US20220387400A1 - Formulations of rbp4 inhibitors and methods of use - Google Patents

Formulations of rbp4 inhibitors and methods of use Download PDF

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US20220387400A1
US20220387400A1 US17/620,427 US202017620427A US2022387400A1 US 20220387400 A1 US20220387400 A1 US 20220387400A1 US 202017620427 A US202017620427 A US 202017620427A US 2022387400 A1 US2022387400 A1 US 2022387400A1
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pharmaceutical composition
compound
certain embodiments
formula
trifluoromethyl
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Yu-Hsin Tom Lin
Cheng-Chi Irene Wang
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Belite Bio LLC
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Belite Bio LLC
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Publication of US20220387400A1 publication Critical patent/US20220387400A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
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    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • C07D471/02—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 two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • RBP4 retinol-binding protein 4
  • a pharmaceutical composition comprising a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof
  • A has the structure
  • A has the structure
  • the compound of Formula (I) has the structure:
  • the compound of Formula (I) is effective to reduce RBP4 concentrations in dosages forms of 1 to 200 mg or 5 to 25 mg.
  • the compound of Formula (I) is a micronized crystalline.
  • the compound of Formula (I) is a polymorph exhibiting an x-ray powder diffraction pattern having at least three characteristic peaks expressed in degrees two theta (+/ ⁇ 0.5 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the compound of Formula (I) is molecularly dispersed in the dispersion polymer. In certain embodiments, the compound of Formula (I) is amorphous and molecularly dispersed in the dispersion polymer In some embodiments, the compound of Formula (I) is amorphous within the dispersion polymer.
  • the dispersion polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS or HPMCAS), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers, and combinations thereof.
  • the dispersion polymer is HPMC.
  • the dispersion polymer is HPMC-AS.
  • the dispersion polymer comprises about 1-99% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises about 20-80% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises about 40-60% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises about 1-99% by weight, 20-80% by weight, or 40-60% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 1-99% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises 20-80% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 40-60% by weight of the solid dispersion.
  • the ratio of the compound of Formula (I):dispersion polymer is about 20:80 (w/w) in the solid dispersion. In certain embodiments, the ratio of the compound of Formula (I):dispersion polymer is about 40:60 (w/w) in the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 1-99% by weight, about 20-80% by weight, or about 40-60% by weight of the solid dispersion.
  • the ratio of the compound of Formula (I):dispersion polymer is about 20:80 (w/w) in the solid dispersion. In certain embodiments, the ratio of the compound of Formula (I):dispersion polymer is about 40:60 (w/w) in the solid dispersion.
  • the compound of Formula (I) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the dispersion polymer is HPMC-AS.
  • the dispersion polymer is HPMC-AS, M or HPMC-AS, H. In certain embodiments, the dispersion polymer is HPMC-AS, M. In certain embodiments, the dispersion polymer is HPMC-AS, H. In certain embodiments, the dispersion polymer is HPMC-AS having an acetyl content from 7-11 wt %, a succinyl content from 10-14 wt %, a methoxyl content from 21-25 wt %, and a hydroxypropyl content from 5-9 wt %.
  • the dispersion polymer is HPMC-AS having an acetyl content from 10-14 wt %, a succinyl content from 4-8 wt %, a methoxyl content from 22-26 wt %, and a hydroxypropyl content from 6-10 wt %.
  • the dispersion polymer comprises polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the PVP is present in a ratio with the compound of Formula (I) from about 10:1 to about 1:1.
  • the PVP is a present in a ratio with the compound of Formula (I) of about 2:1, about 3:1, or about 5:1.
  • the PVP has a molecular weight average molecular weight from about 7,000 Daltons to about 11,000 Daltons.
  • the pharmaceutical composition further comprises a filler, a sweetener, a disintegrant, a wetting agent, a glidant, a lubricant, or a surfactant, or any combinations thereof.
  • the solid dispersion further comprises a filler, a sweetener, a disintegrant, a wetting agent, a glidant, a lubricant, or a surfactant, or any combinations thereof.
  • the solid dispersion has an average particle size of less than 10 ⁇ m. In certain embodiments, the solid dispersion has an average particle size of less than 20 ⁇ m. In certain embodiments, the solid dispersion has an average particle size from about 10 ⁇ m to 20 ⁇ m. In certain embodiments, the solid dispersion has an average particle size of less than 10 ⁇ m or less than 20 ⁇ m.
  • a nanosuspension pharmaceutical composition comprising a compound of Formula (I), a pharmaceutically acceptable salt, crystalline, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, wherein the compound of Formula (I) is suspended in a pharmaceutically acceptable solvent.
  • the compound of Formula (I) is Compound 1, or a pharmaceutically acceptable salt, crystalline, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof.
  • the compound of Formula (I) is a polymorph exhibiting an x-ray powder diffraction pattern having at least three characteristic peaks expressed in degrees two theta (+/ ⁇ 0.5 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the concentration of the compound of Formula (I) is from about 1 mg/mL to about 50 mg/mL.
  • the compound of Formula (I) is micronized.
  • the compound of Formula (I) has an average particle size of less than 1000 nm.
  • the nanosuspension further comprises a surfactant.
  • the surfactant comprises sodium dodecyl sulfate, a poloxamer, or a polysorbate.
  • the nanosuspension further comprises an excipient.
  • the excipient comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers, or any combinations thereof.
  • the excipient is present at a concentration from about 0.1% to about 5%.
  • the pharmaceutical composition is encapsulated. In certain embodiments, the pharmaceutical composition is in the form of a tablet. In certain embodiments, the pharmaceutical composition is in the form of a capsule. In certain embodiments, the pharmaceutical composition is a liquid formulation. In certain embodiments, the pharmaceutical composition is formulated as an oral suspension.
  • the eye disease is a disease characterized by excessive lipofuscin accumulation in the retina.
  • the disease characterized by excessive lipofuscin accumulation is Age-Related Macular Degeneration, dry (atrophic) Age-Related Macular Degeneration, Juvenile Macular Degeneration (Stargardt Disease), Best disease, adult vitelliform maculopathy, Geographic Atrophy, Stargardt-like macular dystrophy, diabetic retinopathy, or an ABCA4 gene associated retinal disease.
  • the therapeutically effective amount of the pharmaceutical composition comprises about 0.1 mg to about 400 mg of the compound of Formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 0.5 mg to about 400 mg of the compound of Formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 0.5 mg to about 50 mg of the compound of Formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 0.1 mg of the compound of Formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 0.5 mg of the compound of Formula (I).
  • the therapeutically effective amount of the pharmaceutical composition comprises about 1 mg of the compound of Formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 5 mg of the compound of Formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 10 mg of the compound of Formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 25 mg of the compound of Formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 50 mg of the compound of Formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 100 mg of the compound of Formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 200 mg of the compound of Formula (I).
  • the therapeutically effective amount of the pharmaceutical composition comprises about 400 mg of the compound of Formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 400 mg of the compound of Formula (I).
  • the pharmaceutical composition is administered one, two, three, or four times daily. In certain embodiments, the pharmaceutical composition is administered daily, every other day, every other day 3 times a week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 3 days, every 4 days, every 5 days, every 6 days, weekly, bi-weekly, 3 times a week, 4 times a week, 5 times a week, 6 times a week, once a month, twice a month, 3 times a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months. In certain embodiments, the pharmaceutical composition is administered once daily. In certain embodiments, the pharmaceutical composition is administered orally. In certain embodiments, the serum RBP4 concentration of the subject is reduced to below 1 ⁇ M after treatment.
  • a method of manufacturing a solid dispersion comprising the steps of adding a solvent to a vessel; adding a compound of Formula (I) or its pharmaceutically acceptable salt to the vessel; adding a dispersion polymer to the vessel to obtain a first mixture; mixing the first mixture until the compound of Formula (I) or its pharmaceutically acceptable salt and the dispersion polymer are dissolved in the solvent to obtain a first solution; and dry spraying the first solution to obtain a first solid; wherein the compound of Formula (I) has the structure:
  • the solvent comprises an organic solvent.
  • the solvent is selected from the group consisting of ethanol, methanol, acetone, isopropyl alcohol, n-butanol, tetrahydrofuran, dichloromethane, ethyl acetate, methyl acetate, acetonitrile, chloroform, carbon tetrachloride, benzene, toluene, diethyl ether, dioxane, pentane, hexane, cyclohexane, heptane, methyl t-butyl ether, petroleum ether, 1-propanol, and combinations thereof.
  • the solvent is 90:10 dichloromethane:methanol (v/v).
  • the dispersion polymer selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers, and combinations thereof.
  • the dispersion polymer is HPMC-AS.
  • the dispersion polymer is HPMC.
  • the dispersion polymer is polyvinyl pyrrolidine.
  • the compound of Formula (I) has the structure:
  • the solvent comprises acetic acid, acetone, acetonitrile, benzene, tert-butyl alcohol, tert-butyl methyl ether, carbon tetrachloride, chloroform, cyclohexane, 1,2-dichloroethane, dichloromethane, diethyl ether, diglyme, 1,2,-dimethoxyethane, dimethyl acetamide, dimethylformamide, dimethyl sulfoxide, dioxane, ethanol, ethyl acetate, ethyl methyl ketone, ethylene glycol, hexanes, hexamethylphosphoramide, methanol, nitromethane, pentanes, 2-proponal, pyridine, tetrahydrofuran, toluene
  • a method for lowering the serum concentration of RBP4 in a subject comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure
  • the pharmaceutical composition comprises the compound in an amount of about 10 mg; wherein the pharmaceutical composition is administered daily; and wherein the serum or plasma levels of RBP4 of the subject are reduced to below 1 ⁇ M.
  • a polymorph of Compound 1 wherein the polymorph exhibits an x-ray powder diffraction pattern having at least three characteristic peaks expressed in degrees two theta (+/ ⁇ 0.5 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the polymorph is crystalline.
  • the polymorph exhibits an x-ray powder diffraction pattern having at least five characteristic peaks expressed in degrees two theta (+/ ⁇ 0.5 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern having characteristic peaks expressed in degrees two theta (+/ ⁇ 0.5 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the polymorph is micronized.
  • the polymorph has an average particle size of less than 20 ⁇ m, less than 10 ⁇ m, less than 1 ⁇ m, or less than 100 nm.
  • FIG. 1 illustrates a schematic of a mechanism of action for dry (atrophic) macular degeneration and Stargardt disease.
  • RBP4 transports retinol (a precursor to cytotoxic A2E) into the retina by way of the visual cycle.
  • RBP4 inhibitors such as Compound 1, are in some instances used to treat RBP4-related visual diseases and disorders.
  • FIG. 3 is a graph of outer nuclear layer (ONL) thickness ( ⁇ m) as a function of distance ( ⁇ m) from the optic nerve (ONH).
  • ONL is the cell layer consisting of photoreceptor cell bodies (rods and cones). Dry AMD or STGD is often associated with thinning of the ONL and the loss of photoreceptor cells, indicating macular degeneration.
  • ONL thickness was significantly decreased in the diseased group (abcd4/rdh8 knockout mice), as compared to the diseased group treated with Compound 1 wherein the ONL was preserved.
  • FIG. 4 A is a graph of percent mean RBP4 reduction from baseline as a function of time (hours) for five cohorts comprising a total of 32 healthy adults in a randomized, double-blind, placebo-controlled Phase 1 clinical trial. Each cohort was given a single dose of 50 mg (Cohort 1), 100 mg (Cohort 2), 200 mg (Cohort 3), 400 mg (Cohort 4), 25 mg (Cohort 5) of Compound 1, or a placebo. Individuals receiving placebo were not included in the graph.
  • FIG. 4 B is a graph of RBP4 concentration (ng/mL) as a function of time (hours) for five cohorts comprising a total of 32 healthy adults in a randomized, double-blind, placebo-controlled Phase 1 clinical trial. Each cohort was given a single dose of 50 mg (Cohort 1), 100 mg (Cohort 2), 200 mg (Cohort 3), 400 mg (Cohort 4), 25 mg (Cohort 5) of Compound 1, or a placebo. Individuals receiving placebo were not included in the graph
  • FIG. 5 is a graph of percent mean RBP4 reduction from baseline as a function of time (hours) for cohort 5 in a randomized, double-blind, placebo-controlled Phase 1 clinical trial.
  • Each subject in the cohort was given a single dose of 25 mg of Compound 1, or a placebo.
  • Six subjects received Compound 1 and two subjects were dosed with placebo.
  • Subjects FF and GG likely received the placebo.
  • FIG. 6 is a graph of RBP4 concentration (ng/mL) as a function of time (hours) for cohort 5 in a randomized, double-blind, placebo-controlled Phase 1 clinical trial.
  • Each subject in the cohort was given a single dose of 25 mg of Compound 1, or a placebo.
  • Six subjects received Compound 1 and two subjects were dosed with placebo.
  • Subjects FF and GG likely received the placebo.
  • FIG. 7 is a graph of Compound 1 concentration (ng/mL) as a function of time (hours) for five cohorts comprising a total of 32 healthy adults in a randomized, double-blind, placebo-controlled Phase 1 clinical trial. Each cohort was given a single dose of 50 mg (Cohort 1), 100 mg (Cohort 2), 200 mg (Cohort 3), 400 mg (Cohort 4), 25 mg (Cohort 5) of Compound 1, or a placebo. Individuals receiving placebo were not included in the graph.
  • FIG. 8 are graphs of Compound 1 concentration (ng/mL) as a function of time (hours) (left) and RBP4 concentration (ng/mL) as a function of time (hours) (right) for cohort 5 in a randomized, double-blind, placebo-controlled Phase 1 clinical trial.
  • Each subject in the cohort was given a single dose of 25 mg of Compound 1, or a placebo.
  • Subjects FF and GG likely received the placebo.
  • FIG. 9 is a graph of the RBP4 concentration ( ⁇ m) as a function of dose of compound 1 (mg, modeled from a Phase 1 clinical study) and fenretinide (modeled from a Phase 2 clinical study).
  • the Phase 2 fenretinide study showed that a sub-population with significant RBP4 lowering had slower lesion growth.
  • Compound 1 is more potent than fenretinide and can lower RBP4 significantly at doses with clinical relevance.
  • FIG. 10 A is a graph generated in an X-ray powder diffraction (XRPD) experiment of crystalline Compound 1.
  • FIG. 10 B is a graph generated in a differential scanning calorimetry (DSC) experiment of crystalline Compound 1 showing heat flow Q(W/g) as a function of temperature (deg C).
  • FIG. 10 C is a graph generated in a differential scanning calorimetry (DSC) experiment of crystalline Compound 1 showing reverse heat flow Q rev (mW) as a function of temperature (deg C).
  • FIG. 10 D are images of crystalline Compound 1 generated by SEM (scanning electron microscope).
  • Compound 1's morphology consists of high aspect ratio orthogonal acicular crystals.
  • FIG. 10 E is a graph of Compound 1 solubility ( ⁇ gA/mL) as a function of time (minutes) for mixtures of Compound 1 and various polymers in a 20:80 ratio.
  • FIG. 10 F is graph of Compound 1 solubility ( ⁇ gA/mL) as a function of time (minutes) for mixtures of Compound 1 and various polymers in a 40:60 ratio.
  • FIG. 11 A is a graph generated of X-ray powder diffraction (XRPD) experiments of multiple spray-dried dispersions of Compound 1 and polymers. They are compared to crystalline API and show the spray-dried dispersions are amorphous.
  • XRPD X-ray powder diffraction
  • FIG. 11 B is a graph generated in a differential scanning calorimetry (DSC) experiment of spray-dried dispersions of Compound 1: and polymers showing reverse heat flow Q rev (mW) as a function of temperature (deg C).
  • DSC differential scanning calorimetry
  • FIG. 11 C is a graph generated in a differential scanning calorimetry (DSC) experiment of spray-dried dispersions of Compound 1: and polymers showing heat flow Q(W/g) as a function of temperature (deg C).
  • DSC differential scanning calorimetry
  • FIG. 11 D are images of spray-dried Compound 1/polymer mixtures generated by SEM (scanning electron microscope).
  • the dispersions' morphology consists of collapsed spheres. The majority of particles are less than 20 microns in diameter for all polymers.
  • FIG. 11 E is graph of Compound 1 solubility ( ⁇ gA/mL) as a function of time (minutes) in a non-sink dissolution experiment for spray-dispersions of Compound 1 and a polymer.
  • FIG. 12 A is a graph generated in a differential scanning calorimetry (DSC) experiment of spray-dried Compound 1 compositions showing reverse heat flow Q rev (mW) as a function of temperature (deg C) for various relative humidity samples.
  • DSC differential scanning calorimetry
  • FIG. 12 B is a graph generated in a differential scanning calorimetry (DSC) experiment of spray-dried Compound 1 compositions showing reverse heat flow Q rev (mW) as a function of temperature (deg C) for various relative humidity samples.
  • DSC differential scanning calorimetry
  • FIG. 12 C is a graph generated in a plurality of differential scanning calorimetry (DSC) experiment of spray-dried Compound 1 compositions showing the glass transition temperature (deg C) vs. relative humidity (percent).
  • DSC differential scanning calorimetry
  • FIG. 12 D is a graph showing the effect of RH on the glass transition temperature of various solid dispersion formulations of Compound 1.
  • FIG. 13 A is an image of Compound 1 compositions suspended in 0.5% Methocel A4M comprising a polymer as a spray dried dispersion composition or an API control. Images were taken at time point 0. All suspensions were amorphous.
  • FIG. 13 B is an image of Compound 1 compositions suspended in 0.5% Methocel A4M comprising a polymer as a spray dried dispersion composition or an API control. Images were taken at time point 2 hours. All suspensions were amorphous.
  • FIG. 13 C is an image of Compound 1 compositions suspended in 0.5% Methocel A4M comprising a polymer as a spray dried dispersion composition or an API control. Images were taken at time point 6 hours. All suspensions were amorphous.
  • FIG. 14 is a graph generated in a plurality of differential scanning calorimitery (DSC) experiment of spray-dried Compound 1 compositions comprising polyvinyl pyrrolidine showing the glass transition temperature (deg C) of each mixture
  • FIG. 15 shows an XRPD pattern of Compound 1 in polymorph Form A.
  • FIG. 16 shows an XRPD pattern of Compound 1 in polymorph Form C.
  • FIG. 17 shows, from top to bottom, XRPD patterns of Compound 1 in polymorph Form A, Form C, and Form E.
  • FIG. 18 shows a graph of the results of a solubility experiment comparing micronized and non-micronized Compound 1 in polymorph Form C.
  • Amino refers to the —NH 2 radical.
  • Niro refers to the —NO 2 radical.
  • Oxa refers to the —O— radical.
  • Oxo refers to the ⁇ O radical.
  • Thioxo refers to the ⁇ S radical.
  • Oximo refers to the ⁇ N—OH radical.
  • “Hydrazino” refers to the ⁇ N—NH 2 radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C 1 -C 15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C 1 -C 13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C 1 -C 8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C 1 -C 5 alkyl).
  • an alkyl comprises one to four carbon atoms (e.g., C 1 -C 4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C 1 -C 3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C 1 -C 2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C 1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C 5 -C 15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C 5 -C 8 alkyl).
  • an alkyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C 3 -C 5 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl).
  • alkyl is attached to the rest of the molecule by a single bond.
  • an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR a , —SR a , —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —C(O)N(R a ) 2 , —N(R a )C(O)OR a , —OC(O)—N(R a ) 2 , —N(R a )C(O)R a , —N(R a )S(O) t R a (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2)
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula —O-alkyl, where alkyl is an alkyl chain as defined above.
  • Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR a , —SR a , —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —C(O)N(R a ) 2 , —N(R a )C(O)OR a , —OC(O)—N(R a ) 2 , —N(R a )C(O)R a , —N(R a )S(O) t R a (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t R a (where t is 1 or
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR a , —SR a , —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —C(O)N(R a ) 2 , —N(R a )C(O)OR a , —OC(O)—N(R a ) 2 , —N(R a )C(O)R a , —N(R a )S(O) t R a (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t R
  • Alkylene or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
  • an alkylene comprises one to eight carbon atoms (e.g., C 1 -C 8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C 1 -C 5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C 1 -C 4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C 1 -C 3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C 1 -C 2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C 1 alkylene).
  • an alkylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkylene).
  • an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR a , —SR a , —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —C(O)N(R a ) 2 , —N(R a )C(O)OR a , —OC(O)— N(R a ) 2 , —N(R a )C(O)R a , —N(R a )S(O) t R a (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t R a
  • Alkenylene or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkenylene comprises two to eight carbon atoms (e.g., C 2 -C 8 alkenylene).
  • an alkenylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkenylene).
  • an alkenylene comprises two to four carbon atoms (e.g., C 2 -C 4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C 2 -C 3 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkenylene).
  • an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR a , —SR a , —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —C(O)N(R a ) 2 , —N(R a )C(O)OR a , —OC(O)— N(R a ) 2 , —N(R a )C(O)R a , —N(R a )S(O) t R a (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t R a (where t is 1 or
  • Alkynylene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkynylene comprises two to eight carbon atoms (e.g., C 2 -C 8 alkynylene).
  • an alkynylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkynylene).
  • an alkynylene comprises two to four carbon atoms (e.g., C 2 -C 4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C 2 -C 3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (e.g., C 2 alkylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkynylene).
  • an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR a , —SR a , —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —C(O)N(R a ) 2 , —N(R a )C(O)OR a , —OC(O)—N(R a ) 2 , —N(R a )C(O)R a , —N(R a )S(O) t R a (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t R
  • Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hückel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—OR a , —R b —OC(O)—N(R
  • Alkyl refers to a radical of the formula —R-aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • Alkenyl refers to a radical of the formula —R d -aryl where R d is an alkenylene chain as defined above.
  • the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
  • the alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
  • Alkynyl refers to a radical of the formula —R e -aryl, where R e is an alkynylene chain as defined above.
  • the aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group.
  • the alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula —O—R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • Carbocyclyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms.
  • a carbocyclyl comprises three to ten carbon atoms.
  • a carbocyclyl comprises five to seven carbon atoms.
  • the carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds).
  • a fully saturated carbocyclyl radical is also referred to as “cycloalkyl.”
  • monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • An unsaturated carbocyclyl is also referred to as “cycloalkenyl.”
  • Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • carbocyclyl is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—OR a , —R b —OC(O)—N(R
  • Carbocyclylalkyl refers to a radical of the formula —R c -carbocyclyl where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.
  • Carbocyclylalkynyl refers to a radical of the formula —R c -carbocyclyl where R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical are optionally substituted as defined above.
  • Carbocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula —O—R c -carbocyclyl where R c is an alkylene chain as defined above.
  • R c is an alkylene chain as defined above.
  • the alkylene chain and the carbocyclyl radical are optionally substituted as defined above.
  • carboxylic acid bioisostere refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety.
  • Examples of carboxylic acid bioisosteres include, but are not limited to,
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo substituents.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
  • Heterocyclyl refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s).
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thio
  • heterocyclyl is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—OR a , —R b —OC(O)—N(
  • N-heterocyclyl or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical.
  • An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
  • C-heterocyclyl or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical.
  • a C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.
  • Heterocyclylalkyl refers to a radical of the formula —R c -heterocyclyl where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.
  • Heterocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula —O—R c -heterocyclyl where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.
  • Heteroaryl refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hückel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothienyl (benzothion
  • heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—R a , —R b —OC(O)—R
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
  • An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
  • a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • Heteroarylalkyl refers to a radical of the formula —R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
  • Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula —O—R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.
  • the compounds disclosed herein in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included.
  • geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
  • positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers around a benzene ring.
  • a “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997.
  • deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 ( 125 I) or carbon-14 (14C).
  • isotopes such as for example, deuterium (2H), tritium (3H), iodine-125 ( 125 I) or carbon-14 (14C).
  • Isotopic substitution with 2 H, 11 C, 13 C, 14C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
  • Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • CD 3 I iodomethane-d 3
  • LiAlD 4 lithium aluminum deuteride
  • Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.
  • the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 1 H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.
  • ratios e.g. 1:2, 1:3, 1:4, or 1:5 and the like. Unless otherwise specified, such ratios refer to the ratio of each component by weight.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the heterocyclic RBP4 inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al
  • treatment or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder.
  • the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • Prodrug is meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to a biologically active compound described herein.
  • prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
  • prodrugs as Novel Delivery Systems
  • A.C.S. Symposium Series Vol. 14
  • Bioreversible Carriers in Drug Design ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound, as described herein are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like
  • XRPD x-ray powder diffraction
  • Compound 1 or “CMPD-1” refers to Compound No. 1 as indicated in Table 1.
  • Compound 1 has the structure
  • Compound 1 is also referred to by its full chemical name of 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one.
  • RBP4 inhibitory compounds and pharmaceutical compositions comprising said compounds.
  • the subject compounds and compositions are useful for inhibiting RPB4 and for the treatment of eye diseases or disorders, such as Age-Related Macular Degeneration, dry (atrophic) Age-Related Macular Degeneration, Juvenile Macular Degeneration (Stargardt Disease), Best disease, adult vitelliform maculopathy, Geographic Atrophy, Stargardt-like macular dystrophy, diabetic retinopathy, or ABCA4 gene associated retinal diseases.
  • Some embodiments provided herein describe a compound, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, for use in treating a metabolic disease or disorder, having the structure of Formula (I):
  • Some embodiments provided herein describe a compound, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, having the structure of Formula (I) wherein:
  • Some embodiments provided herein describe a compound, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, having the structure of Formula (I) wherein:
  • substituents are selected from among a subset of the listed alternatives.
  • each R 1 is independently halogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 heterocyclyl, optionally substituted C 3-10 heterocycloalkyl, —COR 7 , —CON(R 7 ) 2 , optionally substituted (C 0 -C 4 alkylene)-CN, optionally substituted (C 0 -C 4 alkylene)—OR 7 , optionally substituted (C 0 -C 4 alkylene)-N(R 7 ) 2 , optionally substituted (C 0 -C 4 alkylene)N(R 8 )—COR 7 , optionally substituted (C 0 -C 4 alkylene)-SO 2 N(R 7 ) 2 , optionally substituted (C 0 -C 4 alkylene)-SO 2 R 7 , optionally substituted (C 0 -C 4 alkylene)N(R 8 )—SO 2 N(
  • each R 1 is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-6 heterocyclyl, C 3 0.10 heterocycloalkyl, —COR 7 , —CON(R 7 ) 2 , (C 0 -C 4 alkylene)-CN, (C 0 -C 4 alkylene)-OR 7 , (C 0 -C 4 alkylene)-N(R 7 ) 2 , (C 0 -C 4 alkylene)N(R 8 )—COR 7 , (C 0 -C 4 alkylene)-SO 2 N(R 7 ) 2 , (C 0 -C 4 alkylene)-SO 2 R 7 , (C 0 -C 4 alkylene)N(R 8 )—SO 2 N(R 7 ) 2 , or (C 0 -C 4 alkylene)N(R 8 )—SO 2 R 7 .
  • each R 1 is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, —COR 7 , —CON(R 7 ) 2 , (C 0 -C 4 alkylene)-CN, (C 0 -C 4 alkylene)—OR 7 , or (C 0 -C 4 alkylene)-N(R 7 ) 2 .
  • each R 1 is independently (C 0 -C 4 alkylene)N(R′)—COR 7 , (C 0 -C 4 alkylene)-SO 2 N(R 7 ) 2 , (C 0 -C 4 alkylene)-SO 2 R 7 , (C 0 -C 4 alkylene)N(R 8 )—SO 2 N(R 7 ) 2 , or (C 0 -C 4 alkylene)N(R 8 )—SO 2 R 7 .
  • each R 1 is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, —COR 7 , —CON(R 7 ) 2 , —CN, (C 0 -C 4 alkylene)—OR 7 , or (C 0 -C 4 alkylene)-N(R 7 ) 2 .
  • each R 1 is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, or —CN.
  • each R 1 is independently F, Br, Cl, C 1-6 haloalkyl, or C 1-6 alkyl.
  • each R 1 is independently F or CF 3 .
  • each R 7 is independently selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 carbocyclyl, optionally substituted C 3-10 carbocyclylalkyl, optionally substituted C 2-6 heterocyclyl, optionally substituted C 2-10 heterocyclylalkyl; or two R 11 groups together with the nitrogen to which they are attached join to form an optionally substituted C 2-6 N-heterocyclyl.
  • each R 7 is independently selected from H, C 1-6 alkyl, C 3-6 carbocyclyl, C 3-10 carbocyclylalkyl, C 2-6 heterocyclyl, C 2-10 heterocyclylalkyl; or two R 11 groups together with the nitrogen to which they are attached join to form a C 2-6 N-heterocyclyl.
  • each R 7 is independently selected from H, C 1-6 alkyl, or C 3-6 carbocyclyl.
  • two R 11 groups together with the nitrogen to which they are attached join to form an optionally substituted C 2-6 N-heterocyclyl.
  • each R 7 is independently selected from H or C 1-6 alkyl.
  • each R 7 is H or Me.
  • each R 8 is independently selected from H, C 1-6 alkyl, or C 1-6 haloalkyl. In some embodiments, each R 8 is independently selected from H or C 1-6 alkyl. In some embodiments, each R 8 is independently selected from H or Me. In some embodiments, each R 8 is H.
  • p is 0, 1, 2, 3, or 4. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1 or 2. In some embodiments, p is O or 1. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 2, 3, or 4. In some embodiments, p is 2 or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 1.
  • R 2 is —H, —OH, optionally substituted alkyl, or halogen. In some embodiments, R 2 is —H, —OH, alkyl, haloalkyl, or halogen. In some embodiments, R 2 is —H, —OH, C 1-6 alkyl, C 1-6 haloalkyl, or halogen. In some embodiments, R 2 is —H, —OH, Me, CF 3 , or halogen. In some embodiments, R 2 is —H, —OH, Me, CF 3 , Cl, or F. In some embodiments, R 2 is —H, —OH, Me, CF 3 , or F.
  • R 2 is —H, —OH, or halogen. In some embodiments, R 2 is —H, —OH, or F. In some embodiments, R 2 is —H. In some embodiments, R 2 is —OH. In some embodiments, R 2 is F. In some embodiments, R 2 is Cl.
  • A has the structure
  • each of Y 1 , Y 2 , Y 3 , and each occurrence of Y 4 are independently C(R 5 ) 2 , NR 6 , O, or SO 2 .
  • ⁇ and ⁇ are present. In some embodiments, ⁇ , ⁇ , ⁇ , and ⁇ are absent. In some embodiments, Z 1 is N. In some embodiments, Z 2 is 0, S, or NR 3 ; wherein R 3 is H, C 1 -C 4 alkyl, or oxetane. In some embodiments, X is C. In certain embodiments, ⁇ and ⁇ are present; ⁇ , ⁇ , ⁇ , and ⁇ are absent; Z 1 is N; Z 2 is O, S, or NR 3 ; R 3 is H, C 1 -C 4 alkyl, or oxetane; and X is C.
  • ⁇ , ⁇ , ⁇ , and ⁇ are present. In some embodiments, ⁇ , and ⁇ are absent. In some embodiments, Z 1 is N. In some embodiments, Z 2 is O or NR 3 , wherein R 3 is H, C 1 -C 4 alkyl, or oxetane. In some embodiments, X is C. In certain embodiments, ⁇ , ⁇ , ⁇ , and ⁇ are present; ⁇ , and x are absent; Z 1 is N; Z 2 is O or NR 3 ; R 3 is H, C 1 -C 4 alkyl, or oxetane; and X is C.
  • A has the structure:
  • A has the structure:
  • A has the structure:
  • A has the structure:
  • A has the structure:
  • A has the structure:
  • A has the structure:
  • A has the structure:
  • A has the structure:
  • R 6 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —(C 1 -C 6 alkylene)CF 3 , —(C 1 -C 6 alkylene)OCH 3 , —(C 1 -C 6 alkylene)-halogen, —SO 2 —C 1 -C 6 alkyl, —SO 2 (C 1 -C 6 alkylene)-CF 3 , —SO 2 (C 1 -C 6 alkylene)OCH 3 , —SO 2 (C 1 -C 6 alkylene)-halogen, —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkylene)CF 3 , —C(O)(C 1 -C 6 alkylene)OCH 3 , —C(O)(C 1 -C 6 alkylene)-halogen, —C(O)NH(C 1 -C 6
  • R 6 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —(C 1 -C 6 alkylene)CF 3 , —(C 1 -C 6 alkylene)OCH 3 , —(C 1 -C 6 alkylene)-halogen, —SO 2 —C 1 -C 6 alkyl, —SO 2 (C 1 -C 6 alkylene)-CF 3 , —SO 2 (C 1 -C 6 alkylene)OCH 3 , —SO 2 (C 1 -C 6 alkylene)-halogen, —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkylene)CF 3 , —C(O)(C 1 -C 6 alkylene)OCH 3 , —C(O)(C 1 -C 6 alkylene)-halogen, —C(O)NH(C 1 -C 6 alkyl
  • R 6 is —C(O)(C 1 -C 6 alkyl). In some embodiments, R 6 is H, C 1 -C 4 alkyl, —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , t-Bu, —CH 2 OCH 3 , —CH 2 CF 3 , —CH 2 Cl, —CH 2 F, —CH 2 CH 2 OCH 3 , —CH 2 CH 2 CF 3 , —CH 2 CH 2 C 1 , —CH 2 CH 2 F,
  • R 6 is —C(O)(C 1 -C 6 alkyl). In some embodiments, R 6 is H, C 1 -C 4 alkyl, —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , t-Bu, —CH 2 OCH 3 , —CH 2 CF 3 , —CH 2 Cl, —CH 2 F, —CH 2 CH 2 OCH 3 , —CH 2 CH 2 CF 3 , —CH 2 CH 2 C 1 , —CH 2 CH 2 F, or
  • R 6 is —SO 2 CH 3 , —SO 2 CH 2 CH 3 , —SO 2 CH 2 CH 2 CH 3 , —SO 2 CH(CH 3 ) 2 , —SO 2 CH 2 CH(CH 3 ) 2 , —SO 2 (t-Bu), —SO 2 CH 2 OCH 3 , —SO 2 CH 2 CF 3 , —SO 2 CH 2 Cl, —SO 2 CH 2 F, —SO 2 CH 2 CH 2 OCH 3 , —SO 2 CH 2 CH 2 CF 3 , —SO 2 CH 2 CH 2 Cl, —SO 2 CH 2 CH 2 F, or
  • R 6 is C(O)CH 3 , C(O)CH 2 CH 3 , —C(O)CH 2 CH 2 CH 3 , —C(O)CH(CH 3 ) 2 , —C(O)CH 2 CH(CH 3 ) 2 , —C(O)t-Bu, —C(O)CH 2 OCH 3 , —C(O)CH 2 CF 3 , —C(O)CH 2 C 1 , —C(O)CH 2 F, —C(O)CH 2 CH 2 OCH 3 , —C(O)CH 2 CH 2 CF 3 , —C(O)CH 2 CH 2 C 1 , —C(O)CH 2 CH 2 F,
  • A has the structure:
  • Y 1 , Y 2 , Y 3 and Y 4 are CH. In some embodiments, Y 1 , Y 2 , Y 3 are CH and Y 4 is N. In some embodiments, Y 1 , Y 2 , Y 4 are CH and Y 3 is N. In some embodiments,
  • A has the structure:
  • R 3 is H, halogen, C 1 -C 10 alkyl, C 1 -C 10 cycloalkyl, —O(C 1 -C 10 alkyl), —C(O)OH, —C(O)O(C 1 -C 10 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)N(C 1 -C 4 alkyl) 2 , —NHC(O)NH(C 1 -C 10 alkyl), —NHC(O)N(C 1 -C 4 alkyl) 2 , —SO 2 NH(C 1 -C 10 alkyl), —SO 2 N(C 1 -C 10 alkyl) 2 , —CN, or —CF 3 .
  • R 3 is H, halogen, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, —O(C 1 -C 6 alkyl), —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)N(C 1 -C 4 alkyl) 2 , —NHC(O)NH(C 1 -C 6 alkyl), —NHC(O)N(C 1 -C 4 alkyl) 2 , —SO 2 NH(C 1 -C 6 alkyl), —SO 2 N(C 1 -C 6 alkyl) 2 , —CN, or —CF 3 .
  • R 4 is H, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, —O(C 1 -C 4 alkyl), —CN, —CF 3 , —C(O)OH, —C(O)NH 2 , —C(O)N(CH 3 ) 2 , —C(O)NHCH 3 , or —NHC(O)N(CH 3 ) 2 .
  • R 4 is H, halogen, methyl, methoxy, —CN, —CF 3 , —C(O)N(CH 3 ) 2 , —C(O)NHCH 3 , or —C(O)Me.
  • heterocyclic compounds of Formula (I) are provided in Table 1.
  • the heterocyclic compound of Formula (I) is 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1l-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one; 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one; (4-(3-fluoro-2,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(4, 5, 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(2-chloro-3-fluorophenyl)piperidin-1-
  • Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J.
  • Retinol-binding protein 4 (RBP4), the sole retinol transporter in blood, is secreted from adipocytes and the liver.
  • Lowering levels of RBP4 can lead to reduction in the accumulation of lipofuscin that leads to vision loss in diseases like Age-Related Macular Degeneration, dry (atrophic) Age-Related Macular Degeneration, Juvenile Macular Degeneration (Stargardt Disease), Best disease, adult vitelliform maculopathy, Geographic Atrophy, Stargardt-like macular dystrophy, diabetic retinopathy, or ABCA4 gene associated retinal diseases.
  • lowering RBP4 reduces the accumulation of lipofuscin in the retina.
  • compounds and formulations described herein lower serum or plasma RBP4 and thus delay or stop vision loss from excessive accumulation of lipofuscin in the retina.
  • the serum or plasma levels of RBP4 are reduced by at least 30% from baseline. In some embodiments, 48 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 40% from baseline.
  • the serum or plasma levels of RBP4 are reduced by at least 50% from baseline. In other embodiments, 48 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 65% from baseline.
  • the serum or plasma levels of RBP4 are reduced by at least 80% from baseline. In some embodiments, 48 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 85% from baseline.
  • the serum or plasma levels of RBP4 are reduced by at least 50% from baseline. In other embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 65% from baseline.
  • the serum or plasma levels of RBP4 are reduced by at least 80% from baseline. In some embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 85% from baseline.
  • the serum or plasma levels of RBP4 are reduced by at least 30% from baseline. In some embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 40% from baseline.
  • the serum or plasma levels of RBP4 are reduced by at least 50% from baseline. In other embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 65% from baseline.
  • the serum or plasma levels of RBP4 are reduced by at least 80% from baseline. In some embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 85% from baseline.
  • the serum or plasma levels of RBP4 are reduced by at least 30% from baseline. In some embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 40% from baseline.
  • the serum or plasma levels of RBP4 are reduced by at least 50% from baseline. In other embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 65% from baseline.
  • the serum or plasma levels of RBP4 are reduced by at least 80% from baseline. In some embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 85% from baseline.
  • the serum or plasma levels of RBP4 are reduced by at least 20% from baseline. In some embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 25% from baseline.
  • the serum or plasma levels of RBP4 are reduced by at least 30% from baseline. In some embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 40% from baseline.
  • the serum or plasma levels of RBP4 are reduced by at least 50% from baseline. In other embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 65% from baseline.
  • the serum or plasma levels of RBP4 are reduced by at least 80% from baseline. In some embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 85% from baseline.
  • the serum or plasma levels of RBP4 are reduced by at least 1 mg/dL. In other embodiments, 48 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 2 mg/dL.
  • the serum or plasma levels of RBP4 are reduced by at least 5 mg/dL. In certain embodiments, 48 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 10 mg/dL.
  • the serum or plasma levels of RBP4 are reduced by at least 15 mg/dL.
  • the serum or plasma levels of RBP4 are reduced by at least 15 mg/dL.
  • the serum or plasma levels of RBP4 are reduced by at least 1 mg/dL. In other embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 2 mg/dL.
  • the serum or plasma levels of RBP4 are reduced by at least 5 mg/dL. In certain embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 10 mg/dL.
  • the serum or plasma levels of RBP4 are reduced by at least 15 mg/dL.
  • the serum or plasma levels of RBP4 are reduced by at least 15 mg/dL.
  • the serum or plasma levels of RBP4 are reduced by at least 1 mg/dL. In other embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 2 mg/dL.
  • the serum or plasma levels of RBP4 are reduced by at least 5 mg/dL. In certain embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced by at least 10 mg/dL.
  • the serum or plasma levels of RBP4 are reduced by at least 15 mg/dL.
  • the serum or plasma levels of RBP4 are reduced to below 1 ⁇ M.
  • 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof the serum or plasma levels of RBP4 are reduced to below 1 ⁇ M.
  • the serum or plasma levels of RBP4 are reduced to below 1 ⁇ M.
  • 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof the serum or plasma levels of RBP4 are reduced to below 1 ⁇ M.
  • the serum or plasma levels of RBP4 are reduced to below 1 ⁇ M.
  • the serum or plasma levels of RBP4 are reduced to below 1.5 ⁇ M.
  • 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof the serum or plasma levels of are reduced to below 1.5 ⁇ M.
  • the serum or plasma levels of RBP4 are reduced to below 1.5 ⁇ M. In certain embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma levels of RBP4 are reduced to below 1.5 ⁇ M.
  • the serum or plasma levels of RBP4 are reduced to below 1.5 ⁇ M.
  • the serum or plasma levels of RBP4 are reduced to below 2 ⁇ M.
  • 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof the serum or plasma levels of are reduced to below 2 ⁇ M.
  • the serum or plasma levels of RBP4 are reduced to below 2 ⁇ M.
  • 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof the serum or plasma levels of RBP4 are reduced to below 2 ⁇ M.
  • the serum or plasma levels of RBP4 are reduced to below 2 ⁇ M.
  • a compound disclosed herein is used to treat or ameliorate a disease associated with altered RBP4 pathways when administered to a subject in need thereof.
  • a compound disclosed herein is used to treat or ameliorate the effects of a disease associated with altered RBP4 pathway when administered to a subject in need thereof.
  • Exemplary diseases associated with altered RBP4 include eye diseases.
  • the eye disease is characterized by excessive lipofuscin accumulation in the retina.
  • a compound disclosed herein is used to treat or ameliorate an eye disease when administered to a subject in need thereof.
  • Exemplary eye disease include Age-Related Macular Degeneration, dry (atrophic) Age-Related Macular Degeneration, Juvenile Macular Degeneration (Stargardt Disease), Best disease, adult vitelliform maculopathy, Geographic Atrophy, Stargardt-like macular dystrophy, diabetic retinopathy, or an ABCA4 gene associated retinal disease.
  • Age-related macular degeneration is a common eye condition and a leading cause of vision loss among people age 50 and older. It causes damage to the macula, a small spot near the center of the retina and the part of the eye needed for sharp, central vision. As AMD progresses, a blurred area near the center of vision is a common symptom. Over time, the blurred area may grow larger and the subject may develop blank spots in his or her central vision.
  • Some embodiments provided herein describe the use of the compounds of Formula (I) described herein for treating AMD in a subject in need thereof.
  • the compounds of Formula (I) inhibit AMD.
  • the compounds of Formula (I) arrest development of AMD or its clinical symptoms.
  • the compounds of Formula (I) reduce development of AMD or its clinical symptoms.
  • the compounds of Formula (I) relieve the subject of AMD.
  • the compounds of Formula (I) cause regression, reversal, or amelioration of AMD.
  • the compounds of Formula (I) reduce the number, frequency, duration, or severity of AMD clinical symptoms.
  • the compounds of Formula (I) are used prophylactically. In certain embodiments, the compounds of Formula (I) are used to prevent or reduce the risk of developing AMD. In certain embodiments, the compounds of Formula (I) cause the clinical symptoms of AMD to not develop in a subject who may be predisposed to AMD but who does not yet experience or display symptoms of AMD.
  • atrophic AMD represents a slowly progressing neurodegenerative disorder in which specialized neurons (rod and cone photoreceptors) die in the central part of the retina called the macula.
  • RPE retinal pigment epithelium
  • A2E pyridinium bisretinoid A2E
  • Additional cytotoxic bisretinoids are isoA2E, atRAL di-PE, and A2-DHP-PE.
  • A2E and other lipofuscin bisretinoids begins in photoreceptor cells in a non-enzymatic manner and can be considered as a by-product of the properly functioning visual cycle.
  • A2-DHP-PE A2-dihydropyridine-phosphatidylethanolamine
  • atRALdi-PE all-trans-retinal dimer-phosphatidylethanolamine
  • Some embodiments provided herein describe the use of the compounds of Formula (I) described herein for treating dry (atrophic) AMD in a subject in need thereof.
  • the compounds of Formula (I) inhibit dry (atrophic) AMD.
  • the compounds of Formula (I) arrest development of dry (atrophic) AMD or its clinical symptoms.
  • the compounds of Formula (I) reduce development of dry (atrophic) AMD or its clinical symptoms.
  • the compounds of Formula (I) relieve the subject of dry (atrophic) AMD.
  • the compounds of Formula (I) cause regression, reversal, or amelioration of dry (atrophic) AMD.
  • the compounds of Formula (I) reduce the number, frequency, duration, or severity of dry (atrophic) AMD clinical symptoms.
  • the compounds of Formula (I) are used prophylactically. In certain embodiments, the compounds of Formula (I) are used to prevent or reduce the risk of developing dry (atrophic) AMD. In certain embodiments, the compounds of Formula (I) cause the clinical symptoms of dry (atrophic) AMD to not develop in a subject who may be predisposed to dry (atrophic) AMD but who does not yet experience or display symptoms of dry (atrophic) AMD.
  • STGD Stargardt Disease
  • STGD is an inherited form of juvenile-onset macular degeneration. STGD is characterized by the dramatic accumulation of lipofuscin in the retina. STGD is linked to defects in the ABCA4 gene. Excessive production of lipofuscin bisretinoids is thought to be the sole biochemical trigger of monogenic STGD caused by recessive mutations in the ABCA4 gene. Symptoms include wavy vision, blind spots, blurriness, loss of depth perception, sensitivity to glare, impaired color vision, and difficulty adapting to dim lighting. Symptoms typically develop before age 20.
  • Some embodiments provided herein describe the use of the compounds of Formula (I) described herein for treating STGD in a subject in need thereof.
  • the compounds of Formula (I) inhibit STGD.
  • the compounds of Formula (I) arrest development of STGD or its clinical symptoms.
  • the compounds of Formula (I) reduce development of STGD or its clinical symptoms.
  • the compounds of Formula (I) relieve the subject of STGD.
  • the compounds of Formula (I) cause regression, reversal, or amelioration of STGD.
  • the compounds of Formula (I) reduce the number, frequency, duration, or severity of STGD clinical symptoms.
  • the compounds of Formula (I) are used prophylactically. In certain embodiments, the compounds of Formula (I) are used to prevent or reduce the risk of developing STGD. In certain embodiments, the compounds of Formula (I) cause the clinical symptoms of STGD to not develop in a subject who may be predisposed to STGD but who does not yet experience or display symptoms of STGD.
  • Vitelliform dystrophy is a hereditary retinal dystrophy involving the retinal pigment epithelium (RPE), and leads to a characteristic bilateral yellow “egg-yolk” appearance of the macula. This disease tends to present itself in childhood or early adulthood. Best disease is caused by mutations in the BEST1 gene, which encodes the transmembrane protein bestrophin 1. The mutations lead to a buildup of lipofuscin between the outer retina and the retinal pigment epithelium.
  • Some embodiments provided herein describe the use of the compounds of Formula (I) described herein for treating Best disease in a subject in need thereof.
  • the compounds of Formula (I) inhibit Best disease.
  • the compounds of Formula (I) arrest development of Best disease or its clinical symptoms.
  • the compounds of Formula (I) reduce development of Best disease or its clinical symptoms.
  • the compounds of Formula (I) relieve the subject of Best disease.
  • the compounds of Formula (I) cause regression, reversal, or amelioration of Best disease.
  • the compounds of Formula (I) reduce the number, frequency, duration, or severity of Best disease clinical symptoms.
  • the compounds of Formula (I) are used prophylactically. In certain embodiments, the compounds of Formula (I) are used to prevent or reduce the risk of developing Best disease. In certain embodiments, the compounds of Formula (I) cause the clinical symptoms of Best disease to not develop in a subject who may be predisposed to Best disease but who does not yet experience or display symptoms of Best disease.
  • Geographic atrophy is a chronic progressive degeneration of the macula and can be seen as part of late-stage age-related macular degeneration (AMD).
  • AMD age-related macular degeneration
  • the condition leads to central scotomas and permanent loss of visual acuity.
  • the disease is characterized by localized sharply demarcated atrophy of outer retinal tissue, retinal pigment epithelium and choriocapillaris.
  • Some embodiments provided herein describe the use of the compounds of Formula (I) described herein for treating geographic atrophy in a subject in need thereof.
  • the compounds of Formula (I) inhibit geographic atrophy.
  • the compounds of Formula (I) arrest development of geographic atrophy or its clinical symptoms.
  • the compounds of Formula (I) reduce development of geographic atrophy or its clinical symptoms.
  • the compounds of Formula (I) relieve the subject of geographic atrophy.
  • the compounds of Formula (I) cause regression, reversal, or amelioration of geographic atrophy.
  • the compounds of Formula (I) reduce the number, frequency, duration, or severity of geographic atrophy clinical symptoms.
  • the compounds of Formula (I) are used prophylactically. In certain embodiments, the compounds of Formula (I) are used to prevent or reduce the risk of developing geographic atrophy. In certain embodiments, the compounds of Formula (I) cause the clinical symptoms of geographic atrophy to not develop in a subject who may be predisposed to geographic atrophy but who does not yet experience or display symptoms of geographic atrophy.
  • Rat vitelliform maculopathy is an eye disorder that can cause progressive vision loss.
  • the condition causes the accumulation of lipofuscin in the cells underlying the macula.
  • the condition typically manifests after the age of 40.
  • the condition can be caused by mutations in the RDS and VMD2 genes.
  • Some embodiments provided herein describe the use of the compounds of Formula (I) described herein for treating adult vitelliform maculopathy in a subject in need thereof.
  • the compounds of Formula (I) inhibit adult vitelliform maculopathy.
  • the compounds of Formula (I) arrest development of adult vitelliform maculopathy or its clinical symptoms.
  • the compounds of Formula (I) reduce development of adult vitelliform maculopathy clinical symptoms or its clinical symptoms.
  • the compounds of Formula (I) relieve the subject of adult vitelliform maculopathy.
  • the compounds of Formula (I) cause regression, reversal, or amelioration of adult vitelliform maculopathy.
  • the compounds of Formula (I) reduce the number, frequency, duration, or severity of adult vitelliform maculopathy clinical symptoms.
  • the compounds of Formula (I) are used prophylactically. In certain embodiments, the compounds of Formula (I) are used to prevent or reduce the risk of developing adult vitelliform maculopathy. In certain embodiments, the compounds of Formula (I) cause the clinical symptoms of adult vitelliform maculopathy to not develop in a subject who may be predisposed to adult vitelliform maculopathy but who does not yet experience or display symptoms of adult vitelliform maculopathy.
  • Stargardt-like macular dystrophy is similar in symptoms and presentation to Stargardt disease, but typically presents later in childhood than Stargardt disease.
  • Stargardt-like macular dystrophy is linked with mutations in the EVOVL4 gene.
  • Some embodiments provided herein describe the use of the compounds of Formula (I) described herein for treating Stargardt-like macular dystrophy in a subject in need thereof.
  • the compounds of Formula (I) inhibit Stargardt-like macular dystrophy.
  • the compounds of Formula (I) arrest development Stargardt-like macular dystrophy or its clinical symptoms.
  • the compounds of Formula (I) reduce development of Stargardt-like macular dystrophy or its clinical symptoms.
  • the compounds of Formula (I) relieve the subject of Stargardt-like macular dystrophy.
  • the compounds of Formula (I) cause regression, reversal, or amelioration of Stargardt-like macular dystrophy.
  • the compounds of Formula (I) reduce the number, frequency, duration, or severity of Stargardt-like macular dystrophy clinical symptoms.
  • the compounds of Formula (I) are used prophylactically. In certain embodiments, the compounds of Formula (I) are used to prevent or reduce the risk of developing Stargardt-like macular dystrophy. In certain embodiments, the compounds of Formula (I) cause the clinical symptoms of Stargardt-like macular dystrophy to not develop in a subject who may be predisposed to Stargardt-like macular dystrophy but who does not yet experience or display symptoms of Stargardt-like macular dystrophy.
  • Diabetic retinopathy is a diabetes complication that affects the eyes. It may be caused by damage to the blood vessels of the light sensitive tissue at the back of the eye, and can eventually cause blindness. Diabetic retinopathy can be caused when new blood vessels in the retina fail to grow. Diabetic retinopathy may also result from blood vessels becoming damaged and closing off, causing the growth of new, abnormal blood vessels in the retina.
  • Some embodiments provided herein describe the use of the compounds of Formula (I) described herein for treating diabetic retinopathy in a subject in need thereof.
  • the compounds of Formula (I) inhibit diabetic retinopathy.
  • the compounds of Formula (I) arrest development diabetic retinopathy or its clinical symptoms.
  • the compounds of Formula (I) reduce development of diabetic retinopathy or its clinical symptoms.
  • the compounds of Formula (I) relieve the subject's diabetic retinopathy.
  • the compounds of Formula (I) cause regression, reversal, or amelioration of diabetic retinopathy.
  • the compounds of Formula (I) reduce the number, frequency, duration, or severity of diabetic retinopathy clinical symptoms.
  • the compounds of Formula (I) are used prophylactically. In certain embodiments, the compounds of Formula (I) are used to prevent or reduce the risk of developing diabetic retinopathy. In certain embodiments, the compounds of Formula (I) cause the clinical symptoms of diabetic retinopathy to not develop in a subject who may be predisposed to diabetic retinopathy but who does not yet experience or display symptoms of diabetic retinopathy.
  • ATP-binding cassette, subfamily A, member 4 (ABCA4) is a protein encoded by the ABCA4 gene in humans and other eukaryotes.
  • the ABCA4 protein is expressed almost exclusively in the retina and is implicated in Stargardt and other eye diseases, including but not limited to fundus flavimaculatus, cone-rod dystrophy, retinitis pigmentosa, and age-related macular degeneration. Diminished ABCA4 activity is linked with excessive accumulation of toxic retinoids and lipofuscin. Such mutations in some instances are detected by sequencing a subject's DNA or RNA.
  • Some embodiments provided herein describe the use of the compounds of Formula (I) described herein for treating ABCA4 gene associated retinal diseases in a subject in need thereof.
  • the compounds of Formula (I) inhibit ABCA4 gene associated retinal diseases.
  • the compounds of Formula (I) arrest development ABCA4 gene associated retinal diseases or their clinical symptoms.
  • the compounds of Formula (I) reduce development of ABCA4 gene associated retinal diseases or their clinical symptoms.
  • the compounds of Formula (I) relieve the subject ABCA4 gene associated retinal diseases.
  • the compounds of Formula (I) cause regression, reversal, or amelioration ABCA4 gene associated retinal diseases.
  • the compounds of Formula (I) reduce the number, frequency, duration, or severity of ABCA4 gene associated retinal disease clinical symptoms.
  • the compounds of Formula (I) are used prophylactically. In certain embodiments, the compounds of Formula (I) are used to prevent or reduce the risk of developing ABCA4 gene associated retinal diseases. In certain embodiments, the compounds of Formula (I) cause the clinical symptoms ABCA4 gene associated retinal diseases to not develop in a subject who may be predisposed to ABCA4 gene associated retinal diseases but who does not yet experience or display symptoms of ABCA4 gene associated retinal diseases.
  • the compound of Formula (I) as described herein is administered as a pure chemical.
  • the heterocyclic RBP4 inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, Pa. (2005)).
  • composition comprising at least one heterocyclic RBP4 inhibitory compound, or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers.
  • the carrier(s) or excipient(s) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or patient) of the composition.
  • compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.
  • the heterocyclic RBP4 inhibitory compound as described by Formula (I) is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Suitable dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract.
  • suitable nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, Pa. (2005)).
  • the pharmaceutical compositions provided herein are formulated for oral administration in tablet, capsule, powder, or liquid form.
  • the pharmaceutical formulation is formulated as a tablet.
  • the pharmaceutical formulation is formulated as a capsule.
  • a tablet comprises a solid carrier or an adjuvant.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil, or synthetic oil.
  • physiological saline solution, dextrose or other saccharide solution, or glycols are optionally included.
  • a capsule comprises a solid carrier such as gelatin.
  • the pharmaceutical compositions are provided in a dosage form for parenteral administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has a suitable pH, isotonicity, and stability.
  • isotonic vehicles such as Sodium Chloride injection, Ringer's injection, or Lactated Ringer's injection.
  • preservatives, stabilizers, buffers, antioxidants, and/or other additives are included.
  • compositions are provided in a dosage form for topical administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions of the present invention comprise solid dispersions.
  • a pharmaceutical composition comprises a solid dispersion comprising a compound of Formula (I).
  • a solid dispersion is in some instances a solid composition having at least two components, for example a drug and a polymer. Components of a solid dispersion may be molecularly dispersed, wherein there is a random distribution of drug, polymer, and any additional elements in the dispersion.
  • the molecular dispersion is amorphous.
  • the compound of Formula (I) is amorphous within the molecular dispersion.
  • Solid dispersions can be prepared using many methods known in the art.
  • the solid dispersion is prepared by a melting method, a solvent evaporation method, a fusion method, a kneading method, a melting method, a spray drying method, a co-grinding method, a lyophilization technique, hot melt extrusion, melt agglomeration, or supercritical fluid (SCF) technology.
  • the solid dispersion is prepared using a spray drying method.
  • the solid dispersion is prepared using a hot melt extrusion method.
  • the solid dispersion comprises a compound of Formula (I) and a dispersion polymer.
  • the dispersion polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS or HPMCAS), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers, and derivatives or combinations thereof.
  • HPMC hydroxypropyl methylcellulose
  • HPMC-AS or HPMCAS HPMC-AS or HPMCAS
  • HPC hydroxypropyl cellulose
  • the dispersion polymer comprises about 1-99% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises about 20-80% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises about 40-60% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises about 95% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises about 90% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises about 80% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises about 70% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises about 60% by weight of the solid dispersion.
  • the dispersion polymer comprises about 50% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises about 40% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises about 30% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises about 20% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises about 10% by weight of the solid dispersion.
  • the dispersion polymer comprises at least about 10% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises at least about 20% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises at least about 30% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises at least about 40% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises at least about 50% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises at least about 60% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises at least about 70% by weight of the solid dispersion.
  • the dispersion polymer comprises at least about 80% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises at least about 90% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises at least about 95% by weight of the solid dispersion.
  • the dispersion polymer comprises up to about 10% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises up to about 20% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises up to about 30% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises up to about 40% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises up to about 50% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises up to about 60% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises up to about 70% by weight of the solid dispersion.
  • the dispersion polymer comprises up to about 80% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises up to about 90% by weight of the solid dispersion. In certain embodiments, the dispersion polymer comprises up to about 95% by weight of the solid dispersion.
  • the dispersion polymer is HPMC-AS.
  • the HPMC-AS can be of any grade, including HPMC-AS, LF; HPMC-AS, M; HPMC-AS, H; HPMC-AS, HF; and HPMC-AS, HG.
  • the HPMC-AS can also be of any viscosity, including low, normal, and high.
  • the dispersion polymer comprises HPMC-AS, LF.
  • the dispersion polymer comprises HPMC-AS, M.
  • the dispersion polymer comprises HPMC-AS, HF.
  • the dispersion polymer comprises HPMC-AS, HG.
  • the indicator “L,” “M,” or “H” refers to a low, medium, or high ratio of acetyl to succinyl substituents on the HPMC backbone, respectively.
  • the indicator “F” or “G” refers to either a fine or granular particle size, respectively.
  • a particular grade of HPMC-AS is specified, such as L, M, or H.
  • the grade refers to the ratio of acetyl to succinyl substituents on the HPMC backbone, with “L” grade being a low ratio, “M” grade being a medium ratio, and “H” grade being a high ratio.
  • HPMC-AS, L comprises an acetyl content of about 5-9% and a succinyl content of about 14-18%.
  • the HPMC-AS, L further comprises a methoxyl content of about 20-24% and a hydroxypropyl content of about 5-9%.
  • HPMC-AS, M comprises an acetyl content of about 7-11% and a succinyl content of about 10-14%. In some embodiments, the HPMC-AS, M further comprises a methoxyl content of about 21-25% and a hydroxypropyl content of about 5-9%. In some embodiments, HPMC-AS, H comprises an acetyl content of about 10-14% and a succinyl content of about 4-8%. In some embodiments, the HPMC-AS, H further comprises a methoxyl content of 22-26% and a hydroxypropyl content of about 60-10%. The percentages referred to in this paragraph refer to percentages by weight of the HPMC-AS composition.
  • the dispersion polymer is HPMC.
  • the HPMC is an HPMC derivative.
  • the HPMC or HPMC derivative can be of any grade, including low, normal, or high viscosity grades.
  • suitable HPMC or HPMC derivatives include MethocelTM K100M, K15M, F4M, E4M, K4M, K100LV, K3, E15LV, E15LN, E15CLV, E50, E5, E5LV, E3, and E3LV (available from Dow Chemical, Midland Mich.).
  • the dispersion polymer is HPMC E3LV.
  • the compound of Formula (I) comprises about 1-99% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 10-80% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 10-60% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 10-50% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 10-40% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 20-80% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 20-60% by weight of the solid dispersion.
  • the compound of Formula (I) comprises about 20-50% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 20-40% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 40-60% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 95% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 90% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 80% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 70% by weight of the solid dispersion.
  • the compound of Formula (I) comprises about 60% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 50% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 40% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 30% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 20% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 10% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 5% by weight of the solid dispersion.
  • the compound of Formula (I) comprises at least about 5% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises at least about 10% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises at least about 20% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises at least about 30% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises at least about 40% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises at least about 50% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises at least about 60% by weight of the solid dispersion.
  • the compound of Formula (I) comprises at least about 70% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises at least about 80% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises at least about 90% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises at least about 95% by weight of the solid dispersion.
  • the compound of Formula (I) comprises up to about 5% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises up to about 10% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises up to about 20% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises up to about 30% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises up to about 40% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises up to about 50% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises up to about 60% by weight of the solid dispersion.
  • the compound of Formula (I) comprises up to about 70% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises up to about 80% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises up to about 90% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises up to about 95% by weight of the solid dispersion.
  • the ratio of the compound of Formula (I):dispersion polymer is about 5:95 (w/w) in the solid dispersion. In certain embodiments, the ratio of the compound of Formula (I):dispersion polymer is about 10:90 (w/w) in the solid dispersion. In certain embodiments, the ratio of the compound of Formula (I):dispersion polymer is about 20:80 (w/w) in the solid dispersion. In certain embodiments, the ratio of the compound of Formula (I):dispersion polymer is about 30:70 (w/w) in the solid dispersion. In certain embodiments, the ratio of the compound of Formula (I):dispersion polymer is about 40:60 (w/w) in the solid dispersion.
  • the ratio of the compound of Formula (I):dispersion polymer is about 50:50 (w/w) in the solid dispersion. In certain embodiments, the ratio of the compound of Formula (I):dispersion polymer is about 60:40 (w/w) in the solid dispersion. In certain embodiments, the ratio of the compound of Formula (I):dispersion polymer is about 70:30 (w/w) in the solid dispersion. In certain embodiments, the ratio of the compound of Formula (I):dispersion polymer is about 80:20 (w/w) in the solid dispersion. In certain embodiments, the ratio of the compound of Formula (I):dispersion polymer is about 90:10 (w/w) in the solid dispersion. In certain embodiments, the ratio of the compound of Formula (I):dispersion polymer is about 95:5 (w/w) in the solid dispersion.
  • the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of from about 5:95 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of from about 5:95 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of from about 10:90 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of from about 15:85 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of from about 20:80 to about 50:50.
  • the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of from about 5:95 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of from about 10:90 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of from about 15:85 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of from about 20:80 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 10:90.
  • the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 20:80. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 30:70. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 50:50.
  • the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of from about 5:95 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of from about 5:95 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of from about 10:90 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of from about 15:85 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of from about 20:80 to about 50:50.
  • the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of from about 5:95 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of from about 10:90 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of from about 15:85 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of from about 20:80 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of about 10:90.
  • the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of about 20:80. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of about 30:70. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of about 50:50. In some embodiments, the HPMC-AS, H comprises an acetyl content of about 10-14% and a succinyl content of about 4-8%.
  • the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of from about 5:95 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of from about 5:95 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of from about 10:90 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of from about 15:85 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of from about 20:80 to about 50:50.
  • the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of from about 5:95 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of from about 10:90 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of from about 15:85 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of from about 20:80 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 10:90.
  • the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 20:80. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 30:70. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 50:50. In some embodiments, the HPMC-AS, M comprises an acetyl content of about 7-11% and a succinyl content of about 10-14%.
  • the solid dispersion comprises Compound 1 and PVP.
  • the ratio of Compound 1:PVP is from about 1:10 to about 1:1. In some embodiments, the ratio of Compound 1:PVP is from about 1:10 to about 1:2. In some embodiments, the ratio of Compound 1:PVP is from about 1:5 to about 1:2. In some embodiments, the ratio of Compound 1:PVP is from about 1:5 to about 1:1. In some embodiments, the ratio of Compound 1:PVP is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, or about 1:10. In some embodiments, the ratio of Compound 1:PVP is about 1:2. In some embodiments, the ratio of Compound 1:PVP is about 1:3. In some embodiments, the ratio of Compound 1:PVP is about 1:5. In some embodiments, molecular weight of the PVP is from about 7,000 Daltons to about 11,000 Daltons.
  • the solid dispersion has an average particle size of less than 5 ⁇ m. In certain embodiments, the solid dispersion has an average particle size of less than 10 ⁇ m. In certain embodiments, the solid dispersion has an average particle size of less than 20 ⁇ m. In certain embodiments, the solid dispersion has an average particle size of less than 30 ⁇ m. In certain embodiments, the solid dispersion has an average particle size of less than 40 ⁇ m. In certain embodiments, the solid dispersion has an average particle size of less than 50 ⁇ m. In certain embodiments, the solid dispersion has an average particle size from about 1 ⁇ m to 20 ⁇ m. In certain embodiments, the solid dispersion has an average particle size from about 5 ⁇ m to 20 ⁇ m.
  • the solid dispersion has an average particle size from about 10 ⁇ m to 20 ⁇ m. In certain embodiments, the solid dispersion has an average particle size from about 15 ⁇ m to 20 ⁇ m. In certain embodiments, the solid dispersion has an average particle size from about 1 ⁇ m to 5 ⁇ m. In certain embodiments, the solid dispersion has an average particle size from about 1 ⁇ m to 10 ⁇ m. In certain embodiments, the solid dispersion has an average particle size from about 5 ⁇ m to 10 ⁇ m.
  • the solid dispersion comprises 1-100% by weight of the pharmaceutical composition. In certain embodiments, the solid dispersion comprises 20-80% by weight of the pharmaceutical composition. In certain embodiments, the solid dispersion comprises 40-60% by weight of the pharmaceutical composition. In certain embodiments, the solid dispersion comprises about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% by weight of the pharmaceutical composition.
  • the pharmaceutical composition comprising a solid dispersion comprises a therapeutically effective amount of a compound of Formula (I). In certain embodiments, the pharmaceutical composition comprises about 1 mg of a compound of Formula (I). In certain embodiments, the pharmaceutical composition comprises about 5 mg of a compound of Formula (I). In certain embodiments, the pharmaceutical composition comprises about 10 mg of a compound of Formula (I). In certain embodiments, the pharmaceutical composition comprises about 25 mg of a compound of Formula (I). In certain embodiments, the pharmaceutical composition comprises about 50 mg of a compound of Formula (I). In certain embodiments, the pharmaceutical composition comprises about 100 mg of a compound of Formula (I). In certain embodiments, the pharmaceutical composition comprises about 200 mg of a compound of Formula (I). In certain embodiments, the pharmaceutical composition comprises about 400 mg of a compound of Formula (I).
  • the solid dispersion improves the solubility of a compound of Formula (I). In certain embodiments, the solid dispersion improves the solubility of a compound of Formula (I) by at least two-fold. In certain embodiments, the solid dispersion improves the solubility of a compound of Formula (I) by at least four-fold. In certain embodiments, the solid dispersion improves the solubility of a compound of Formula (I) by at least eight-fold. In certain embodiments, the solid dispersion improves the solubility of a compound of Formula (I) by at least ten-fold. In certain embodiments, the solid dispersion improves the solubility of a compound of Formula (I) by at least 20-fold.
  • the solid dispersion improves the solubility of a compound of Formula (I) by at least 30-fold. In certain embodiments, the solid dispersion improves the solubility of a compound of Formula (I) by at least 40-fold. In certain embodiments, the solid dispersion improves the solubility of a compound of Formula (I) by at least 50-fold. In certain embodiments, the solid dispersion improves the solubility of a compound of Formula (I) by at least 60-fold. In some embodiments, the improvement is measured as compared to a crystalline form of the compound of Formula (I). In some embodiments, the improvement is measured as compared to an amorphous form of the compound of Formula (I). In some embodiments,
  • the pharmaceutical composition further comprises a filler, a sweetener, a disintegrant, a wetting agent, a glidant, a lubricant, or a surfactant, or any combinations thereof.
  • the solid dispersion of the pharmaceutical composition further comprises a filler, a sweetener, a disintegrant, a wetting agent, a glidant, a lubricant, or a surfactant, or any combinations thereof.
  • the pharmaceutical composition further comprises a filler.
  • the solid dispersion of the pharmaceutical composition further comprises a filler.
  • Fillers may be any biocompatible substance that is unreactive with the compound of Formula (I) and the compound of Formula (I).
  • Non-limiting examples of fillers include lactose monohydrate, mannitol, sorbitol, cellulose, calcium phosphate, starch, sugar, cellulose, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, dibasic calcium phosphate, sucrose, lactose, corn starch, potato starch, or any combination thereof.
  • the filler comprises about 1-99% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 10% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 20% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 30% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 40% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 50% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 60% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 70% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 80% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 90% by weight of the pharmaceutical composition.
  • the filler comprises up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises up to about 20% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises up to about 90% by weight of the pharmaceutical composition.
  • the filler comprises at least about 10% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises at least about 20% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises at least about 30% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises at least about 40% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises at least about 50% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises at least about 60% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises at least about 70% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises at least about 80% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises at least about 90% by weight of the pharmaceutical composition.
  • the pharmaceutical composition comprising a compound of Formula (I) further comprises a sweetener.
  • the solid dispersion of the pharmaceutical composition further comprises a sweetener.
  • sweeteners include water-soluble sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), high fructose corn syrup, maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, and dihydrochalcones; water-soluble artificial sweeteners such as the soluble saccharin salts, i.e., sodium or calcium saccharin salts, cyclamate salts, the sodium, ammonium or calcium salt of 3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one
  • the sweetener comprises about 1-99% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 10% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 20% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 30% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 40% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 50% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 60% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 70% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 80% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 90% by weight of the pharmaceutical composition.
  • the sweetener comprises up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises up to about 20% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises up to about 90% by weight of the pharmaceutical composition.
  • the sweetener comprises at least about 10% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises at least about 20% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises at least about 30% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises at least about 40% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises at least about 50% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises at least about 60% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises at least about 70% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises at least about 80% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises at least about 90% by weight of the pharmaceutical composition.
  • the pharmaceutical composition comprising a compound of Formula (I) further comprises a disintegrant.
  • the solid dispersion of the pharmaceutical composition further comprises a disintegrant.
  • disintegrants include agar-agar, algins, calcium carbonate, carboxymethylcellulose, cellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose, clays, croscarmellose sodium, crospovidone, gums, magnesium aluminum silicate, methylcellulose, polacrilin potassium, sodium alginate, sodium starch glycolate, maize starch, potato starch, tapioca starch, or any combination thereof.
  • the disintegrant comprises about 1-99% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 10% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 20% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 30% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 40% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 50% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 60% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 70% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 80% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 90% by weight of the pharmaceutical composition.
  • the disintegrant comprises up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises up to about 20% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises up to about 90% by weight of the pharmaceutical composition.
  • the disintegrant comprises at least about 10% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises at least about 20% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises at least about 30% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises at least about 40% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises at least about 50% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises at least about 60% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises at least about 70% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises at least about 80% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises at least about 90% by weight of the pharmaceutical composition.
  • the pharmaceutical composition comprising a compound of Formula (I) further comprises a wetting agent.
  • the solid dispersion of the pharmaceutical composition further comprises a wetting agent.
  • wetting agents include sodium lauryl sulfate, cetostearyl alcohol, cetomacrogol emulsifying wax, gelatin, casein, docusate sodium, benzalkonium chloride, calcium stearate, polyethylene glycols, phosphates, polyoxyethylene sorbitan fatty acid esters, gum acacia, cholesterol, tragacanth, polyoxyethylene 20 stearyl ethers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, PEGylated hydrogenated castor oils, sorbitan esters of fatty acids, Vitamin E or tocopherol derivatives, vitamin E TPGS, tocopheryl esters, lecithin, phospholipids and their derivatives, poloxamers, stearic acid, ole
  • the wetting agent comprises about 1-99% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 10% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 20% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 30% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 40% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 50% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 60% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 70% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 80% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 90% by weight of the pharmaceutical composition.
  • the wetting agent comprises up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises up to about 20% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises up to about 90% by weight of the pharmaceutical composition.
  • the wetting agent comprises at least about 10% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises at least about 20% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises at least about 30% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises at least about 40% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises at least about 50% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises at least about 60% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises at least about 70% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises at least about 80% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises at least about 90% by weight of the pharmaceutical composition.
  • the pharmaceutical composition comprising a compound of Formula (I) further comprises a glidant.
  • the solid dispersion of the pharmaceutical composition further comprises a glidant.
  • glidants include colloidal silicon dioxide, talk, corn starch, metal silicates, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, and metal hydroxides or any combination thereof.
  • the glidant comprises about 1-99% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 10% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 20% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 30% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 40% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 50% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 60% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 70% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 80% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 90% by weight of the pharmaceutical composition.
  • the glidant comprises up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises up to about 20% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises up to about 90% by weight of the pharmaceutical composition.
  • the glidant comprises at least about 10% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises at least about 20% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises at least about 30% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises at least about 40% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises at least about 50% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises at least about 60% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises at least about 70% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises at least about 80% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises at least about 90% by weight of the pharmaceutical composition.
  • the pharmaceutical composition comprising a compound of Formula (I) further comprises a lubricant.
  • the solid dispersion of the pharmaceutical composition further comprises a lubricant.
  • lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate, or any combination thereof.
  • the lubricant comprises about 1-99% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 10% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 20% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 30% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 40% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 50% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 60% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 70% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 80% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 90% by weight of the pharmaceutical composition.
  • the lubricant comprises up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises up to about 20% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises up to about 90% by weight of the pharmaceutical composition.
  • the lubricant comprises at least about 10% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises at least about 20% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises at least about 30% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises at least about 40% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises at least about 50% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises at least about 60% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises at least about 70% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises at least about 80% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises at least about 90% by weight of the pharmaceutical composition.
  • the pharmaceutical composition further comprises a surfactant.
  • the solid dispersion of the pharmaceutical composition further comprises a surfactant.
  • surfactants include sodium dodecyl sulfate (SDS), sodium laurel sulfate (SLS), macroglycerol ricinoleate (Kolliphor EL® or Cremophor EL®), caprylocaproyl polyoxyl-8 glyceride (Labrasol®), lauroyl polyoxyl-6 glycerides (Labrafil® M 2130 CS), lauroyl polyoxyl-32 glyceride (Gelucire® 44/14), polyethylene glycol monostearate (Gelucire® 48/16), polyoxyethylene hydrogenated castor oil 60 (HCO-60), polysorbate 80 (Tween®-80), polyethylene glycol sorbitan monolaurate (Tween®-20), polyoxyethylene sorbitan trioleate
  • the surfactant comprises about 1-99% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 10% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 20% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 30% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 40% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 50% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 60% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 70% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 80% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 90% by weight of the pharmaceutical composition.
  • the surfactant comprises up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises up to about 20% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises up to about 90% by weight of the pharmaceutical composition.
  • the surfactant comprises at least about 10% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises at least about 20% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises at least about 30% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises at least about 40% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises at least about 50% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises at least about 60% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises at least about 70% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises at least about 80% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises at least about 90% by weight of the pharmaceutical composition.
  • Described herein are methods of manufacturing pharmaceutical compositions, such as those comprising a compound of Formula (I).
  • the methods provided herein may be used to prepare any of the solid dispersion formulations provided herein.
  • a method of manufacturing a solid dispersion comprises the steps of
  • the solvent is an organic solvent.
  • the solvent is selected from the group consisting of ethanol, methanol, acetone, isopropyl alcohol, n-butanol, tetrahydrofuran, dichloromethane, ethyl acetate, methyl acetate, acetonitrile, chloroform, carbon tetrachloride, benzene, toluene, diethyl ether, dioxane, pentane, hexane, cyclohexane, heptane, methyl t-butyl ether, petroleum ether, 1-propanol, methyl ethyl ketone, and combinations thereof.
  • the solvent is a mixture of a non-polar solvent and polar solvent. In certain embodiments, the solvent is 95:5 non-polar:polar. In certain embodiments, the solvent is 95:5 non-polar:polar. In certain embodiments, the solvent is 90:10 non-polar:polar. In certain embodiments, the solvent is 85:15 non-polar:polar. In certain embodiments, the solvent is 80:20 non-polar:polar. In certain embodiments, the solvent is 75:25 non-polar:polar. In certain embodiments, the solvent is 70:30 non-polar:polar. In certain embodiments, the solvent is 60:40 non-polar:polar. In certain embodiments, the solvent is 50:50 non-polar:polar.
  • the solvent is 40:60 non-polar:polar. In certain embodiments, the solvent is 30:70 non-polar:polar. In certain embodiments, the solvent is 20:80 non-polar:polar. In certain embodiments, the solvent is 10:90 non-polar:polar.
  • the solvent is a mixture of chloroform and methanol. In certain embodiments, the solvent is 95:5 chloroform:methanol. In certain embodiments, the solvent is 95:5 chloroform:methanol. In certain embodiments, the solvent is 90:10 chloroform:methanol. In certain embodiments, the solvent is 85:15 chloroform:methanol. In certain embodiments, the solvent is 80:20 chloroform:methanol. In certain embodiments, the solvent is 75:25 chloroform:methanol. In certain embodiments, the solvent is 70:30 chloroform:methanol. In certain embodiments, the solvent is 60:40 chloroform:methanol. In certain embodiments, the solvent is 50:50 chloroform:methanol.
  • the solvent is 40:60 d chloroform:methanol. In certain embodiments, the solvent is 30:70 chloroform:methanol. In certain embodiments, the solvent is 20:80 chloroform:methanol. In certain embodiments, the solvent is 10:90 chloroform:methanol
  • the solvent is a mixture of dichloromethane and methanol. In certain embodiments, the solvent is 95:5 dichloromethane:methanol. In certain embodiments, the solvent is 95:5 dichloromethane:methanol. In certain embodiments, the solvent is 90:10 dichloromethane:methanol. In certain embodiments, the solvent is 85:15 dichloromethane:methanol. In certain embodiments, the solvent is 80:20 dichloromethane:methanol. In certain embodiments, the solvent is 75:25 dichloromethane:methanol. In certain embodiments, the solvent is 70:30 dichloromethane:methanol. In certain embodiments, the solvent is 60:40 dichloromethane:methanol.
  • the solvent is 50:50 dichloromethane:methanol. In certain embodiments, the solvent is 40:60 dichloromethane:methanol. In certain embodiments, the solvent is 30:70 dichloromethane:methanol. In certain embodiments, the solvent is 20:80 dichloromethane:methanol. In certain embodiments, the solvent is 10:90 dichloromethane:methanol.
  • the solvent is a mixture of dichloromethane and ethanol. In certain embodiments, the solvent is 95:5 dichloromethane:ethanol. In certain embodiments, the solvent is 95:5 dichloromethane:ethanol. In certain embodiments, the solvent is 90:10 dichloromethane:ethanol. In certain embodiments, the solvent is 85:15 dichloromethane:ethanol. In certain embodiments, the solvent is 80:20 dichloromethane:ethanol. In certain embodiments, the solvent is 75:25 dichloromethane:ethanol. In certain embodiments, the solvent is 70:30 dichloromethane:ethanol. In certain embodiments, the solvent is 60:40 dichloromethane:ethanol. In certain embodiments, the solvent is 50:50 dichloromethane:ethanol.
  • the solvent is 40:60 dichloromethane:ethanol. In certain embodiments, the solvent is 30:70 dichloromethane:ethanol. In certain embodiments, the solvent is 20:80 dichloromethane:ethanol. In certain embodiments, the solvent is 10:90 dichloromethane:ethanol.
  • the solvent is a mixture of acetone and methanol. In certain embodiments, the solvent is 95:5 acetone:methanol. In certain embodiments, the solvent is 90:10 acetone:methanol. In certain embodiments, the solvent is 85:15 acetone:methanol. In certain embodiments, the solvent is 80:20 acetone:methanol. In certain embodiments, the solvent is 75:25 acetone:methanol. In certain embodiments, the solvent is a 70:30 acetone:methanol. In certain embodiments, the solvent is 60:40 acetone:methanol. In certain embodiments, the solvent is 50:50 acetone:methanol. In certain embodiments, the solvent is 40:60 acetone:methanol. In certain embodiments, the solvent is 30:70 acetone:methanol. In certain embodiments, the solvent is 20:80 dichloromethane:methanol. In certain embodiments, the solvent is 10:90 acetone:methanol.
  • the solvent is a mixture of ethyl acetate and acetonitrile. In certain embodiments, the solvent is 95:5 ethyl acetate:acetonitrile. In certain embodiments, the solvent is 95:5 ethyl acetate:acetonitrile. In certain embodiments, the solvent is 90:10 ethyl acetate:acetonitrile. In certain embodiments, the solvent is 85:15 ethyl acetate:acetonitrile. In certain embodiments, the solvent is 80:20 ethyl acetate:acetonitrile. In certain embodiments, the solvent is 75:25 ethyl acetate:acetonitrile.
  • the solvent is 70:30 ethyl acetate:acetonitrile. In certain embodiments, the solvent is 60:40 ethyl acetate:acetonitrile. In certain embodiments, the solvent is 50:50 ethyl acetate:acetonitrile. In certain embodiments, the solvent is 40:60 ethyl acetate:acetonitrile. In certain embodiments, the solvent is 30:70 ethyl acetate:acetonitrile. In certain embodiments, the solvent is 20:80 ethyl acetate:acetonitrile. In certain embodiments, the solvent is 10:90 ethyl acetate:acetonitrile.
  • the dispersion polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS or HPMCAS), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers, and derivatives or combinations thereof.
  • the dispersion polymer is HPMC-AS.
  • the dispersion polymer is HPMC.
  • the dispersion polymer is PVP.
  • the dispersion polymer is a particular grade of HPMC-AS. In some embodiments, the dispersion polymer is HPMC-AS, L. In some embodiments, the dispersion polymer is HPMC-AS, M. In some embodiments, the dispersion polymer is HPMC-AS, H. In some embodiments, the dispersion polymer is PVP. In some embodiments, the PVP has a molecular weight from about 7000 Daltons to about 11000 Daltons.
  • the method further comprises the step of adding an additional element to the first mixture.
  • the additional element is a filler, a sweetener, a disintegrant, a wetting agent, a glidant, a lubricant, a surfactant, or any combinations thereof.
  • the compound of Formula (I) has the structure:
  • the compound of formula (1) or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof.
  • the compound of formula (1) or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof.
  • Formula (I) has the structure:
  • a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is formulated as a solid dispersion.
  • Nanosuspension pharmaceutical compositions comprising compounds of Formula (I), especially Compound 1.
  • Nanosuspensions are formulations ideally suited to compounds with low solubility in pharmaceutically acceptable solvents. Such formulations can offer improved bioavailabiliy of such compounds.
  • Nanosuspension typically comprises the desired API in a stable polymorphic form with an average particle size of less than 1000 nm, which is then suspended in a liquid (such as water). Ideally, the API will remain stably suspended in the formulation for an extended period of time without any change to the polymorphic form of the API.
  • Such formulations often comprise additional reagents, such as surfactants or emulsifiers to aid in keeping the API in the suspension.
  • a nanosuspension pharmaceutical composition comprising: a compound of Formula (I), a pharmaceutically acceptable salt, crystalline, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, suspended in a pharmaceutically acceptable solvent.
  • the compound of Formula (I) is Compound 1.
  • Compound 1 is the polymorph “Form C” provided herein.
  • the nanosuspension pharmaceutical formulation comprises an indicated amount of the compound of Formula (I). In some embodiments, the compound of Formula (I) is present in an amount of about 1 mg/mL to about 500 mg/mL. In some embodiments, the compound of Formula (I) is present in an amount of about 1 mg/mL to about 200 mg/mL.
  • the compound of Formula (I) is present in an amount of about 1 mg/mL to about 5 mg/mL, about 1 mg/mL to about 10 mg/mL, about 1 mg/mL to about 25 mg/mL, about 1 mg/mL to about 50 mg/mL, about 1 mg/mL to about 100 mg/mL, about 1 mg/mL to about 200 mg/mL, about 5 mg/mL to about 10 mg/mL, about 5 mg/mL to about 25 mg/mL, about 5 mg/mL to about 50 mg/mL, about 5 mg/mL to about 100 mg/mL, about 5 mg/mL to about 200 mg/mL, about 10 mg/mL to about 25 mg/mL, about 10 mg/mL to about 50 mg/mL, about 10 mg/mL to about 100 mg/mL, about 10 mg/mL to about 200 mg/mL, about 25 mg/mL to about 50 mg/mL, about 10 mg/mL to about 100 mg/mL, about 10 mg
  • the compound of Formula (I) is present in an amount of about 1 mg/mL, about 5 mg/mL, about 10 mg/mL, about 25 mg/mL, about 50 mg/mL, about 100 mg/mL, or about 200 mg/mL. In some embodiments, the compound of Formula (I) is present in an amount of at least about 1 mg/mL, about 5 mg/mL, about 10 mg/mL, about 25 mg/mL, about 50 mg/mL, or about 100 mg/mL.
  • the compound of Formula (I) is present in an amount of at most about 5 mg/mL, about 10 mg/mL, about 25 mg/mL, about 50 mg/mL, about 100 mg/mL, or about 200 mg/mL. In some embodiments, the compound of Formula (I) is present in an amount of about 1 mg/mL to about 200 mg/mL. In some embodiments, the compound of Formula (I) is present in an amount of about 1 mg/mL to about 10 mg/mL. In some embodiments, the compound of Formula (I) is present in an amount of about 5 mg/mL to about 10 mg/mL In some embodiments, the compound of Formula (I) is present in an amount of about 5 mg/mL or about 10 mg/mL.
  • the compound of Formula (I) has an average particle size of less than 1000 nm. In some embodiments, the compound of Formula (I) has an average particle size of about 50 nm to about 1,000 nm. In some embodiments, the compound of Formula (I) has an average particle size of about 50 nm to about 100 nm, about 50 nm to about 250 nm, about 50 nm to about 500 nm, about 50 nm to about 750 nm, about 50 nm to about 1,000 nm, about 100 nm to about 250 nm, about 100 nm to about 500 nm, about 100 nm to about 750 nm, about 100 nm to about 1,000 nm, about 250 nm to about 500 nm, about 250 nm to about 750 nm, about 250 nm to about 1,000 nm, about 500 nm to about 750 nm, about 500 nm to about 1,000 nm, or about 750 nm to about 1,000
  • the compound of Formula (I) has an average particle size of about 50 nm, about 100 nm, about 250 nm, about 500 nm, about 750 nm, or about 1,000 nm. In some embodiments, the compound of Formula (I) has an average particle size of at least about 50 nm, about 100 nm, about 250 nm, about 500 nm, or about 750 nm. In some embodiments, the compound of Formula (I) has an average particle size of at most about 100 nm, about 250 nm, about 500 nm, about 750 nm, or about 1,000 nm.
  • the particle size distribution of the resultant suspensions can be measured using any instrumentation.
  • An example is laser diffraction using a Cilas Particle Size Analyser 1190.
  • the images of the particles can be taken using, for example, the microscope “Olympus”.
  • the resolution rates can be determined, for example, by a pION ⁇ DISS Profiler.
  • the compound of Formula (I) is micronized.
  • the compound can be micronized by any suitable method, such as milling or jet milling.
  • the compound is milled in a solution comprising any additional additives that will be in the final formulation, such as surfactant or excipients.
  • the solvent is water. In some embodiments, the solvent is water and an additional solvent. Solvents include, but are not limited to, ethanol, t-butanol, hexane and glycol.
  • the pH of the aqueous dispersion media can be adjusted by techniques known to those skilled in the art. Ideally, the pH should be one that will be tolerable by the subject, such as near neutral.
  • the pH of the nanosuspension pharmaceutical formulation is about 7. In some embodiments, the pH of the nanosuspension pharmaceutical formulation is about 6. In some embodiments, the pH of the nanosuspension pharmaceutical formulation is from about 6 to about 8. In some embodiments, the pH of the nanosuspension pharmaceutical formulation is from about 5 to about 9. In some embodiments, the pH of the nanosuspension pharmaceutical formulation is from about 6 to about 7. In some embodiments, the pH of the nanosuspension pharmaceutical formulation is from about 5 to about 7.
  • the nanosuspension pharmaceutical formulation further comprises a surfactant.
  • Surfactants are wetting agents that lower the surface tension of a liquid allowing easier spreading and lower the interfacial tension between two liquids.
  • Surfactants are usually organic compounds that are amphiphilic, therefore, they are soluble in both organic solvents and water. Surfactants reduce the surface tension of water by adsorbing at the liquid-gas interface. They also reduce the interfacial tension between oil and water by adsorbing at the liquid-liquid interface.
  • Surfactants are classified into two primary groups: ionic (anionic, cationic and zwitterionic) (dual charge) and non-ionic.
  • non-ionic surfactants include, but are limited to, alkyl poly(ethylene oxide), copolymers of poly(ethylene oxide) and poly(propylene oxide) (a.k.a. poloxamers), (alkyl polyglucosides, such as octyl glucoside, decyl maltoside, fatty alcohols, cetyl alcohol, oleyl alcohol, cocamide MEA, cocamide DEA, polysorbates, such as Tween 20, Tween 80, and dodecyl dimethylamine oxide.
  • the surfactant comprises a poloxamer.
  • the surfactant comprises a polysorbate.
  • ionic surfactants include, but are limited to, rerfluorooctanoate (PFOA or PFO), pertluorooctanesulfonate (PFOS), sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, sodium lauryl ether sulfate (SLES), alkyl benzene sulfonate, soaps, or a fatty acid salts (anionic), cetyl tri ammonium bromide (CTAB) a.k.a.
  • the surfactant comprises SDS.
  • nanosuspension comprises a surfactant at a concentration of about 0.01% to about 1%. In some embodiments, nanosuspension comprises a surfactant at a concentration of about 0.01% to about 0.05%, about 0.01% to about 0.1%, about 0.01% to about 0.2%, about 0.01% to about 0.35%, about 0.01% to about 0.5%, about 0.01% to about 0.75%, about 0.01% to about 1%, about 0.05% to about 0.1%, about 0.05% to about 0.2%, about 0.05% to about 0.35%, about 0.05% to about 0.5%, about 0.05% to about 0.75%, about 0.05% to about 1%, about 0.1% to about 0.2%, about 0.1% to about 0.35%, about 0.1% to about 0.5%, about 0.1% to about 0.75%, about 0.1% to about 1%, about 0.2% to about 0.35%, about 0.1% to about 0.5%, about 0.1% to about 0.75%, about 0.1% to about 1%, about 0.2% to about 0.35%, about
  • nanosuspension comprises a surfactant at a concentration of about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.35%, about 0.5%, about 0.75%, or about 1%. In some embodiments, nanosuspension comprises a surfactant at a concentration of at least about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.35%, about 0.5%, or about 0.75%. In some embodiments, nanosuspension comprises a surfactant at a concentration of at most about 0.05%, about 0.1%, about 0.2%, about 0.35%, about 0.5%, about 0.75%, or about 1%.
  • nanosuspension comprises SDS at a concentration of about 0.01% to about 1%. In some embodiments, nanosuspension comprises SDS at a concentration of about 0.01% to about 0.05%, about 0.01% to about 0.1%, about 0.01% to about 0.2%, about 0.01% to about 0.35%, about 0.01% to about 0.5%, about 0.01% to about 0.75%, about 0.01% to about 1%, about 0.05% to about 0.1%, about 0.05% to about 0.2%, about 0.05% to about 0.35%, about 0.05% to about 0.5%, about 0.05% to about 0.75%, about 0.05% to about 1%, about 0.1% to about 0.2%, about 0.1% to about 0.35%, about 0.1% to about 0.5%, about 0.1% to about 0.75%, about 0.1% to about 1%, about 0.2% to about 0.35%, about 0.1% to about 0.5%, about 0.1% to about 0.75%, about 0.1% to about 1%, about 0.2% to about 0.35%, about 0.2% to about 0.5%
  • nanosuspension comprises SDS at a concentration of about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.35%, about 0.5%, about 0.75%, or about 1%. In some embodiments, nanosuspension comprises SDS at a concentration of at least about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.35%, about 0.5%, or about 0.75%. In some embodiments, nanosuspension comprises SDS at a concentration of at most about 0.05%, about 0.1%, about 0.2%, about 0.35%, about 0.5%, about 0.75%, or about 1%.
  • the nanosuspension comprises one or more excipients.
  • Suitable excipients include, but are not limited to, PVP, CMC, HPMC, HPC, PEG, PEO, transcutol and glycerin.
  • the excipient comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers, or any combinations thereof.
  • the excipient is a low mole
  • the excipient is HPMC, HPMC-AS, HPC, or PVP. In some embodiments, the excipient is HPC.
  • nanosuspension comprises an excipient at a concentration of about 0.1% to about 5%. In some embodiments, nanosuspension comprises an excipient at a concentration of about 0.1% to about 0.5%, about 0.1% to about 1%, about 0.1% to about 1.5%, about 0.1% to about 2%, about 0.1% to about 3%, about 0.1% to about 4%, about 0.1% to about 5%, about 0.5% to about 1%, about 0.5% to about 1.5%, about 0.5% to about 2%, about 0.5% to about 3%, about 0.5% to about 4%, about 0.5% to about 5%, about 1% to about 1.5%, about 1% to about 2%, about 1% to about 3%, about 1% to about 4%, about 1% to about 5%, about 1.5% to about 2%, about 1.5% to about 3%, about 1.5% to about 4%, about 1.5% to about 5%, about 2% to about 3%, about 2% to about 4%, about 2% to about 5%, about 2% to about 3%, about 1.5%
  • nanosuspension comprises an excipient at a concentration of about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 3%, about 4%, or about 5%. In some embodiments, nanosuspension comprises an excipient at a concentration of at least about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 3%, or about 4%. In some embodiments, nanosuspension comprises an excipient at a concentration of at most about 0.5%, about 1%, about 1.5%, about 2%, about 3%, about 4%, or about 5%.
  • nanosuspension comprises HPC at a concentration of about 0.1% to about 5%. In some embodiments, nanosuspension comprises HPC at a concentration of about 0.1% to about 0.5%, about 0.1% to about 1%, about 0.1% to about 1.5%, about 0.1% to about 2%, about 0.1% to about 3%, about 0.1% to about 4%, about 0.1% to about 5%, about 0.5% to about 1%, about 0.5% to about 1.5%, about 0.5% to about 2%, about 0.5% to about 3%, about 0.5% to about 4%, about 0.5% to about 5%, about 1% to about 1.5%, about 1% to about 2%, about 1% to about 3%, about 1% to about 4% about 1% to about 5%, about 1.5% to about 2%, about 1.5% to about 3%, about 1.5% to about 4% about 1.5% to about 5%, about 2% to about 3%, about 2% to about 4%, about 2% to about 5%, about 3% to about 4%, about 2% to about 5%, about
  • nanosuspension comprises HPC at a concentration of about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 3%, about 4%, or about 5%. In some embodiments, nanosuspension comprises HPC at a concentration of at least about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 3%, or about 4%. In some embodiments, nanosuspension comprises HPC at a concentration of at most about 0.5%, about 1%, about 1.5 00 about 2%, about 3%, about 4%, or about 5%.
  • a nanosuspension wherein the resulting nanosuspension is stable for more than 1, 5, 10, 15, 20 or 25 days at a room temperature (22° C.). In certain embodiments, provided is a nanosuspension wherein the resulting nanosuspension is stable for more than 1, 2, 3 or 4 weeks at a room temperature (22° C.). In certain embodiments, provided is a nanosuspension wherein the resulting nanosuspension is stable for more than 1, 3, 6, 12, 18 or 24 months at a room temperature (22° C.). In some embodiments, stability is measured by a change in particle size or particle size distribution of the compound. In some embodiments, stability is measured by the chemical stability of the compound. In some embodiments, stability is measured by a change in the polymorph of the compound.
  • Form C is a crystalline solid having high thermodynamic stability, making it well suited for pharmaceutical formulations of Compound 1.
  • FIG. 16 shows numerous peaks at many degrees two theta, including with limitation at approximately 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • XRPD peak values in the application refer to those obtained using a copper source with a wavelength of 1.5406 angstrom unless otherwise noted.
  • the compound of Formula (I) exhibits an x-ray powder diffraction pattern having at least three characteristic peaks expressed in degrees two theta (+/ ⁇ 0.5 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern having at least four characteristic peaks expressed in degrees two theta (+/ ⁇ 0.5 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern having at least five characteristic peaks expressed in degrees two theta (+/ ⁇ 0.5 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0. In some embodiments, the polymorph exhibits an x-ray powder diffraction pattern having at least six characteristic peaks expressed in degrees two theta (+/ ⁇ 0.5 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern having characteristic peaks expressed in degrees two theta (+/ ⁇ 0.5 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern having at least three characteristic peaks expressed in degrees two theta (+/ ⁇ 1.0 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern having at least four characteristic peaks expressed in degrees two theta (+/ ⁇ 1.0 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern having at least five characteristic peaks expressed in degrees two theta (+/ ⁇ 1.0 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0. In some embodiments, the polymorph exhibits an x-ray powder diffraction pattern having at least six characteristic peaks expressed in degrees two theta (+/ ⁇ 1.0 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern having characteristic peaks expressed in degrees two theta (+/ ⁇ 1.0 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern having at least three characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern having at least four characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern having at least five characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0. In some embodiments, the polymorph exhibits an x-ray powder diffraction pattern having at least six characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern having characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and/or 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 6.7, 9.3, and 14.1. In some embodiments, the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 6.7, 9.3, and 17.2. In some embodiments, the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 6.7, 9.3, and 23.5.
  • the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 6.7, 9.3, and 27.1. In some embodiments, the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 6.7, 9.3, and 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 6.7, 14.1, and 17.2. In some embodiments, the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 6.7, 14.1, and 23.5. In some embodiments, the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 6.7, 14.1, and 27.1. In some embodiments, the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 6.7, 14.1, and 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 9.3, 14.1, and 17.2. In some embodiments, the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 9.3, 14.1, and 23.5. In some embodiments, the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 9.3, 14.1, and 27.1. In some embodiments, the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 9.3, 14.1, and 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 9.3, 14.1, and 17.2. In some embodiments, the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 9.3, 14.1, and 23.5. In some embodiments, the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 9.3, 14.1, and 27.1. In some embodiments, the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 9.3, 14.1, and 29.0.
  • the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 14.1, 17.2, and 23.5.
  • the XRPD pattern further comprises a peak at 29.0 (+/ ⁇ 0.2 degree theta).
  • the XRPD pattern further comprises a peak at 27.1 (+/ ⁇ 0.2 degree theta).
  • the XRPD pattern further comprises a peak at 9.3 (+/ ⁇ 0.2 degree theta).
  • the XRPD pattern further comprises a peak at 6.7 (+/ ⁇ 0.2 degree theta).
  • the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 9.3, 17.2, 23.5, and 27.1.
  • the XRPD pattern further comprises a peak at 14.1(+/ ⁇ 0.2 degree theta).
  • the XRPD pattern further comprises a peak at 29.0 (+/ ⁇ 0.2 degree theta).
  • the XRPD pattern further comprises a peak at 6.7 (+/ ⁇ 0.2 degree theta).
  • the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 6.7, 9.3, 17.2, and 23.5.
  • the XRPD pattern further comprises a peak at 14.1(+/ ⁇ 0.2 degree theta).
  • the XRPD pattern further comprises a peak at 29.0 (+/ ⁇ 0.2 degree theta).
  • the XRPD pattern further comprises a peak at 27.1 (+/ ⁇ 0.2 degree theta).
  • the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.2 degree theta) at 6.7, 9.3, 17.2, 23.5, and 27.1.
  • the XRPD pattern further comprises a peak at 14.1(+/ ⁇ 0.2 degree theta). In some embodiments, the XRPD pattern further comprises a peak at 29.0 (+/ ⁇ 0.2 degree theta).
  • the polymorph exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees two theta (+/ ⁇ 0.5 degree theta) at 6.7, 9.3, 17.2, 23.5, and 27.1.
  • the XRPD pattern further comprises a peak at 14.1(+/ ⁇ 0.5 degree theta). In some embodiments, the XRPD pattern further comprises a peak at 29.0 (+/ ⁇ 0.5 degree theta).
  • the XRPD pattern comprises peaks substantially identical to those shown in FIG. 16 .
  • the polymorph exhibits Differential Scanning calorimetry (DSC) of an endotherm at about 228° C.
  • DSC Differential Scanning calorimetry
  • Form A a polymorph of Compound 1, referred to herein as Form A, having an XRPD pattern substantially identical to that shown in FIG. 15 .
  • the dose of the composition comprising at least one compound of Formula (I) as described herein differ, depending upon the patient's condition, that is, stage of the disease, general health status, age, and other factors.
  • compositions are administered in a manner appropriate to the disease to be treated (or prevented).
  • An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome), or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • the compounds described herein, or a pharmaceutically acceptable salt thereof are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from administration of any one of the compounds disclosed.
  • 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.
  • compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient 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 patient's health status, weight, and response to the drugs, and the judgment of the treating physician. 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 patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.”
  • a patient susceptible to or otherwise at risk of a particular disease, disorder or condition is defined to be a “prophylactically effective amount or dose.”
  • dose a pharmaceutically effective amount or dose.
  • the precise amounts also depend on the patient's state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • prophylactic treatments include administering to a mammal, in which the mammal 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 patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
  • Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day. In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg to 5000 mg per day. In certain embodiments, oral doses range from about 0.1 mg to about 20 mg per day. In certain embodiments, oral doses range from about 0.5 mg to about 50 mg per day. In certain embodiments, oral dosages range from about 1 mg to about 10 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one 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.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 225 mg, about
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, or about 20 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to about 0.1 mg, up to about 0.5 mg, up to about 1 mg, up to about 5 mg, up to about 10 mg, up to about 15 mg, up to about 20 mg, up to about 25 mg, up to about 30 mg, up to about 35 mg, up to about 40 mg, up to about 45 mg, up to about 50 mg, up to about 55 mg, up to about 60 mg, up to about 65 mg, up to about 70 mg, up to about 75 mg, up to about 80 mg, up to about 85 mg, up to about 90 mg, up to about 95 mg, up to about 100 mg, up to about 105 mg, up to about 110 mg, up to about 115 mg, up to about 120 mg, up to about 125 mg, up to about 130 mg, up to about 135 mg, up to about 140 mg,
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to about 0.1 mg, up to about 0.5 mg, up to about 1 mg, up to about 5 mg, up to about 10 mg, up to about 15 mg, or up to about 20 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least 0.1 mg, least 0.5 mg, least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least 0.1 mg, at least 0.5 mg, at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, or about 20 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 0.1 mg, up to 0.5 mg, up to 1 mg, up to 5 mg, up to 10 mg, up to 25 mg, up to 50 mg, up to100 mg, or up to 200 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least 0.1 mg, at least 0.5 mg, at least 1 mg, at least 5 mg, at least 10 mg, at least 25 mg, at least 50 mg, at least 100 mg, or at least 200 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.1 mg per day, about 0.5 mg per day, about 1 mg per day, about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 50 mg per day, about 75 mg per day, about 100 mg per day, about 150 mg per day, about 200 mg per day, or about 400 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.1 mg per day, about 0.5 mg per day, about 1 mg per day, about 5 mg per day, about 10 mg per day, about 25 mg per day, or about 50 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 0.1 mg per day, up to 0.5 mg per day, up to 1 mg per day, up to 5 mg per day, up to 10 mg per day, up to 25 mg per day, up to 50 mg per day, up to 100 mg per day, or up to 200 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least 0.1 mg per day, at least 0.5 mg per day, at least 1 mg per day, at least 5 mg per day, at least 10 mg per day, at least 25 mg per day, at least 50 mg per day, at least 100 mg per day, or at least 200 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 1 mg to about 20 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 1 mg to about 10 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.1 mg to about 20 mg. In some embodiments, a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.5 mg to about 50 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.1 mg to about 10 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.1 mg to about 100 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 1 mg to about 500 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 400 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 200 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 150 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 100 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 75 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 50 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 25 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 10 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 5 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 1 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 0.5 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 0.1 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 400 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 200 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 150 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 100 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 75 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 50 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 25 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 10 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 5 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 1 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 0.5 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 0.1 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 400 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 200 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 150 mg. In some embodiments, a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 100 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 75 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 50 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 25 mg. In some embodiments, a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 10 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 5 mg. In some embodiments, a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 1 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.5 mg. In some embodiments, a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.1 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 400 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 200 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 150 mg per day. In some embodiments, a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 100 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 75 mg per day. In some embodiments, a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 50 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 25 mg per day. In some embodiments, a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 10 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 5 mg per day. In some embodiments, a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 1 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.5 mg per day. In some embodiments, a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.1 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 400 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 200 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 150 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 100 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 75 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 50 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 25 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 10 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 5 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 1 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 0.5 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 0.1 mg.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 400 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 200 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 150 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 100 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 75 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 50 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 25 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 10 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 5 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 1 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 0.5 mg per day.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least about 0.1 mg per day.
  • the daily dosages appropriate for the compound of Formula (I) described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight. In certain embodiments the daily dosages are from about 0.01 to about 25, about 0.01 to about 1, about 0.1 to about 5, about 1 to about 10, about 1 to about 5, about 0.5 to about 5 or about 5 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.
  • 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.
  • 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 certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • 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.
  • 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.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered orally or parenterally to the subject in need thereof.
  • Parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered orally or intravenously to a subject in need thereof.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered orally to a subject in need thereof.
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered intravenously to a subject in need thereof.
  • 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, e.g., two, three, four or more times daily.
  • the compounds of Formula (I) described herein are administered daily, every other day, every other day 3 times a week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 3 days, every 4 days, every 5 days, every 6 days, weekly, bi-weekly, 3 times a week, 4 times a week, 5 times a week, 6 times a week, once a month, twice a month, 3 times a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months.
  • the heterocyclic RBP4 inhibitory compounds described herein, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof are administered daily.
  • 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 every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours.
  • the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (e.g., 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 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 7 days. In one embodiment, the length of the drug holiday is 7 days. In one embodiment, the length of the drug holiday is 14 days. In one embodiment, the length of the drug holiday is 28 days.
  • a compound of Formula (I) is administered as a pharmaceutical composition.
  • a compound of Formula (I) is administered to a subject as a pharmaceutical composition comprising a solid dispersion comprising the compound of Formula (I).
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg as a pharmaceutical composition comprising a solid dispersion comprising the compound of Formula (I).
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.1 mg, about 0.5 mg about 1 mg, about 5 mg, about 10 mg, about 15 mg, or about 20 mg as a pharmaceutical composition comprising a solid dispersion comprising the compound of Formula (I).
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of up to 0.1 mg, up to 0.5 mg, up to 1 mg, up to 5 mg, up to 10 mg, up to 25 mg, up to 50 mg, up to 100 mg, or up to 200 mg as part of a pharmaceutical composition comprising a solid dispersion comprising the compound of Formula (I).
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of at least 0.1 mg, at least 0.5 mg, at least 1 mg at least 5 mg, at least 10 mg, at least 25 mg, at least 50 mg, at least 100 mg, or at least 200 mg as a pharmaceutical composition comprising a solid dispersion comprising the compound of Formula (I).
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.1 mg as a pharmaceutical composition comprising a solid dispersion comprising a compound of Formula (I).
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.5 mg as a pharmaceutical composition comprising a solid dispersion comprising a compound of Formula (I).
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 1 mg as a pharmaceutical composition comprising a solid dispersion comprising a compound of Formula (I).
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 5 mg as a pharmaceutical composition comprising a solid dispersion comprising a compound of Formula (I).
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 10 mg as a pharmaceutical composition comprising a solid dispersion comprising a compound of Formula (I).
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 15 mg as a pharmaceutical composition comprising a solid dispersion comprising the compound of Formula (I).
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 20 mg as a pharmaceutical composition comprising a solid dispersion comprising the compound of Formula (I).
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 1 mg to about 20 mg as a pharmaceutical composition comprising a solid dispersion comprising the compound of Formula (I).
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 1 mg to about 100 mg as a pharmaceutical composition comprising a solid dispersion comprising the compound of Formula (I).
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 1 mg to about 500 mg as a pharmaceutical composition comprising a solid dispersion comprising the compound of Formula (I).
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.1 mg to about 1000 mg as a pharmaceutical composition comprising a solid dispersion comprising the compound of Formula (I).
  • a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered to a subject or patient in an amount of about 0.1 mg to about 20 mg as a pharmaceutical composition comprising a solid dispersion comprising the compound of Formula (I).
  • Example 1 Compound 1 Treatment of a Macular Degeneration Mouse Model
  • Abcd4/rdh8 double knockout mice were either untreated or treated with Compound 1. Wild type C 57 BL/6J mice were also used as a normal control. Mice treated with Compound 1 had significantly lower levels of A2E in the retina, and lower levels of RBP4 in serum. ( FIG. 2 ). Diseases such as dry AMD or Stargardt are associated with thinning of the outer nuclear layer (ONL) of the eye and the loss of photoreceptor cells, indicating macular degeneration. ONL thickness was significantly decreased in the diseased group (abcd4/rdh8 knockout mice), as compared to the diseased group treated with Compound 1, wherein the ONL was preserved ( FIG. 3 ).
  • the subject population consisted of 40 healthy volunteers.
  • Objectives of the study were to characterize the systemic and ocular safety of single doses of Compound 1, characterize the pharmacokinetics (PK) of single doses of Compound 1, and determine effects of single doses of Compound 1 on serum levels of retinol binding protein 4 (RBP4), a pharmacodynamics (PD) marker.
  • PK pharmacokinetics
  • RBP4 retinol binding protein 4
  • PD pharmacodynamics
  • the study was a randomized, double blind, placebo-controlled, sequential single dose study. There were 5 dose levels. Each cohort consisted of 8 subjects, 6 receiving Compound 1 and 2 subjects receiving placebo.
  • Cohorts 1-3 resided in the research unit from Day ⁇ 1 through Day 3; Cohorts 4 and 5 on Days ⁇ 1 to 4. On Day ⁇ 1 baseline safety and PD markers were obtained. Subjects received a single oral dose on the morning of Day 1. Safety, PK and PD were obtained through Day 3 in early cohorts, though Day 4 in later.
  • Safety evaluation was evaluated by collecting adverse events, physical examination, Ocular examination (including slit lamp biomicroscopy, dilated ophthalmoscopy and intraocular pressure), Visual acuity, D-28 color vision text, Visual fields, Night vision questionnaire (multiple dose only), Vital signs (blood pressure, heart rate, temperature, respiratory rate), Weight, CBC with differential and platelets, serum chemistry, urinalysis, and ECG.
  • ECGs were performed following recommendations in ICH E14 regarding evaluation of QTc prolongation in patients in early stage clinical trials.
  • ECGs were performed in triplicate on Days 1, 2, 8, 15, and 16.
  • Visual acuity was measured using Early Treatment of Diabetic Retinopathy Study (ETDRS) Visual Acuity charts 1 and 2.
  • the chart was placed on an ETDRS light box which is hung at eye level on the wall or placed on a stand. Room lighting was at office levels and uniform between the subject and the light box. The distance from the patient's eyes to the Visual Acuity Chart was 4.0 meters. If vision tests were performed on the same day as an ERG, they were completed prior to pupil dilation.
  • EDRS Early Treatment of Diabetic Retinopathy Study
  • PK sampling of plasma was conducted in all subjects (for example predose, 0.5, 1, 1.5, 2, 3, 4, 8, 8, 10, 12, 16, 24, 36 and 48 hours post dose on Days 1-3 and 15-17; trough predose on other days; and times were finalized based on toxicokinetics).
  • Compound 1 concentrations were determined using a high-pressure liquid chromatography coupled with a mass spectrometer (LC/MS/MS) method.
  • Serum RBP4 was measured using a validated commercial ELISA assay. Full-field ERG measurements were recorded after pupil dilation using 10% tropicamide and 30 minutes of dark adaptation at baseline and on Day 1 (approximately 6 hours), Day 2 (24-36 hours post dose), and Day 4 (highest dose cohorts only).
  • Inhibition of the visual cycle was evidenced by the delay in restoration of the ERG b-wave amplitude following the photobleach is measured. After a 10-minute exposure to a full-field bleaching light (556 cd/m 2 ), recovery of the ERG was measured for 60 minutes at 10-minute intervals.
  • Compound 1 was provided as micronized powder in capsules. The dose levels were 25 mg, 50 mg, 100 mg, 200 mg, and 400 mg.
  • Target therapeutic range Defined as reducing and maintaining RBP4 serum concentration below 1 ⁇ M (2 mg/dL) was defined in Fenretinides Phase 2b trial in dry AMD patients with geographic atrophy.
  • Statistical Analysis All subjects who received IP are included in the safety population. All subjects who received IP and have at least one post-treatment sample or determination were included in the PK analysis population. Analysis was by treatment assignment. Safety was evaluated by monitoring AEs, and by change from baseline on examinations and laboratory studies. The AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by system organ class (SOC) and preferred term, by severity, by relationship to study drug and study procedure, and by study drug dose. ECG parameters analyzed include heart rate, PR, QRS, QT, QTcB and QTcF intervals. Analysis of other examinations were specified in the protocol.
  • MedDRA Medical Dictionary for Regulatory Activities
  • SOC system organ class
  • ECG parameters analyzed include heart rate, PR, QRS, QT, QTcB and QTcF intervals. Analysis of other examinations were specified in the protocol.
  • Results All Cohorts demonstrated a significant reduction in RBP4 levels from baseline ( FIG. 4 A ), reaching less than 2 mg/dL ( FIG. 4 B ). Results for an example individual Cohorts (cohort 5) are shown in FIGS. 5 and 6 . The other Cohorts showed similar results. Subjects in Cohort 5 had an 80% reduction in RBP4 serum levels and at least a 70% reduction that was maintained for 3 days. Subjects in Cohorts 1 and 2 had a 90% reduction in RBP4 serum levels and at least a 70% reduction that was maintained for 3 days. Subjects in Cohort 3 had a90% reduction in RBP4 serum levels and at least a 70% reduction that was maintained for 4 days.
  • Example 2 The general format of the clinical study of Example 2 was followed, with modification.
  • the study comprises up to 3 cohorts, and up to a total of 24 subjects (8 subjects per cohort).
  • the starting dose of Compound 1 is 10 mg and doses for subsequent cohorts are 25 mg and 50 mg.
  • Compound 1 was administered as a formulation described herein. Doses will be administered daily.
  • the study will consist of a screening period (Days ⁇ 28 to ⁇ 1), Check-in (Day ⁇ 1), study drug administration (Day 1-14), treatment period (Days 2 to 17), a follow-up telephone call (Day 20), and an end-of-study (EOS) visit (Day 23).
  • Subjects will be randomly assigned to receive a pharmaceutical composition of Compound 1 or placebo as follows: 6 subjects will receive active drug and 2 subjects will receive placebo.
  • Additional cohorts (8 subjects per cohort) may be enrolled if after evaluation it is determined that an intermediate or higher dose level should be tested.
  • the institutional review board (IRB) will be notified of this revised approach.
  • Safety data through Day 23 will be reviewed by the safety review committee in a blinded fashion for each dose cohort before escalating to the next dose cohort. Additional data (e.g., PK data) may be reviewed as deemed necessary by the committee.
  • Subjects will fast overnight (nothing to eat or drink except water) for at least 10 hours before study drug administration on Days 1-14. Subjects will remain fasted for 4 hours after dosing with study drug. Subjects will be confined to the clinical unit from Day ⁇ 1 until discharge on Day 17. The duration of the study, including a 28-day screening period, is approximately 51 days.
  • FIG. 5 F shows results from a study carried out as indicated above.
  • Subjects in this cohort received repeated daily doses of 10 mg of Compound 1 over a period of 14 days.
  • This treatment regimen consistently reduced RBP4 to below 1 ⁇ M serum concentration (equivalent to 70% RBP4 reduction from baseline) in all subjects receiving Compound 1.
  • Subjects displayed 50% RBP4 reduction after the first initial dose on day 1, which was further reduced down to 90% after subsequent doses. 90% RBP4 reduction was maintained throughout the two weeks of 10 mg daily dosing.
  • STGD1 autosomal recessive Stargardt disease
  • STGD1 autosomal recessive Stargardt disease
  • STGD1 autosomal recessive Stargardt disease
  • Primary outcomes are PK/PD, RBP4 reduction, and the mean rate of change in the area of ellipsoid zone defect measured by en face SD-OCT, as measured by spectral Domain-Optical Coherence Tomography (SD-OCT).
  • SD-OCT spectral Domain-Optical Coherence Tomography
  • neovascular/wet AMD including active primary or recurrent subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) are randomly assigned to receive a pharmaceutical composition of Compound 1 or the standard of care, for up to 48 weeks.
  • Primary outcomes are change in the best corrected visual acuity score measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol by Week 16.
  • EDRS Early Treatment Diabetic Retinopathy Study
  • BCVA Best Corrected Visual Acuity
  • ETDRS Early Treatment Diabetic Retinopathy Study
  • GCL Ganglion Cell Layer
  • SD-OCT Spectral Domain Optical Coherence Tomography
  • icroaneurysm turnover assessed by Colour Fundus Photography.
  • Outcomes are assessed at 0, 6, 12, 18, and 24 months. The results are analyzed following methods well known to the skilled artisan.
  • CMPD-1 Compound 1
  • XRPD X-Ray Powder Diffraction
  • thermogram A sample of Compound 1 was analyzed by Differential Scanning Calorimetry using a TA Discovery DSC2500 with RCS90 chiller according to standard instrument procedures provided by manufacturer. Parameters used for the analysis are shown below in Table 3. Two replicates of the experiment were run with reproducible results. The resulting thermogram, shown in FIG. 10 B , indicated a melting temperature (Tm) of Compound 1 of about 229° C. and no degradation up to 275° C.
  • Tm melting temperature
  • a sample of Compound 1 was analyzed by Modulated Differential Scanning Calorimetry using a TA Discovery DSC2500 with RCS90 chiller according to standard instrument procedures provided by manufacturer. Parameters used for the analysis are shown below in Table 4. Two replicates of the experiment were run with reproducible results.
  • the resulting thermogram shown in FIG. 10 C , indicates a glass transition temperature (T g ) of about 93° C., a crystallization temperature (T c ) of about 136° C., and a T m /T g ratio of 1.37.
  • the T m /T g ratio of 1.37 is indicative of moderate physical stability. Without being bound by theory, the T, observed quickly after Compound 1 entering a rubbery state was indicative of a propensity to crystallize.
  • CMPD-1 Compound 1
  • SEM scanning electron microscopy
  • a solvent shift assay was performed in order to assess the effect of polymer excipients in improving supersaturation and sustainment in biorelevant media.
  • Compound 1 was dissolved in DMSO to generate concentrated dissolved stock solution at 25 mg/mL.
  • Stock API solution was then added to Fasted State Simulated Intestinal Fluid (FaSSDF) solution or FaSSIF solution containing predissolved polymer excipients to final concentration of compound 1 at 0.5 mg/mL.
  • Ratios of Compound 1:polymer excipient in the final solution were either 20:80 or 40:60 (w/w).
  • Samples were analyzed by TIPLC to assess dynamic solubility of Compound 1 at various time points over a one hour period. The resulting chromatograms are shown in FIG. 10 E and FIG. 10 F .
  • Table 5 shows calculations of polymer performance in maintaining Compound 1 in solution during the experiment.
  • Solid dispersions of Compound 1 and lead polymers identified from the solvent shift assay in Example 12 were prepared in ratios of Compound 1:polymer of 20:80 and 40:60.
  • the TIPMCAS-L, TIPMCAS-M, and TIPMCAS-H were Ashland Aquasolv® brand. Characteristics of these polymers are shown below in Table 6A
  • Mixtures of Compound 1 and the desired amount ofpolymer were mixed in a spray solvent, then spray dried on a Buchi B-290 Lab Scale Spray Dryer with 2-fluid nozzle, 1.5 mm Air Cap, and 0.7 mm Liquid tip.
  • the spray drier was operated according to standard instrument procedures provided by manufacturer. Specific parameters used for each composition are shown below in Table 6B and Table 7 below.
  • X-Ray Powder Diffraction (XRPD) diffractograms of the solid dispersions containing Compound 1 prepared above were acquired using a Rigaku Miniflex 6G according to standard instrument procedures provided by manufacturer. Parameters used for the analysis are shown below in Table 8. The resulting diffractograms are shown in FIG. 11 A . The diffraction patterns indicate that amorphous dispersions were obtained for each preparation of polymers and Compound 1.
  • thermograms of non-reversing heat flow The samples containing 40:60 Compound 1:HPMCAS-H and 40:60 Compound 1:HPMCAS-M displayed an exothermic event occurring at around 150-160° C., indicating a possible recrystallization event.
  • Sample of solid dispersions containing Compound 1 were analyzed in a non-sink dissolution experiment. Dispersion samples and neat Compound 1 were suspended in 0.1N HCl media at a concentration of 1000 ug/mL Compound 1. Concentration of each sample was then measured by centrifugation to pellet undissolved material, and an aliquot of the supernatant was assessed by HPLC for concentration. Material was then agitated in a Distek 210° C. Dissolution apparatus, USP Type II. Instrument was operated according to standard instrument procedures provided by manufacturer. Parameters used for the experiment are shown below in Table 11.
  • the media was modulated to FaSSIF by adding equivalent volume of FaSSIF buffer with bile salts, bringing the theoretical concentration of compound 1 to 500 ⁇ g/mL. Dissolved concentration of Compound 1 in each sample was then assessed periodically by HPLC. A plot of the resulting concentrations at each time point can be shown in FIG. 11 E .
  • FIG. 12 B Thermograms showing reversing heat flow for the 20:80 CMPD-1:HPMCAS-H and 40:60 CMPD-1:HPMCAS-H dispersion are shown in FIG. 12 B .
  • FIG. 12 C Thermograms showing reversing heat flow for the 20:80 CMPD-1:HPMCAS-M and 40:60 CMPD-1:HPMCAS-M dispersion are shown in FIG. 12 C .
  • Glass transition temperatures for each experiment were determined and are shown in Table 14 below. Additionally, a plot showing the effect of RH on the glass transition temperature of each sample was prepared and can be seen in FIG. 12 D . For each dispersion, increased relative humidity was associated with a lower glass transition temperature.
  • PLM polarized light microscopy
  • FIG. 13 B shows PLM data for the same samples at the two hour time point. All suspensions were still amorphous, with no change in visual appearance or consistency.
  • FIG. 13 C shows PLM data for the samples at the six hour time point.
  • the 2000 Compound 1 dispersions showed no change in visual appearance or syringeability after six hours.
  • the 4000 Compound 1 dispersions showed a decrease in syringeability of the suspensions at this time point, likely due to increased agglomeration.
  • Example 14 Additional Solid Dispersions Comprising Compound 1 and Polyvinyl Pyrrolidine
  • Kollidon® 17 PF is a polyvinyl pyrrolidine polymer having a weight average molecular weight from about 7,000 to about 11,000 daltons and a bulk density of about 400-600 g/L.
  • FIG. 14 shows the resulting DSC trace for each of the mixtures, as well as Compound 1 by itself both before and after being subject to the spray drying process.
  • Solubilities of Compound 1 in a few solvents were estimated. The experiments were carried out by adding the test solvent in aliquots to weighed portions of solid. Whether dissolution had occurred was judged by visual inspection after addition of each solvent aliquot. The results are shown in Table 16. Solubility numbers were calculated by dividing the total amount of solvent used to dissolve the sample by the weight of the sample. The actual solubilities may be greater than the numbers calculated because of the use of solvent aliquots that were too large or because of slow dissolution rates. The solubility number is expressed as “less than” if dissolution did not occur during the experiment. The solubility number is expressed as “greater than or equal to” if dissolution occurred on addition of the first solvent aliquot.
  • Form B Characterization data are shown in Table 21. It is a dichloromethane solvate; TG results show 6.51% weight loss below 125° C. which corresponds to 0.4 moles of dichloromethane. Approximately 0.25 moles of dichloromethane is observed in the NMR spectrum, suggesting it is a quarter-dichloromethane solvate. The discrepancy in the amount of dichloromethane calculated from the TG and NMR is likely due to solvent loss prior to NMR analysis. The amount of dichloromethane incorporated in the crystal structure may vary. Karl Fischer analysis shows a negligible amount of water, 0.19%. The endothermic event observed by DSC at 233.55° C. is likely melting. It is not hygroscopic.
  • Form C Characterization data are shown in Table 23. It is unsolvated; TG results show 0.51% weight loss below 230° C. Karl Fischer analysis shows a negligible amount of water, 0.20%. The endothermic event observed by DSC at 227.82° C. is likely melting. It is not Hygroscopic. An exemplary XRPD pattern of form C can be seen in FIG. 15 , which shows degrees 2 theta on the X-axis and counts on the Y axis.
  • Form D Characterization data are shown in Table 24. It is a dichloromethane solvate; TG results show 9.95% weight loss below 125° C. which corresponds to 0.6 moles of dichloromethane. However, that weight loss may not be a reliable measure of the volatile content since loss was occurring at the beginning of the experiment. Approximately 1.1 moles of dichloromethane is observed in the NMR spectrum, suggesting it is a mono-dichloromethane solvate. Karl Fischer analysis shows a negligible amount of water, 0.25%. The endothermic event observed by DSC at 233.37° C. is likely melting. It is not hygroscopic.
  • Form D was found to be unstable, and rapidly converts to form B under ambient conditions.
  • Form B was found to convert to form A when heated.
  • Form C was found to be more thermodynamically stable than form A in the temperature range of 5 to 60° C. Form A has a higher melting point than form C, suggesting that the two forms are enantiotropically related. Form C was determined to be the best target polymorph form for crystallization and further development.
  • Raw material of Compound 1 in polymorph Form C was characterized by X-ray powder diffraction (XRPD) and polarized light microscopy (PLM). The material was found to be highly crystalline.
  • 0.4 mL vehicle (list in Table 24B) was mixed with the 0.2 mL milling beads (0.5 mm) at the ratio of 2:1 in 1.5 mL plastic tube, then adequate compound of Compound 1 was added to the system, aiming to obtain a target concentration of 200 mg/mL. Then place them on MM400 for continuous milling. From characterization results: 5 vehicles were tried at small scale of 0.4 mL by MM-400 instrument at 2500 rpm for 12.5 hours, 3 vehicles (F2, F3 and F5) showed better and similar results of PSD at 240 ⁇ 260 nm in D50 and 400-440 nm in D90.
  • the obtained nanosuspensions were transferred into 2-mL glass vials, and then stored under 5° C. and 25° C. After storing for 1-4 week, the suspensions were sampled for XRPD, ZPPS and UPLC analysis to check possible physical and chemical changes. Based on stability results in, the particle size of prototype F1, F2, F3, and D4 increased, but the particle size of prototype F5 (nanosuspension with vehicle 0.5% HPM SL/0.2% SDS in water) almost remained unchanged. All four formulations were physically and chemically stable. Prototype F5 was selected for the following scale up for PK and Tox study.
  • the nanosuspension product was transferred to a 10 mL tube and diluted to 5 mg/mL (50 mL, Compound 1-suspension-5 mg/mL) and 10 mg/mL (50 mL, Compound 1-suspension-10 mg/mL) with the vehicle (FR00965-2-0505-vehicle) and test the samples (5 mg/mL and 10 mg/mL) by UPLC and ZPPS.
  • Compound 1 was weighed into 2 mL vial and 1 mL vehicle (FR00965-2-0505-vehicle) will be added to target of 200 mg/mL, then 0.5 mL of 0.5 mm zirconium beads was added. Make two samples in parallel. Grind the sample with MM400. The sample was test by ZPPS, purity and XRPD. The obtained nanosuspensions were transferred into 2-mL glass vials, and then stored under 4° C. and ⁇ 20° C. After storing for 1 week ⁇ 3 months, the suspensions were sampled for XRPD, ZPPS and UPLC analysis to check possible physical and chemical changes.
  • vehicle FR00965-2-0505-vehicle
  • F5 targeting 200 mg/mL, vehicle: 2% HPC SL/0.2% SDS
  • vehicle 2% HPC SL/0.2% SDS
  • All the other stability characterization were kept same with initial.
  • Physicochemical characterization of Compound 1 was performed to support formulation development. Experiments were conducted to study solid-state properties (e.g. physical state, thermal analysis, water vapor sorption, and polymorphism), physical properties (e.g. particle morphology and particle size), intrinsic stability (e.g. API chemical stability at elevated temperature), and biopharmaceutical properties (e.g. solubility, dissolution, and biopharmaceutical parameters) of the active pharmaceutical ingredient (API).
  • solid-state properties e.g. physical state, thermal analysis, water vapor sorption, and polymorphism
  • physical properties e.g. particle morphology and particle size
  • intrinsic stability e.g. API chemical stability at elevated temperature
  • biopharmaceutical properties e.g. solubility, dissolution, and biopharmaceutical parameters
  • Form E Since the third batch contained a polymorph not previously analyzed (Form E), there was a need to check whether this batch is reproducible by provided crystallization conditions at a relatively smaller scale of 500 mg.
  • 500 mg of the compound was dissolved in approximately 20 mL of approximately 10:1 DCM/MeOH, solvent removed under vacuum, and the resulting solid dried for one day in vacuum oven.
  • XRPD data indicated that both wet (before drying) and dried (after drying) solids were Form E. This demonstrated that the generation of Form E was reproducible. From pharmaceutical development point of view, the most thermodynamically stable form is highly preferred. Therefore, polymorphic relationship, in term of relative physical stability, needs to be further understood.
  • Form C is a thermodynamically stable form (over the temperature range of 5 to 60 C) (Example 15).
  • the determination of relative polymorphic stability between the reported stable form and newly discovered form was of importance.
  • the relative physical stability between Form C and Form E was initially assessed by storage of the two samples at high relative humidity (RH) levels (e.g. 88% and 95% RH). There was no polymorph change when Form C was exposed to 88% RH for 7 days, followed by 95% RH for additional 8 days.
  • RH relative humidity
  • Form E the polymorph was also unchanged after 16 days storage at 88% RH. However, it turned to a mixture of Form A, C and E after the material was exposed to 95% RH for additional 7 days. This observation highly suggested that Form C could be more thermodynamically stable than Form E at ambient temperature and high RH % kinetically facilitated the conversion of Form E to Form C.
  • Thermal analysis was further employed to characterize the three batches of Compound 1. Differential scanning calorimetry (DSC) thermograms showed an endotherm peak at 234° C., 229° C., and 235° C. for batches of Form A, Form C, and Form E, respectively.
  • thermogravimetric analysis (TGA) data indicated no weight loss for the Form E batch.
  • the relatively lower melting temperature for Form C indicated that Form C is in enantiotropic relationship with Form A or Form E because a polymorph with higher thermodynamic stability based on slurry experiments is expected to show a higher melting temperature if it is in monotropic relationship with another polymorph. Relative stability of an enantiotropic polymorph pair of polymorphs reverses once a transition temperature is passed.
  • Solvent Screening Ambient Temperature: To screen the API solubility (as a part of feasibility assessment of liquid dosage form in formulation development and dissolution method development), a number of solvent systems were selected for solubility enhancement at ambient temperature. The suspension of the material (Form C) in a variety of solvent was prepared and stirred at ambient temperature for three or four days. The equilibrated suspensions were isolated by centrifuge and the filtrates were injected into HPLC to determine equilibrium solubility of the API in each solvent system. The detailed equilibrium solubility data at ambient temperature are summarized in Table 5. Solubility higher than 10 mg/mL was observed in concentrated sodium lauryl sulfate (SLS) solutions at 100 ⁇ critical micelle concentration (CMC).
  • SLS sodium lauryl sulfate
  • solubility of the API between 1 and 5 mg/mL were observed in EtOH, PEG 400, Propylene glycol, Capmul MCM, NF, Kolliphor EL, Capmul MCM, EP, Plurol Oleique CC 497, Peceol, Labrasol, SLS at 5 ⁇ and 10 ⁇ CMC, and Transcutol HP.
  • the glass transition temperature of the material was determined by modulated differential scanning calorimetry (mDSC).
  • mDSC modulated differential scanning calorimetry
  • Preliminary TGA data suggested that the material started a continuous weight loss due to decomposition as the API was heated up to 260° C. Therefore, as preparing an in-situ amorphous material in DSC pan, the end temperature should not ramp beyond 260° C.
  • the amorphous samples were generated by heating the raw APIs from 25 to 250° C., followed by a rapid cooling to ⁇ 60° C.
  • the glass transition temperature (Tg) was measured by a slow heating of the generated amorphous samples from ⁇ 60° C. to 250° C.
  • the Tg for in-situ generated amorphous material from C and Form A was 93° C. and 97° C., respectively. The discrepancy in the two Tg values may simply due to the variation of water content in the samples or chemical purity.
  • micronization of the batch with stable polymorph was conducted.
  • This powder batch was micronized using a 2-inch Sturtevant SDM2 Micronizer jet mill using 70 psi for feed pressure and 40 psi for grind pressure.
  • the resulted micronized material was examined for particle morphology by polarized-light optical microscopy, particle sizing by particle size analyzer using a wet method, and physical form by XRPD.
  • the micronized material lost regular needle-like morphology and converted into fine particles with particle size approximately less than 10 m. However, the birefringence of the particles remained, supported from crystalline nature of the material by XRPD analysis after micronization.
  • the unmicronized Form C and micronized Form C API materials were evaluated for dissolution at non-sink conditions for a higher sensitivity of differentiating formulation effect (e.g. particle size).
  • the required amount (approximately 222 mg) of each API was rinsed into dissolution vessel containing 500 mL of 0.36% SLS in water with nominal solubility of the API of ⁇ 0.46 mg/mL.
  • the solubility of the API in 0.36% SLS in water was calculated as 0.4447 mg/mL based on SLS concentration vs solubility profile.
  • the micronized API exhibited an enhanced dissolution rate and overall release percentage up to 75 min, as is shown in FIG. 18 .
  • the enhancement in dissolution rate from micronized samples was likely due to the increase in surface area after micronization supported by microscopic images and particle sizing.
  • Compound 1 was comprehensively characterized for solid-state properties, physical properties, intrinsic stability, and biopharmaceutical properties. All the batches (e.g. Form A, C, and E) were in crystalline state with the presence of birefringence and low moisture adsorption. The Form C was the most thermodynamically stable polymorph below 100° C. confirmed by humidity and slurry studies.
  • Solubility enhancement of the API was screened for a list of solvent systems with solubility higher than 10 mg/mL in SLS at 100 ⁇ CMC and solubility between 1 and 5 mg/mL in twelve solvent systems.
  • higher solubility e.g. 16 and 20 mg/mL
  • Capmul MCM threshold solubility study at elevated temperature, suggesting promising of dosing from soft gel capsule and for toxicology studies.
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