Ja- lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R2 is H, methyl, ethyl, n-propyl, iso-propyl, -CH2OCH3, CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2OH, or -CH2CH2OH. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb). (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2). (Jb-3), (Jb-4), (11). or (Ill), or a pharmaceutically acceptable salt thereof, wherein R2 is H, Me, or CH2OH. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R2 is Me or CH2OH. In some embodiments, provided herein is a compound of Formula (J). (Ja), (Ja-1), (Ja-la), (Ja- lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R2 is H. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R2 is Me. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja- lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R2 is CH2OH.
[0063] In some embodiments, provided herein is a compound of Formula (J), (Ja), or (Ja-
1), or a pharmaceutically acceptable salt thereof, having a structure of Formula (Ja-la), Formula (Ja-lb), Formula (Ja-lc), or Formula (Ja-ld):
(Ja-la),
(Ja-lb),
(Ja-lc), or (Ja-ld).
[0064] In some embodiments, provided herein is a compound of Formula (J), (Ja), or (Ja- 1), or a pharmaceutically acceptable salt thereof, having a structure of Formula (Jb-1), Formula (Jb-2), Formula (Jb-3), or Formula (Jb-4):
[0065] In some embodiments, provided herein is a compound of Formula (J), (Ja), or (Ja- 1), or a pharmaceutically acceptable salt thereof, having a structure of Formula (Ja-1 a): (Ja-1 a).
[0066] In some embodiments, provided herein is a compound of Formula (J), (Ja), or (Ja- I), or a pharmaceutically acceptable salt thereof, having a structure of Formula (Ja-lb): (Ja-lb). [0067] In some embodiments, provided herein is a compound of Formula (J), (Ja), or (Ja-
I), or a pharmaceutically acceptable salt thereof, having a structure of Formula (Ja-lc): (Ja-lc).
[0068] In some embodiments, provided herein is a compound of Formula (J), (Ja), or (Ja- I), or a pharmaceutically acceptable salt thereof, having a structure of Formula (Ja-ld): (Ja-ld).
[0069] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1 ), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), or (Jb-4), or a pharmaceutically acceptable salt thereof, having a structure of Formula (Jb-1): (Jb-1).
[0070] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2). (Jb-3), or (Jb-4), or a pharmaceutically acceptable salt thereof, having a structure of Formula (Jb-2):
[0071] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), or (Jb-4), or a pharmaceutically acceptable salt thereof, having a structure of Formula (Jb-3): (Jb-3)
[0072] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), or (Jb-4), or a pharmaceutically acceptable salt thereof, having a structure of Formula (Jb-4):
[0073] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2). (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rla is independently Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxyalkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy. - NO2, or -CN. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja- 1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rla is independently Ci-6 alkyl, C1-6 alkoxy, halogen, C1-6 haloalkoxy, or -CN. In some embodiments, provided herein is a compound of Formula (J). (Ja), (Ja-1). (Ja-la), (Ja-lb), (Ja-lc). (Ja-ld). (Jb). (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rla is independently C1-6 alkyl, C1-6 alkoxy, or halogen. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld). (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rla is independently C1-3 alkyl, C1-3 alkoxy, or halogen. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rla is independently Me, MeO, fluoro, or chloro. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rla is independently C1-6 alkoxy. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2). (Jb-3), (Jb-4),
(II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rla is independently C1-6 alkoxy, or halogen. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or
(III), or a pharmaceutically acceptable salt thereof, wherein each Rla is independently methoxy, fluoro, or chloro. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rla is independently halogen. In some embodiments, each Rla is independently fluoro or chloro.
[0074] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript n is 0, 1, 2 or 3. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc). (Ja-ld), (Jb). (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript n is 1. 2 or 3. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb- 1), (Jb-2), ( Jb-3 ). (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript n is 0, 1 or 2. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript n is 0. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript n is 1. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript n is 2. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc). (Ja-ld), (Jb). (Jb-1), (Jb-2), (Jb-3), (Jb-4). (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript n is 1 or 2.
[0075] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rlb is independently Ci-6 alkyl. C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxyalkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, - NO2, or -CN. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja- 1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rlb is independently Ci-6 alkyl, C1-6 alkoxy, halogen, C1-6 haloalkoxy, or -CN. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rlb is independently C1-6 alkyl. C1-6 alkoxy, or halogen. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1). (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld). (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rlb is independently C1-3 alkyl, C1-3 alkoxy, or halogen. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rlb is independently Me, MeO, fluoro, or chloro. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rlb is independently C1-6 alkoxy. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1). (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld). (Jb), (Jb-1), (Jb-2). (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rlb is independently Ci-6 alkoxy, or halogen. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3). (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rlb is independently methoxy, fluoro, or chloro. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4),
(II), or (III), or a pharmaceutically acceptable salt thereof, wherein each Rlb is independently halogen. In some embodiments, each Rlb is independently fluoro or chloro.
[0076] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript m is 0, 1, or 2. In some embodiments, provided herein is a compound of Formula (J). (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript m is 1 or 2. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb- 2), (Jb-3), (Jb-4). (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript m is 0 or 1. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Jb), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript m is 0. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb). (Ja-lc), (Ja-ld), (Jb), (Jb-1). (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript m is 1. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript m is 2. In some embodiments, provided herein is a compound of Formula (J). (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc). (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3). (Jb-4), (II), or
(III), or a pharmaceutically acceptable salt thereof, wherein subscript m is 1 or 2.
[0077] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein Rlc is Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxyalkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, -NO2, or -CN. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja- lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein Rlc is C1-6 alkyl, Ci-6 alkoxy, or halogen. In some embodiments, provided herein is a compound of Formula (J). (Ja), (Ja-1). (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein Rlc is Ci-6 alkoxy, or halogen. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb). (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein Rlc is Ci-6 alkoxy. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein Rlc is Ci-6 alkyl. In some embodiments, provided herein is a compound of Formula (J). (Ja), (Ja-1). (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein Rlc is halogen. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld). (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein Rlb is methoxy, fluoro, or chloro. In some embodiments, Rlc is fluoro or chloro.
[0078] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript p is 0, 1, or 2. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript p is 1 or 2. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1). (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb- 2), (Jb-3), (Jb-4). (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript p is 0 or 1. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript p is 0. In some embodiments, provided herein is a compound of Formula (J), (Ja). (Ja-1), (Ja-la), (Ja-lb). (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript p is 1.
[0079] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2). (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein Rld is Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxyalkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, -NO2, or -CN. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja- lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein Rld is C1-6 alkyl, C1-6 alkoxy, or halogen. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc). (Ja-ld), (Jb). (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein Rld is Ci-6 alkoxy, or halogen. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein Rld is Ci-6 alkoxy. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3). (Jb-4), (II), or (111), or a pharmaceutically acceptable salt thereof, wherein Rld is Ci-6 alkyl. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein Rld is halogen. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1). (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld). (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein Rld is methoxy, fluoro, or chloro. In some embodiments, Rld is fluoro or chloro.
[0080] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld). (Jb), (Jb-1), (Jb-2). (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript r is 0, 1, 2, or 3. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript r is 1, 2. or 3. In some embodiments, provided herein is a compound of Formula (J), (Ja). (Ja-1), (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb- 1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript r is 0 or 1. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1). (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript r is 0. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein subscript r is 1.
[0081] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), or (II), or a pharmaceutically acceptable salt thereof, wherein R3 is H, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 haloalkyl, or Ci-6 haloalkoxy. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld). (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), or (II). or a pharmaceutically acceptable salt thereof, wherein R3 is Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 haloalkyl, or Ci-6 haloalkoxy. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1 ), (Jb-2). (Jb-3), (Jb-4), or (II), or a pharmaceutically acceptable salt thereof, wherein R3 is H or Ci-6 alkyl. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), or (II), or a pharmaceutically acceptable salt thereof, wherein R3 is Ci-6 alky l. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc). (Ja-ld), (Jb). (Jb-1). (Jb-2), (Jb-3), (Jb-4). or (II), or a pharmaceutically acceptable salt thereof, wherein R3 is methyl, ethyl, n-propyl, or iso-propyl. In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), or (II), or a pharmaceutically acceptable salt thereof, wherein R3 is methyl.
[0082] In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein R3a can be absent or Ci-6 alkyl. In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein R3a is Ci-6 alkyl. In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein R3a is methyl, ethyl, n-propyl, or iso-propyl. In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein R3a is methyl. In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein R3a is absent.
[0083] In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond a and b are each a bond, and dashed bond c is absent. In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond a and c are each a bond, and dashed bond b is absent. In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond b and c are each a bond, and dashed bond a is absent.
[0084] In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond a is a bond, and dashed bond b and c are each independently absent or a bond. In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond a is a bond, and dashed bond b and c are each absent.
[0085] In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond b is a bond, and dashed bond a and c are each independently absent or a bond. In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond b is a bond, and dashed bond a and c are each absent.
[0086] In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond c is a bond, and dashed bond a and b are each independently absent or a bond. In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond c is a bond, and dashed bond a and b are each absent.
[0087] In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond a is absent, and dashed bond b and c are each independently absent or a bond. In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond a, b and c are each absent.
[0088] In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, having the structure of Formula (II):
[0089] In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherein dashed bond a, b and c are each a bond.
[0090] In some embodiments, provided herein is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, having the structure of Formula (III):
[0091] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2). (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, having a structure of: pharmaceutically acceptable salt thereof. [0092] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld). (Jb), (Jb-1), (Jb-2). (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, having a structure of pharmaceutically acceptable salt thereof.
[0093] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2). (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, having a structure of:
pharmaceutically acceptable salts thereof.
[0094] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, having a structure of: or pharmaceutically acceptable salts thereof.
[0095] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2). (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, having a structure of: pharmaceutically acceptable salts thereof.
[0096] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, having a structure of:
[0097] In some embodiments, provided herein is a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja-lc), (Ja- Id). (Jb), (Jb-1), (Jb-2). (Jb-3). (Jb-4), (II). or (III), or a pharmaceutically acceptable salt thereof, having a structure of: or pharmaceutically acceptable salts thereof.
[0098] The compounds of the present invention can also be in the salt forms, such as acid or base salts of the compounds of the present invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (fumaric acid, acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non- toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed.. Mack Publishing Company, Easton. Pa., 1985, which is incorporated herein by reference.
[0099] The present invention also includes isotopically-labeled compounds of the present invention, wherein one or more atoms are replaced by one or more atoms having specific atomic mass or mass numbers. In some embodiments, the compounds provided herein, for example, compounds of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb- 1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), are isotopically labeled. In some embodiments, the compounds provided herein, for example, compounds of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1). (Jb-2), (Jb-3), (Jb-4), (II), or (III), are isotopically enriched. Examples of isotopes that can be incorporated into compounds of the invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, 3’S and 36C1). Isotopically - labeled compounds of the present invention are useful in assays of the tissue distribution of the compounds and their prodrugs and metabolites; preferred isotopes for such assays include 3H and 14C. In addition, in certain circumstances substitution with heavier isotopes, such as deuterium (2H), can provide increased metabolic stability, which offers therapeutic advantages such as increased in vivo half-life or reduced dosage requirements. Isotopically - labeled compounds of this invention can generally be prepared according to the methods known by one of skill in the art by substituting an isotopically-labeled reagent for a non- isotopically labeled reagent. Compounds of the present invention can be isotopically labeled at positions adjacent to the basic amine, in aromatic rings, and the methyl groups of methoxy substituents.
[0100] The present invention includes all tautomers and stereoisomers of compounds of the present invention, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at the carbon atoms, and therefore the compounds of the present invention can exist in diastereomeric or enantiomeric forms or mixtures thereof. All conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs and tautomers are within the scope of the present invention. Compounds according to the present invention can be prepared using diastereomers, enantiomers or racemic mixtures as starting materials. Furthermore, diastereomer and enantiomer products can be separated by chromatography, fractional crystallization or other methods known to those of skill in the art.
SYNTHESIS OF COMPOUNDS
[0101] In some embodiments, provided herein is a process for the preparation of a compound of compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), or (Jb-4), or a pharmaceutically acceptable salt thereof. For example, a compound of Formula (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), or (Jb-4) may be synthesized according to the following process:
[0102] In some embodiments, compound 1 undergoes a reduction reaction to yield compound 2. In some embodiments, compound 3 undergoes an alkylation to yield compound 3. In some embodiments, compound 3 undergoes a reduction to yield compound 4. In some embodiments, compound 4 undergoes a cross coupling reaction with compound la to yield compound 5. In some embodiments, compound 5 undergoes a substitution reaction to yield compound 6. In some embodiments, racemic compound 6 is separated into enantiomers compound 7 and compound 8. In some embodiments, R2 is methyl and R3 is methyl. In some embodiments Rla is Me, MeO, fluoro, or chloro. In some embodiments Rlb is Me, MeO, fluoro, chloro, or CN. In some embodiments, n is 0, 1, or 2. In some embodiments, m is 0 or 1.
5-HT
[0103] 5-HT2 agonism has been correlated with the promotion of neural plasticity (Ly et al., 2018). 5-HT2 antagonists abrogate the neuritogenesis and spinogenesis effects of hallucinogenic compounds with 5-HT2 agonist activity, e.g., DMT, LSD, and DOI. Furthermore. DMT and other psychedelic compounds promote increased dendritic arbor complexity, dendritic spine density, and synaptogenesis through a 5-HT2-dependent process. Importantly, the psychoplastogenic effects of compounds provided herein are also blocked under these conditions, implicating the 5-HT2 receptor in their mechanism of action. In addition, modulation of the 5-HT2 receptor appears to be important in neuroplasticity as well as various psychological conditions, such as, for example, anxiety, depression, post-traumatic stress disorder (PTSD), and schizophrenia.
[0104] Furthermore, non-hallucinogenic compounds (e.g., lisuride and 6-MeO-DMT) compete off 5-HT when an 5HT2A sensor assay is run in antagonist mode. Additionally, compounds, such as, for example, 6-F-DET and Ketanserin, which are non-hallucinogenic in animals (e.g., humans), compete with 5HT binding to 5HT2A in an antagonist mode sensor assay. In some embodiments, a compound provided herein prevents binding of 5-HT to 5HT2A. In some embodiments, the 5HT2A sensor assay is in an antagonist mode. In some embodiments, a compound provided herein prevents binding of 5-HT to 5HT2A and has non- hallucinogenic potential. In some embodiments, a compound provided herein prevents binding of 5-HT to 5HT2A and is non-hallucinogenic. In some embodiments, a compound provided herein prevents binding of 5-HT to 5HT2A in antagonist mode has non- hallucinogenic potential. In some embodiments, a compound provided herein prevents binding of 5-HT in antagonist mode is anon-hallucinogenic compound. In some embodiments, a compound provided herein inhibits the response of a sensor assay in antagonist mode has non-hallucinogenic potential. In some embodiments, a compound provided herein inhibits the response of a sensor assay in antagonist mode is a non- hallucinogenic compound.
[0105] In some embodiments, the effect of a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) on an agonist mode sensor assay suggests the compound is a non-hallucinogenic ligand of the 5-HT2A receptor and/or the 5-HT2C receptor. In some embodiments, the effect of a compound provided herein on an antagonist mode sensor assay suggests the compound is a non-hallucinogenic ligand of the 5-HT2A receptor and/or the 5-HT2C receptor. In some embodiments, effect of a compound provided herein on an agonist mode and an antagonist mode sensor assay together suggest the compound is anon-hallucinogenic ligand of the 5-HT2A receptor and/or the 5-HT2C receptor. [0106] Described herein in some embodiments are non-hallucinogenic compounds of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) that demonstrate similar therapeutic potential as hallucinogenic 5-HT2 agonists. In some embodiments, the non-hallucinogenic compounds described herein provide better therapeutic potential than hallucinogenic 5-HT2 agonists for neurological diseases. In some embodiments, the compounds of the present invention are modulators of the 5-HT2A receptor and/or the 5-HT2C receptor and promote neural plasticity (e g., cortical structural plasticity). [0107] In some embodiments, the compounds of Formula (J). (Ja), (Ja-1 ), (Ja-la), (Ja-lb), (Ja-lc). (Ja-ld), (Jb). (Jb-1), (Jb-2), (Jb-3), (Jb-4). (II), or (III) have activity at the 5-HT2A receptor and/or the 5-HT2C receptor. In some embodiments, the compounds provided herein elicit a biological response by activating the 5-HT2A receptor and/or the 5-HT2C receptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT2A receptor and/or the 5-HT2C receptor). In some embodiments, the compounds provided herein are selective 5-HT2A modulators and promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, the compounds provided herein are selective 5-HT2C modulators and promote neural plasticity (e.g., cortical structural plasticity ). In some embodiments, promotion of neural plasticity includes, for example, increased dendritic spine growth, increased synthesis of synaptic proteins, strengthened synaptic responses, increased dendritic arbor complexity, increased dendritic branch content, increased spinogenesis, increased neuritogenesis, or any combination thereof. In some embodiments, increased neural plasticity' includes, for example, increased cortical structural plasticity in the anterior parts of the brain.
[0108] 5-HT2C agonists have been suggested as treatments for multiple symptom domains of schizophrenia including positive, negative, cognitive, and depressive symptoms without the adverse events or tolerability issues associated with existing agents. The 5-HT2C receptor is a highly complex, highly regulated receptor which is widely distributed throughout the brain. The 5-HT2C receptor couples to multiple signal transduction pathways leading to engagement of a number of intracellular signaling molecules. Moreover, there are multiple allelic variants of the 5-HT2C receptor and the receptor is subject to RNA editing in the coding regions. The complexity of this receptor is further emphasized by the utility of either agonists or antagonists in the treatment of schizophrenia. The preclinical profile of 5-HT2C agonists from a neurochemical, electrophysiological, and a behavioral perspective is indicative of antipsychotic-like efficacy. In some embodiments, disclosed herein are compounds having dual 5-HT2a antagonist and 5-HT2C agonist activity'.
[0109] In some embodiments, a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja- lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) (e.g., a 5-HT2A modulator and/or a 5-HT2C modulator) is non-hallucinogenic. In some embodiments, a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) (e.g., a 5-HT2A modulator and/or a 5-HT2C modulator) is used to treat neurological diseases, which modulators do not elicit dissociative side-effects. In some embodiments, the hallucinogenic potential of the compounds described herein is assessed in vitro. In some embodiments, the hallucinogenic potential assessed in vitro of the compounds described herein is compared to the hallucinogenic potential assessed in vitro of hallucinogenic homologs. In some embodiments, the compounds of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) elicit less hallucinogenic potential in vitro than the hallucinogenic homologs.
[0110] In some embodiments, a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja- lc), (Ja-ld), (Jb). (Jb-1). (Jb-2), (Jb-3), (Jb-4). (Il), or (111) (e.g., a 5-HT2A modulator and/or a 5-HT2C modulator) is used to treat neurological diseases. In some embodiments, the neurological diseases comprise decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT2A receptor content, increased 5-HT2C receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof.
[OHl] In some embodiments, a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja- lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4). (II), or (III) (e.g., a 5-HT2A modulator and/or a 5-HT2C modulator) is used for increasing neuronal plasticity. In some embodiments, a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) (e.g., a 5-HT2A modulator and/or a 5-HT2C modulator) is used for treating a brain disorder. In some embodiments, a compound of Formula (J), (Ja), (Ja-1), (Ja- la), (Ja-lb), (Ja-lc), (Ja-ld). (Jb), (Jb-1), (Jb-2). (Jb-3). (Jb-4), (II). or (III) (e.g., a 5-HT2A modulator and/or a 5-HT2C modulator) is used for increasing at least one of translation, transcription, or secretion of neurotrophic factors.
[0112] In some embodiments, a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja- lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4). (II), or (III), including pharmaceutically acceptable salts and solvates thereof, is a non-hallucinogenic psychoplastogen. In some embodiments, the non-hallucinogenic psychoplastogen promotes neuronal grow th, improves neuronal structure, or a combination thereof.
IV. PHARMACEUTICAL COMPOSITIONS AND FORMULATIONS
[0113] In some embodiments, described herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof.
[0114] The compositions of the present invention can be prepared in a wide variety of oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. The compositions of the present invention can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compositions described herein can be administered by inhalation, for example, intranasally. Additionally, the compositions of the present invention can be administered transdermally. The compositions of this invention can also be administered by intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy’ Asthma Immunol. 75:107-111, 1995). Accordingly, the present invention also provides pharmaceutical compositions including a pharmaceutically acceptable carrier or excipient and the compound of the present invention.
[0115] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences. Maack Publishing Co. Easton PA ("Remington's").
[0116] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5% or 10% to 70% of the compound the present invention.
[0117] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; a low melting wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starch from com, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins including, but not limited to, gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate. [0118] Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage). Pharmaceutical preparations of the invention can also be used orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain the compound of the present invention mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the compound of the present invention may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol wi th or without stabilizers.
[0119] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the compound of the present invention is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
[0120] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
[0121] Aqueous solutions suitable for oral use can be prepared by dissolving the compound of the present invention in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty7 acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate. one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity.
[0122] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
[0123] Oil suspensions can be formulated by suspending the compound of the present invention in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281 :93-102, 1997. The pharmaceutical formulations of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally -occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono- oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.
[0124] The compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, microspheres can be formulated for administration via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995: as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863. 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermal routes afford constant delivery for weeks or months.
[0125] In some embodiments, the compositions of the present invention can be formulated for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. The formulations for administration will commonly comprise a solution of the compositions of the present invention dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are stenle and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of the compositions of the present invention in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.
[0126] In some embodiments, the formulations of the compositions of the present invention can be delivered by the use of liposomes w hich fuse with the cellular membrane or are endocytosed, i.e., by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery' of the compositions of the present invention into the target cells in vivo. (See, e.g., Al-Muhammed. J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, A/w. J. Hosp. Pharm. 46: 1576-1587, 1989).
[0127] The compositions of the present invention can be delivered by any suitable means, including oral, parenteral and topical methods. Transdermal administration methods, by a topical route, can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. [0128] The pharmaceutical preparation is preferably in unit dosage form. In such fonn the preparation is subdivided into unit doses containing appropriate quantities of the compounds of the present invention. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
[0129] The compound of the present invention can be present in any suitable amount, and can depend on various factors including, but not limited to, weight and age of the subject, state of the disease, etc. Suitable dosage ranges for the compound of the present invention include from about 0.1 mg to about 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about 750 mg. or about 25 mg to about 500 mg, or about 50 mg to about 250 mg. Suitable dosages for the compound of the present invention include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg.
[0130] The compounds of the present invention can be administered at any suitable frequency, interval and duration. For example, the compound of the present invention can be administered once an hour, or two, three or more times an hour, once a day, or two, three, or more times per day, or once every 2, 3, 4, 5, 6, or 7 days, so as to provide the preferred dosage level. When the compound of the present invention is administered more than once a day, representative interv als include 5, 10. 15. 20, 30, 45 and 60 minutes, as well as 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours. The compound of the present invention can be administered once, twice, or three or more times, for an hour, for 1 to 6 hours, for 1 to 12 hours, for 1 to 24 hours, for 6 to 12 hours, for 12 to 24 hours, for a single day, for 1 to 7 days, for a single week, for 1 to 4 weeks, for a month, for 1 to 12 months, for a year or more, or even indefinitely.
[0131] The composition can also contain other compatible therapeutic agents. The compounds described herein can be used in combination with one another, with other active agents known to be useful in modulating a glucocorticoid receptor, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.
[0132] The compounds of the present invention can be co-administered with another active agent. Co-administration includes administering the compound of the present invention and active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of each other. Co- administration also includes administering the compound of the present invention and active agent simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Moreover, the compound of the present invention and the active agent can each be administered once a day, or two, three, or more times per day so as to provide the preferred dosage level per day.
[0133] In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both the compound of the present invention and the active agent. In some embodiments, the compound of the present invention and the active agent can be formulated separately.
[0134] The compound of the present invention and the active agent can be present in the compositions of the present invention in any suitable weight ratio, such as from about 1 : 100 to about 100:1 (w/w), or about 1:50 to about 50:1, or about 1 :25 to about 25: 1, or about 1: 10 to about 10: 1, or about 1 :5 to about 5: 1 (w/w). The compound of the present invention and the other active agent can be present in any suitable weight ratio, such as about 1: 100 (w/w). 1 :50, 1 :25, 1 :10, 1:5, 1:4, 1 :3, 1:2, 1 : 1, 2: 1, 3: 1, 4:1, 5: 1, 10: 1, 25: 1, 50: 1 or 100: 1 (w/w). Other dosages and dosage ratios of the compound of the present invention and the active agent are suitable in the compositions and methods of the present invention.
V. METHODS OF TREATMENT
[0135] In some embodiments, provided herein is a method of treating a disease or disorder, such as, but not limited to a neurological disease or disorder, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, thereby treating the disease or disorder.
[0136] In some embodiments, provided herein is a method of treating a disease, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, thereby treating the disease.
Neurological Disorders
[0137] Neuronal plasticity, and changes thereof, have been attributed to many neurological diseases and disorders. For example, during development and in adulthood, changes in dendritic spine number and morphology (e.g., lengths, crossings, density) accompany synapse formation, maintenance and elimination; these changes are thought to establish and remodel connectivity' within neuronal circuits. Furthermore, dendritic spine structural plasticity is coordinated with synaptic function and plasticity. For example, spine enlargement is coordinated with long-term potentiation in neuronal circuits, whereas long- term depression is associated with spine shrinkage. [0138] In addition, dendritic spines undergo experience-dependent morphological changes in live animals, and even subtle changes in dendritic spines can affect synaptic function, synaptic plasticity, and patterns of connectivity in neuronal circuits. For example, disease- specific disruptions in dendritic spine shape, size, and/or number accompany neurological diseases and disorders, such as, for example, neurodegenerative (e.g., Alzheimer’s disease or Parkinson's disease) and neuropsychiatric (e.g., depression or schizophrenia) diseases and disorders, suggesting that dendritic spines may serve as a common substrate in diseases that involve deficits in information processing.
[0139] Unless indicated otherwise, a neurological disease or disorder generally refers to a disease or disorder of the central nervous system (CNS) (e.g., brain, spine, and/or nerves) of an individual.
[0140] In some embodiments, provided herein is a method of treating a neurological disease or disorder with a compound provided herein (e.g., a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1 ), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof).
[0141] Provided in some instances herein is a compound useful for the treatment of a variety of brain disorders and other conditions. In some embodiments, the compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4),
(II), or (III) is a 5-HT2A modulator and promotes neural plasticity (e.g., cortical structural plasticity). In some embodiments, the 5-HT2A modulator (e.g., 5-HT2A agonists) is used to treat a brain disorder. In some embodiments, a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) is a 5-HT2C modulator and promotes neural plasticity (e.g., cortical structural plasticity). In some embodiments, the 5-HT2C modulator is used to treat a brain disorder. In some embodiments, the brain disorder comprises decreased neural plasticity, decreased cortical structural plasticity, decreased 5- HT2A receptor content, increased 5-HT2C receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites. or any combination thereof. [0142] In some embodiments, a compound provided herein (e.g., a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or
(III), or a pharmaceutically acceptable salt or solvate thereof), improves dendritic spine number and dendritic spine morphology that is lost in a neurological disease or disorder.
[0143] In some embodiments, a compound of the present invention is used to treat neurological diseases. In some embodiments, the compounds have, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. In some embodiments, the neurological disease is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, the neurological disease is a migraine, headaches (e.g., cluster headache), post- traumatic stress disorder (PTSD), anxiety7, depression, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury7, and addiction (e g., substance use disorder).
[0144] In some embodiments, the disease is headache disorders. In some embodiments, the disease is a migraine or cluster headache. In some embodiments, the disease is migraines. In some embodiments, the disease is cluster headaches. In some embodiments, the disease is addiction. In some embodiments, the disease is substance use disorder. In some embodiments, the disease is alcohol use disorder.
[0145] In some embodiments, the neurological disease is a neurodegenerative disease, Alzheimer’s disease, or Parkinson’s disease. In some embodiments, the neurological disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety7. In some embodiments, the neuropsychiatric disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is addiction (e g., substance use disorder). In some embodiments, the neuropsychiatric disease or neurological disease is depression. In some embodiments, the neuropsychiatric disease or neurological disease is anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD). In some embodiments, the neurological disease is stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disease or neurological disease is schizophrenia.
[0146] In some embodiments, a compound of the present invention is used to treat a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is major depressive disorder, treatment resistant depression, generalized anxiety disorder, post- traumatic stress disorder, obsessive compulsive disorder, substance use disorders, or a psychosis. In some embodiments, the psychosis is schizophrenia, bipolar disorder, or psychosis in Alzheimer’s disease (AD-P).
[0147] In some embodiments, a compound of the present invention is used to treat pain. In some embodiments, a compound of the present invention is used to treat migraine.
[0148] In some embodiments, a compound of the present invention is used to treat a neurodegenerative disease. In some embodiments, the neurodegenerative disease is a dementia, traumatic brain injury, or Parkinson’s disease. In some embodiments, the dementia is Alzheimer’s disease, vascular dementia, Lewy body dementia, frontotemporal dementia. Huntington’s disease, or mixed dementia. In some embodiments, the compound of the present invention is used to treat behavioral and/or psychological symptoms in dementia. In some embodiments, the compound of the present invention is used to treat motor symptoms, behavioral symptoms, and/or psychological symptoms in Parkinson’s disease.
[0149] In some embodiments, the disease is a neuropsychiatric disease. In some embodiments, the diseases is a neurodegenerative disease.
[0150] In some embodiments, a compound of the present invention is used to treat a neurodegenerative, a neuropsychiatric, or substance use disease or disorder. In some embodiments, the neurological disease or disorder is an injury. In some embodiments, the disease or disorder is an anxiety disorder, a mood disorder, a psychotic disorder, a personality7 disorder, an eating disorder, a sleep disorder, a sexuality7 disorder, an impulse control disorder, a substance use disorder, a dissociative disorder, a cognitive disorder, a developmental disorder, or a factitious disorder. In some embodiments, the disease or disorder is a psychotic disorder. In some embodiments, the psychotic disorder is selected from schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, delusional disorder, shared psychotic disorder, substance-induced psychotic disorder, paraphrenia, psychotic depression, bipolar disorder, schizotypal personality disorder, paranoid personality disorder, schizoid personality7 disorder, borderline personality7 disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and dissociative disorders, or psychosis associated with a neurodegenerative disease. In some embodiments, the neurodegenerative disease is selected from Huntington’s disease, Alzheimer’s disease, Lewy7 body7 dementia, and Parkinson’s disease. In some embodiments, the psychotic disorder is schizophrenia or bipolar disorder. In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent. [0151] In some embodiments, a compound of the present invention is used to treat brain disorders. In some embodiments, the compounds have, for example, anti-addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. In some embodiments, the brain disorder is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, brain disorders include, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), anxiety, depression, schizophrenia, and addiction (e.g., substance abuse disorder). In some embodiments, brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety.
[0152] In some embodiments, provided herein is a method for increasing neural plasticity, the method comprising contacting a neuronal cell with a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount sufficient to increase neural plasticity7 of the neuronal cell, wherein the compound produces a maximum number of dendritic crossings with an increase of greater than 1.0 fold by a Sholl Analysis.
[0153] Neural plasticity refers to the ability of the brain to change structure and/or function throughout a subject’s life. New neurons can be produced and integrated into the central nervous system throughout the subject’s life. Increasing neural plasticity includes, but is not limited to, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain. In some embodiments, increasing neural plasticity comprises promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and increasing dendritic spine density.
[0154] In some embodiments, increasing neural plasticity can treat neurodegenerative disease, Alzheimer’s, Parkinson’s disease, psychological disorder, depression, addiction, anxiety7, post-traumatic stress disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury7, or substance use disorder. In some embodiments, the neuropsychiatric disease is bipolar disorder. In some embodiments, the disease is depression. In some embodiments, the disease is post-traumatic stress syndrome (PTSD). In some embodiments, the disease is anxiety. In some embodiments, the disease is a neurodegenerative disease. In some embodiments, the disease is Alzheimer’s disease or Parkinson’s disease. In some embodiments, the disease is Alzheimer’s disease. In some embodiments, the disease is Parkinson’s disease. [0155] In some embodiments, a compound of the present invention is used to increase neural plasticity. In some embodiments, the compounds used to increase neural plasticity have, for example, anti-addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. In some embodiments, decreased neural plasticity is associated with a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, the neuropsychiatric disease includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., substance abuse disorder). In some embodiments, brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety. In some embodiments, the disease is a neuropsychiatric disease. [0156] In some embodiments, the experiment or assay to determine increased neural plasticity of any compound of the present invention is a phenotypic assay, a dendritogenesis assay, a spinogenesis assay, a synaptogenesis assay, a Sholl analysis, a concentration- response experiment, a 5-HT2A agonist assay, a 5-HT2A antagonist assay, a 5-HT2A binding assay, or a 5-HT2A blocking experiment (e.g., ketanserin blocking experiments). In some embodiments, the experiment or assay to determine the hallucinogenic potential of any compounds of the present invention is a mouse head-twitch response (HTR) assay.
[0157] Compounds of the present invention may have activity' as 5-HT2A modulators. In some embodiments, the compounds of the present invention have activity as 5-HT2A modulators. In some embodiments, the compounds of the present invention elicit a biological response by activating the 5-HT2A receptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT2A receptor). 5-HT2A agonism has been correlated with the promotion of neural plasticity. In some embodiments, the 5HT2A sensor assay is in an agonist mode or an antagonist mode. In some embodiments, the 5HT2A sensor assay is in an agonist mode.
[0158] In some embodiments, the compounds described herein are selective 5-HT2A modulators. In some embodiments, the compounds described herein are 5-HT2A modulators and promote neural plasticity’ (e.g., cortical structural plasticity). In some embodiments, the compounds described herein are selective 5-HT2A modulators and promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, promotion of neural plasticity includes, for example, increased dendritic spine growth, increased synthesis of synaptic proteins, strengthened synaptic responses, increased dendritic arbor complexity, increased dendritic branch content, increased spinogenesis, increased neuritogenesis. or any combination thereof. In some embodiments, increased neural plasticity includes, for example, increased cortical structural plasticity in the anterior parts of the brain.
[0159] In some embodiments, non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) are used for treating a disease. In some embodiments, non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) are used for increasing neural plasticity. In some embodiments, non-hallucinogenic 5-HT2A modulators (e.g.. 5-HT2A agonists) are used for increasing neural plasticity and dendritic spine density.
[0160] In some embodiments, the experiment or assay to determine increased neural plasticity of any compound of the present invention is a phenotypic assay, a dendritogenesis assay, a spinogenesis assay, a synaptogenesis assay, a Sholl analysis, a concentration- response experiment, a 5-HT2C agonist assay, a 5-HT2C antagonist assay, a 5-HT2C binding assay, or a 5-HT2C blocking experiment (e.g., ketanserin blocking experiments). In some embodiments, the experiment or assay to determine the hallucinogenic potential of any compounds of the present invention is a mouse head-twitch response (HTR) assay.
[0161] Compounds of the present invention may have activity as 5-HT2C modulators. In some embodiments, the compounds of the present invention have activity' as 5-HT2C modulators. In some embodiments, the compounds of the present invention elicit a biological response by activating the 5-HT2C receptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT2C receptor). 5-HT2C agonism has been correlated with the promotion of neural plasticity. In some embodiments, the 5HT2C sensor assay is in an agonist mode or an antagonist mode. In some embodiments, the 5HT2C sensor assay is in an agonist mode.
[0162] In some embodiments, the compounds described herein are selective 5-HT2C modulators. In some embodiments, the compounds described herein are 5-HT2C modulators and promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, the compounds described herein are selective 5-HT2C modulators and promote neural plasticity (e.g., cortical structural plasticity ). In some embodiments, promotion of neural plasticity includes, for example, increased dendritic spine growth, increased synthesis of synaptic proteins, strengthened synaptic responses, increased dendritic arbor complexity', increased dendritic branch content, increased spinogenesis, increased neuritogenesis, or any combination thereof. In some embodiments, increased neural plasticity' includes, for example, increased cortical structural plasticity in the anterior parts of the brain.
[0163] In some embodiments, non-hallucinogenic 5-HT2C modulators (e.g., 5-HT2C agonists) are used for treating a disease. In some embodiments, non-hallucinogenic 5-HT2C modulators (e.g., 5-HT2C agonists) are used for increasing neural plasticity. In some embodiments, non-hallucinogenic 5-HT2C modulators (e.g.. 5-HT2C agonists) are used for increasing neural plasticity7 and dendritic spine density.
[0164] In some embodiments, provided herein is a method for increasing neural plasticity and increasing dendritic spine density, the method comprising contacting a neuronal cell with a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount sufficient to increase neural plasticity and increase dendritic spine density of the neuronal cell.
[0165] Dendritic spines are dynamic and can have significant changes in density7, shape, and volume over time. The growth or loss of dendritic spines, w hich contribute to the dendritic spine density, can be important for reinforcing neural pathways for learning, memory, and general cognitive function. Increasing dendritic spine density can be useful for treatment of neurological diseases, such as, but not limited to, neurodegenerative diseases and neuropsychiatric diseases.
[0166] Increasing dendritic spine density can be measured by staining and immunocytochemical methods known by one of skill in the art. Staining methods include, but are not limited to electron microscopy, Golgi staining, crystal violet staining, DAPI staining, and eosin staining. For example, Golgi staining can be used to measure dendritic spine density.
[0167] In some embodiments, a compound of Formula (J), (Ja), (Ja-1). (Ja-Ia). (Ja-lb), (Ja- 1c), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or pharmaceutically acceptable salts thereof, is useful for promoting neuronal growth and/or improving neuronal structure.
[0168] In some embodiments, a compound of Formula (J), (Ja), (Ja-1), (Ja-la). (Ja-lb), (Ja- 1c), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4). (II), or (III), or pharmaceutically acceptable salts thereof, is anon-hallucinogenic psychoplastogens useful for treating one or more diseases or disorders associated with loss of synaptic connectivity and/or plasticity7.
[0169] In some embodiments, an individual administered a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb). (Ja-lc), (Ja-ld), (Jb), (Jb-1). (Jb-2), (Jb-3), (Jb-4), (II), or (III) does not have a hallucinogenic event (e.g., at any point after the compound has been administered to the individual).
[0170] In some embodiments, provided herein is a method for treating a disease or disorder in an individual in need thereof, wherein the disease or disorder is a neurological diseases and disorder. [0171] Provided in some embodiments herein is a compound (e.g., or pharmaceutically acceptable salt or solvate thereof) useful for the modulation of a 5-hydroxytryptamine (5-HT) receptor. In some embodiments, the 5-HT receptor modulated by a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III) is 5-hydroxytryptamine receptor 2A (5-HT2A). In some embodiments, the 5-HT receptor modulated by a compound of Formula (J). (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja-lc). (Ja-ld), (Jb). (Jb-1), (Jb-2), (Jb-3). (Jb-4). (II), or (111) is 5-hydroxytryptamine receptor 2C (5-HT2c).
[0172] In some embodiments, provided herein is a modulator of 5-hydroxytryptamine receptor 2A (5-HT2A) that is useful for treating one or more diseases or disorders associated with 5-HT2A activity. In some embodiments, provided herein is a modulator of 5- hydroxy tryptamine receptor 2C (5-HT2c) that is useful for treating one or more diseases or disorders associated with 5-HT2C activity.
[0173] In some embodiments, a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja- lc), (Ja-ld), (Jb). (Jb-1), (Jb-2), (Jb-3), (Jb-4), (II), or (III), or a pharmaceutically acceptable salt thereof, is used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from inhibition or reduction of 5-HT2A activity and/or 5-HT2C activity.
[0174] In some embodiments, a compound of Formula (J), (Ja), (Ja-1), (Ja-la), (Ja-lb), (Ja- lc), (Ja-ld), (Jb), (Jb-1), (Jb-2), (Jb-3), (Jb-4). (II), or (III), or a pharmaceutically acceptable salt thereof, is used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from promoting neuronal growth and/or improving neuronal structure.
[0175] Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.
[0176] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a mammal already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the mammal’s health status, weight, and response to the drugs, and the judgment of a healthcare practitioner. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
[0177] In prophylactic applications, compositions containing the compounds described herein are administered to a mammal susceptible to or otherw ise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use. the precise amounts also depend on the mammal's state of health, weight, and the like. When used in mammals, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the mammal’s health status and response to the drugs, and the judgment of a healthcare professional. In some embodiments, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
[0178] In some embodiments wherein the mammal’s condition does not improve, upon the discretion of a healthcare professional the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the mammal’s life in order to ameliorate or otherwise control or limit the symptoms of the mammal's disease or condition.
[0179] In some embodiments wherein a mammal’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (/.<?., a “drug holiday”). In some embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days. 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
[0180] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In some embodiments, however, the mammal requires intermittent treatment on a long-term basis upon any recurrence of symptoms. [0181] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
[0182] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In some embodiments, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In some embodiments, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
[0183] In some embodiments, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In some embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
[0184] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. In some embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In some embodiments, the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
[0185] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non- systemically or locally to the mammal.
[0186] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
[0187] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose;
(ii) the time between multiple administrations is ever}’ 6 hours; (iii) the compound is administered to the mammal ever ’ 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.
[0188] In some embodiments, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e.. by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
[0189] In some embodiments, different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like. Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens is optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e.. providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, is initiated prior to. during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
[0190] It is understood that the dosage regimen to treat, prevent, or ameliorate the disease(s) for which relief is sought, is modified in accordance with a variety of factors (e.g. the disease or disorder from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
VI. EXAMPLES
Materials and Methods
[0191] All reagents and solvents were obtained from commercial sources and used as received. Reactions were performed using oven-dried glassware (120 °C) under an inert N2 atmosphere unless otherwise noted. Air- and moisture-sensitive liquids and solutions were transferred via syringe or stainless-steel cannula. Organic solutions were concentrated under reduced pressure (~5 Torr) by rotary evaporation.
[0192] Nuclear magnetic resonance (NMR) spectra were acquired on a Bruker 400 operating at 400 and 100 MHz for 'H and 13C. respectively, and are referenced internally according to residual solvent signals. Data for 1H NMR are recorded as follows: chemical shift (5, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m, multiplet), coupling constant (Hz), and integration. Data for 13C NMR are reported in terms of chemical shift (6, ppm). Liquid chromatography -mass spectrometry (LC-MS) was performed using a Waters Alliance 2695 HPLC with a Waters Micromass ZQ Detector.
[0193] For final compounds prepared by chiral SFC, samples were separated on preparative scale using a Berger Multigram II SFC equipped with two SD-1 Varian pumps, a Knauer K- 2501 Spectrophotometer set at 220 nm, CO2 tank dewers with chiller and G700 compression system (Mettler-Toledo, Newark, DE, USA). Analytical chiral SFC was performed on a Berger Analytical SFC system equipped with dual pump (FCM-1200), an autosampler (ALS- 3100), a column oven (TCM-200) and a diode array detector (DAD-1315A) (Mettler-Toledo, Newark, DE. USA).
A. General Procedures
General Procedure 1: C7 borylation of haloindoles
[0194] Following a modified literature procedure (J. Am. Chem. Soc. 2010, 132, 12, 4068- 4069):
[0195] To a mixture of the appropnate haloindole (6 mmol. 1.0 equiv) in toluene (3 mL) was added diethylsilane (1.16 mL, 9.0 mmol, 1.5 equiv) and [Ru(p-cymene)C12]2 (36.7 mg, 0.06 mmol, 0.01 equiv) in a vial. The mixture was sparged with N2 gas (5 min) then sealed and stirred at ambient temperature for 16 h (for fluoroindoles) or at 80 °C for 4 h (for chloroindoles) and then concentrated under reduced pressure.
[0196] To the mixture was added THF (6 mL), dtbpy (8 mg, 0.03 mmol, 0.005 equiv), B2Pin2 (1.52 g, 6.0 mmol, 1.0 equiv), HBpin (0.043 mL, 0.3 mmol, 0.05 equiv) and [Ir(OMe)(cod)]2 (9.9 mg, 0.015 mmol, 0.0025 equiv) in a vial. The mixture was sparged with N2 for 5 min then capped. The mixture was stirred at 80°C for 16 h and then concentrated under reduced pressure.
[0197] The reaction mixture was dissolved in THF (12 mL), followed by the careful dropwise addition of 3M NaOAc<aq) (2 mL) at 0 °C. The solution was warmed to ambient temperature and stirred for 3 h and then H2O (15 mL) was added. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine, dried over N zSCL and concentrated under reduced pressure. The residue was then purified by chromatography on silica gel (95:5, Hexanes/EtOAc) to afford C7 borylated haloindoles.
General Procedure 2: Suzuki coupling of C7 borylated haloindoles
[0198] To a mixture of the specified alkenyl halide (1.0 equiv) and the appropriate C7 borylated haloindole (1.2 equiv, prepared via general procedure 1) in dioxane (0. 1 M) was added 2 M Na2CO3(aq) (TO M) and Pd(PPh3)4 (0.05 equiv). The mixture was heated with stirring to 100 °C for 5h then cooled to ambient temperature. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (conditions reported below for each example) to afford the corresponding Suzuki coupled product.
General Procedure 3: Intramolecular haloindole N-alkylation
[0199] To a 0 °C cooled mixture of the appropriate Suzuki coupled haloindole (1.0 equiv, prepared via general procedure 2) in DCM (0.05 M) was added TsCl (1.25 equiv), tetrabutylammonium hydrogen sulfate (0.05 equiv) and freshly crushed NaOH (4.0 equiv). The mixture was stirred at ambient temperature for 16 h. The mixture was poured into a vigorously stirring solution of 1 M NLLClfaq) (125 mL) and DCM (125 mL). The layers were separated and the aqueous layer was further extracted with DCM (3 x 40 mL). The combined organic extracts were washed with brine, dried over Na2SOq and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (conditions reported below for each example) to afford the corresponding isotryptamine ergoline.
General Synthetic Scheme 1: Alternate General Procedure 1: C7 borylation of haloindoles
[0200] To a stirred solution of the appropriate haloindole (1.0 eq) in dioxane (10 vol) was added bis(pinacolato)diborane (1.5 eq) and KOAc (3.0 eq) at room temperature. The reaction mixture was degassed with nitrogen for 20 minutes and Pd(dppf)Ch DCM (0.05 eq) was added. The resulting reaction was stirred at 90° C for 16 hours at which point it was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with an aqueous solution of NaCl, the organic layer was dried over anhydrous Na2S€>4, solids were removed by filtration and the filtrate was concentrated in vacuo. The crude was purified by silica gel chromatography to afford the requisite C7 borylated haloindole.
Alternate General Procedure 2; Suzuki coupling of C7 borylated haloindoles
[0201] To a stirred solution of the specified alkenyl halide (1.0 eq) in dioxane (10 vol) was added the appropriate C7 borylated haloindole (0.8 eq) followed by Na2COs (3.0 eq) at room temperature. The reaction mixture was purged with nitrogen for 20 minutes and Pd(PPh?)4 (0.05 eq) was added and the resulting reaction was stirred at 90 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with an aqueous solution ofNaCl (10 mL), the organic layer was dried over anhydrous Na2SC>4, solids were removed by filtration and the filtrate was concentrated in vacuo. The crude was purified by silica gel chromatography to afford the corresponding Suzuki coupled target.
Alternate General Procedure 3; Intramolecular indole N-alkylation
[0202] To a stirred solution of the appropriate Suzuki coupled indole (1.0 eq) in CHCfi (10 vol) at 0 °C was added crushed NaOH (8.0 eq) and the reaction mixture was stirred for 10 minutes. After warming to room temperature, p-toluene sulfonyl chloride (1.2 eq) was added and the reaction was allowed to stir for 1 hour, at which point DMSO (10 vol) was added and the reaction was allowed to stir for an additional 1.5 hours. After completion of the reaction, the crude reaction mixture was diluted with cold water and extracted with DCM. The combined organic layers were washed with an aqueous solution ofNaCl, the organic layer was dried over anhydrous Na2SC>4, solids were removed by filtration and the filtrate was concentrated in vacuo. The crude was purified by silica gel chromatography to afford the corresponding isotryptamine ergoline.
General Synthetic Scheme 2;
General Synthetic Scheme 3:
B. Intermediate Compounds
Preparation of (3-bromo-l-methyl-l,2,5,6-tetrahvdropyridin-2-yl)methanol 3-bromo-2-(hydroxymethyl)-l-methylpyridin- 1-ium iodide
[0203] To a solution of (3-bromopyridin-2-yl)methanol (2.060 g, 10.956 mmol, 1.0 equiv) in MeCN (13.7 mL) was added Mel (4.09 mL, 65.738 mmol, 6.0 equiv). The vial was capped, and the solution was heated with stirring at 70°C for 24 h then subsequently cooled to ambient temperature. The suspension was cooled to 0°C, filtered, and washed with hexanes (2 x 10 mL). The resulting pale-yellow solid was dried under reduced pressure to afford 3- bromo-2-(hydroxymethyl)-l-methylpyridin-l-ium iodide (3.400 g, 94%). 1 H NMR (400 MHz, DMSO-<7g) δ = 9. 10 (d, J= 5.8 Hz, 1H), 8.91 (d, J= 8.6 Hz, 1H), 8.01 (dd. J= 8.0 Hz, 6.08 Hz, 1H), 6.19 (t, J= 5.76 Hz, 1H), 5.01 (d, J= 5.76 Hz, 2H), 4.48 (s, 3H) ppm. 13C NMR (100 MHz, DMSO-<76) δ = 154.0, 149.6, 147.2, 127.4, 124.4, 59.1, 46.9 ppm. LRMS (ES+) m/z [M + H]+ calcd for C7H9BrNO+ 201.99; Found 202.09
(3-bromo-l-methyl-l,2,5,6-tetrahydropyridin-2-yl)methanol
[0204] To a 0°C cooled solution of the resulting 2-(hydroxymethyl)-l-methylpyridin-l-ium iodide (3.000 g, 9.092 mmol, 1.0 equiv) in MeOH (181.8 mL) was added AcOH (2.60 mL, 45.460 mmol, 5.0 equiv) followed by portion-wise addition of NaCNBH?, (1.257 g, 20.003 mmol, 2.2 equiv). The solution was warmed to ambient temperature and stirred for 4 h, then concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and added to 1 M NaOH (200 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (3 x 100 mL). The organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3% MeOH in DCM) to afford (3-bromo-l-methyl-l,2,5,6- tetrahydropyridin-2-yl)methanol (1.420 g, 76%) as a pale oil. 'H NMR (400 MHz, CDCl3) δ = 6.24 (t. J= 3.88 Hz, 1H), 4.50 (br s. 1H), 3.89 (dd, J = 11.2, 4.08 Hz, 1H), 3.59 (dd, .7= 1 1.1 , 8.0 Hz, 1H), 3.15 - 3.07 (m, 1H), 3.06 - 2.97 (m, 1H), 2.72 - 2.63 (m, 1H), 2.53 (s, 3H), 2.45 - 2.32 (m, 1H), 2.08 - 1.99 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3) 5 = 129.2, 120.4, 67.8, 60.6, 44.2, 42.2, 23.9 ppm. LRMS (ES+) m/z [M + H]+ calcd for C7HI3NO+ 206.02; Found 206. 12. Preparation of (3-bromo-l,5-dimethyl-l,2,5,6-tetrahvdropyridin-2-yl)methanol
(3-bromo-5-methylpyridin-2-yl)methanol
[0205] To a 0 °C cooled solution of 3-bromo-5-methylpicolinic acid (3.998 g, 18.507 mmol, 1.0 equiv) in THF (92.5 mL) was added CDI (3.601 g, 22.208 mmol, 1.2 equiv). The mixture was warmed to ambient temperature and stirred for 4 h, then subsequently cooled to 0 °C and transferred slowly via cannula into a 0 °C cooled solution of NaBH4 (2. 100 g, 55.521 mmol, 1.0 equiv) in H2O (92.5 mL) with vigorous stirring. The solution was warmed to ambient temperature for 20 min, then saturated NLLClfaq) (100 mL) was added dropwise at 0 °C. The solution was added to H2O (500 mL) and extracted with EtOAc (5x 100 mL). The combined organic extracts were washed with saturated NaHCC>3(aq) (50 mL) and brine (100 mL), dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (75% EtOAc in hexanes) to afford (3-bromo-5- methylpyridin-2-yl)methanol (3.654 g, 98%) as a pale yellow oil. 1H NMR (400 MHz, CDCk) δ = 8.33 (s, 1H), 7.72 - 7.66 (m, 1H), 4.70 (s, 2H), 4.24 - 3.62 (br s , 1H), 2.35 (s, 3H) ppm. 13C NMR (100 MHz, CDCI3) δ = 153.6, 146.9. 140.8, 133.9, 118.4, 63.0, 17.8 ppm. LRMS (ES+) m/z [M + H]+ calcd for C7H9BrNO+ 201.99; Found 202.16.
3-bromo-2-(hydroxymethyl)-l,5-dimethylpyridin- 1-ium iodide
[0206] A solution of (3-bromo-5-methylpyridin-2-yl)methanol (3.505 g, 17.347 mmol, 1.0 equiv) and Mel (6,48 mL, 104.083 mmol, 6.0 equiv) in MeCN (21.7 mL) was heated to 60 °C in a sealed tube for 18 h. The resulting suspension was cooled to ambient temperature and EtOAc (100 mL) and hexanes (50 mL) were added. The mixture was cooled to 0 °C with stirring and subsequently filtered, w ashed with EtOAc (2 x 20 mL), and dried in vacuo to afford 3-bromo-2-(hydroxymethyl)-l,5-dimethylpyridin- 1-ium iodide (5.063 g, 85%) as a pale-yellow solid. ‘H NMR (400 MHz, DMSO-d6) δ = 9.06 (s. 1H), 8.81 (s, 1H), 6.14 (br s, 1H), 4.97 (s, 2H), 4.43 (s, 3H), 2.45 (s, 3H) ppm. 13C NMR (100 MHz, DMSO-d 6) 8 = 151.0, 149.6, 147.0, 138.1. 123.6, 58.6, 46.7, 17.2 ppm. LRMS (ES+) m/z [M + H]+ calcd for CsHnBrNO 216.00; Found 216.14.
(3-bromo-l,5-dimethyl-l,2,5,6-tetrahydropyridin-2-yl)methanol
[0207] To a -10 °C cooled mixture of 3-bromo-2-(hydroxymethyl)-l,5-dimethylpyridin-l- ium iodide (1.219 g, 3.544 mmol, 1.0 equiv) and AcOH (0.61 mL, 10.631 mmol, 3.0 equiv) in MeOH (35.4 mL) was added a -10 °C cooled solution ofNaCNBHs (0.668 g, 10.631 mmol, 3.0 equiv) in MeOH (7.1 mL) slowly via cannula. The mixture was warmed to ambient temperature slowly and stirred for 18 h, then concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and saturated NaHCO3(aq) (500 mL) was added with vigorous stirring. The layers were separated and the aqueous layer was further extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4 and dried under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution: 1% MeOH in DCM to 3% MeOH in DCM) to afford (3-bromo-l,5-dimethyl-l,2,5,6-tetrahydropyridin-2-yl)methanol (0.204 g, 26%) as a pale colorless oil present as a mixture of diastereomers (3: 1 major/minor). 1 H NMR (400 MHz, CDC13) δ = 6. 12 - 6. 10f (m. 1H), 6.08 - 6.06* (m, 0.33), 3.91t (dd. J= 11.4. 1.92 Hz, 1H), 3.84* (dd, .7 = 10.6, 4.36 Hz, 0.33H), 3.77t (dd, .7= 1 1.4 Hz, 3.08 Hz, 1H), 3.45 - 3.38* (m, 0.33H), 3.08 - 3.02* (m, 0.33H), 2.90 - 2.40 (m, 9.33H), 2.21 - 2.121" (m, 1H), 0.98 - 0.92 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3) 8 = 137.2, 134.7, 121.2, 120.6, 68.3, 67.5, 60.9, 59.6, 58.6, 51.0, 43.5, 42.8, 32.8, 28.2, 18.4. 18.1 ppm. LRMS (ES+) m/z [M + H]+ calcd for CsHisBrNO* 220.03; Found 220.1 1. ''"denotes 1H NMR signal arising exclusively from the major diastereomer; ’denotes 1H NMR signal arising exclusively from the minor diastereomer; undesignated signals arise from both. 1?C NMR signals are reported without designation.
Preparation of ethyl 5-bromo-6-(hydroxymethyl)nicotinate methyl 5-bromo-6-(l-cyano-2-ethoxy-2-oxoethyl)nicotinate
[0208] To a solution of methyl 5-bromo-6-chloronicotinate (27.012 g, 107.841 mmol, 1.0 equiv) in DMF (135 mL) was added K2CO3 (74.251 g, 539.205 mmol, 5.0 equiv) followed by ethyl cyanoacetate (28.77 mL, 269.603 mmol, 2.5 equiv.). The mixture was heated to 130 °C with stirring for 1 hour and subsequently cooled to ambient temperature then 0 °C. 4M HCl(aq) (300 mL) was added dropwise over 2 hours with vigorous stirring. H2O (300 mL) was added and the mixture was stirred at 0 °C for 1 hour and then filtered. The filter cake was washed with ice-cold H2O (3 x 100 mL), and dried in vacuo to afford methyl 5-bromo-6-(l- cyano-2-ethoxy-2-oxoethyl)nicotinate (33.191 g, 94%) as a yellow solid comprised of a 9: 1 tautomeric mixture (via 'l l NMR analysis). ’H NMR (400 MHz, DMSO- e) δ = 14.59^ (br s, 1H), 9.07* (d, J= 1.8 Hz, 0.1H). 8.71 f (d, J= 1.92 Hz, 1H). 8.59* (d, J = 1.8 Hz, 0.1H), 8.23f (d, J= 1.92 Hz, 1H), 6.22* (s, 0.1H), 4.28 - 4.18 (m, 2.2H), 3.91* (s, 0.3H), 3.83* (s, 3H), 1.26t (t, J= 7.12 Hz, 3H), 1. 19* (t, J= 7.12 Hz, 0.3H) ppm. 13C NMR (100 MHz, DMSO- 6) 5 = 170.2, 163.0, 152.9, 144.5, 140.3, 117.8, 116.0, 111.4, 66.4, 61.1, 53.0, 14.8 ppm. LRMS (ES+) m/z [M + H]+ calcd for Ci2Hi2BrN2O4+ 327.00; Found 327.17. '’'denotes 1H NMR signal arising exclusively from the major tautomer; ‘denotes 1H NMR signal arising exclusively from the minor tautomer; undesignated signals arise from both. 13C NMR signals are reported only from the major tautomer.
3-bromopyridine-2,5-dicarboxylic acid
[0209] To a solution of NaOH (13.893 g, 347.325 mmol, 3.5 equiv.) in H2O (248 mL) was added methyl 5-bromo-6-(l-cyano-2-ethoxy-2-oxoethyl)nicotinate (32.463 g, 99.236 mmol, 1.0 equiv) with vigorous stirring. The resulting mixture was heated to 40 °C and H2O2(aq) (30%) (73.135 g, 645.033 mmol, 6.5 equiv) was added carefully dropwise over 1 hour before heating to 90 °C for 2 hours. The solution was cooled to ambient temperature, and then H2O (124 mL) was added followed by the dropwise addition of 4M HCl(aq) (124 mL) over 1 hour with vigorous stirring. The resulting suspension was cooled at 0 °C for 2 hours and filtered. The filter cake was washed with ice-cold H2O (3 x 50 mL), and the solid dried and collected. The combined aqueous filtrates were extracted with EtOAc (5 x 150 mL), dried over Na2SC>4, and concentrated under reduced pressure. To the residue was added H2O (48 mL), and the resulting mixture was cooled to 0 °C with stirring and the precipitate was filtered then washed with ice-cold H2O (3 x 10 mL) to afford a second crop. The combined solids were dried in vacuo to afford 3-bromopyridine-2,5-dicarboxylic acid (21.015 g, 86%) as an off- white solid. 'H NMR (400 MHz, DMSO-tfi) δ = 9.01 (d. J= 1.68 Hz, 1H), 8.51 (d, J= 1.72 Hz. 1H) ppm. 13C NMR (100 MHz. DMSO-tfi) δ = 166.6, 164.6. 154.8, 148.5. 141.7. 129.0, 116.1 ppm. LRMS (ES+) m'z [M + H]+ calcd for C7H5BrNO.fi 245.94; Found 246.18. diethyl 3-bromopyridine-2,5-dicarboxylate
[0210] To a 0 °C cooled solution of 3-bromopyridine-2,5-dicarboxylic acid (12.099 g, 49.179 mmol, 1.0 equiv) and DMF (0.25 mL) in DCM (245.9 mL) was added oxalyl chloride (21.09 mL. 245.895 mmol, 5.0 equiv) dropwise. The suspension was warmed to ambient temperature and stirred for 12 h then concentrated under reduced pressure. The residue was taken up in DCM (245.9 mL) and EtOH (123 mL) was added slowly. The solution was stirred for 20 min, then concentrated under reduced pressure. The residue was dissolved in DCM (250 mL) and then carefully added to saturated NaHCOsfaq) (500 mL) with vigorous stirring. The layers were separated, and the aqueous layer was further extracted with DCM (3 x 100 mL). The combined organic extracts were washed with brine (200 mL), dried over Na2SOq, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (15% EtOAc in hexanes) to afford diethyl 3-bromopyridine-2,5-dicarboxylate (12.409 g, 84%) as a yellow oil. 1H NMR (400 MHz, CDCL) δ = 9.14 (d, J= 1.72 Hz, 1H). 8.56 (d, J= 1.76 Hz, 1H), 4.54 - 4.39 (m, 4H), 1.48 - 1.38 (m, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ = 164.75, 163.37, 153.07, 148.64, 142.56, 128.66, 118.28, 62.81, 62.36, 14.32, 14.23 ppm. LRMS (ES+) m/z [M + H]+ calcd for CnHi3BrNO4 + 302.00; Found 302.04. ethyl 5-bromo-6-(hydroxymethyl)nicotinate [0211] To a 0 °C cooled solution of diethyl 3-bromopyridine-2,5-dicarboxylate (12.309 g, 35.257 mmol, 1.0 equiv) in THF (58.8) and EtOH (117.5) was added freshly powdered CaCl3 (11.738 g, 105.771 mmol, 3.0 equiv) followed by NaBH4 (2.134 g, 56.411 mmol, 1.6 equiv) with vigorous stirring. The mixture was warmed to ambient temperature and stirred for 2 h, then cooled to 0 °C. A 40% saturated NH4Cl solution (587.6 mL) was added dropwise, and the solution was warmed to ambient temperature, then THF and EtOH were removed via rotary evaporation. The resulting suspension was stirred at 0 °C for 1 hour then filtered, washed with ice-cold H2O (2 x 80 mL) and dried in vacuo to afford ethyl 5-bromo-6- (hydroxymethyl)nicotinate (5.488 g, 60%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ = 9.11 (d, J = 1.48 Hz. 1H), 8.45 (d, J= 1.68 Hz, 1H), 4.80 (s, 2H), 4.43 (q, J = 7.16 Hz, 2H), 3.87 (br s, 1H), 1.42 (t, J= 7.12 Hz, 3H) ppm. 13C NMR (100 MHz, CDCI3) δ = 164.0, 160.9, 147.7, 141.1, 126.9, 118.5, 63.7, 62.1, 14.4 ppm. LRMS (ES+) m/z [M + H]+ calcd for C9H11BrNO3+ 259.99 ; Found 260.10.
Preparation of 4-fluoro-7-(4,4,5,5-tetramethyl-l,3..2-dioxaborolan-2-yl)-lH-indole
[0212] Following General Procedure 1, 4-fluoroindole was used to prepare 4-fluoro-7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1H-indole (0.700 g, 45%) as a brown solid. 1H NMR (400 MHz, CDCI3) δ 9.34 (s, 1H). 7.62 (dd. J= 7.9, 5.6 Hz, 1H). 7.24 (dd. J= 3.3, 2.3 Hz, 1H), 6.82 (dd, J= 10.5, 7.9 Hz, 1H), 6.65 (dd, J= 3.3, 2.3 Hz, 1H), 1.41 (s, 12H). 13C NMR (100 MHz, CDC13) δ 160.40, 157.89, 144.18 (d, 1JCF= 12.8 Hz), 130.68 (d, 2JCF = 8.13 Hz), 124.05, 115.88 (3 JCF = 21.6 Hz), 104.68 (4JCF = 18.6 HZ), 98.13, 83.90, 25.01. LRMS (ES+) m/z [M + H]+ calcd for C 14H 18BFNO2 = 262.14; Found 262.37.
Preparation of 5-fluoro-7-(4.4.,5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)-lH-indole
[0213] Following General Procedure 1, 5-fluoroindole was used to prepare 5-fluoro-7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1H-indole (1.15 g, 73%) as lime white solid. 1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 7.44 - 7.37 (m, 2H), 7.31 (t, J= 2.9 Hz, 1H), 6.52 (dd, J= 3.2. 2.1 Hz, 1H), 1.41 (s. 12H). 13C NMR (100 MHz, CDC13) δ 158.86, 156.53, 137.64, 127.53 (1JCF= 9.54 Hz), 125.83, 116.44 (2JCF = 24.5 Hz), 109.14 (3JCF= 23.6 Hz), 102.03, 84.19, 25.01. LRMS (ES+) m/z [M + H]+ calcd for C14H18BFNO2 + = 262.14;
Found 262.37.
Preparation of 6-fluoro-7-(4,4.,5,5-tetraniethyl-l,3.,2-dioxaborolan-2-yl)-lH-indole
[0214] Following General Procedure 1, 6-fluoroindole was used to prepare 6-fluoro-7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lF7-indole (1.30 g, 83%) as light purple solid. 1H NMR (400 MHz, CDCl3) δ 9.37 (s, 1H), 7.68 (ddd, J= 8.6, 5.4, 0.8 Hz, 1H), 7.25 (dd, J = 3.2, 2.3 Hz, 1H), 6.87 (dd, J= 10.0, 8.6 Hz, 1H), 6.53 (dd, J= 3.3, 2.2 Hz, 1H), 1.43 (s, 12H). 13C NMR (100 MHz, CDC13) δ 166.25, 163.82, 140.83 (1JCF= 13.2 HZ), 125.34 (2JCF = 11.0 Hz), 124.40 (3JCF= 3.77 Hz), 123.43, 108.30 (4JCF= 27.2 Hz), 102.10, 83.86. LRMS (ES+) m/z [M + H]+ calcd for Ci4Hi8BFNO2 + = 262.14; Found 262.30.
Preparation of 4-chloro-7-(4.4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-l H-indole
[0215] Following General Procedure 1, 4-chloroindole was used to prepare 4-chloro-7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1H-indole (1.23 g, 74%) as a brown solid. 'H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 7.58 (d, J= 7.5 Hz, 1H), 7.30 (dd, J= 3.3, 2.3 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 6.67 (dd, J= 3.2, 2.3 Hz, 1H), 1.41 (s, 12H). 13C NMR (100 MHz, CDC13) δ 141.75, 129.99, 129.90, 125.81, 124.72, 119.32, 100.71, 84.05, 25.02. LRMS (ES+) m/z [M + H]+ calcd for CI4HI8BC1NO2 + = 278.11; Found 278.17.
Preparation of 5-ch loro-7-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)-1 H-indole
[0216] Following General Procedure 1, 5-chloroindole was used to prepare 5-chloro-7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-H -indole (1.350 g, 81%) as a white solid. H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 7.74 (d, J= 2.1 Hz, 1H), 7.64 (d, J= 2.2 Hz, 1H), 7.29 (dd, J= 3.2, 2.4 Hz, 1H), 6.51 (dd, J= 3.2, 2.2 Hz, 1H), 1.42 (s, 12H). 13C NMR (100 MHz, CDC13) δ 139.36, 128.88, 128.21, 125.56, 125.29, 123.42, 101.72, 84.24, 25.02.
LRMS (ES+) m/z [M + H]+ calcd for C I4H isBCINCh = 278. 11 : Found 278. 11.
Preparation of 6-chloro-7-(4.4,5,5-tetramethyl-l,3.,2-dioxaborolan-2-yl)-lH-indole [0217] Following General Procedure 1, 6-chloroindole was used to prepare 6-chloro-7-
(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-1H-indole (1.25 g, 75%) as a green solid. 1 H NMR (400 MHz, CDCl3) 8 9.58 (s, 1H), 7.66 (d, J= 9.1 Hz, 1H), 7.30 - 7.25 (m, 1H), 7.17 (d, J= 8.4 Hz, 1H), 6.55 (dd, J= 3.3, 2.2 Hz, 1H), 1.47 (s, 12H). 13C NMR (100 MHz, CDC13) δ 142.12, 135.20, 125.48, 124.69. 124.49, 121.80, 102.06, 83.93, 25.04. LRMS (ES+) m/z [M + H]+ calcd for C 14H18BClNO2+ = 278.11; Found 278.17.
Preparation of Int-5a (((2S,5R)-l,5-dimethyl-3-(2-methyl-lH-indol-7-yl)-l,2,5,6- tetrahydr opyridin-2-yl)methanol):
[0218] Using Alternate General procedure 2, Int-4 (1.0 g, 4.5 mmol, 1.0 eq) was converted to Int-5a and this was purified by column chromatography to afford 320 mg (26%) of the title compound as a pale yellow semi solid. ESI-MS m/z: 271.10 [M+H]+.
Preparation of Int-B (7-bromo-4-chloro-5-fluoro-lH-indole): [0219] To a stirred solution of l-bromo-4-chloro-5-fluoro-2-nitrobenzene (5.0 g, 20 mmol, 1.0 eq) in THF (100 mL) was added vinyl magnesium bromide (IM in THF) (79.4 mL, 79.4 mmol, 4.00 eq) at -78 0 C through a dropping funnel over 20 minutes and then the reaction was allowed to slowly warm to room temperature and stirred for 2 hours. The reaction mixture quenched with a saturated ammonium chloride solution (200 ml) and extracted with ethyl acetate (2 x 150 ml). The combined organic layers were washed with a saturated brine solution (100 mL). dned over anhydrous Na2SO4, and concentrated. Crude material was purified by comb-flash (25 % EtOAc in Hexane) to afford 1 g (20%) of Int-B as a yellow gummy solid. ESI-MS m/z: 249.6 [M+H]+. Preparation of Int-lb (4-chloro-5-fluoro-7-(4,4..5,5-tetraniethyl-l,3-2-dioxaborolan-2-yl)- IH-indole): n -
[0220] Using Alternate General procedure 1, Int-B (1.0 g, 4.0 mmol. 1.0 eq) was converted to Int-lb and this was purified by column chromatography to afford 0.8 g (41%) of the title compound as a yellow solid. ESI-MS m/z: 296.1 [M+H]+.
Preparation of Int-5b (((2S,5R)-3-(4-chloro-5-fluoro-lH-indol-7-yl)-l,5-dimethyl-l,2,5,6- tetrahvdropyridin-2-yl)methanol): lnt-5b [0221] Using Alternate General procedure 2, Int-4 (0.50 g, 2.3 mmol, 1.0 eq) was converted to Int-5b and this was purified by column chromatography to afford 140 mg (20%) of the title compound as a pale yellow semi solid. ESI-MS m/z: 309.0 [M+H]+.
Preparation of Int-D (7-bromo-5-chloro-4-fluoro-lH-indole);
[0222] To a stirred solution of Tnt-C (5.0 g, 20 mmol, 1.0 eq) in THF ( 100 mL), vinyl magnesium bromide (IM in THF) (79.4 mL, 79.4 mmol, 4.00 eq) was added through a dropping funnel at -78 °C over 20 minutes and then allowed to slowly warm to room temperature and stirred for 2 hours. The reaction mixture quenched with a saturated ammonium chloride solution (200 ml) and extracted with ethyl acetate (2 x 150 ml). The combined organic layers were washed with a saturated brine solution (100 mL), dried over anhydrous Na2SC>4, and concentrated. The crude material was purified by combi-flash (25 % EtOAc in Hexane) afford 0.9 g (18%) of Int-D as an off-white semi solid. ESI-MS m/z: 249.2 [M+H]+.
Preparation of Int-lc (5-methoxy-7-(4,4,5,5-tetramethyl-l,3,2-dioxabor olan-2-yl)-lH- indole):
[0223] Using Alternate General procedure 1, Int-D (0.90 g, 3.7 mmol, 1.0 eq) was converted to Int-lc and this was purified by column chromatography to afford 1 g (93%) of the title compound as a yellow solid. ESI-MS m/z: 296.4 [M+H]+. Preparation of Int-5c ((2S,5R)-3-(5-chloro-4-fluoro-lH-indol-7-yl)-l,5-dimethyl-l,2,5,6- tetrahvdropyridin-2-yl)methanol) ;
[0224] Using Alternate General procedure 2, Int-4 (0.40 g. 1.8 mmol, 1.0 eq) was converted to Int-5c and this was purified by column chromatography to afford 130 mg (23%) of the title compound as a brown solid. ESI-MS m/z: 309.1 [M+H]+.
Preparation of Int-F (7-bromo-4,5-difluoro-lH-indole); n -
[0225] To a stirred solution of Int-E (25.0 g, 105 mmol, 1.00 eq) in THF at -78 °C (250 mL) was added vinyl magnesium bromide (IM in THF) (420 mL, 420 mmol, 4.00 eq) dropwise over 20 minutes. The resulting reaction mixture was allowed to room temperature and stirred for 3 hours at which point the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 X 500 mL). The combined organic layers were washed with an aqueous solution of NaCl (50 mL), the organic layer was dried over anhydrous NazSCL, solids were removed by filtration and the filtrate was concentrated in vacuo. The crude was punfied by silica gel chromatography (10 % EtOAc in Hexane) to afford 8 g (33%) of Int-F as a pale-yellow solid. ESI-MS m/z: 233.0 [M+H] +. Preparation of Int-ld (Synthesis of 4,5-difluoro-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indole):
Int-F
[0226] Using Alternate General procedure 1, Int-F (2.50 g, 10.8 mmol, 1.00 eq) was converted to Int-ld and this was purified by column chromatography to afford 1.4 g (51%) of the title compound as a pale yellow solid. ESI-MS m/z: 280.2 [M+H]+.
Preparation of Int-5d (((2S,5R)-3-(4,5-difluoro-lH-indol-7-yl)-l,5-dimethyl-l,2,5,6- tetrahy dropyridin-2-yl)methanol): [0227] Using Alternate General procedure 2, Int-4 (1.0 g, 4.5 mmol, 1.0 eq) was converted to Int-5d and this was purified by column chromatography to afford 160 mg (12%) of the title compound as a pale yellow gummy solid. ESI-MS m/z: 393.2 [M+H] +. Preparation of Int-H (7-bromo-4-methyl-lH-indole):
Int-G lnt’H
[0228] To a stirred solution of Int-G (5.0 g. 23 mmol, 1.0 eq) in THF (100 mL), vinyl magnesium bromide (IM in THF) (93.5 mL, 93.5 mmol, 4.00 eq) was added over 20 minutes through a dropping funnel at -78 0 C and the reaction was allowed to slowly warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with a saturated ammonium chloride solution (200 ml) and extracted with ethyl acetate (2 x 150 ml). The combined organic layers were washed with a saturated brine solution (100 mL), dried over anhydrous ISfeSCh. and concentrated. The crude material was purified by combi-flash (25 % EtOAc in Hexane) to afford 2 g (40%) of Int-H as an off brown semi solid. ESI-MS m/z: 211.2 [M+H]+.
Preparation of Int-le (4-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indole); lnt-1e [0229] Using Alternate General procedure 1, Int-H (1.5 g, 7.1 mmol, 1.0 eq) was converted to Int-le and this was purified by column chromatography to afford 1 g (55%) of the title compound as an off-white solid. ESI-MS m/z: 258. 1 [M+H]+. Preparation of Int-5e (((2S,5R)-l,5-dimethyl-3-(4-methyl-lH-indol-7-yr)-l,2,5,6- tetrahydr opyridin-2-yl)methanol):
[0230] Using Alternate General procedure 2, Int-4 (1.0 g, 4.5 mmol, 1.0 eq) was converted to lnt-5e and this was purified by column chromatography to afford 320 mg (26%) of the title compound as a pale yellow semi solid. ESI-MS m/z: 271.0 [M+H]+.
Preparation of Int-J (7-bromo-5-methyl-lH-indole): lnt-1 Int-J
[0231] To a stirred solution of Int-I (5.0 g, 23 mmol, 1.0 eq) in THF (100 mL), vinyl magnesium bromide (IM in THF) (93.5 mL, 93.5 mmol, 4.00 eq) was added over 20 minutes by a dropping funnel at -78 0 C and the reaction was allowed to slowly warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with a saturated ammonium chloride solution (200 ml) and extracted with ethyl acetate (2 x 150 ml). The combined organic layers were washed with a saturated brine solution (100 mL), dried over anhydrous Na2SC>4, and concentrated. The crude material was purified by combi-flash (25 % EtOAc in Hexane) to afford 2 g (40%) of Int-J as an off white solid. ESI-MS m/z: = 21 1.4 [M+H]+. Preparation of Int-lf (5-methyl-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-l H- indole):
[0232] Using Alternate General procedure 1, Int-J (1.0 g, 4.8 mmol, 1.0 eq) was converted to Int-lf and this was purified by column chromatography to afford 0.8 g (66%) of the title compound. ESI-MS m/z: = 258.1 [M+H]+.
Preparation of Int-5f (((2S,5R)-l,5-dimethyl-3-(5-methyl-lH-indol-7-yl)-l,2,5,6- tetrahydro pyridin-2-yl)methanol): [0233] Using Alternate General procedure 2, Int-4 (340 mg, 1.54 mmol, 1.00 eq) was converted to Int-5f and this was purified by column chromatography to afford 100 mg (24%) of the title compound as a brown gummy solid. ESI-MS m/z: =271.0 [M+H]+.
Preparation of Int-L (7-bromo-4-methoxy-lH-indole):
Int-K Int-L [0234] To a stirred solution of Int-K (5.0 g, 22 mmol, 1.0 eq) in THF (100 mL), vinyl magnesium bromide (IM in THF) (86.2 mL, 86.2 mmol, 4.00 eq) was added over 20 minutes by a dropping funnel at -78 0 C and the reaction was allowed to slowly warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with a saturated ammonium chloride solution (200 ml) and extracted with ethyl acetate (2 x 200 ml). The combined organic layers were washed with a saturated brine solution (100 mL), dried over anhydrous Na2SC>4, and concentrated. The crude material was purified by combi-flash (20 % EtOAc in Hexane) to afford 1.9 g (93%) of Int-L as an off-white semi solid. ESI-MS m/z: 227.8 [M+H]+.
Preparation of Int-lg (4-methoxy-7-(4,4,5.,5-tetramethyl-l.,3.,2-dioxaborolan-2-yl)-lH- indole.
Int-L lnt-1g
[0235] Using Alternate General procedure 1, Int-L (1. 0 g. 6.69 mmol, 1.00 eq) was converted to Int-lg and this was purified by column chromatography to afford 1.2 g (66%) of the title compound as a pale yellow solid. ESI-MS m/z: 273. 17 [M+H]+.
Preparation of Int-5g (((2S,5R)-3-(4-methoxy-l H-indol-7-yl)-l ,5-dimethyl-l ,2,5,6- tetrahydr opyridin-2-yl)methanol): lnt-5g [0236] Using Alternate General procedure 2, Int-4 (0.90 g, 4.1 mmol, 1.0 eq) was converted to Int-5g and this was purified by column chromatography to afford 400 mg (34%) of the title compound as a pale yellow solid. ESI-MS m/z: 287.0 [M+H]+.
Preparation of Int-N (7-bromo-5-methoxy-lH-indole):
[0237] To a stirred solution of Int-M (10 g, 43 mmol, 1.0 eq) in THF (100 mL), vinyl magnesium bromide (IM in THF) (172 mL, 172 mmol, 4.00 eq) was added over 20 minutes by a dropping funnel at -78 0 C and the reaction was allowed to slowly warm to room temperature and stirred for 3 hours. Then reaction mixture was quenched with a saturated ammonium chloride solution (200 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with a saturated brine solution (100 mL), dried over anhydrous Na2SO4, and concentrated. The crude material was purified by combi-flash (2 % EtOAc in Hexane) to afford 2.2 g (23%) of Int-N as an off white solid. ESI-MS m/z: 227.4 [M+H]+.
Preparation of Int-lh (5-methoxy-7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-l H- indole) :
[0238] Using Alternate General procedure 1, Int-N (1.0 g, 4.4 mmol. 1.0 eq) was converted to Int-lh and this was purified by column chromatography to afford 900 mg (75%) of the title compound as a yellow solid. ESI-MS m/z: 273.18 [M+H]+. Preparation of Int-5h (( (2S.5R)-3-(5-methoxy-l H-indol-7-yl)-l ,5-dimethyl-l .2,5,6- tetrahyd ropyridin-2-yl)methanol:
[0239] Using Alternate General procedure 2, Int-4 (0.40 g, 1.8 mmol, 1.0 eq) was converted to Int-5h and this was purified by column chromatography to afford 220 mg (42%) of the title compound as a pale yellow semi solid. ESI-MS m/z: 287.6.0 [M+H]+.
Preparation of Int-P (7-bromo-lH-indole-3-carboxylic acid);
[0240] To a stirred solution of Int-O (10 g, 51 mmol, 1.0 eq) in DMF (10 vol) was added lithium tert-butoxide (1 M in THF) (255 mL, 255 mmol, 5.00 eq) at -78 ° C. Following this,
CO2 gas was introduce using dry ice over a period of 1 hour and the reaction mixture was warmed to room temperature. The resulting reaction was heated to 90°C and stirred for 24 hours. After completion, the reaction mixture was quenched with a saturated ammonium chloride solution and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with a brine solution, dried over anhydrous sodium sulphate and concentrated to get crude which was purified by combi -flash (30 % EtOAc in Hexane) to afford 8g (65%) of Int- P. ESI-MS m/z: 239.2 [M-H] +. Preparation of Int-Q (7-bromo-3-fluoro-lH-indole);
[0241] To a stirred solution of Int-P at 0°C (10 g, 42 mmol, 1.0 eq ) in DCM (100 mL) was added H2O (50 mL) followed by lithium carbonate (12.3 g, 167 mmol, 4.00 eq) and Selectfluor (29.5 g , 83.3 mmol, 2.00 eq). The resulting reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was diluted with ice cold water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with a brine solution (40 mL), dried over sodium sulphate and concentrated. The crude was purified using combi flash chromatography to afford 5 g (56%) of Int-Q as a yellow solid. ESI-MS m/z: 216.0 [M+H]
Preparation of Int-li (3-flu oro-7-(4,4,5,5-tetramethyl- 13,2-dioxaborolan-2-yl)-1 H- indole):
[0242] Using Alternate General procedure 1, Int-Q (5.0 g, 19 mmol. 1.0 eq) was converted to Int-li and this was purified by column chromatography to afford 2 g (48%) of the title compound as a brown solid. ESI-MS m/z: 263.1 [M+H]+.
Preparation of Int-5i (((2S,5R)-3-(3-fluoro-lH-indol-7-yl)-l,5-dimethyl-l,2,5,6- tetrahydrop yridin-2-yl)methanol):
[0243] Using Alternate General procedure 2, Int-4 (0.80 g, 3.6 mmol, 1.0 eq) was converted to Int-5i and this was purified by column chromatography to afford 600 mg (60%) of the title compound as a brown solid. ESI-MS m/z:275.26 [M+H]+.
Preparation of Int-5j (((2S,5R)-3-(3-chloro-lH-indol-7-yl)-l,5-dimethyl-l,2,5,6- tetrahydro pyridin-2-yl)methanol): [0244] Using Alternate General procedure 2, Int-4 (0.50 g, 2.3 mmol, 1.0 eq) was converted to Int-5j and this was purified by column chromatography to afford 250 mg (38%) of the title compound as a brown solid. ESI-MS m/z: 292.2 [M+H]+. Preparation of Int-5k (((2S,5R)-l,5-dimethyl-3-(3-methyl-lH-indol-7-yl)-l,2,5,6- tetrahydr o pyridin-2-yl)methanol):
[0245] Using Alternate General procedure 2, Int-4 (0.40 g, 1.8 mmol, 1.0 eq) was converted to Int-5k and this was purified by column chromatography to afford 200 mg (40%) of the title compound as an off-white solid. ESI-MS m/z: 270.9 [M+H]+.
Preparation of Int-51 (((2S,5R)-3-(2-chloro-lH-indol-7-yl)-l,5-dimethyl-l,2,5,6- tetrahydr opyridin-2-yl)methanol); n - [0246] Using Alternate General procedure 2, Int-4 (0.60 g. 2.7 mmol, 1.0 eq) was converted to Int-51 and this was purified by column chromatography to afford 150 mg (19%) of the title compound as a pale yellow semi solid. ESI-MS m/z: 290.9 [M+H]+. Preparation of Int-S (7-bromo-lH-indole-4-carbonitrile);
[0247] To a stirred solution of Int-R (10 g, 44 mmol, 1.0 eq) in THF (200 mL), vinyl magnesium bromide (IM in THF) (178 mL, 178 mmol, 4.00 eq) was added over 20 minutes by a dropping funnel at -78 ° C and the reaction was allowed to slowly warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with a saturated ammonium chloride solution (200 ml) and extracted with ethyl acetate (2 x 150 ml). The combined organic layers were washed with a saturated brine solution (100 mL), dried over anhydrous Na2SC>4 and concentrated. The crude material was purified by combi-flash (25 % EtOAc in Hexane) to afford 3 g (30%) of Int-S as a brown solid. ESI-MS m/z: 222.4 [M+H]+.
Preparation of Int-lm (7-(4,4,5,5-tetramethyl-l,3..2-dioxaborolan-2-yl)-lH-indole-4- carbonitrile:
Int-S lnt-1m [0248] Using Alternate General procedure 1, Int-S (2.0 g, 9.0 mmol, 1.0 eq) was converted to Int-lm and this was purified by column chromatography to afford 1 g (41%) of the title compound as a yellow solid. ESI-MS m/z: 269.2 [M+H]+. Preparation of Int-5m (7-((2S,5R)-2-(hydroxymethyl)-l,5-dimethyl-l,2,5,6-tetrahvdropy rid in-3-yl)- lH-indole-4-carbonitrile) :
[0249] Using Alternative General procedure 2, Int-4 (0.50 g. 2.3 mmol, 1.0 eq) was converted to Int-5m and this was purified by column chromatography to afford 220 mg (34%) of the title compound as a pale yellow semi solid. ESI-MS m/z: 281.9 [M+H] +. Preparation of Int-5n (((2S,5R)-3-(4-chloro-lH-indol-7-yl)-l,5-dimethyl-l,2,5,6- tetrahydro pyridin-2-yl)methanol): [0250] Using Alternate General procedure 2, Int-4 (0.50 g, 2.3 mmol, 1.0 eq) was converted to Int-5n and this was purified by column chromatography to afford 230 mg (35%) of the title compound as a pale yellow semi solid. ESI-MS m/z: 290.8 [M+H]+. Preparation of Int-5o (3-(4-fluoro-lH-indol-7-yl)-l,5-dimethyl-l,2,5,6- tetrahvdropyridin-2-yl)methanol:
[0251] Using Alternate General procedure 2, Int-4 (3.0 g, 14 mmol, 1.0 eq) was converted to Int-5o and this was purified by column chromatography to afford 950 mg (25%) of the title compound as a brown gummy solid. ESI-MS m/z: 275.20 [M+H]+.
Preparation of Int-5p (Synthesis of (3-(5-fluoro-lH-indol-7-yl)-1.5-dimethyl-l,2,5,6- tetrahydrop yridin-2-yl)methanol: [0252] Using Alternate General procedure 2, Int-4 (0.80 g, 3.6 mmol, 1.0 eq) was converted to Int-5p and this was purified by column chromatography to afford 380 mg (32%) of the title compound as a pale yellow semi solid. ESI-MS m/z: 281.9 [M+H]+. Preparation of Int-9p & Int-lOp:
[0253] 380 mg of racemic Int-5p was purified by Chiralpak IG (30X250mm,5pm) MP(A)C02: 81 g/min MP(B)Co-Solvent: 9 ml/min (7N Methanoic Ammonia in MeOH) Total Flow rate (mL/min) 90g-10%-100 Ba. The faster eluting peak was assigned as Int-9p (80 mg), and the more slowly eluting peak was assigned as Int-lOp (100 mg).
Preparation of Int-5q (Synthesis of (3-(5-chloro-lH-indol-7-yl)-l,5-dimethyl-l,2,5,6- tetrahy dropyridin-2-yl) methanol); [0254] Using Alternate General procedure 2, Int-4 (0.50 g, 2.3 mmol, 1.0 eq) was converted to Int-5q and this was purified by column chromatography to afford 240 mg (37%) of the title compound as a pale yellow semi solid. ESI-MS m/z: 281.9 [M+H]+.
Preparation of Int-9q & Int-lOq:
[0255] 240 mg of racemic Int-5q was purified by Column IH (30 X250*mm,5u) Mobile phase A 0.1 % DEA in n-Hexane Mobile phase B DCM:MEOH (1 :1) Eluent A: B:-90:10 Total Flow rate (mL/min) 42 ml/min. The faster eluting peak was assigned as Int-9q (40 mg), and the more slowly eluting peak was assigned as Int-lOq (40 mg).
C. Compound Examples
Example 1: 8-methyl-7a,8,9,10-tetrahvdro-7H-indolo[7,l-fg] [1,7]naphthyridine
(3-(lH-indol-7-yl)- 1-methyl- 1,2,5,6-tetrahy dropyridin-2-yl)methanol
[0256] A solution of (3-bromo-l-methyl-l,2,5,6-tetrahydropyridin-2-yl)methanol (1.386 g, 6.726 mmol, 1.0 equiv) and indole-7-boronic acid pinacol ester (2.452 g, 10.088 mmol, 1.5 equiv) in a mixture of 2 M Na2CO3(.iq) (6.73 mL) and dioxane (67.3 mL) were sparged with N2 for 10. Pd(PPhs)4 (0.389 g, 0.336 mmol, 0.05 equiv). was added, and the mixture was heated to 100 °C for 10 h with vigorous stirring, then cooled to ambient temperature. The mixture was added to H2O (600 mL) and extracted with EtOAc (5 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4. and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient elution: 100% DCM to 30% MeOH in DCM) to afford (3-(17T-indol-7-yl)-l-methyl-l,2,5,6- tetrahydropyridin-2-yl)methanol (0.901 g, 55%) as an off white semi-solid. 'H NMR (400 MHz, CDCl3) δ = 9.01 (br s, 1H), 7.56 (d, J= 7.88 Hz, 1H), 7.19 (t, J = 2.8 Hz, 1H), 7.08 (t, J= 7.28 Hz, 1H), 6.94 (dd, J= 7.28 Hz, 0.8 Hz. 1H), 6.55 (dd, J= 3.22 Hz, 2. 12 Hz. 1H), 6.10 - 6.05 (m, 1H), 3.84 - 3.48 (m, 2H), 3.36 - 3.24 (m, 2H), 3.12 - 3.00 (m, 1H), 2.78 - 2.68 (m, 1H), 2.41 - 2.20 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3) δ = 135.3, 134.1, 128.1, 127.6, 124.7, 124.6, 120.8, 119.7, 119.5, 102.5, 66.1, 59.8, 48.8, 42.9, 24.8 ppm. LRMS (ES+) m/z [M + H]+ calcd for CI5HI9N2O+ 243. 15; Found 243.09.
8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,l-fg][1,7]naphthyridine
[0257] To a 0 °C cooled solution of (3-(lH-indol-7-yl)-l-methyl-l,2,5,6-tetrahydropyridin- 2-yl)methanol (0.789 g, 3.256 mmol, 1.0 equiv), in DCM (65.1 mL) was added TsCl (0.745 g, 3.907 mmol. 1.2 equiv) and tetrabutyl ammonium hydrogen sulfate (0.055 g, 0.163 mmol, 0.05 equiv) followed by freshly crushed NaOH (0.521 g, 13.024 mmol, 4.0 equiv). The mixture was warmed to ambient temperature and stirred for 2 hours then poured into 50% saturated NH4Cl(aq) (400 mL). The solution was extracted with DCM (4 x 100 mL), washed with brine (100 mL). dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (1% MeOH in DCM) and then re-purified with column chromatography on silica gel (1% MeOH in EtOAc) to afford 8- methyl-7a,8,9,10-tetrahydro-7H-indolo[7,L/i,'||l,7|naphthyridiiie (0.381 g, 52%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ = 7.50 (d, J= 7.04 Hz, 1H), 7.28 - 7.22 (m, 1H), 7. 12 - 7.08 (m. 2H), 6.51 - 6.44 (m. 2H), 4.65 (dd, J= 11.2, 5.32 Hz, 1H), 3.82 (t, J= 11.08 Hz, 1H), 3.44 - 3.33 (m, 1H), 3.05 - 2.95 (m, 1H), 2.72 - 2.54 (m, 5H), 2.31 - 2.20 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ = 133.2, 130.9, 126.5, 126.3, 120.4, 120.2, 119.9, 119.6, 114.3, 101.3, 60.7, 52.9, 48.4, 44.4, 26.1 ppm. LRMS (ES+) m/z [M + H | calcd for CI5CI7N2+ 225.14; Found 225.21.
Chiral Separation of 8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,l-fg] [1,7]naphthyridine [0258] Racemic 8-methyl-7a,8,9,10-tetrahydro-H7-indolo[7,1-Jg][1,7]naphthyridine was separated into its enantiomers by preparatory chiral SFC (Chiralpak-IG 15 cm x 2 cm; Isocratic method: 25% MeOH (0.1% diethylamine)/CO2; 100 bar, 60 mL/min; injection volume 0.5 mL, 3 mg/mL in MeOH). [0259] 8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthyridine (Example 1A, First eluting peak): Analytical chiral SFC >99.9%ee. Rt = 4.42 min (Chiralpak-IG 25 cm x 0.46 cm; Isocratic method: 25% MeOH (0.1% diethylamine)/CO2; 100 ban 3 mL/min, wavelength 220 nm). Yellow wax; LC-MS: m/z = 225.1 [M+H]+.
[0260] 8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthyridine (Example IB, Second eluting peak): Analytical chiral SFC >99.9%ee. Rt = 6.90 min (Chiralpak-IG 25 cm x 0.46 cm; Isocratic method: 25% MeOH (0.1% diethylamine)/CO2; 100 bar. 3 mL/min. wavelength 220 nm). Yellow wax; LC-MS: m/z = 225.2 [M+H]+.
Example 2: 8A0-dimethyl-7a,8,9,10-tetrahvdro-7/Z-indolo[7,l-/g] [1,7]naphthyridine (major)
(3-(lH-indol-7-yl)-l,5-dimethyl-l,2,5,6-tetrahydropyridin-2-yl)methanol
[0261] A solution of (3-bromo-l,5-dimethyl-l,2,5,6-tetrahydropyridin-2-yl)methanol (0.170 g, 0.772 mmol, 1.0 equiv) and indole-7-boronic acid pinacol ester (0.282 g, 1.159 mmol, 1.5 equiv) in a mixture of dioxane (7.72 mL) and 2 M Na COsiaq) (1.54 mL) was sparged with N2 for 5 min. Pd(PPhs)4 (0.022 g, 0.0190 mmol, 0.025 equiv) was added and the mixture was heated to 100 °C with stirring for 5 h, then cooled to ambient temperature. The mixture was added to H2O (150 mL) and extracted with EtOAc (4 x 75 mL). The combined organic extracts were washed with brine (50 mL) dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution: 10% MeOH in EtOAc to 20% MeOH in EtOAc) to afford (3-(LH-indoI-7-yl)-l,5- dimethyl-l,2,5,6-tetrahydropyridin-2-yl)methanol (0.146 g, 74%) as a brown semi solid present as a mixture of diastereomers (4: 1 major/minor). 1 H NMR (400 MHz, CDCl3) δ = 9.311 (br s, 1H), 9.25* (br s, 0.25H), 7.62 - 7.52 (m, 1.25H), 7.22* (t, J = 2.72 Hz, 0.25H), 7.18t (t, J= 2.68 Hz, 1H), 7.10 - 7.04 (m, 1.25H), 6.96 - 6.89 (m, 1.25H), 6.58 - 6.50 (m, 1.25H), 6.0* (d, J= 2.6 Hz, 0.25H), 5.861 (s, 1H), 4.74 (br s, 1.25H), 3.75 - 3.671 (m 1H)
3.65 - 3.52* (m, 0.5H), 3.44 - 3.27* (m, 0.25H). 3.31 - 3.201 (m, 2H), 3.051 (dd, j= 11.0, 4.8 Hz. 1H), 2.92 - 2.87* (m, 0.5H). 2.74 - 2.60 (m, 2H), 2.531 (s 3H), 2.35r (t, J = 10.28 Hz. 1H), 2.06* (s, 0.25H), 1.18* (d, J= 7.0 Hz, 0.75H), 1.021 (d, J= 7.12 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ = 135.3, 134.9, 134.7, 134.5, 133.2, 133.0, 128.3, 128.2, 124.8, 124.8, 124.4, 123.8, 121.1. 120.8, 120.1, 119.7, 119.6, 119.3, 102.6, 102.3, 66.7, 64.9, 59.8, 59.6, 58.8, 53.8, 43.0, 42.4, 30.3, 26.8, 19.1, 18.6 ppm. LRMS (ES+) m/z [M + H]+ calcd for C16H21N2O+ 257. 17; Found 257.26. Idenotes ’H NMR signal arising exclusively from the major diastereomer; ‘denotes 1H NMR signal arising exclusively from the minor diastereomer; undesignated signals arise from both. 13C NMR signals are reported without designation.
8,10-dimethyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthyridine (major) [0262] To a 0 °C cooled solution of (3-(1H-indol-7-yl)-l,5-dimethyl-l, 2,5,6- tetrahydropyridin-2-yl)methanol (3: 1 dr) (0.140 g, 0.546 mmol, 1.0 equiv) in DCM (10.9 mL) was added TsCl (0.125 g, 0.655 mmol, 1.2 equiv) and tetrabutylammonium hydrogen sulfate (0.009 g. 0.027 mmol, 0.05 equiv) followed by freshly crushed NaOH (0.087 g, 4.0 equiv. 2. 184 mmol). The mixture was warmed to ambient temperature and stirred vigorously for 3 h, then poured into H2O (200 mL) and extracted with DCM (4 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0.5% MeOH in EtOAc) to afford 8,10-dimethyl-7a,8,9,10-tetrahydro-7H-indolo[7,l- fg][1,7]naphthyridine (major) (0.089 g, 68%) as a light brown semi-solid. The minor diastereomer was not isolated. ’H NMR (400 MHz, CDCl3) δ = 7.50 (d. J= 7.84 Hz, 1H), 7.28 (d, J= 7.32 Hz, 1H), 7.12 - 7.06 (m, 2H), 6.48 (d, J= 3.0 Hz, 1H), 6.31 - 6.28 (m, 1H),
4.65 (dd, J= 5.36, 11.2 Hz, 1H), 3.80 (t, J= 1 1.04 Hz, 1H), 3.35 - 3.26 (m, 1H), 3.0 (dd, J = 5.0, 11.2 Hz, 1H), 2.83 - 2.70 (m, 1H), 2.56 (s, 3H), 2.20 (t, J= 10.68 Hz, 1H), 1.09 (d, J = 7.08 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ = 133.4, 130.0, 126.44, 126.35, 120.4, 119.6, 114.4, 101.3, 61.5, 60.7, 48.4, 44.2, 30.8. 18.8 ppm. LRMS (ES+) m/z [M + H]+ calcd for C16H19N2+ 239. 15; Found 239.25. Chiral Separation of 8,10-dimethyl-7a,8,9,10-tetrahydro-7H-indolo[7,l- fg][1,7]naphthyridine (major)
[0263] Racemic 8,10-dimethyl-7a,8,9,10-tetrahydro-7H-indolo|7,l-
/ ][1,7]naphthyridine (major) was separated into its enantiomers by preparatory chiral SFC (Chiralpak-IG 25 cm x 2 cm; Isocratic method: 25% MeOH (0.1% diethylamine)/CO2; 100 bar, 60 mL/min; injection volume 0.5 mL. 10 mg/mL in MeOH).
[0264] 8.10-dimethyl-7a,8,9, 10-tetrahy dro-7H-indolo[7, 1 -fg] [1 ,7]naphthyridine (Example 2A, First eluting peak): Analytical chiral SFC >99.5%ee. Rt = 4.41 min (Chiralpak-IG 25 cm x 0.46 cm; Isocratic method: 25% MeOH (0.1% diethylamine)/CO2; 100 bar, 3 mL/min, wavelength 220 nm). Yellow solid; LC-MS: m/z = 239.1 [M+H]+.
[0265] 8.10-dimethyl-7a,8,9, 10-tetrahy dro-7H-indolo[7, 1 -fg] [ 1 ,7]naphthyridine (Example 2B, Second eluting peak): Analytical chiral SFC >99.9%ee. Rt = 5.40 min (Chiralpak-IG 25 cm x 0.46 cm; Isocratic method: 25% MeOH (0.1% diethylamine)/CO2; 100 bar, 3 mL/min, wavelength 220 nm). Yellow solid; LC-MS: m/z = 239.1 [M+H]+.
Example 3: (8-methyl-7a.,8.,9,10-tetrahvdro-7H-indolo[7,l-fgl[l.,7]naphthyridin-10- vDmethanol (major) (8-nietliyl-7a.8.9.10-tetralivdro-711-iiid()lol7.1- fgl [ 1.7 lnaphthyridin-10-yljmethanol (minor) ethyl 6-(hydroxymethyl)-5-(lH-indol-7-yl)nicotinate
[0266] A solution of ethyl 5-bromo-6-(hydroxymethyl)nicotinate (1.108 g, 4.260 mmol, 1.0 equiv) and indole-7-boronic acid pinacol ester (1.243 g. 5.1 12 mmol. 1.2 equiv) in dioxane (42.6 mL) and 2 M Na2COs(aq) (4.26 mL) was sparged with N2 for 5 min. Pd(PPhs)4 (0.246 g, 0.213 mmol, 0.05 equiv) was added and the mixture was heated to 90 °C and stirred for 8 hours and subsequently cooled to ambient temperature. The mixture was poured into H2O (500 mL) and extracted with EtOAc (5 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution: 30% EtOAc in hexanes to 50% EtOAc in hexanes) to afford ethyl 6-(hydroxymethyl)-5-(LF7- indol-7-yl)nicotinate (0.956 g, 76%) as an off-white solid. ’H NMR (400 MHz, CDCl3) 6 = 9.21 (d, J= 1.96 Hz, 1H), 8.43 (br s, 1H), 8.34 (d, J= 2.0 Hz, 1H), 7.74 (d, J= 7.96 Hz, 1H), 7.24 - 7.18 (m, 2H), 7.06 - 7.02 (m, 1H), 6.65 (dd, J= 2.04, 3.29 Hz, 1H), 4.60 (s, 2H), 4.42 (q, .7= 7.16 Hz, 2H), 3.31 (br s, 1H), 1.41 (t, J= 7.16 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ = 165.1, 161.2, 148.8, 139.2, 133.9. 132.1, 128.7. 125.5, 125.3. 122.7, 121.6, 120.1, 119.6, 103.3, 62.4, 61.8, 14.4 ppm. LRMS (ES’) m z [M + H]+ calcd for Ci7Hi7N2O3 + 297.33; Found 297.38.
10-(ethoxycarbonyl)-8-methyl-7H-indolo[7,l-fg][1,7]naphthyridin-8-ium iodide
[0267] To a 0 °C cooled solution of ethyl 6-(hydroxymethyl)-5-(1H-indol-7-yl)nicotinate (0.261 g, 0.881 mmol, 1.0 equiv) in DCM (17.6 mL) was added TsCl (0.202 g. 1.057 mmol, 1.2 equiv) and tetrabutyl ammonium hydrogen sulfate (0.015 g, 0.044 mmol, 0.05 equiv) followed by freshly crushed NaOH (0.141 g, 3.523 mmol, 4.0 equiv). The mixture was warmed to ambient temperature and stirred for 2 h, then poured into a vigorously stirring mixture of DCM (150 mL) and 1 M NHiCl^q) (250 mL). The layers were separated, and the aqueous layer was further extracted with DCM (3 x 80 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by chromatography on silica gel (40% EtOAc in hexanes) to afford ethyl H -indolo[7,l-:/g][1,7]naphthyridine-10-carboxylate as a white solid. ’H NMR (400 MHz, CDCI3) δ = 8.98 (d, J= 1.96 Hz. 1H), 8.64 (d. J= 2.0 Hz. 1H), 7.55 - 7.46 (m, 2H), 7.15 (d, .7= 3.08 Hz, 1H), 7.09 (t, J= 7.68 Hz, 1H), 3.55 (d, .7= 3.04 Hz, 1H), 5.64 (s, 2H), 4.46 (q, J= 7.12 Hz, 2H), 1.46 (t, J= 7.16 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ = 165.18, 154.5. 148.9, 133.0, 130.7, 126.7, 126.4, 126.3, 125.9, 122.3, 120.7, 115.5. 114.8, 103.0. 61.7. 50.7. 14.5 ppm. LRMS (ES+) m/z [M + H]+ calcd for C17H15N2OA 279.11 ; Found 279.31. [0268] ethyl 7H-indolo [7,1-fg] [1,7]naphthyridine-10-carboxylate was immediately taken up in MeCN (2.2 mL) and Mel (1.1 mL) and heated in a sealed tube at 50 °C for 22 h. The suspension was cooled to room temperature and concentrated under reduced pressure. The resulting solid was stirred in 1 : 1 hexanes/EtOAc (20 mL) at 0 °C for 1 hour then filtered, washed with additional 1 : 1 hexanes/EtOAc (10 mL) and dried in vacuo to afford 10- (etli()xycarbonyl)-8-m eth yl-7H-indolo[7,1-fg| [ l,7]naphthyridin-8-ium iodide (0.294 g, 79%) as a yellow solid. 1 H NMR (400 MHz. DMSO-d 6) δ = 9.45 (d. J = 1.08 Hz. 1H), 9.27 (d, J= 1.12 Hz, 1H), 7.95 (d, J= 7.4 Hz, 1H), 7.65 (d, J= 7.92 Hz, 1H), 7.53 (d, J= 3.08 Hz, 1H), 7.13 (t, J= 7.68 Hz, 1H), 6.63 (d, J= 3.08 Hz, 1H), 6.18 (s, 2H), 4.49 (q, J= 7.12 Hz, 2H), 4.37 (s, 3H), 1.43 (t, J= 7.16 Hz. 3H) ppm. 13C NMR (100 MHz, DMSO-d 6)) δ = 161.7, 152.4. 145.3, 136.1. 132.1, 131.7, 128.5, 127.5, 125.8. 124.2, 121.0. 116.8, 112.3. 103.1, 62.7, 47.1, 45.7, 14.0 ppm. LRMS (ES+) m/z [M + H]’ calcd for C18H17N2O2+ 293.13; Found 293.23.
(8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,l-fg][1,7]naphthyridin-10-yl)methanol (major) (8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,l-fg][1,7]naphthyridin-10- yl)methanol (minor)
[0269] To a 0 °C cooled mixture of 10-(ethoxycarbonyl)-8-methyl-7H-indolo[7,1- fg][1,7]naphthyridin-8-ium iodide (0.179 g, 0.426 mmol, 1.0 equiv) was added LiBH4 (4M in THF) (0.53 mL, 2. 130 mmol, 5.0 equiv) dropwise. The mixture was warmed to ambient temperature and stirred for 2 hours. 3 additional equivalent portions of LiBH4 were added every 2 hours thereafter, and then the solution w as subsequently stirred for 18 additional hours. The solution w as poured in to saturated NaHCO3(aq) (400 mL) and EtOAc (200 mL) with vigorous stirring, and the layers were separated. The aqueous layer was further extracted with EtOAc (3 x 100 mL). and the combined organic extracts were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue w as purified by column chromatography on silica gel (gradient elution: 4% MeOH in EtOAc to 8% MeOH in EtOAc) to afford (8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][l,7|naphthyridin- 10-yl)methanol (major) (0.041 g. 38%) and (8-methyl-7a,8,9,10-tetrahydro-7H- indolo[7,1-fg][1,7]naphthyridin-10-yl)methanol (minor) (0.031 g, 29%) as pale yellow solids.
[0270] 7a, 8, 9, 10-tetrahydro-7H-indolo[7, 1 -fg] [ 1 ,7]naphthy ridin-10-yl)methanol (maj or). 1H NMR (400 MHz. DMSO-d 6) δ = 7.41 (d, J= 7.8 Hz, 1H). 7.33 (d, J = 3.0 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 7.00 (t, J = 7.64 Hz. 1H), 6.40 (d. J = 3.0 Hz. 1H), 6.39 - 6.36 (m. 1H), 4.83 (dd, J= 5.36, 11.48 Hz, 1H), 4.78 - 4.70 (m, 1H), 3.59 (t, J= 11.24 Hz, 1H), 3.51 - 3.44 (m, 1H), 3.41 - 3.34 (m, 1H), 3.22 - 3.13 (m, 1H), 3.02 (dd, J= 5.2, 11.21 Hz, 1H), 2.75 - 2.64 (m, 1H), 2.46 (s, 3H). 2.15 (1. J= 10.76 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-rf6) 5 = 131.6, 130.9, 127.3, 125.9, 122.0, 119.9, 119.2, 119.1, 113.8, 100.5, 63.5, 60.4, 56.64,
47.4, 43.7, 38.9 ppm. LRMS (ES+) m/z [M + H]+ calcd for CI6HI9N2O+ 255. 15; Found 255.25.
[0271] (8-methyl-7a,8.9.10-tetrahydro-7H-indolo[7, 1 -fg [ 1 ,7]naphthyridin-l 0-yl)methanol (minor). 1H NMR (400 MHz. MeOD) δ = 7.39 (d, J = 7.88 Hz, 1H). 7.21 (d, J = 7.24 Hz 1H), 7.13 (d, J= 3.04 Hz, 1H), 6.98 (t, J= 7.64 Hz, 1H), 6.42 - 6.36 (m, 2H), 4.72 (dd, J =
5.4, 11.52 Hz, 1H), 3.76 - 3.59 (m, 3H), 3.28 - 3.20 (m, 1H), 3.07 - 3.01 (m, 1H), 2.68 - 2.61 (m, 1H), 2.50 (s, 3H), 2.48 - 2.40 (m, 1H) ppm. 13C NMR (100 MHz, MeOD) 3 = 134.5, 134.1. 127.8, 127.7. 121.2, 121.1, 120.6, 120.4, 115.2. 101.9, 65.4, 62.1, 55.7. 49.0. 44.2, 39.6 ppm. LRMS (ES+) m'z [M + H]+ calcd for Ci6Hi9N2O+ 255. 15; Found 255.25.
Chiral Separation of (8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,l- fg] [1,7]naphthyridin-10-yl)methanol (major)
[0272] Racemic (8-methyl-7a.8.9.10-tetrahydro-7H-indolo[7.1- g][1.7]naphthyridin-10- yl)methanol (major) was separated into its enantiomers by preparatory chiral SFC using an (Chiralpak-AD-H 25 cm x 3 cm; Isocratic method: 40% EtOH (0.1% diethylamine)/CO2; 100 bar, 85 mL/min; injection volume 1 mL, 4 mg/mL in EtOH).
[0273] (8-methyl-7a,8.9.10-tetrahydro-7H-indolo[7, 1 -fg} [ 1 ,7]naphthyridin-l 0-yl)methanol (Example 3A, First eluting peak): Analytical chiral SFC >99.9%ee. Rt = 2.76 min (Chiralpak-AD-H 25 cm x 0.46 cm; Isocratic method: 40% MeOH (0.1% diethylamine)/CO2;
100 bar, 3 mL/min). Tan solid; LC-MS: m/z = 255.2 [M+H]+
[0274] (8-methyl-7a,8.9.10-tetrahydro-7H-indolo[7,1-yg][1,7]naphthyridin-10-yl)methanol (Example 3B, Second eluting peak): Analytical chiral SFC >99.9%ee. Rt = 3.32 min (Chiralpak-AD-H 25 cm x 0.46 cm; Isocratic method: 40% MeOH (0.1% diethylamine)/CO2;
100 bar, 3 mL/min). Tan solid; LC-MS: m/z = 255.2 [M+H]+
Chiral Separation of (8-methyl-7a,8,9,10-tetrahydro-7/Z-indolo[7,l- fg] [1,7]naphthyridin-10-yl)methanol (minor)
[0275] Racemic (8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7, L/g][l,7]naphthyridin-10- yljmethanol (minor) was separated into its enantiomers by preparatory chiral SFC (Chiralpak-AD-H 25 cm x 3 cm; Isocratic method: 40% EtOH (0.1% diethylamine)/CO2; 100 bar, 85 mL/min; injection volume 1 mL. 1 mg/mL in MeOH).
[0276] (8-methyl-7a,8.9.10-tetrahydro-7/7-indolo[7, 1 -/g] [ 1 ,7]naphthyridin- 10-yl)methanol (Example 3C, First eluting peak): Analytical chiral SFC >99.9%ee. Rt = 2.50 min (Chiralpak-AD-H 25 cm x 0.46 cm; Isocratic method: 40% MeOH (0.1% diethylaminel/CCh: 100 bar, 3 mL/min). Yellow solid; LC-MS: m/z = 255.2 [M+H]+.
[0277] (8-methyl-7a,8,9, 10-tetrahydro-727-indolo[7, 1 -/g] [ 1 ,7]naphthyridin-l 0-yl)methanol (Example 3D, Second eluting peak): Analytical chiral SFC 98.2%ee. Rt = 3.05 min (Chiralpak-AD-H 25 cm x 0.46 cm; Isocratic method: 40% MeOH (0.1% diethylamine)/CO2;
100 bar, 3 mL/min). Yellow solid; LC-MS: m/z = 255.2 [M+H]+.
Example 13: 3-fluoro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo|7,l- fg][1,7] naphthyridine (3-(4-fluoro-1H-indol-7-yl)-l-niethyl-1,2,5,6-tetrahydropyridin-2-yl)methanol
[0278] Following General Procedure 2, (3-bromo-l -methyl- 1,2,5, 6-tetrahy dropyridin-2- yl)methanol (2.43 mmol) was used to prepare (3-(4-fluoro- 1H-indol-7-yl)-l -methyl- 1,2, 5,6- tetrahydropyri din-2 -yl)methanol (378 mg, 60 %) as a brown foam after purification by column chromatography on silica gel (Gradient: 90: 10: 1 to 85: 15: 1, DCM/MeOH/NH4OH). 1H NMR (400 MHz, CDC13) 8 = 9.21 (s, 1H), 7.14 (t, J= 2.8 Hz, 1H), 6.83 (dd, J= 8.0, 4.9 Hz, 1H), 6.73 (dd, J= 10.2, 8.0 Hz, 1H), 6.61 (dd, J= 3.2, 2.1 Hz, 1H), 6.01 (s, 1H), 3.60 (dd, J= 10.7. 3.0 Hz, 1H), 3.45 (s, 1H), 3.31 - 3.16 (m, 2H), 3.02 (dt, J= 11.9. 5.1 Hz, 1H), 2.69 (ddd, J= 12.1, 8.1, 4.4 Hz, 1H), 2.52 (s, 3H), 2.41 - 2.28 (m, 1H). 2.29 - 2.18 (m, 1H). 13C NMR (100 MHz, CDC13) δ = 155.65 (1JCF= 246.4 Hz), 137.55 (2JCF= 11.64 Hz), 134.75, 128.17, 124.47, 121.21 (3JCF= 7.53 Hz), 121.06 (4JCF= 4.11 Hz), 104.05 (5JCF= 19.48 Hz), 98.52, 66.30, 59.53, 49.02, 42.82, 23.99. LRMS (ES+) m/z [M + H]+ calcd for C15H18FN2O+ = 261.14; Found 261.23. 3-fluoro-8-methyl-7a,8,9,10-tetrahydro-7/7-indolo[7,1-fg][1,7]naphthyridine
[0279] Following General Procedure 3, (3-(4-fluoro-lH-indol-7-yl)-l -methyl- 1, 2,5,6- tetrahydropyri din-2 -yl)methanol (0.769 mmol) was used to prepare 3-fluoro-8-methyl- 7a.8.9. I O-tetrahydro-7/V-indolo|7. l -/g|| l .7|naphthyridine (94.7 mg, 51%) as a red/brown oil after purification by column chromatography on silica gel (Gradient: 100:0 to 95:5, EtOAc/MeOH). 1H NMR (400 MHz, CDCl3) δ = 7.14 (dd, J= 8.0. 4.3 Hz, 1H), 7.06 (d, J = 3.2 Hz. 1H), 6.73 (dd, J = 10.8, 8.0 Hz, 1H), 6.52 (d, J = 3.2 Hz, 1H), 6.40 (d, J = 6.2 Hz, 1H), 4.63 (dd, J= 11.3, 5.4 Hz, 1H), 3.80 (t, J= 11.1 Hz, 1H), 3.34 (d, J= 10.8 Hz, 1H), 3.05 - 2.93 (m, 1H), 2.70 - 2.59 (m, 2H), 2.56 (s, 3H), 2.32 - 2.15 (m, 1H). 13C NMR (100 MHz, CDC13) δ = 155.63 (1JCF= 248.8 Hz), 135.40 (2JCF= 12.54 Hz), 130.03, 126.35, 119.66 (3JCF = 1.91 Hz). 116.32 (4JCF= 3.73 Hz). 114.99 (5JCF= 7.46 Hz), 114.88 6JCF= 23.52 Hz), 105.17 71JJ = 19.44 Hz), 97.64 (2JCF = 1.46 HZ), 60.52, 52.77, 48.25, 44.26, 25.84. LRMS (ES+) m/z [M + H]+ calcd for CI5HI6FN2 + = 243.13; Found 243.34.
Chiral Separation of 3-fluoro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,l- fg] [1,7]naphthyridine.
[0280] Racemic 3-fluoro-8-niethyl-7a,8,9,10-tetrahydro-7H-indolo|7,l-
/ ][1,7]naphthyridine was separated into its enantiomers by preparatory7 chiral SFC (Chiralpak-IG 25 cm x 2 cm; Isocratic method: 25% MeOH (0.1% diethylamine)/CO2; 100 bar, 60 mL/min; injection volume 0.75 mL, 5 mg/mL in MeOH).
[0281] 3-fluoro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthyridine (Example 13A, First eluting peak): Analytical chiral SFC 99.8% ee. Rt = 3.16 min (Chiralpak-IG 25 cm x 0.46 cm; Isocratic method: 30% MeOH (0.1 % diethylamine)/CO2; 100 bar, 3 mL/min). Yellow solid; LC-MS: m/z = 243.1 [M+H]+.
[0282] 3-fluoro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][l,7]naphthyridine (Example 13B, Second eluting peak): Analytical chiral SFC 99.9 % ee. Rt = 4.7 min (Chiralpak-IG 25 cm x 0.46 cm; Isocratic method: 30% MeOH (0.1% diethylamine)/CO2; 100 bar, 3 mL/min). Yellow solid; LC-MS: m/z = 243.1 [M+H]+.
Example 14; 2-fluoro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,l- (3-(5-fliioro-lH-indol-7-yl)-l-methyl-l,2,5,6-tetrahydropyridin-2-yl)methanol
[0283] Following General Procedure 2, (3-bromo-l-methyl-l,2,5,6-tetrahydropyridin-2- yl)methanol (2.43 mmol) was used to prepare (3-(5-fluoro-l/f-indol-7-yl)-l-methyl-l,2,5,6- tetrahydropyri din-2 -yl)methanol (320 mg, 51 %) as a brown foam after purification by column chromatography on silica gel (Gradient: 90:10: 1 to 85: 15: 1, DCM/MeOH/NH4OH). 1H NMR (400 MHz, CDCl3) δ = 9.02 (s, 1H), 7.24 - 7. 15 (m, 2H), 6.72 (dd, J= 10.0, 2.4 Hz, 1H), 6.49 (dd, J= 3.2, 2.1 Hz, 1H), 6. 13 - 6.02 (m, 1H), 3.67 - 3.38 (m, 2H), 3.31 - 3.19 (m, 2H), 3.04 (dt, J= 12.1, 5.2 Hz, 1H), 2.70 (ddd, J= 12.1, 7.8, 4.6 Hz, 1H), 2.53 (s, 3H), 2.42 - 2.18 (m, 2H). 13C NMR (100 MHz, CDC13) δ = 157.67 (1JCF = 234.9 Hz), 134.48 (2JCF=
1.79 Hz), 131.50, 128.36, 128.20 (3JCF= 10.73 Hz), 126.20, 125.50 (4JCF= 9.11 Hz), 109.11 (5JCF= 26.57 Hz), 104.19 (6JCF = 23.03 Hz). 102.59 (,JCF= 5.76 Hz), 65.88, 59.62, 48.77, 42.79, 23.79. LRMS (ES+) m/z [M + H]+ calcd for CI5HI8FN2O+ = 261.14; Found 261.29.
2-fluoro-8-methyl-7a,8,9,10-tetrahydro-7/Z-indolo[7,1-fg][1,7]naphthyridine
[0284] Following General Procedure 3, (3-(5-fluoro-1H-indol-7-yl)-l-methyl-l,2,5,6- tetrahydropyri din-2 -yl)methanol (0.769 mmol) was used to prepare 2-fluoro-8-methyl- 7a,8,9,10-tetrahydro-7H-indolo[7.1T/^][l,7]naphthyridine (77.8 mg, 42%) as a red/brown oil after purification by column chromatography on silica gel (Gradient: 100:0 to 95:5, EtOAc/MeOH). 1H NMR (400 MHz, CDC13) δ = 7.16 - 7.07 (m, 2H), 6.98 (dd, J= 10.3, 2.2 Hz, 1H), 6.46 (d, J= 6.3 Hz, 1H), 6.42 (d, J= 3.0 Hz, 1H), 4.63 (dd, J= 11.2, 5.4 Hz, 1H),
3.79 (t, J= 11.1 Hz, 1H), 3.40 - 3.29 (m, 1H). 3.05 - 2.95 (m, 1H). 2.69 - 2.59 (m, 2H), 2.56 (s, 3H), 2.32 - 2. 18 (m, 1H). 13C NMR (100 MHz, CDC13) δ = 158.97 (1JCF= 233.4 Hz), 130.23 (2JCF = 2.49 Hz), 129.72, 127.70, 126.08 (3JCF= 10.58 Hz), 121.68, 120.43 (4JCF= 9.81 Hz), 104.33 (5JCF= 25.03 Hz), 102.80 (6 JCF= 27.71 Hz), 101.25 (7JCF= 5.26 Hz), 60.54, 52.67, 48.21. 44.21, 25.90. LRMS (ES+) m/z [M + H]+ calcd for C15H16FN2 + = 243.13;
Found 243.21.
Chiral Separation of 2-fluoro-8-methyI-7a,8,9,10-tetrahydro-7H-indolo[7,l- fg] [1,7]naphthyridine
[0285] Racemic 2-fluoro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,l- fg][1,7]naphthyridine was separated into its enantiomers by preparatory chiral SFC (Chiralpak-IG 25 cm x 2 cm; Isocratic method: 25% MeOH (0.1% diethylamine)/CO2: 100 bar, 60 mL/min; injection volume 0.75 mL, 5 mg/mL in methanol).
[0286] 2-fluoro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][l,7]naphthyridine
(Example 14A, First eluting peak): Analytical chiral SFC 99.9% ee. Rt = 3.31 min (Chiralpak-IG 25 cm x 0.46 cm; Isocratic method: 30% MeOH (0.1% diethylamine)/CO2;
100 bar, 3 mL/min). Yellow solid; LC-MS: m/z = 243.2 [M+H]+
[0287] 2-fluoro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][l,7]naphthyridine
(Example 14B, Second eluting peak): Analytical chiral SFC 99.9% ee. Rt = 4.98 min (Chiralpak-IG 25 cm x 0.46 cm; Isocratic method: 30% MeOH (0.1% diethylamine)/CO2;
100 bar, 3 mL/min). Yellow solid; LC-MS: m/z = 243.2 [M+H]+
Example 15: l-fluoro-8-methyl-7a,8,9,10-tetrahvdro-7H-indolo[7,l- fg] [ 1.71naphthyridine
(3-(6-fluoro-LH-indol-7-yl)-l-methyl-l,2,5,6-tetrahydropyridin-2-yl)methanol
[0288] Following General Procedure 2, (3-bromo-l-methyl-l,2,5,6-tetrahydropyridin-2- yljmethanol (2.43 mmol) was used to prepare (3-(6-fluoro-1 H-indol-7-yl)-l-methyl-l, 2,5,6- tetrahydropyri din-2 -yljmethanol (0.400 mg, 63%) as a light purple foam after purification by column chromatography on silica gel (Gradient: 90:10: 1 to 85: 15: 1, DCM/MeOH/NH-iOH). JH NMR (400 MHz, CDCl3) δ = 9.01 (s, 1H), 7.45 (dd, J= 8.6, 5.1 Hz, 1H), 7.17 (dd, J = 3.3, 2.3 Hz, 1H), 6.84 (dd, J= 10.3, 8.6 Hz, 1H), 6.49 (dd, J= 3.3, 2.1 Hz, 1H), 6.06 (dt. J = 5.6, 2.1 Hz, 1H), 3.65 (dd, J= 10.8, 2.9 Hz, 1H), 3.37 - 2.83 (m, 4H), 2.82 - 2.68 (m, 1H), 2.52 (s, 3H), 2.47 - 2.33 (m, 1H), 2.32 - 2.18 (m, 1H). 13C NMR (100 MHz, CDC13) δ = 155.99 (1JCF= 236.2 Hz), 135.95 (2JCF= 8.77 Hz), 130.29, 130.14, 125.06 (3JCF= 4.16 Hz), 124.21. 120. I 4 (4JCF. = 10.34 HZ), 111.13 (5JCF= 21.93 Hz). 108.30 6JCF= 25.23 Hz), 102.33, 65.53, 59.64. 49.67, 42.92. 24.80. LRMS (ES+) m/z [M + H]’ calcd for CI5HI8FN2O+ = 261.14; Found 261.23. l-fluoro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthyridine
[0289] Following General Procedure 3, (3-(6-fluoro-1H-indol-7-yl)-l-methyl-l,2,5,6- tetrahydropyri din-2 -yl)methanol (0.769 mmol) was used to prepare l-fluoro-8-methyl- 7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthyridine (400 mg, 84%) as ayellow oil after purification by column chromatography on silica gel (Gradient: 100:0 to 95:5, EtOAc/MeOH). 1H NMR (400 MHz, CDCl3) δ = 7.35 (dd, J= 8.6. 4.3 Hz, 1H), 7.05 (d, J = 3.0 Hz. 1H), 6.86 (dd, J = 12.1, 8.6 Hz, 1H), 6.76 (d, J = 5.8 Hz, 1H), 6.43 (d, J = 3.0 Hz, 1H), 4.59 (dd, J= 11.3, 5.2 Hz, 1H), 3.80 (t, J= 11.2 Hz, 1H), 3.35 - 3.24 (m, 1H), 3.03 - 2.93 (m, 1H), 2.40 - 2.26 (m, 1H). 13C NMR (100 MHz, CDC13) δ = 155.58 (1JCF= 243.2 Hz), 133.36 (2JCF = 9.56 Hz), 126.65 (3JCF= 3.85 Hz), 126.30 (4JCF= 11.31 Hz), 126.26 (5JCF = 11.64 Hz), 122.51. 199.50 (6JCF= 10.02 Hz), 109.62 (7JCF= 25.95 Hz). 106.42 (8JCF= 16. 12 Hz), 101.16, 60.25, 52.46, 48. 11, 44.35, 26. 14. LRMS (ES+) m/z [M + H]+ calcd for CI5HI6FN2 + = 243.13; Found 243.28.
Chiral Separation of l-fluoro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1- fg] [1,7]naphthyridine
[0290] Racemic l-fluoro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1- fg][1,7]naphthyridine was separated into its enantiomers by preparatory chiral SFC (Chiralpak-IG 25 cm x 2 cm; Isocratic method: 25% MeOH (0.1% diethylamine)/CO2; 100 bar, 60 mL/min; injection volume 0.75 mL, 5 mg/mL in MeOH).
[0291] l-fluoro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthyridine (Example 15A, First eluting peak): Analytical chiral SFC 99.9% ee. Rt = 3.05 min (Chiralpak-IG 25 cm x 0.46 cm; Isocratic method: 30% MeOH (0.1% diethylamine)/CO2; 100 bar, 3 mL/min). Yellow solid; LC-MS: m/z = 243.2 [M+H]+.
[0292] l-fluoro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][l,7]naphthyridine (Example 15B, Second eluting peak): Analytical chiral SFC 99.8% ee. Rt = 4.13 min (Chiralpak-IG 25 cm x 0.46 cm; Isocratic method: 30% MeOH (0.1% diethylamine)/CO2; 100 bar, 3 mL/min). Yellow solid; LC-MS: m/z = 243.2 [M+H]+. Example 16: 3-chloro-8-methyl-7a,8,9,10-tetrahvdro-7H-indolo[7,l-
(3-(4-chloro-lH-indol-7-yl)-l-methyl-l,2,5,6-tetrahydropyridin-2-yl)methanol
[0293] Following General Procedure 2, (3-bromo-l-methyl-l,2,5,6-tetrahydropyridin-2- yl)methanol (0.613 mmol) was used to prepare (3-(4-chloro-1H-indol-7-yl)-l-methyl-l, 2,5,6- tetrahydropyridin-2-yl)methanol (90 mg, 53%) as a brown foam after purification by column chromatography on silica gel (Gradient: 90: 10: 1 to 85: 15:1, DCM/MeOH/NFUOH). JH NMR (400 MHz, CDCl3) δ = 9.34 (s, 1H), 7.22 (t, J= 2.9 Hz, 1H), 7.06 (d, J= 7.8 Hz, 1H), 6.83 (d, J= 7.8 Hz, 1H), 6.68 - 6.55 (m, 1H), 6.03 (t, J = 4.6 Hz, 1H), 4.05 (s, 1H), 3.61 (d, J = 8.0 Hz, 1H), 3.33 - 3.19 (m, 2H), 3.14 - 2.99 (m, 1H), 2.74 (ddd, J= 12.1, 7.8, 4.6 Hz, 1H), 2.55 (s, 3H), 2.43 - 2.19 (m, 2H). 13C NMR (100 MHz, CDC13) δ = 135.62, 134.25, 128.33. 126.75, 125.28, 124.93, 123.38, 121.46. 119.11, 101.12, 66.01, 59.38, 48.96. 42.70, 23.86. LRMS (ES ) m z |M + H | calcd for CI5H18C1N2O = 277.1 1; Found 277.10.
3-chloro-8-methyl-7a,8,9,10-tetrahydro-H7-indolo[7,1-fg][1,7]naphthyridine
[0294] Following General Procedure 3, (3-(4-chloro-1H-indol-7-yl)-l-methyl-l, 2,5,6- tetrahydropyri din-2 -yl)methanol (0.73 mmol) was used to prepare 3-chloro-8-methyl- 7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][l,7]naphthyridine (0.106 g. 56%) as a brown semi- solid after purification by column chromatography on silica gel (EtOAc). 1H NMR (400 MHz, CDCl3) δ = 7.13 (d, J= 7.8 Hz, 1H), 7.09 (d, J= 3.08 Hz, 1H), 7.06 (d, J= 7.84 Hz, 1H), 6.54 (d, J= 3.04 Hz, 1H), 6.46 - 6.41 (m, 1H), 4.61 (dd, J = 11.6, 5.36 Hz, 1H), 3.78 (t, J= 11.12 Hz, 1H), 3.33 - 3.25 (m. 1H), 3.00 - 2.92 (m, 1H), 2.68 - 2.50 (m, 5H), 2.28 - 2.18 (m. 1H) ppm. 13C NMR (100 MHz. CDC13) δ = 133.6. 130.0, 127.0. 125.0, 124.4. 120.8, 120.1, 118.8, 115.2, 100.0. 60.4, 52.7, 48.4, 44.3, 26.0 ppm. LRMS (ES+) m/z [M + H]+ calcd for C15H16ClN2 + = 259. 10; Found 259. 15.
Chiral Separation of 3-chloro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,l- fg] [1,7]naphthyridine
[0295] Racemic 3-chloro-8-methyl-7a, 8,9,10-tetrahyd ro-7H-indolo [7,1- fg][1,7]naphthyridine was separated into its enantiomers by preparatory chiral SFC (Chiralpak-IG 25 cm x 2 cm; Isocratic method: 30% MeOH (0.1% diethylamine)/CO2; 100 bar, 60 mL/min; injection volume 0.75 mL, 6 mg/mL in MeOH).
[0296] 3-chloro-8-methyl-7 a, 8, 9, 10-tetrahy dro-7H-indolo| 7.1 -fg] [ 1 ,7]naphthyridine (Example 16A. First eluting peak): Analytical chiral SFC 99.9% ee. Rt = 5.0 min (Chiralpak- IG 25 cm x 0.46 cm; Isocratic method: 30% MeOH (0.1% diethylamine)/CO2; 100 bar, 3 mL/min). Yellow solid; LC-MS: m/z = 259.1 [M+H]+
[0297] 3-chloro-8-methyl-7 a, 8, 9, 10-tetrahy dro-7H-indolo| 7.1 -fg] [ 1 ,7]naphthyridine (Example 16B, Second eluting peak): Analytical chiral SFC 99.9% ee. Rt = 7.6 min (Chiralpak-IG 25 cm x 0.46 cm; Isocratic method: 30% MeOH (0.1% diethylamine)/CO2;
100 bar, 3 mL/min). Yellow solid; LC-MS: m/z = 259.1 [M+H]+.
Example 17: 2-chloro-8-methyl-7a,8,9,10-tetrahydro-7/Z-indolo[7,l- fg] [ l,7]naphthyridine
(3-(5-chloro-1H-indol-7-yl)-l-methyl-l,2,5,6-tetrahydropyridin-2-yl)methanol
[0298] Following General Procedure 2, (3-bromo-l -methyl- 1,2,5, 6-tetrahy dropyridin-2- yl)methanol (1.02 mmol) was used to prepare (3-(5-chloro-1H-indol-7-yl)-l-methyl-l,2,5,6- tetrahydropyri din-2 -yl)methanol (165 mg. 58%) as a brown foam after purification by column chromatography on silica gel (Gradient: 90: 10: 1 to 85: 15: 1, DCM/MeOH/NH4OH). 1H NMR (400 MHz, CDC13) 8 = 9.13 (s, 1H), 7.51 (d, J= 1.9 Hz, 1H), 7.18 (s, 1H), 6.91 (d, J= 1.9 Hz, 1H), 6.47 (s, 1H), 6.05 (s, 1H), 3.67 - 3.57 (m, 1H), 3.46 (s, 1H), 3.28 - 3.16 (m, 2H), 3.08 - 2.97 (m, 1H), 2.69 (ddd, J= 12.1, 8.2. 4.4 Hz, 1H), 2.52 (s, 3H), 2.40 - 2.30 (m, 1H), 2.29 - 2.15 (m, 1H). 13C NMR (100 MHz. CDC13) δ = 134.41, 133.50, 129.01. 128.64, 125.93, 124.98, 121.00, 118.89, 102.16, 66.05, 59.51, 49.07, 42.84, 24.01. LRMS (ES+) m/z [M + H]+ calcd for C15H18C1N2O+ = 277. 11; Found 277.35.
2-chloro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthyridine
[0299] Following General Procedure 3, (3-(5-chloro-1H-indol-7-yl)-l-methyl-l, 2,5,6- tetrahydropyridin-2-yl)methanol (0.397 mmol) was used to prepare 2-chloro-8-methyl- 7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][l,7]naphthyridine (0.068 g, 66%) as a brown oil after purification by column chromatography on silica gel (EtOAc). 1 H NMR (400 MHz, CDCl3) 5 = 7.44 (d, J= 1.4 Hz, 1H), 7.20 (d, J = 1.28 Hz, 1H), 7.09 (d, J= 3.0 Hz, 1H), 6.49 - 6.44 (m. 1H), 6.40 (d. J = 3.0 Hz. 1H), 4.61 (dd, J= 11.6, 5.36 Hz, 1H), 3.78 (d, J= 11.12 Hz, 1H), 3.36 - 3.28 (m, 1H), 3.02 - 2.94 (m, 1H), 2.69 - 2.53 (m, 5H), 2.29 - 2.20 (m, 1H) ppm. 13C NMR (100 MHz, CDC13) δ = 131.5, 130.0, 127.6, 127.1, 126.2, 121.8, 120.9, 118.8, 114.8, 101.0, 60.5, 52.7, 48.3, 44.3, 26.0 ppm. LRMS (ES+) m/z [M + H]+ calcd for C15H16C1N2+ = 259. 10: Found 259.22.
Chiral Separation of 2-chloro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,l- fg} [1,7]naphthyridine
[0300] Racemic 2-chloro-8-methyl-7a, 8, 9,10-tetrahy dro-7H-indolo [7,1- fg][1,7]naphthyridine was separated into its enantiomers by preparatory chiral SFC (Chiralpak-IG 25 cm x 2 cm; Isocratic method: 32% MeOH (0.1% diethylamine)/CO2: 100 bar, 60 mL/min; injection volume 0.75 mL, 6 mg/rnL in MeOH).
[0301] 2-chloro-8-methyl-7 a, 8, 9, 10-tetrahy dro-7H-indolo| 7.1 -fg] [ 1 ,7]naphthyridine (Example 17A. First eluting peak): Analytical chiral SFC 99.9% ee. Rt = 5.6 min (Chiralpak- IG 25 cm x 0.46 cm; Isocratic method: 30% MeOH (0.1% diethylamine)/CO2; 100 bar, 3 mL/min). Yellow solid; LC-MS: m/z = 259.1 [M+H]+.
[0302] 2-chloro-8-methyl-7 a, 8, 9, 10-tetrahy dro-7H-indolo| 7.1 - fg] [ 1 ,7]naphthyridine (Example 17B, Second eluting peak): Analytical chiral SFC 99.8% ee. Rt = 7.8 min (Chiralpak-IG 25 cm x 0.46 cm; Isocratic method: 30% MeOH (0.1% diethylamine)/CO2; 100 bar, 3 mL/min). Yellow solid; LC-MS: m/z = 259.1 [M+H]+. Example 18: l-chloro-8-methyl-7a,8,9,10-tetrahvdro-7H-indolo[7,l-
(3-(6-chloro-lH-indol-7-yl)-l-methyl-l,2,5,6-tetrahydropyridin-2-yl)methanol
[0303] Following General Procedure 2, (3-bromo-l-methyl-l,2,5,6-tetrahydropyridin-2- yl)methanol (1.46 mmol) was used to prepare (3-(6-chloro-17f-indol-7-yl)-l-methyl-1.2.5.6- tetrahydropyridin-2-yl)methanol (270 mg, 67%) as a brown foam after purification by column chromatography on silica gel (Gradient: 90:10: 1 to 85: 15: 1, DCM/MeOH/NF OH). 1H NMR (400 MHz, CDCl3) δ = 9.33 (s, 1H), 7.47 (d, J= 8.4 Hz, 1H), 7.18 (t, J= 2.8 Hz, 1H), 7.10 (d, J= 8.4 Hz, 1H), 6.55 - 6.46 (m, 1H), 5.98 (d, J = 6.2 Hz, 1H), 3.66 (dd, J = 11.2, 3.2 Hz, 2H), 3.32 (s, 1H), 3.16 (d, J= 11.2 Hz, 1H), 3.01 (d, J= 3.0 Hz, 1H), 2.79 (dt, J = 10.8, 5.4 Hz, 1H), 2.62 - 2.34 (m, 4H), 2.24 (d, J= 17.3 Hz, 1H). 13C NMR (100 MHz, CDC13) δ = 136.85, 133.45, 130.29, 126.42, 125.99, 125.49, 122.65, 120.74, 120.43, 102.30, 65.18, 59.33. 50.36, 42.99. 25.33. LRMS (ES+) m/z [M + H | calcd for Ci5Hi8ClN2O+ = 277.1 1; Found 277.35. l-chloro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo[7,1-fg][1,7]naphthyridine
[0304] Following General Procedure 3, (3-(6-chloro-1H-indol-7-yl)-l-methyl-l,2,5,6- tetrahydropyri din-2 -yl)methanol (0.485 mmol) was used to prepare l-chloro-8-methyl- 7a.8.9.10-tetrahvdro-7H-indolo|7. l -/g|| l .7|naphthyridine (0.091 g. 73%) as a brown oil after purification by column chromatography on silica gel (EtOAc). 1 H NMR (400 MHz, CDCl3) 5 = 7.34 (d, J= 8.4 Hz, 1H), 7.12 - 7.08 (m, 1H), 7.07 (d, J= 8.4 Hz, 1H), 7.05 (d, J= 3.04 Hz, 1H), 6.43 (d, J= 3.04 Hz, 1H), 4.57 (dd, J= 11.4, 5.2 Hz, 1H), 3.87 (t, J = 11. 12 Hz, 1H), 3.37 - 3.28 (m, 1H), 2.98 - 2.91 (m, 1H), 2.66 (td. J= 10.4, 3.84 Hz, 1H), 2.61 - 2.49 (m, 4H), 2.46 - 2.36 (m, 1H) ppm. 13C NMR (100 MHz, CDCH) δ = 133.9, 128.3, 127.6, 126.7, 124.9, 123.2, 122.9, 119.9, 117.3, 101.2, 59.9, 51.2, 48.9, 44.5, 26.1 ppm. LRMS (ES+) m/z [M + H]+ calcd for CI5HI6C1N2+ = 259. 10; Found 259.28. Chiral Separation of l-chloro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo [7,1- fg][1,7]naphthyridine
[0305] Racemic l-chloro-8-methyl-7a,8,9,10-tetrahydro-7H-indolo [7,1- fg][1,7]naphthyridine was separated into its enantiomers by preparatory chiral SFC (Chiralpak-IG 25 cm x 2 cm; Isocratic method: 30% MeOH (0.1% diethylamine)/CO2; 100 bar, 60 mL/min; injection volume 0.75 mL, 5 mg/mL in MeOH).
[0306] 1 -chloro-8-methy 1-7 a, 8, 9, 10-tetrahy dro-7H-indolo| 7.1 -fg] [ 1 ,7]naphthyridine
(Example 18A, First eluting peak): Analytical chiral SFC >99.9% ee. Rt = 3.9 min (Chiralpak-IG 25 cm x 0.46 cm; Isocratic method: 30% MeOH (0.1% diethylamine)/CO2;
100 bar, 3 mL/min). Yellow solid; LC-MS: m/z = 259.1 [M+H]+.
[0307] 1 -chloro-8-methyl-7 a, 8, 9, 10-tetrahy dro-7H-indolo| 7.1 -fg] [ 1 ,7]naphthyridine
(Example 18B, Second eluting peak): Analytical chiral SFC >99.9% ee. Rt = 5.7 min (Chiralpak-IG 25 cm x 0.46 cm; Isocratic method: 30% MeOH (0.1% diethylamine)/CO2;
100 bar, 3 mL/min). Yellow solid; LC-MS: m/z = 259.1 [M+H]+.
Example 19: Synthesis of 6a ((7aS,10R)-5,8,10-triniethyl-7a,8,9,10-tetrahvdro-7H- indoloH.l-fg] [1,7]naphthyridine):
[0308] Using Alternate General procedure 3, Int-5a (250 mg, 0.924 mmol. 1.00 eq) was converted to 6a and this was purified by column chromatography to afford 80 mg (34%) of the title compound as a pale-yellow semi solid. ESI-MS m/z: 253.2 [M+H]+.
Example 20: Synthesis of 7a & 8a: [0309] 80 mg of racemic 6a was purified by Chiral Pak AD-H (20mmX250 mm
,5p), Mobile Phase-A: 0.1% Isopropyle Amine in n-Hexane, Mobile Phase-B: ETOH, Mobile Phase-A: B- 90: 10, Flow: 20 mL/min, The faster eluting peak was assigned as 7a, and the more slowly eluting peak was assigned as 8a.
[0310] 7a: 15 mg, = 7.31 - 7.26 (m, 1H), 7.15 (d, J= 7.3 Hz, 1H), 6.96 - 6.92 (m, 1H), 6.29 (s, 1H). 6.13 (d, J = 0.9 Hz. 1H), 4.72 (dd, J = 5.5. 11.1 Hz, 1H), 3.50 (t, J= 11. 1 Hz. 1H), 3.29 - 3.24 (m, 1H), 3.08 - 3.02 (m, 1H), 2.75 (m, J= 3.5, 5.4, 7.0, 8.8 Hz, 1H), 2.59 (s, 3H), 2.43 (d, J= 0.9 Hz, 3H), 2.21 (t, J= 10.9 Hz, 1H), 1.09 (d, J= 7.0 Hz, 3H) ppm.
[0311] 8a: 16 mg. ESI-MS m/z: 253.2 [M+H]+; ’H NMR (400 MHz, DMSO-ti6) δ = 7.27 (d, J= 7.6 Hz, 1H), 7.12 (d, J = 7.1 Hz, 1H), 6.94 - 6.90 (m, 1H). 6.25 (s. 1H), 6.14 (d. J = 0.8 Hz, 1H), 4.72 - 4.68 (m, 1H), 3.45 - 3.40 (m, 1H), 3.17 - 3.11 (m, 1H), 2.97 - 2.93 (m, 1H), 2.68 - 2.62 (m, 1H), 2.52 - 2.51 (m, 3H), 2.43 - 2.40 (m, 3H), 2.09 - 2.04 (m, 1H), 1.01 (d, J = 7.0 Hz, 3H) ppm.
Example 21: Synthesis of 6b ((7aS,10R)-3-chloro-2-fluoro-8,10-dimethyl-7a.,8.,9,10- tetrahvdro-7H-indolo[7J-fgl[1.71naphthyridine): lnt-5b 6b
[0312] Using Alternate General procedure 3, Int-5b (120 mg, 0.389 mmol, 1.00 eq) was converted to 6b and this was purified by column chromatography to afford 28 mg (25%) of the title compound as a pale-yellow gummy solid. ESI-MS m/z: 291.0 [M+H]+.
Example 22: Synthesis of 7b & 8b:
6b 7b 8b [0313] 25 mg of Racemic 6b was purified Column AD-H (20 X250*mm,5pm) Mobile phase A hexane Mobile phase B EtOH Eluent A: B:90: 10 Total Flow rate (mL/min) 20 ml/min was assigned as 7b, and the more slowly eluting peak was assigned as 8b.
[0314] 7b: 4 mg, ESI-MS m/z: 291.3 [M+H]+; 1H NMR (400 MHz, DMSO-d 6) 3 = 7.52 (d, J= 3.0 Hz, 1H), 7.31 (d, J= 10.8 Hz, 1H), 6.47 (d, J= 3.0 Hz, 1H), 6.44 (s, 1H), 4.87 (dd, J = 5.4, 11.8 Hz, 1H), 3.59 (t, J= 11.3 Hz, 1H), 3.19 - 3.15 (m, 1H), 2.96 (dd, J= 5.4, 11.2 Hz, 1H), 2.46 - 2.44 (m, 3H), 2.39 - 2.39 (m, 1H). 2.07 (t. J = 10.6 Hz, 1H), 1.01 (d, J= 1A Hz, 3H)
[0315] 8b: 4 mg, ESI-MS m/z: 291.3 [M+H]+; 1H NMR (400 MHz, DMSO-rfe) 3 = 7.52 (d, .7= 3.1 Hz, 1H), 7.31 (d, J= 10.8 Hz, 1H), 6.48 - 6.44 (m, 2H), 4.87 (dd, J= 5.4. 11.8 Hz, 1H), 3.59 (t, J= 11.3 Hz, 1H). 3.20 - 3. 13 (m. 2H), 2.96 (br dd. J= 5.3. 10.4 Hz. 1H), 2.46 - 2.45 (m, 3H), 2.11 - 2.04 (m, 1H), 1.02 (d, J = 7 A Hz, 3H) ppm.
Example 23: Synthesis of 6c ((7aS,10R)-2-chloro-3-fluoro-8,10-dimethyl-7a,8,9,10- tetrahydro-7H-indolo[7,l-fg][1,7]naphthyridine):
[0316] Using Alternate General procedure 3, Int-5c (130 mg, 0.422 mmol, 1.00 eq) was converted to 6c and this was purified by column chromatography to afford 30 mg (25%) of the title compound as a pale-yellow gummy solid. ESI-MS m/z: 291.0 [M+H]+.
Example 24: Synthesis of 7c & 8c:
6c 7c 8c
[0317] 30 mg of racemic 6c was purified by Column IG (10 X250*mm,5pm) Mobile phase A 0.1% IP Amin in n-HEXANE Mobile phase B ETOH Eluent A: B:99:01 Total Flow rate (mL/min) 8 ml/min The faster eluting peak was assigned as 7c. and the more slowly eluting peak was assigned as 8c.
[0318] 7c: 7 mg, ESI-MS m/z: 291.3 [M+H]+; 1H NMR (400 MHz, DMSO-d 6) δ = 7.47 - 7.46 (m, 1H), 7.33 (s, 1H), 6.51 (d, J= 3.0 Hz, 1H), 6.39 (s, 1H), 4.87 (br d, J= 6.5 Hz, 1H), 3.59 (s, 1H), 3.15 - 3.12 (m, 1H), 2.95 (br d, J= 5.8 Hz, 1H), 2.63 (br d, J= 3.6 Hz, 1H), 2.44 (s, 3H). 2.06 (s, 1H), 1.02 (s. 3H) ppm.
[0319] 8c: 7 mg, ESI-MS m/z: 291.3 [M+H]+; 1H NMR (400 MHz, DMSO-d 6) δ = 7.46 (d.
J= 3.0 Hz, 1H), 7.34 (br d, J= 6.1 Hz, 1H), 6.52 (d, J= 3.0 Hz, 1H), 6.39 (br s, 1H), 4.87 (br dd, J= 5.3, 11.6 Hz, 1H), 3.59 (br t, J= 11.4 Hz, 1H), 3.20 - 3.11 (m, 1H), 2.95 (br dd, J = 5.3, 10.6 Hz, 1H), 2.65 - 2.57 (m, 1H), 2.46 - 2.42 (m, 3H), 2.06 (br t, J= 10.5 Hz, 1H), 1.01 (d, J = 7.0 Hz, 3H) ppm.
Example 25: Synthesis of 6d ((7aS J0R)-2.3-difluoro-8J0-dimethyl-7a,8,9,10- tetrahydro-7H-indo lo[7,l-fg] [1,7]naphthyridine):
[0320] Using Alternate General procedure 3, Int-5d (130 mg, 0.445 mmol, 1.00 eq) was converted to 6d and this was purified by column chromatography to afford 20 mg (14%) of the title compound as a pale-yellow gummy solid. ESI-MS m/z: 275.36 [M+H]+.
Example 26: Synthesis of 7d & 8d:
[0321] 20 mg of racemic 6d was purified by Column IG (10 X250*mm,5pm) Mobile phase A n-hexane Mobile phase B MEOH:ETOH(1 : 1) Eluent A: B:90-10 Total Flow rate (mL/min) 5 ml/min The faster eluting peak was assigned as 7d, and the more slowly eluting peak was assigned as 8d.
[0322] 7d: 8 mg, ESI-MS m/z: 274.9 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-J6) 5 = 7.11 - 7.04 (m, 2H), 6.53 (d, J= 3.0 Hz, 1H), 6.18 (s, 1H), 4.62 (dd, J = 5.3, 11.3 Hz, 1H), 3.75 (t, J= 11.1 Hz, 1H), 3.28 - 3.22 (m, 1H), 2.98 (dd, J = 52, 11.1 Hz, 1H), 2.79 - 2.70 (m, 1H), 2.54 (s, 3H), 2.17 (t, J = 10.7 Hz. 1H), 1.07 (d. J = 7.1 Hz. 3H) ppm.
[0323] 8d: 8 mg, ESI-MS m/z: 274.9 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) 6 = 7.13 - 7.05 (m, 2H), 6.56 - 6.51 (m, 1H), 6.18 (s, 1H), 4.62 (dd, J= 5.3, 11.3 Hz, 1H), 3.75 (t, J = 11.2 Hz, 1H), 3.28 - 3.22 (m, 1H), 2.99 (dd, J = 5.2, 11.1 Hz, 1H), 2.74 (br d, J= 3.1 Hz, 1H), 2.54 (s, 3H), 2.18 (t, J = 10.7 Hz, 1H), 1.07 (d, J = 7.1 Hz, 3H) ppm.
Example 27: Synthesis of 6e (Synthesis of (7aS J0R)-3,8,10-trimethyl-7a.8.,9.,10- tetrahvdro-7H-indolo[7J-fgl[1.7]naphthyridine): lnt-5e 6e
[0324] Using Alternate General procedure 3, Int-5e (250 mg. 0.925 mmol. 1.00 eq) was converted to 6e and this was purified by column chromatography to afford 70 mg (30%) of the title compound as a pale-yellow semi solid. ESI-MS m/z: 252.4 [M+H]+.
Example 28: Synthesis of 7e & 8e:
[0325] 70 mg of racemic Int-6e was purified by Column Cellulose-3 (20 X250*mm,5pm) Mobile phase A n-HEXANE Mobile phase B ETOH-MEOH (1-1) Eluent A: B: 50-50 Total Flow rate (mL/min) 20 ml/min. The faster eluting peak was assigned as 7e. and the more slowly eluting peak was assigned as 8e. [0326] 7e: 17.3 mg, ESI-MS m/z: 253.2 [M+H]+; 1H NMR (400 MHz, METHANOL-^) <>' = 7.18 - 7.13 (m. 2H), 6.83 - 6.78 (m, 1H), 6.43 (d, J= 3.1 Hz, 1H), 6.26 (s, 1H). 4.81 - 4.77 (m, 1H), 3.67 (t, J= 11.3 Hz, 1H), 3.29 - 3.24 (m, 1H), 3.09 - 3.01 (m, 1H), 2.79 - 2.70 (m, 1H), 2.57 (s, 3H), 2.48 (s, 3H), 2.19 (t, J= 10.9 Hz, 1H), 1.08 (d, J= 7.0 Hz, 3H) ppm.
[0327] 8e: 17. 1 mg, ESI-MS m/z: 253.3 [M+H]+; JH NMR (400 MHz, METH ANOL-t/4) d = 7.19 - 7.13 (m, 2H), 6.83 - 6.76 (m, 1H), 6.43 (d, J= 3.1 Hz, 1H), 6.26 (s, 1H). 4.83 - 4.78 (m. 1H), 3.67 (t, J = 11.3 Hz, 1H). 3.29 - 3.22 (m. 1H), 3.04 (dd, J = 5.1. 11.0 Hz, 1H), 2.79 - 2.71 (m, 1H), 2.57 (s, 3H), 2.48 (s, 3H), 2.19 (t, J = 10.9 Hz, 1H), 1.08 (d, J= 1A Hz, 3H) ppm.
Example 29: Synthesis of 6f ((7aS,10R)-2,8,10-trimethyl-7a,8,9,10-tetrahydro-7H- indolo[7,l-fg] H, 7]nanhthyridine):
[0328] Using Alternate General procedure 3, Int-5f (100 mg. 0.370 mmol. 1.00 eq) was converted to 6f and this was purified by column chromatography to afford 30 mg (32%) of the title compound as a pale-yellow semi solid. ESI-MS m/z: 252.4 [M+H]+.
Example 30: Synthesis of 7f and 8f;
[0329] 30 mg of racemic 6f was purified by Column: Chiral Pak-IG (30mmX250 mm, 5p), Mobile Phase-A: n-Hexane. Mobile Phase-B: ETOH: MeOH (1: 1), Mobile Phase-A: B- 80:20, Flow: 42 mL/min. The faster eluting peak was assigned as 7f, and the more slowly eluting peak was assigned as 8f.
[0330] 7f: 8.5 mg, ESI-MS m/z 253.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ = 7.27 - 7.25 (m, 1H), 7.19 (s, 1H). 7.05 (s, 1H), 6.29 (d, J= 3.0 Hz, 1H), 6.27 (s, 1H), 4.79 (dd, J = 5.4, 11.5 Hz. 1H), 3.55 (t, J = 11.3 Hz, 1H). 3.19 - 3.11 (m. 1H), 2.95 (dd, J = 5.1. 11.0 Hz, 1H), 2.65 - 2.60 (m, 1H), 2.44 (s, 3H), 2.38 (s, 3H), 2.05 (t, J = 10.6 Hz, 1H), 1.01 (d, J= 1A Hz. 3H) ppm.
[0331] 8f: 4 mg, ESI-MS m/z =253.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 3 = 7.26 (d, J= 3.0 Hz, 1H), 7.19 (s, 1H), 7.05 (s, 1H), 6.29 (d, J= 2.9 Hz, 1H), 6.28 - 6.25 (m, 1H), 4.79 (dd, J= 5.4, 11.5 Hz, 1H), 3.55 (t, J= 11.3 Hz, 1H), 3.20 - 3.10 (m, 1H), 2.95 (br dd, J = 5.1, 11.0 Hz, 1H), 2.65 - 2.58 (m, 1H), 2.44 (s, 3H), 2.38 (s, 3H), 2.05 (br t, J= 10.6 Hz, 1H), 1.01 (d, J= 7.1 Hz, 3H) ppm.
Example 31: Synthesis of 6g ((7aS,10R)-3-methoxy-8,10-dimethyl-7a.,8,9,10-tetrahvdro- 7H-indolo [7,l-fg][1,7]naphthyridine):
[0332] Using Alternate General procedure 3, Int-5g (200 mg, 0.699 mmol, 1.00 eq) was converted to 6g and this was purified by column chromatography to afford 50 mg (26%) of the title compound as a pale-yellow semi solid. ESI-MS m/z: 269.58 [M+H]+.
Example 32: Synthesis of 7g & 8g:
[0333] 50 mg of racemic 6g was purified by Column IG (30 X250*mm, 5pm) Mobile phase A n-HEXANE Mobile phase B ETOH-MEOH Eluent A: B: 60:40 Total Flow rate (mL/min) 42 ml/min. The faster eluting peak was assigned as 7g, and the more slowly eluting peak was assigned as 8g.
[0334] 7g: 15 mg, ESI-MS m/z: 269.3 [M+H]+; 1H NMR (400 MHz. DMSO-d 6) 3 = 7.21 (d, J= 3.0 Hz, 1H), 7.14 (d, J= 8.0 Hz, 1H), 6.50 (d, J= 8.0 Hz, 1H), 6.39 (d, J= 3.0 Hz, 1H), 6.14 (s, 1H), 4.79 (dd, J = 5.3, 11.6 Hz, 1H), 3.86 (s, 3H), 3.55 (t, J = 11.3 Hz, 1H), 3.14 - 3.08 (m, 1H), 2.93 (dd, J= 4.9. 11.1 Hz, 1H), 2.65 - 2.58 (m, 1H), 2.44 (s, 3H), 2.04 (t, J = 10.6 Hz, 1H), 1.00 (d, J= TA Hz, 3H) ppm.
[0335] 8g: 18 mg, ESI-MS m/z: 269.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6 ) δ = 7.21 (d, J= 3.0 Hz, 1H), 7.14 (d, J= 8.0 Hz, 1H), 6.50 (d, J= 8.0 Hz, 1H), 6.39 (d, J= 3.0 Hz, 1H), 6.14 (s, 1H), 4.79 (dd, J= 5.4, 11.7 Hz, 1H), 3.86 (s, 3H), 3.55 (t, J= 11.3 Hz, 1H), 3.14 - 3.09 (m, 1H), 2.93 (dd, J= 4.8. 10.8 Hz, 1H), 2.54 - 2.53 (m, 1H), 2.45 - 2.44 (m, 3H), 2.04 (t, J = 10.6 Hz. 1H), 1.00 (d. J = 7.1 Hz. 3H) ppm.
Example 33: Synthesis of 6h ((7aS,10R)-2-methoxy-8,10-dimethyl-7a,8,9,10-tetrahvdro- 7H-indol o [7,l-fg][1,7]naphthyridine):
[0336] Using Alternate General procedure 3, 5h (180 mg, 0.629 mmol. 1.00 eq) was converted to Int-6h and this was purified by column chromatography to afford 55 mg (33%) of the title compound as a pale-yellow semi solid. ESI-MS m/z: 269.58 [M+H]+.
34: Synthesis of 7h & 8h:
[0337] 55 mg of racemic 6h was purified by Column IG (30 X250*mm,5pm) Mobile phase A 0.1 % of IPamine in n-HEXANE Mobile phase B ETOH-MEOH (1-1) Eluent A: B: 80:20 Total Flow rate (mL/min) 42 ml/min. The faster eluting peak was assigned as 7h, and the more slowly eluting peak was assigned as 8h.
[0338] 7h: 8 mg, ESI-MS m/z: 269.6 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ = 7.30 - 7.25 (m, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.87 (d, J= 2.0 Hz, 1H), 6.30 (d, J= 3.0 Hz, 2H), 4.78 (dd, J = 5.3, 11.6 Hz, 1H), 3.77 - 3.74 (m, 3H), 3.54 (t, J= 11.3 Hz, 1H), 3.17 - 3.11 (m, 1H), 2.95 (dd, J = 5.3, 11.0 Hz, 1H), 2.65 - 2.58 (m, 1H). 2.44 (s, 3H), 2.05 (t, J= 10.6 Hz, 1H), 1.01 (d, J= 7.1 Hz, 3H) ppm.
[0339] 8h: 8 mg, ESI-MS m/z: 269.2 [M+H]+; 1H NMR (400 MHz, DMSO-rf6) δ = 7.27 (d, J= 3.0 Hz, 1H), 6.94 (d, J= 2.0 Hz, 1H), 6.87 (d, J= 2.0 Hz, 1H), 6.30 (br d, J= 2.9 Hz, 2H), 4.78 (dd, J = 5.3, 11.4 Hz, 1H), 3.76 (s, 3H), 3.54 (t, J= 11.3 Hz, 1H), 3.17 - 3.12 (m, 1H), 2.95 (dd, J= 5.3, 10.6 Hz, 1H). 2.65 - 2.60 (m. 1H), 2.45 - 2.44 (m, 3H), 2.05 (1, J = 10.6 Hz, 1H), 1.01 (d, J = 7.1 Hz, 3H) ppm.
Example 35: Synthesis of 6i (7aS,10R)-4-fluoro-8,10-dimethyl-7a.,8,9,10-tetrahvdro-7H- indolo[7,l-fg][1,7]naphthyridine:
[0340] Using Alternate General procedure 3, Int-5i (250 mg, 0.912 mmol, 1.00 eq) was converted to 6i and this was purified by column chromatography to afford 70 mg (30%) of the title compound as a pale-yellow semi solid. ESI-MS m/z: 257.32 [M+H]+.
Example 36: Synthesis of 7i & 8i:
[0341] 70 mg of racemic 6i Column AD-H (20X250mm, 5 pm) MP(A)C02 86.0 g/min MP(B)Co-Solvent 14.0 ml/ min (AMM IN ACN:IPA) (1 : 1) Total Flow rate (mL/min) 70g- 20%-100 bar. The faster eluting peak was assigned as 7i, and the more slowly eluting peak was assigned as 8i.
[0342] 7i: 12.3 mg, ESI-MS m/z: 257.3 [M+H]+; 1H NMR (400 MHz, DMSO-d 6) S = 7.39 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 2.9 Hz, 1H), 7.28 (d, J = 7.3 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.33 (s, 1H), 4.69 (dd, J= 5.4, 11.5 Hz, 1H). 3.53 (t. J= 11.1 Hz, 1H), 3.21 - 3.15 (m, 1H), 2.95 (dd, J= 5.3, 11.1 Hz, 1H). 2.65 - 2.60 (m. 1H), 2.45 - 2.42 (m, 3H), 2.07 (t, J= 10.6 Hz, 1H), 1.01 (d, J= 1A Hz, 3H) ppm.
[0343] 8i: 9.9 mg, ESI-MS m/z: 257.3 [M+H]+; 1H NMR (400 MHz, DMSO-r/6) 8 = 7.41 - 7.38 (m, 1H), 7.35 (d, J= 2.9 Hz, 1H), 7.28 (d, J= 7.3 Hz, 1H), 7.04 (t, J= 7.6 Hz, 1H), 6.34 (s, 1H), 4.69 (dd, J= 5.4, 11.6 Hz, 1H), 3.53 (t, J= 11.3 Hz, 1H), 3.21 - 3.15 (m, 1H), 2.95 (dd, J= 4.8, 11.1 Hz, 1H), 2.65 - 2.60 (m, 1H), 2.45 - 2.43 (m, 3H), 2.06 (t, J= 10.5 Hz, 1H), 1.01 (d, J = 7.2 Hz, 3H) ppm.
Example 37: Synthesis of 6j ((7aS,10R)-4-chloro-8,10-dimethyl-7a,8,9,10-tetrahydro- 7H-indolo[7., l-fg][1,7]naphthyridine):
[0344] Using Alternate General procedure 3, Int-5j (150 mg, 0.517 mmol, 1.00 eq) was converted to 6j and this was purified by column chromatography to afford 40 mg (28%) of the title compound as a pale-yellow semi solid. ESI-MS m/z: 273.32 [M+H]+.
[0345] 40 mg of racemic 6j was purified Column AD-H (20X250mm, 5 pm) MP(A)C02 86.0 g/min MP(B)Co-Solvent 14.0 ml/ min (AMM IN ACN:IPA) (1 : 1) Total Flow rate (mL/min) 70g-20%-100 bar. The faster eluting peak was assigned as 7j, and the more slowly eluting peak was assigned as 8j.
[0346] 7k: 9.8 mg, ESI-MS m/z: 273.2 [M+H]+; ' H NMR (400 MHz, DMSO-d6) δ = 7.51 (s, 1H), 7.35 (d, J= 7.9 Hz, 1H), 7.32 (d, J= 7.3 Hz, 1H), 7.14 - 7.09 (m, 1H), 6.35 (s, 1H), 4.79 (dd, J= 5.4, 11.6 Hz, 1H), 3.58 (t, J= 11.3 Hz, 1H), 3.20 - 3.13 (m, 1H), 2.95 (dd, J = 5.4, 11.0 Hz, 1H), 2.65 - 2.58 (m, 1H), 2.44 (s, 3H), 2.07 (t, J= 10.6 Hz, 1H), 1.02 (d, J= 7.0 Hz. 3H) ppm.
[0347] 8j: 7.1 mg, ESI-MS m/z: 273.2 [M+H]+; 1H NMR (400 MHz, DMSO-76) 8 = 7.53 - 7.50 (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 7.3 Hz, 1H), 7.14 - 7.09 (m, 1H), 6.35 (s, 1H), 4.81 - 4.77 (m, 1H), 3.58 (t, 7= 11.3 Hz, 1H), 3.17 (tdd, J= 3.5, 5.4, 7.3 Hz, 1H), 2.95 (dd, 7= 5.1, 11.0 Hz, 1H), 2.66 - 2.59 (m, 1H), 2.44 (s, 3H), 2.07 (t, J= 10.6 Hz. 1H), 1.02 (d, 7 = 7.1 Hz, 3H) ppm.
Example 39: Synthesis of 6k (Synthesis of (7aS,10R)-4,8,10-trimethyl-7a,8,9,10- tetrahydro-7H-indolo[7,l-fg] |l,7|naphthyridine):
[0348] Using Alternate General procedure 3, Int-5k (200 mg, 0.740 mmol, 1.00 eq) was converted to 6k and this was purified by column chromatography to afford 80 mg (30%) of the title compound as a pale-yellow semi solid. ESI-MS m/z: 253.3 [M+H]+.
Example 40: Synthesis of 7k & 8k:
[0349] 80 mg of racemic 6k was purified by Column CHIARALPAK-IC (30X250mm,5pm) MP(A)C02 63 g/min MP(B)Co-Solvent 37 ml/min (0.1% MeONH2 in EtOH) Total Flow rate (mL/min) 90g-30%- lOObar Diluent EtOH+MeOH+3 Drops Of THF. The faster eluting peak was assigned as 7k, and the more slowly eluting peak was assigned as 8k
[0350] 7k: 12 mg, ESI-MS m/z: 253.3 [M+H]+; 1H NMR (400 MHz, DMSO-76) 6 = 7.35 (d, 7= 7.8 Hz, 1H), 7.20 (d, 7= 7.3 Hz, 1H), 7.08 (d, 7= 0.9 Hz, 1H), 6.97 (t, 7= 7.6 Hz, 1H), 6.27 (s, 1H), 4.73 (dd, 7= 5.3, 11.4 Hz, 1H), 3.51 (t, 7= 11.1 Hz, 1H), 3.16 - 3.10 (m, 1H), 2.95 (dd, J= 5.2, 10.9 Hz, 1H). 2.65 - 2.60 (m. 1H), 2.46 - 2.44 (m, 3H), 2.26 - 2.23 (m, 3H), 2.06 (t, J= 10.6 Hz, 1H), 1.01 (d, J= 7.1 Hz, 3H) ppm.
[0351] 8k: 13 mg, ESI-MS m/z: 253.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ = 7.37 - 7.32 (m, 1H), 7.20 (d, J = 1.3 Hz, 1H), 7.08 (d, J= 1.0 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.27 (s, 1H), 4.76 - 4.71 (m, 1H), 3.51 (t, J= 11.2 Hz, 1H), 3.16 - 3.11 (m, 1H), 2.95 (dd, J= 5.1, 11.2 Hz, 1H), 2.65 - 2.58 (m, 1H), 2.46 - 2.44 (m, 3H), 2.25 (d, J= 0.9 Hz, 3H), 2.06 (t, J = 10.6 Hz, 1H), 1.01 (d, J = 1A Hz, 3H) ppm.
Example 41: Synthesis of 61 (Synthesis of (7aS,10R)-5-chloro-8,10-dimethyl-7a,8,9J0- tetrahydro-7H-indolo [7,1-fg] [1,7]naphthyridine):
[0352] Using Alternate General procedure 3, Int-51 (150 mg, 0.517 mmol, 1.00 eq) was converted to 61 and this was purified by column chromatography to afford 50 mg (35%) of the title compound as a pale-yellow semi solid. ESI-MS m/z: 273.1 [M+H]+.
Example 42: Synthesis of 71 & 81;
[0353] 45 mg of racemic 61 was purified by chiral CHIRALPAK AD-H (250 X4.6mm, 5pm) Mobile phase A: 0.1% IP AMINE in n-HEXANE Mobile phase B: ETOH A:B : 80:20 FLOW : 1.0 ml/min PDA : AD-H_013. The faster eluting peak was assigned as 71, and the more slowly eluting peak was assigned as 81.
[0354] 71: 7 mg, ESI-MS m/z: 273.0 [M+H]+; 1H NMR (400 MHz, METHA NOL-rZ4) δ = 7.34 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.07 - 7.03 (m, 1H), 6.40 (s, 1H), 6.36 (s, 1H), 4.81 - 4.79 (m, 1H), 3.52 - 3.46 (m, 1H), 3.37 - 3.34 (m, 1H), 3.07 (dd, J= 5.0, 11.1 Hz, 1H), 2.79 - 2.72 (m, 1H), 2.63 - 2.58 (m, 3H), 2.23 (t, J= 10.8 Hz, 1H), 1.10 (d, J= TA Hz, 3H) [0355] 81: 10 mg, ESI-MS m/z: 273.0 [M+H]+; ’H NMR (400 MHz, METHANOL-^) 8 = 7.38 - 7.32 (m, 1H), 7.27 (d, J= 7.5 Hz, 1H), 7.08 - 7.02 (m, 1H), 6.42 - 6.34 (m, 2H), 4.81 - 4.79 (m, 1H), 3.55 - 3.46 (m, 1H), 3.35 - 3.33 (m, 1H), 3.06 (dd, J= 5.2, 11.2 Hz, 1H), 2.8O - 2.71 (m, 1H), 2.60 (s, 3H), 2.22 (t, J= 10.9 Hz, 1H), 1.10 (d, J= 7.0 Hz, 3H) ppm.
Example 43: Synthesis of 6m ((7aS,10R)-8,10-dimethyl-7a,8,9,10-tetrahydro-7H- indolo[7,l-fg] [1,7]naphthyridine-3-carbonitrile):
[0356] Using Alternate General procedure 3, Int-5m (200 mg, 0.711 mmol, 1.00 eq) was converted to 6m and this was purified by column chromatography to afford 45 mg (24%) of the title compound as a pale-yellow semi solid. ESI-MS m/z: 264.31 [M+H]+.
Example 44: Synthesis of 7m & 8m:
[0357] 45 mg of racemic 6m was purified by Column IC3 (20X250*mm,5pm) Mobile phase A n-hexane Mobile phase B ETOH-MEOH (1-1) Eluent A: B: 80:20 Total Flow rate (mL/min) 20 ml/min. The faster eluting peak was assigned as 7m, and the more slowly eluting peak was assigned as 8m.
[0358] 7m: 8 mg, ESI-MS m/z: 264.2 [M+H]+; ‘H NMR (400 MHz, METHANOL-^) h' = 7.47 . 7.40 (m, 2H), 7.39 - 7.35 (m, 1H), 6.59 - 6.54 (m, 2H), 4.94 - 4.90 (m, 1H), 3.72 (t, J = 11.3 Hz, 1H), 3.38 - 3.34 (m, 1H), 3.09 - 3.05 (m, 1H), 2.83 - 2.74 (m, 1H), 2.59 (s, 3H), 2.23 (t, J= 10.8 Hz. 1H), 1.11 (d. J= 7.1 Hz. 3H) ppm.
[0359] 8m: 8 mg, ESI-MS m/z: 264.2 [M+H]+; 1H NMR (400 MHz, METHANOL-^) 8 = 7.48 - 7.42 (m, 2H), 7.39 - 7.35 (m, 1H), 6.59 - 6.54 (m, 2H), 4.94 - 4.90 (m, 1H), 3.72 (t, J = 11.3 Hz, 1H), 3.37 - 3.34 (m, 1H), 3.07 (dd, J= 5.0, 11.3 Hz, 1H), 2.83 - 2.74 (m, 1H), 2.60 - 2.56 (m, 3H), 2.23 (1, J= 10.8 Hz. 1H), 1.11 (d, J= 7.1 Hz. 3H) ppm.
Example 45: Synthesis of 6n (Synthesis of (7aS,10R)-3-chloro-8,10-dimethyl-7a,8,9J0- tetrahydro-7H-indolo[7.,l-fg][l.,7]naphthyridine): lnt-5n lnt-6n
[0360] Using Alternate General procedure 3, Int-5n (200 mg, 0.689 mmol, 1 .00 eq) was converted to 6n and this was purified by column chromatography to afford 45 mg (24%) of the title compound as a pale-yellow semi solid. ESI-MS m/z: 273.20 [M+H]+.
Example 46: Synthesis of 7n & 8n:
6n 7n 8n
[0361] 45 mg of racemic 6n was purified by Column IG (30 X250*mm,5u) Mobile phase A IP AMINE IN n-HEX Mobile phase B DCM-IPA Eluent A: B: 95-05 Total Flow rate (mL/min) 42 ml/min The faster eluting peak was assigned as 7n, and the more slowly eluting peak was assigned as 8n.
[0362] 7n: 6 mg, ESI-MS m/z: 273.2 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.17 (d, J = 7.9 Hz, 1H), 7.11 (d, J= 3.0 Hz, 1H), 7.05 (d, J= 7.9 Hz, 1H), 6.53 (d, J= 3.0 Hz, 1H), 6.27 (br s, 1H), 4.64 (br dd, J= 5.3, 11.1 Hz, 1H), 3.81 (br t, J= 10.8 Hz, 1H), 3.33 - 3.24 (m, 1H), 3.06 - 2.97 (m, 1H), 2.82 - 2.71 (m, 1H), 2.57 (s, 3H), 2.20 (br t, J= 10.6 Hz, 1H), 1.08 (d, J= 7.0 Hz, 3H) ppm.
[0363] 8n: 8 mg, ESI-MS m/z: 273.2 [M+H]+; 1H NMR (400 MHz, CHLOROFOR M-d) δ = 7.17 (d, J= 7.9 Hz, 1H), 7.11 (d, J= 3.1 Hz, 1H), 7.05 (d, J= 7.9 Hz, 1H), 6.53 (d, J= 3.1 Hz, 1H), 6.27 (s, 1H), 4.64 (dd, J= 5.4, 11.3 Hz, 1H), 3.80 (t, J= 11.1 Hz, 1H), 3.29 (br dd, J = 3.3, 5.6 Hz, 1H), 3.01 (br dd, J= 4.8, 10.9 Hz, 1H), 2.83 - 2.71 (m, 1H), 2.56 (s, 3H), 2.20 (br t, J = 11.0 Hz, 1H). 1.08 (d, J= 7.1 Hz, 3H) ppm.
Example 47: Synthesis of 6o (Synthesis of (7aS,10R)-3-fluoro-8,10-dimethyl-7a,8,9,10- tetrahvdro-7H-indolo[7,l-fg][1,7]naphthyridine):
[0364] Using Alternate General procedure 3, Int-5o (950 mg, 3.47 mmol, 1.00 eq) was converted to 6o and this was purified by column chromatography to afford 390 mg (44%) of the title compound as a pale-yellow semi solid. ESI-MS m/z: 273.1 [M+H]+.
Example 48: Synthesis of 7o & 8o:
[0365] 390 mg of racemic 6o was purified by chiral CHIRALPAK AD-H (250 X4.6mm, 5pm) Mobile phase A: 0.1% IP AMINE in n-HEXANE Mobile phase B: ETOH A:B : 80:20 FLOW : 1.0 ml/min PDA : AD-H_013. The faster eluting peak was assigned as 7o, and the more slowly eluting peak was assigned as 8o.
[0366] 7o: 160 mg, ESI-MS m/z: 257.2 [M+H]+; 1H NMR (400 MHz, CHLOR OFORM- d) d = 7.18 - 7.14 (m, 1H), 7.05 (d, J= 3.1 Hz, 1H), 6.73 (dd, J= 8.1, 10.8 Hz, 1H), 6.52 (d, J = 3.1 Hz, 1H), 6.21 (s, 1H), 4.64 (dd, J= 5.3, 11.3 Hz, 1H). 3.87 - 3.75 (m. 1H), 3.34 - 3.26 (m. 1H), 3.04 - 2.97 (m, 1H), 2.83 - 2.70 (m, 1H). 2.60 - 2.54 (m. 3H), 2.24 - 2.17 (m, 1H), 1.07 (d, J= 1A Hz, 3H) ppm.
[0367] So: 120 mg, ESI-MS m/z: 257.2 [M+H]+; 1H NMR (400 MHz, CHLORO FORM- d) d = 7.18 - 7.13 (m, 1H), 7.06 (d, J= 3.1 Hz, 1H), 6.73 (dd, J= 8.0, 10.7 Hz, 1H), 6.52 (d, J = 3.2 Hz. 1H), 6.22 (s, 1H), 4.64 (dd, J= 5.2, 11.2 Hz, 1H). 3.93 - 3.67 (m. 1H), 3.39 - 3.19 (m, 1H), 3.08 - 2.89 (m, 1H), 2.87 - 2.70 (m, 1H), 2.58 (br s, 3H). 2.28 - 2. 12 (m, 1H), 1.08
(d, J= 7.1 Hz, 3H) ppm.
Example 49: Synthesis of lip:
[0368] Using Alternate General procedure 3, Int-9p (50 mg, 0. 18 mmol, 1.0 eq) was converted to 11p and this was purified by column chromatography to afford 13 mg (27%) of the title compound. ESI-MS m/z: 257.2 [M+H]+; 1H NMR (400 MHz, DMSO-d 6) δ = 7.40 (d, J = 2.9 Hz. 1H), 7.17 (dd, J = 2.2. 10.1 Hz, 1H). 7.09 (dd. J = 2.2, 10.5 Hz. 1H). 6.39 (d. J = 3.1 Hz, 2H), 4.83 (dd, J= 5.4, 11.7 Hz, 1H), 3.57 (t, J= 11.3 Hz, 1H), 3. 16 (dddd, J= 2.1, 3.5, 5.4, 10.9 Hz, 1H), 2.96 (dd, J= 5.2, 11.2 Hz, 1H), 2.53 - 2.52 (m, 1H), 2.45 (s, 3H), 2.06 (t, J = 10.6 Hz, 1H), 1.02 (d, J = 7.1 Hz, 3H) ppm.
Example 50: Synthesis of 12p;
[0369] Using Alternate General procedure 3, Int-lOp (50 mg, 0.18 mmol, 1.0 eq) was converted to 12p and this was purified by column chromatography to afford 15 mg (32%) of the title compound. ESI-MS m/z: 257.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 = 7.41 - 7.39 (m, 1H), 7.17 (dd, J= 2.2, 10.1 Hz, 1H), 7.09 (dd, J = 2.1, 10.6 Hz, 1H), 6.39 (d, J = 2.9 Hz, 2H), 4.83 (dd, J= 5.4, 11.7 Hz, 1H), 3.59 - 3.54 (m, 1H), 3.16 (dddd, J = 2.1, 3.5, 5.3, 11.0 Hz, 1H), 2.96 (dd, J= 5.4, 11.0 Hz, 1H), 2.69 - 2.62 (m, 1H), 2.45 (s, 3H), 2.06 (t, J = 10.6 Hz, 1H), 1.02 (d, J= 7.2 Hz, 3H) ppm. Example 51: Synthesis llq; lnt-9q 11q
[0370] Using Alternate General procedure 3, Int-9q (40 mg, 0.14 mmol, 1.0 eq) was converted to 11q and this was purified by column chromatography to afford 7 mg (19%) of the title compound. ESI-MS m/z: 273.2 [M+H]+; 1H NMR (400 MHz, DMSO-d 6) δ = 7.47 - 7.44 (m, 1H), 7.41 (d, J= 3.1 Hz, 1H), 7.24 (d, J= 1.6 Hz, 1H), 6.42 - 6.39 (m, 2H), 4.84 (dd, J= 5.3, 11.7 Hz, 1H), 3.58 (t, J= 11.3 Hz, 1H), 3.18 - 3.12 (m, 1H), 2.98 - 2.93 (m, 1H), 2.68 - 2.63 (m, 1H), 2.44 (s, 3H), 2.06 (t, J= 10.6 Hz. 1H), 1.02 (d. J= 7.1 Hz. 3H) ppm.
Example 52: Synthesis of 12q :
[0371] Using Alternate General procedure 3, Int-lOq (40 mg, 0.18 mmol, 1.0 eq) was converted to 12q and this was purified by column chromatography to afford 8 mg (21%) of the title compound. ESI-MS m/z: 273.2 [M+H]+; 1H NMR (400 MHz, DMSO-A) δ = 7.46 - 7.43 (m, 1H), 7.41 (d, J= 2.9 Hz, 1H), 7.24 (d, J= 1.6 Hz, 1H), 6.42 - 6.39 (m, 2H), 4.84 (dd, J= 5.4, 11.6 Hz, 1H), 3.61 - 3.55 (m, 1H), 3.17 - 3.12 (m, 1H), 2.96 (dd. J= 5.3, 11.3 Hz. 1H), 2.68 - 2.62 (m, 1H), 2.44 (s, 3H), 2.06 (t, J= 10.6 Hz. 1H), 1.02 (d. J= 7.2 Hz. 3H) ppm. Example 53: Synthesis of 7r ((7aS,10R)-10-methyl-7,7a,9.,10-tetrahvdro-8H-indolol7,l- fgl I l,71naphthyridine-8-carbonitrile):
[0372] To a stirred solution of 6r (Example 2; 0.65 g, 2.7 mmol, 1.0 eq) in CH2CI2 (20 Vol) was added cyanogen bromide (2.89 g, 27.3 mmol, 10.0 eq) at 0° C portion wise over 20 min and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with cold water (10 mL) and extracted with DCM (2 X 10 mL). The combined organic layers were washed with an aqueous solution of NaCl (10 mL), the organic layer was dried over anhydrous Na2SC>4, solids were removed by filtration and the filtrate was concentrated in vacuum to provide crude. The crude was purified by combi-flash (25% EtOAc/Hexane) to afford 350 mg (51%) of 7r as an off-white solid. ESI-MS m/z: 249.9 [M+H] 1.
Example 54: Synthesis of 8r ((7aS,10R)-N,N-diethyl-7a,8,9,10-tetrahvdro-7H- indolo[7.1-fg][l,71naphthyridine-10-carboxamide):
[0373] To a stirred solution of 7r (0.35 g, 1.4 mmol, 1.0 eq) were added glacial acetic acid, (16 mL) zinc dust (1.18 g, 18.2 mmol, 13.0 eq) and water (1.2 mL) were added. The resulting mixture was purged with nitrogen and heated to 100°C for 3 h. The reaction mixture was diluted with EtOAc (10 mL) and quenched with a saturated sodium bicarbonate solution (2 x 10 mL). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated. The crude was purified by combi-flash (4 % MeOH in DCM) to provide 180 mg (57%) of 8r as a colourless gummy solid. ESI-MS m/z: 225.2 [M+H] +. Example 55: Synthesis of 9r-a & 9r-b;
8r 9r-a gr.b
[0374] 30 mg of racemic 8r was purified by chiral CHIRALPAK AD-H (250 X4.6mm.5pm) Mobile phase A :0. 1% IP AMINE in n-HEXANE Mobile phase B: ETOH A:B : 80:20 FLOW : 1 .0 ml/min PDA : AD-H 013. The faster eluting peak was assigned as 9r-a, and the more slowly eluting peak was assigned as 9r-b.
[0375] 9r-a: 10 mg, ESI-MS m/z: 225.2 [M+H]+; 1H NMR (400 MHz, METHANOL-d4) δ = 7.43 - 7.38 (m. 1H), 7.26 (d, J= 7.4 Hz. 1H), 7.17 (d, J= 3.1 Hz. 1H), 7.01 (t, J= 7.6 Hz, 1H), 6.40 (d, J= 3.0 Hz, 1H), 6.36 - 6.33 (m, 1H), 4.48 - 4.43 (m, 1H), 3.96 (dddd, J= 2.3, 3.4, 5.7, 11.3 Hz, 1H), 3.76 - 3.69 (m, 1H), 3.29 - 3.24 (m, 1H), 2.71 - 2.61 (m, 1H), 2.61 - 2.53 (m, 1H), 1.09 (d, J = 6.9 Hz, 3H) ppm.
[0376] 9r-b: 10 mg, ESI-MS m/z: 225.2 [M+H]+; 1H NMR (400 MHz, METHANOL-d4) δ = 7.41 (d, J= 7.8 Hz, 1H), 7.26 (d, J= 7.3 Hz, 1H), 7.17 (d, J= 3.1 Hz, 1H), 7.01 (t, J= 7.6 Hz, 1H), 6.41 (d, J= 3.1 Hz, 1H), 6.35 (s, 1H), 4.46 (dd, J= 5.7, 11.2 Hz, 1H), 3.97 (dddd, J = 2.3, 3.4, 5.7, 11.2 Hz, 1H), 3.77 - 3.70 (m, 1H), 3.27 (br d, J= 5.4 Hz, 1H), 2.72 - 2.62 (m, 1H), 2.60 - 2.54 (m, 1H), 1.10 (d, J= 7.0 Hz, 3H) ppm.
D. Biological Examples
Biological Example 1 : Assays
[0377] Radioligand Binding Assays (5-HT2AR and 5-HT2CR). The 5-HT2AR and 5- HT2CR competitive radioligand binding assays were performed at Epics Therapeutics S.A. (Belgium, FAST-0505B. FAST-0507B) using conventional methods. Experiments were performed using the free bases of all compounds, except for 5.35 which was used as the hydrochloride salt. Briefly, competition binding was performed in duplicate in the wells of a 96-well plate (Master Block, Greiner, 786201) containing binding buffer, membrane extracts, radiotracer [3H]-DOI and test compound. Nonspecific binding was determined by co- incubation with 200-fold excess of cold competitor DOI. The samples were incubated in a final volume of 0. 1 mL at a temperature and for a duration optimized for either the 5-HT2AR or 5-HT2CR and then filtered over filter plates. Filters were washed six times with 0.5 mL of ice-cold washing buffer (optimized for 5-HT2AR) and 50 pL of Microscint 20 (Packard) were added in each well. The plates were incubated for 15 min on an orbital shaker and then counted with a TopCountTM for 1 min/well.
[0378] Radioligand Binding Assays (5-HT2BR). The 5-HT2BR competitive radioligand binding assays were performed at Eurofms Cerep SA (Celle 1’Evescault, France) using conventional methods (Catalog #1333). Experiments were performed using the free bases of all compounds, except for 5.35 which was used as the hydrochloride salt. Cell membrane homogenates (10 pg protein) are incubated for 60 min at room temperature with 0.2 nM [125I](±)DOI in the absence or presence of the test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MgC12, 10 pM pargyline and 0.1% ascorbic acid. Nonspecific binding is determined in the presence of 1 pM (±)DOI. Following incubation, the samples are filtered rapidly under vacuum through glass fiber filters (GF/B. Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). The filters are dried then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as a percent inhibition of the control radioligand specific binding. The standard reference compound is (±)DOI, which is tested in each experiment at several concentrations to obtain a competition curve from which its IC50 is calculated.
[0379] IP1 Assays (5-HT2AR and 5-HT2CR). The 5-HT2AR and 5-HT2CR IPOne HTRF assays were performed at Epics Therapeutics S.A. (Belgium, FAST-05051, FAST- 05071) using conventional methods. Experiments were performed using the free bases of all compounds, except 5.35 which was used as the hydrochloride salt . Briefly, CHO-K1 cells expressing human recombinant 5-HT2AR or 5-HT2CR grown to mid-log phase in culture media without antibiotics were detached with PBS-EDTA, centrifuged, and resuspended in stimulation buffer.
[0380] For agonist testing, 5 pl of test compounds or reference agonist (a-Me-5-HT) diluted in stimulation buffer are dispensed in the wells of a 384-well plate. Then, 5 pl of cells suspension (20,000 cells) are added and the plate is incubated 60 min at 37°C with 5% CO2. After addition of the lysis buffer containing IPl-d2 and anti-IPl cryptate detection reagents (5 pl each), plates are incubated for 1 h at room temperature and fluorescence ratios are measured according to the manufacturer’s specifications using the HTRF kit.
[0381] For antagonist testing, 5 pl of test compounds or reference antagonist (Ketanserin for 5-HT2AR and Methysergide for 5-HT2CR) diluted in stimulation buffer with reference agonist (oc-Me-5-HT for a final concentration corresponding to its EC so) are dispensed in the wells of a 384-well plate. Then, 5 pl of cells suspension (20,000 cells) are added and the plate is incubated 60 min at 37°C with 5% CO2. After addition of the lysis buffer containing IPl-d2 and anti-IPl cryptate detection reagents (5 pl each), plates are incubated for 1 h at room temperature and fluorescence ratios are measured according to the manufacturer’s specifications using the HTRF kit.
[0382] IP1 Assays (5-HT2BR). The 5-HT2BR IP1 assays were performed at Eurofins Cerep SA (Celle 1’Evescault, France) using conventional methods (Catalog #3344). Experiments were performed using the free bases except for 5.35 which was used as the hydrochloride salt. The cells are suspended in a buffer containing 10 mM Hepes/NaOH (pH 7.4), 4.2 mM KC1, 146 mM NaCl, 1 mM CaC12, 0.5 mM MgC12, 5.5 mM glucose and 50 mM LiCl, then distributed in microplates at a density of about 20,000 cells/well.
[0383] For agonist testing, plates are incubated for 30 min at 37°C in the presence of buffer (basal control), test compound or reference agonist. For stimulated control measurement, separate assay wells contain 1 pM 5-HT. Following incubation, the cells are lysed and the fluorescence acceptor (D2- labeled IP 1 ) and fluorescence donor (anti-IPl antibody labeled with europium cryptate) are added. After 60 min at room temperature, the fluorescence transfer is measured at Zex=337 nm and Zem=620 and 665 nm using a microplate reader (Envision, Perkin Elmer). The IP1 concentration is determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio). The results are expressed as a percent of the control response to 1 pM 5-HT. The standard reference agonist is 5-HT. which is tested in each experiment at several concentrations to generate a concentration-response curve from which its EC50 value is calculated.
[0384] For antagonist testing plates are preincubated for 5 min at room temperature in the presence of buffer (basal control), test compound or reference antagonist. Thereafter, the reference agonist 5-HT is added at a final concentration of 30 nM. For basal control measurements, separate assay wells do not contain 5-HT. Following 30 min incubation at 37°C, the cells are lysed and the fluorescence acceptor (D2 -labeled IP1) and fluorescence donor (anti-IPl antibody labeled with europium cryptate) are added. After 60 min at room temperature, the fluorescence transfer is measured at Zex=337 nm and Zem=620 and 665 nm using a microplate reader (Envision, Perkin Elmer). The IP1 concentration is determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio). The results are expressed as a percent inhibition of the control response to 30 nM 5-HT. The standard reference antagonist is SB 206553, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its IC50 value is calculated.
Table 1. Radioligand binding affinities, IP1 accumulation (agonism) assays, and IP1 agonist inhibition (antagonism) for 5-HT2A
Table 2. Radioligand binding affinities, 1P1 accumulation (agonism) assays, and IP1 agonist inhibition (antagonism) for 5-HT2B
Table 3. Radioligand binding affinities, IP1 accumulation (agonism) assays, and IP1 agonist inhibition (antagonism) for 5-HT2C
[0385] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Claims

WHAT IS CLAIMED IS:
1. A compound, or a pharmaceutically acceptable salt thereof, having a structure of Formula (J): wherein: each Rla, Rlb, Rlc, and Rld is independently Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxy alkyl, halogen, C1-6 haloalkyl, Ci-6 haloalkoxy, -NO2, or - CN; alternatively, two Rla groups on adjacent ring atoms are combined to form a C4-8 cycloalkyl or 4 to 8 membered heterocycloalkyl having 1 to 2 heteroatoms, each independently N, O, or S;
R2 is H, C1-6 alkyl, C3-6 cycloalkyl. C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, or C1-6 haloalkoxy,;
R3 is absent, H, Ci-6 alkyl, C1-6 alkoxy, C1-6 alkoxy alkyd, C1-6 haloalkyl, or Ci-6 haloalkoxy;
R3a is absent or Ci-6 alkyl; alternatively, R3 and R3a are combined to form a 3 to 8 membered heterocycloalkyl having 1 to 2 heteroatoms, each independently N, O, or S; dashed bond a, b and c are each independently absent or a bond; wherein when dashed bond b is a bond then R3a is absent; subsenpts m and p are each independently 0, 1 or 2; and subscripts n and r are each independently 0, 1, 2 or 3.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of Formula (Ja): (Ja).
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, having the structure of Formula (Ja-1):
4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, having the structure of Formula (Jb):
5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is H, Ci-6 alkyl, Ci-6 alkoxyalkyl, or Ci-6 hydroxyalkyl.
6. The compound of any one of claims 1 to 5. or a pharmaceutically acceptable salt thereof, wherein R2 is H, Me, or CH2OH.
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R2 is Me, or CH2OH.
8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein each Rla is independently C1-6 alkyl, C1-6 alkoxy, halogen, Ci- 6 haloalkoxy, or -CN.
9. The compound of any one of claims 1 to 8. or a pharmaceutically acceptable salt thereof, wherein each Rla is independently Ci-6 alkyl, Ci-6 alkoxy, or halogen.
10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein each Rla is independently C1-3 alkyl, C1-3 alkoxy, or halogen.
11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein each Rla is independently Me, MeO, fluoro, or chloro.
12. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein each Rla is halogen.
13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein each Rla is independently fluoro or chloro.
14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.
15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein n is 0.
16. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein n is 1, or 2.
17. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein n is 1.
18. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein n is 2.
19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein each Rlb is independently Ci-6 alkyd, C1-6 alkoxy, halogen, Ci- 6 haloalkoxy, or -CN.
20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein each Rlb is independently C1-6 alkyd, C1-6 alkoxy, or halogen.
21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each Rlb is independently C1.3 alkyl, C1-3 alkoxy, or halogen.
22. The compound of any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein each Rib is independently Me. MeO, fluoro, or chloro.
23. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein each Rb is halogen.
24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein each Rb is independently fluoro or chloro.
25. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein each Rb is C1-3 alkyl.
26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein n is 0. 1, or 2.
27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein n is 0.
28. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein n is 1, or 2.
29. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein n is 1.
30. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein n is 2.
31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R3 is H or C 1-6 alkyl.
32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R3 is C1-6 alkyd.
33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R3 is methyl.
34. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II):
35. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of Formula (III):
36. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:
pharmaceutically acceptable salt thereof.
37. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof.
38. A method of treating a disease, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, thereby treating the disease.
39. The method of claim 38, wherein the disease is a neuropsychiatric disease.
40. The method of claim 39, wherein the neuropsychiatric disease is schizophrenia.
41. The method of claim 39, wherein the neuropsychiatric disease is bipolar disorder.
42. The method of claim 38, wherein the disease is depression.
43. The method of claim 38, wherein the disease is post-traumatic stress disorder (PTSD).
44. The method of claim 38, wherein the disease is anxiety.
45. The method of claim 38, wherein the disease is a neurodegenerative disease.
46. The method of claim 38, wherein the disease is Alzheimer’s disease or Parkinson’s disease.
47. The method of claim 38, wherein the disease is Alzheimer’s disease.
48. The method of claim 38, wherein the disease is Parkinson’s disease.
49. The method of claim 38, wherein the disease is headache disorders.
50. The method of claim 38, wherein the disease is migraines.
51. The method of claim 38, wherein the disease is cluster headaches.
52. The method of claim 38, wherein the disease is addiction.
53. The method of claim 38, wherein the disease is substance use disorder.
54. The method of claim 38, wherein the disease is alcohol use disorder.
55. The method of claim 38, wherein the disease is an anxiety disorder, a mood disorder, a psychotic disorder, a personality disorder, an eating disorder, a sleep disorder, a sexuality disorder, an impulse control disorder, a substance use disorder, a dissociative disorder, a cognitive disorder, a developmental disorder, or a factitious disorder.
56. The method of claim 38, wherein the disease is a psychotic disorder.
57. The method of claim 56, wherein the psychotic disorder is selected from schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, delusional disorder, shared psychotic disorder, substance-induced psychotic disorder, paraphrenia, psychotic depression, bipolar disorder, schizotypal personality disorder, paranoid personality disorder, schizoid personality disorder, borderline personality disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and dissociative disorders, or psychosis associated with a neurodegenerative disease.
58. The method of claim 45, wherein the neurodegenerative disease is selected from Huntington’s disease, Alzheimer’s disease, Lewy body dementia, and Parkinson’s disease.
59. The method of claim 56, wherein the psychotic disorder is schizophrenia or bipolar disorder.
60. A method for increasing neural plasticity, the method comprising contacting a neuronal cell with a compound of any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, in an amount sufficient to increase neural plasticity of the neuronal cell, wherein the compound produces a maximum number of dendritic crossings with an increase of greater than 1.0 fold by a Sholl Analysis.
61. A method for increasing neural plasticity and increasing dendritic spine density, the method comprising contacting a neuronal cell with a compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, in an amount sufficient to increase neural plasticity and increase dendritic spine density of the neuronal cell.
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