Formulations of RBP4 inhibitors and methods of use

Abstract

To provide compositions for effective treatment of retinol binding protein 4 (RBP4)-related visual diseases and disorders.SOLUTION: A pharmaceutical composition comprising (i) a compound of formula (I), or a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, and (ii) a dispersion polymer.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 871,622, filed July 8, 2019, the entirety of which is incorporated herein by reference. [Background technology]

[0002] There is a need in the medical field for effective treatments for visual diseases and disorders associated with retinol binding protein 4 (RBP4).

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 871,622, filed July 8, 2019, the disclosure of which is incorporated herein by reference in its entirety. Summary of the Invention

[0004] In one aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof,

[0005] [ka] During the ceremony, R 1 are each independently halogen, haloalkyl, or alkyl; R 2 is -H, -OH, or a halogen, p is 0, 1, 2, 3, 4, or 5; A has the following structure:

[0006] [ka] During the ceremony, α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C, Z1 is S, O, or N; Z2 is S, O, N, or NR 3 and R 3 is H, C1-C4 alkyl, or oxetane, and B is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure; The composition comprises a solid dispersion that includes a dispersion polymer.

[0007] In certain embodiments, A has the structure:

[0008] [ka] During the ceremony, n is 0, 1, or 2; α, β, χ, δ, ε, and φ are each independently absent or present, and when present, each is a bond; Z1 is S, O, or N; Z2 is S, O, N, or NR 3 and where R 3 is H, C1-C4 alkyl, or oxetane; X is C, Y1, Y2, Y3, and each occurrence of Y4 are independently 4 , C(R 5 )2, NR 6 , O, N, SO2, or -(C=O)-, wherein R 4 H, halogen, C1-C 10 Alkyl, C1-C 10 Cycloalkyl, -O(C1-C 10 alkyl), -C(O)OH, -C(O)O(C1-C 10 alkyl), -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -NHC(O)NH(C1-C 10alkyl), -NHC(O)N(C1-C4 alkyl)2, -SO2NH(C1-C 10 alkyl), -SO2N(C1-C 10 alkyl), -CN, or -CF; R 5 is H or C1-C 10 alkyl, and R 6 is H, C1-C 10 Alkyl, C3-C6 cycloalkyl, -(C1-C 10 alkylene)CF3, -(C1-C 10 alkylene)OCH3, -(C1-C 10 Alkylene)-halogen, -SO2(C1-C 10 alkyl), -SO2(C1-C 10 alkylene)-CF3, -SO2(C1-C 10 alkylene)OCH3, -SO2(C1-C 10 alkylene)-halogen, -C(O)(C1-C 10 alkyl), -C(O)(C1-C 10 alkylene)CF3, -C(O)(C1-C 10 alkylene)OCH3, -C(O)(C1-C 10 alkylene)-halogen, -C(O)NH(C1-C 10 alkyl), -C(O)N(C1-C 10 alkyl)2, -(C1-C 10 alkyl)C(O)OH, —C(O)NH2, or oxetane.

[0009] In certain embodiments, A has the structure:

[0010] [ka] During the ceremony, n is 0, R 3 is H, C1-C4 alkyl, or oxetane; Y1 and Y3 are each CH2 or C(CH3)2; Y2 is O, SO2, or NR 6and R 6 is H, C1-C4 alkyl, C3-C6 cycloalkyl, -(C1-C4 alkylene)CF3, -(C1-C4 alkylene)OCH3, -(C1-C4 alkylene)-halogen, -SO2(C1-C4 alkyl), -SO2(C1-C4 alkylene)CF3, -SO2(C1-C4 alkylene)OCH3, -SO2(C1-C4 alkylene)-halogen, - C(O)(C1-C4 alkyl), -C(O)(C1-C4 alkylene)CF3, -C(O)(C1-C4 alkylene)OCH3, -C(O)(C1-C4 alkylene)-halogen, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -(C1-C4 alkylene)C(O)OH, -C(O)NH2, or oxetane.

[0011] In certain embodiments, compounds of formula (I) have the following structure:

[0012] [ka] or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof.

[0013] In certain embodiments, the compound of Formula (I) is effective in reducing RBP4 levels in a dosage form of 1 mg to 200 mg or 5 mg to 25 mg. In certain embodiments, the compound of Formula (I) is a micronized crystal. In certain embodiments, the compound of Formula (I) is a polymorph that exhibits an X-ray powder diffraction pattern with at least three characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees 2-theta (+ / - 0.5 degrees theta).

[0014] In certain embodiments, 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 certain embodiments, the compound of formula (I) is amorphous within the dispersion polymer. In certain embodiments, the dispersion polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS or HPMCAS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, and combinations thereof. In certain embodiments, the dispersion polymer is HPMC. In certain embodiments, the dispersion polymer is HPMC-AS.

[0015] In certain embodiments, 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%, 20-80%, 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. In certain embodiments, the ratio of the compound of Formula (I) to the dispersion polymer is about 20:80 (w / w) in the solid dispersion. In certain embodiments, the ratio of the compound of Formula (I) to the 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.

[0016] In certain embodiments, the ratio of compound of Formula (I) to dispersion polymer in the solid dispersion is about 20:80 (w / w). In certain embodiments, the ratio of compound of Formula (I) to dispersion polymer in the solid dispersion is about 40:60 (w / w).

[0017] In certain embodiments, the compound of formula (I) is

[0018] [ka] and the dispersion polymer is HPMC-AS.

[0019] In certain embodiments, 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 of 7-11 wt%, a succinyl content of 10-14 wt%, a methoxyl content of 21-25 wt%, and a hydroxypropyl content of 5-9 wt%. In certain embodiments, the dispersion polymer is HPMC-AS having an acetyl content of 10-14 wt%, a succinyl content of 4-8 wt%, a methoxyl content of 22-26 wt%, and a hydroxypropyl content of 6-10 wt%.

[0020] In certain embodiments, the dispersion polymer comprises polyvinylpyrrolidone (PVP). In certain embodiments, the PVP is present in a ratio of about 10:1 to about 1:1 with respect to the compound of Formula (I). In certain embodiments, the PVP is present in a ratio of about 2:1, about 3:1, or about 5:1 with respect to the compound of Formula (I). In certain embodiments, the PVP has a molecular weight average molecular weight of about 7,000 daltons to about 11,000 daltons.

[0021] In certain embodiments, the pharmaceutical composition further comprises a filler, a sweetener, a disintegrant, a wetting agent, a glidant, a lubricant, or a surfactant, or any combination thereof. In certain embodiments, the solid dispersion further comprises a filler, a sweetener, a disintegrant, a wetting agent, a glidant, a lubricant, or a surfactant, or any combination thereof.

[0022] In certain embodiments, the solid dispersion has an average particle size of less than 10 μm. In certain embodiments, the solid dispersion has an average particle size of less than 20 μm. In certain embodiments, the solid dispersion has an average particle size of about 10 μm to 20 μm. In certain embodiments, the solid dispersion has an average particle size of less than 10 μm or less than 20 μm.

[0023] In one aspect, provided herein is a nanosuspension pharmaceutical composition comprising a compound of Formula (I), a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, wherein the compound of Formula (I) is suspended in a pharmaceutically acceptable solvent. In some embodiments, the compound of Formula (I) is Compound 1, or a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In some embodiments, the compound of Formula (I) is a polymorph that exhibits an X-ray powder diffraction pattern with at least three characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 °2-theta (+ / - 0.5 °theta). In some embodiments, the concentration of the compound of Formula (I) is from about 1 mg / mL to about 50 mg / mL. In some embodiments, the compound of formula (I) is micronized. In some embodiments, the compound of formula (I) has an average particle size of less than 1000 nm.

[0024] In some embodiments, the nanosuspension further comprises a surfactant. In some embodiments, the surfactant comprises sodium dodecyl sulfate, a poloxamer, or a polysorbate. In some embodiments, the nanosuspension further comprises an excipient. In some embodiments, the excipient comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethylcellulose, polyvinyl alcohol-polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol-polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyethylene-polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, or any combination thereof. In some embodiments, the excipient is present at a concentration of about 0.1% to about 5%.

[0025] In certain embodiments, 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.

[0026] In another aspect, there is provided a method for treating an ocular disease, comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition according to any one of the preceding claims. In certain embodiments, the ocular disease is a disease characterized by excessive accumulation of lipofuscin in the retina. In certain embodiments, the disease characterized by excessive accumulation of lipofuscin 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 ABCA4 gene-associated retinal disease.

[0027] Another aspect includes a method for reducing the serum concentration of RBP4 in a subject, the method comprising administering a therapeutically effective amount of a pharmaceutical composition to the subject. In certain embodiments, 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). In certain embodiments, 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, a therapeutically effective amount of the pharmaceutical composition comprises about 25 mg of the compound of Formula (I). In certain embodiments, a therapeutically effective amount of the pharmaceutical composition comprises about 50 mg of the compound of Formula (I). In certain embodiments, a therapeutically effective amount of the pharmaceutical composition comprises about 100 mg of the compound of Formula (I). In certain embodiments, a therapeutically effective amount of the pharmaceutical composition comprises about 200 mg of the compound of Formula (I). In certain embodiments, a therapeutically effective amount of the pharmaceutical composition comprises about 400 mg of the compound of Formula (I). In certain embodiments, a 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).

[0028] In certain embodiments, the pharmaceutical composition is administered 1, 2, 3 or 4 times daily.In certain embodiments, the pharmaceutical composition is administered every day, every other day, every other day 3 days 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, every week, every other week, 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 a day.In certain embodiments, the pharmaceutical composition is administered orally.In certain embodiments, the serum RBP4 concentration of the subject is reduced to less than 1 μM after treatment.

[0029] In another aspect, described herein is a method of making a solid dispersion, the method comprising the steps of adding a solvent to a container; adding a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the container; adding a dispersion polymer to the container to obtain a first mixture; mixing the first mixture until the compound of Formula (I) or a pharmaceutically acceptable salt thereof 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:

[0030] [ka] During the ceremony, R 1 are each independently halogen, haloalkyl, or alkyl; R 2 is -H, -OH, or a halogen, p is 0, 1, 2, 3, 4, or 5; A has the following structure:

[0031] [ka] During the ceremony, α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C, Z1 is S, O, or N; Z2 is S, O, N, or NR 3 and R 3 is H, C1-C4 alkyl, or oxetane, and B is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure; The composition comprises a solid dispersion that includes a dispersion polymer.

[0032] In certain embodiments, the solvent comprises an organic solvent. In certain embodiments, 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. In certain embodiments, the solvent is 90:10 dichloromethane:methanol (v / v).

[0033] In certain embodiments, the dispersion polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethylcellulose, polyvinyl alcohol-polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol-polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyethylene-polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, and combinations thereof. In certain embodiments, the dispersion polymer is HPMC-AS. In certain embodiments, the dispersion polymer is HPMC. In certain embodiments, the dispersion polymer is polyvinylpyrrolidine.

[0034] In certain embodiments, the compound of formula (I) has the following structure:

[0035] [ka] Alternatively, it may have a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In certain embodiments, 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, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, dioxane, ethanol, ethyl acetate, ethyl methyl ketone, ethylene glycol, hexane, hexamethylphosphoramide, methanol, nitromethane, pentane, 2-proponal, pyridine, tetrahydrofuran, toluene, xylene, or any combination thereof.

[0036] In another aspect, described herein is a method for reducing the serum concentration of RBP4 in a subject, the method comprising administering to a subject a compound of the following structure:

[0037] [ka] or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, wherein the pharmaceutical composition comprises the compound in an amount of about 10 mg, wherein the pharmaceutical composition is administered daily, and the serum or plasma level of RBP4 in the subject is reduced to less than 1 μM.

[0038] In one aspect, provided herein are polymorphs of Compound 1, wherein the polymorph exhibits an X-ray powder diffraction pattern with at least three characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 °2-theta (+ / - 0.5 °theta). In some embodiments, the polymorph is crystalline. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with at least five characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 °2-theta (+ / - 0.5 °theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 °2-theta (+ / - 0.5 °theta). In some embodiments, the polymorph is micronized, hi some embodiments, the polymorph has an average particle size of less than 20 μm, less than 10 μm, less than 1 μm, or less than 100 nm.

[0039] Incorporation by Reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the particular purposes identified herein. [Brief explanation of the drawings]

[0040] The novel features of the invention are set forth with particularity in the appended claims. For a better understanding of the features and advantages of the present invention, reference should be made to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings. [Figure 1] Illustrate the schematic diagram of the mechanism of action of dry (atrophic) macular degeneration and Stargardt's disease.Without being bound by theory, RBP4 transports retinol (the precursor of cytotoxic A2E) to the retina through the visual cycle.RBP4 inhibitors such as Compound 1 are sometimes used to treat RBP4-related visual diseases and disorders. [Figure 2]Graph of bisretinoid A2E (intraocular pmol) and RBP4 (serum) levels in ABCA4- / -RDH8- / - mice untreated, vehicle-treated, or treated with Compound 1. Mice treated with Compound 1 had an 80% reduction in bisretinoid accumulation (p=0.003, unpaired t-test). [Figure 3] This graph shows the thickness (μm) of the outer nuclear layer (ONL) as a function of distance (μm) from the optic nerve (ONH). The ONL is a cell layer composed of photoreceptor cells (rods and cones). Dry AMD or STGD is often associated with ONL thinning and photoreceptor cell loss, indicating macular degeneration. ONL thickness was significantly reduced in the diseased group (abcd4 / rdh8 knockout mice) compared to the affected group treated with Compound 1, which preserved the ONL. [Figure 4A] 1 is a graph showing the mean percent RBP4 reduction from baseline as a function of time (hours) for five cohorts totaling 32 healthy adults in a randomized, double-blind, placebo-controlled Phase 1 clinical trial. Each cohort received a single dose of 50 mg (Cohort 1), 100 mg (Cohort 2), 200 mg (Cohort 3), 400 mg (Cohort 4), or 25 mg (Cohort 5) of Compound 1, or placebo. Individuals who received placebo are not included in the graph. [Figure 4B] Figure 1 shows a graph of RBP4 concentration (ng / mL) as a function of time (hours) for five cohorts totaling 32 healthy adults in a randomized, double-blind, placebo-controlled Phase 1 clinical trial. Each cohort received a single dose of 50 mg (Cohort 1), 100 mg (Cohort 2), 200 mg (Cohort 3), 400 mg (Cohort 4), or 25 mg (Cohort 5) of Compound 1, or placebo. Individuals who received placebo are not included in the graph. [Figure 5]

[0023] Figure 1 is a graph depicting the mean percent 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 received a single dose of 25 mg of Compound 1 or placebo. Six subjects received Compound 1 and two subjects received placebo. Subjects FF and GG appeared to receive placebo. [Figure 6]

[0023] Figure 1 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 received a single dose of 25 mg of Compound 1 or placebo. Six subjects received Compound 1 and two subjects received placebo. Subjects FF and GG appeared to receive placebo. [Figure 7] This graph shows the concentration of Compound 1 (ng / mL) as a function of time (hours) for five cohorts totaling 32 healthy adults in a randomized, double-blind, placebo-controlled Phase 1 clinical trial. Each cohort received a single dose of 50 mg (Cohort 1), 100 mg (Cohort 2), 200 mg (Cohort 3), 400 mg (Cohort 4), or 25 mg (Cohort 5) of Compound 1, or placebo. Individuals who received placebo are not included in the graph. [Figure 8] Graphs depicting 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 received a single dose of 25 mg of Compound 1 or placebo. Subjects FF and GG appeared to receive placebo. [Figure 9]Figure 1 shows a graph of RBP4 concentration (µm) as a function of dose for compound 1 (mg, modeled from a Phase 1 clinical trial) and fenretinide (modeled from a Phase 2 clinical trial). Phase 2 fenretinide studies showed that subpopulations with significantly reduced RBP4 had slower lesion growth. Compound 1 is more potent than fenretinide and can significantly reduce RBP4 at clinically relevant doses. [Figure 10A] 1 is a graph generated in an X-ray powder diffraction (XRPD) experiment of crystalline Compound 1. [Figure 10B] 1 is a graph generated from a differential scanning calorimetry (DSC) experiment of crystalline Compound 1 showing heat flow Q (W / g) as a function of temperature (° C.). [Figure 10C] 1 is a graph generated from a differential scanning calorimetry (DSC) experiment of crystalline Compound 1 showing reversing heat flow Qrev (W / g) as a function of temperature (° C.). [Figure 10D] 1 is a SEM (scanning electron microscope) image of crystalline Compound 1. The morphology of Compound 1 consists of high aspect ratio orthogonal needle-like crystals. [Figure 10E] 1 is a graph of the solubility of Compound 1 (μgA / mL) as a function of time (minutes) for mixtures of Compound 1 and various polymers in a 20:80 ratio. [Figure 10F] 1 is a graph of the solubility of Compound 1 (μgA / mL) as a function of time (minutes) for mixtures of Compound 1 and various polymers in a 40:60 ratio. [Figure 11A] 1 is a graph generated from X-ray powder diffraction (XRPD) experiments of several spray-dried dispersions of Compound 1 and a polymer, which are compared to the crystalline API and show that the spray-dried dispersions are amorphous. [Figure 11B] 1 is a graph generated from a differential scanning calorimetry (DSC) experiment of spray-dried dispersions of Compound 1 and polymer showing the reversing heat flow, Qrev (mW), as a function of temperature (° C.). [Figure 11C]1 is a graph generated from a differential scanning calorimetry (DSC) experiment of spray-dried dispersions of Compound 1 and polymer showing heat flow Q (W / g) as a function of temperature (° C.). [Figure 11D] 1 shows SEM (scanning electron microscope) images of spray-dried Compound 1 / polymer mixtures produced. The morphology of the dispersion consists of collapsed spheres. The majority of particles are less than 20 microns in diameter for all polymers. [Figure 11E] 1 is a graph of the solubility of Compound 1 (μgA / mL) as a function of time (minutes) in non-sink dissolution experiments for spray-dispersions of Compound 1 and polymer. [Figure 12A] 1 is a graph generated from a differential scanning calorimetry (DSC) experiment of spray-dried Compound 1 compositions showing reversing heat flow Qrev (mW) as a function of temperature (° C.) for various relative humidity samples. [Figure 12B] 1 is a graph generated from a differential scanning calorimetry (DSC) experiment of spray-dried Compound 1 compositions showing reversing heat flow Qrev (mW) as a function of temperature (° C.) for various relative humidity samples. [Figure 12C] 1 is a graph generated from multiple differential scanning calorimetry (DSC) experiments of spray-dried Compound 1 compositions showing glass transition temperature (° C.) versus relative humidity (%). [Figure 12D] 1 is a graph showing the effect of RH on the glass transition temperature of various solid dispersion formulations of Compound 1. [Figure 13A] 1 shows images of spray-dried dispersion compositions or Compound 1 compositions suspended in 0.5% Methocel A4M with polymer as API control. Images were taken at time 0. All suspensions were amorphous. [Figure 13B] 1 shows images of Compound 1 compositions suspended in 0.5% Methocel A4M containing spray-dried dispersion compositions or polymer as API control. Images were taken at 2 hours. All suspensions were amorphous. [Figure 13C]1 shows images of spray-dried dispersion compositions or Compound 1 compositions suspended in 0.5% Methocel A4M with polymer as API control. Images were taken at 6 hours. All suspensions were amorphous. [Figure 14] 1 is a graph generated from multiple differential scanning calorimetry (DSC) experiments of spray-dried Compound 1 compositions containing polyvinylpyrrolidine, showing the glass transition temperature (° C.) of each blend. [Figure 15] 1 shows the XRPD pattern of polymorphic form A of Compound 1. [Figure 16] 1 shows the XRPD pattern of polymorphic form C of Compound 1. [Figure 17] 1 shows, from top to bottom, the XRPD patterns of polymorphic Form A, Form C, and Form E of Compound 1. [Figure 18] 1 shows a graph of the results of a solubility experiment comparing micronized Compound 1 in polymorph Form C with non-micronized Compound 1. DETAILED DESCRIPTION OF THE INVENTION

[0041] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to an "agent" includes a plurality of such agents, a reference to a "cell" includes a reference to one or more cells (or cells), and equivalents known to those of skill in the art, and so forth. When ranges for physical properties, such as molecular weight, or chemical properties, such as formula, are used herein, all combinations and subcombinations of ranges and specific embodiments within the ranges are intended to be encompassed. The term "about," when referring to a number or range of numbers, means that the referenced number or range of numbers is approximate within experimental variation (or within statistical experimental error), and thus the number or range of numbers may, in some cases, vary by 1%-15% of the stated number or range of numbers. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other embodiments, such as, for example, any composition of matter, composition of matter, method, or process described herein, "consist of" or "consist essentially of" the described features. Definitions

[0042] As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings specified below.

[0043] "Amino" refers to the -NH2 radical.

[0044] "Cyano" refers to the -CN radical.

[0045] "Nitro" refers to the -NO2 radical.

[0046] "Oxa" refers to the -O- radical.

[0047] "Oxo" refers to the =O radical.

[0048] "Thioxo" refers to the =S radical.

[0049] "Imino" refers to the =NH radical.

[0050] "Oximo" refers to the =N-OH radical.

[0051] "Hydrazino" refers to the =N-NH2 radical.

[0052] "Alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 15 carbon atoms (e.g., C1-C 15 In some embodiments, alkyl contains 1 to 13 carbon atoms (e.g., C-C 13 In some embodiments, an alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, an alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, an alkyl contains 5 to 15 carbon atoms (e.g., C5-C 15In other embodiments, an alkyl group contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl group contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl group contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, an 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), and 1-pentyl (n-pentyl). An alkyl is attached to the remainder of the molecule by a single bond. Unless otherwise specified in the specification, an alkyl group is optionally substituted with 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 (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2) (where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0053] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0054] "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 2 to 12 carbon atoms. In some embodiments, an alkenyl contains 2 to 8 carbon atoms. In other embodiments, an alkenyl contains 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond and is, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like. Unless otherwise specified in the specification, an alkenyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, and the like. a , -SR a , -OC(O)-Ra , -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 (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0055] "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, and having from 2 to 12 carbon atoms. In some embodiments, an alkynyl contains from 2 to 8 carbon atoms. In other embodiments, an alkynyl contains from 2 to 6 carbon atoms. In other embodiments, an alkynyl contains from 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule by a single bond and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless otherwise stated in the specification, alkynyl groups are optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O-R ... 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 (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2) (where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0056] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the radical group to the rest of the molecule, consists solely of carbon and hydrogen, contains no unsaturation, and has 1 to 12 carbon atoms, such as 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 atom in the alkylene chain or any two carbon atoms within the chain. In some embodiments, alkylene contains 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene contains 1 to 2 carbon atoms (e.g., a C1-C2 alkylene). In other embodiments, an alkylene contains 1 carbon atom (e.g., a C1 alkylene). In other embodiments, an alkylene contains 5 to 8 carbon atoms (e.g., a C5-C8 alkylene). In other embodiments, an alkylene contains 2 to 5 carbon atoms (e.g., a C2-C5 alkylene). In other embodiments, an alkylene contains 3 to 5 carbon atoms (e.g., a C3-C5 alkylene). Unless stated otherwise in the specification, an alkylene chain is optionally substituted with 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(t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0057] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having 2 to 12 carbon atoms, linking a radical group to the rest of the molecule. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, alkenylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, alkenylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, alkenylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, alkenylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, alkenylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, an alkenylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise in the specification, an alkenylene chain is optionally substituted with 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 (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a)2 (t is 1 or 2), where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0058] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having 2 to 12 carbon atoms, connecting the radical group to the rest of the molecule. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, alkynylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, alkynylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, alkynylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, alkynylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, alkynylene contains 2 carbon atoms (e.g., C2 alkylene). In other embodiments, an alkynylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise in the specification, an alkynylene chain is optionally substituted with 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 (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a)2 (t is 1 or 2) (where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0059] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms from 5-18 carbon atoms, where at least one ring in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel's theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless stated otherwise in the specification, the term "aryl" or the prefix "ar" (as in "aralkyl") is meant to include aryl radicals that are optionally substituted by one or more substituents independently selected from the following: 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 a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a, -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2) (where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted).

[0060] "Aralkyl" is a group of the formula -R c -refers to the aryl radical, R cis an alkylene chain as defined above, e.g., methylene, ethylene, etc. 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.

[0061] "Aralkenyl" refers to a group of the formula -R d -refers to the aryl radical, R d is an alkenylene chain as defined above. The aryl group part of the aralkenyl radical is optionally substituted as defined above for an aryl group. The alkenylene group part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0062] "Aralkynyl" has the formula -R e -refers to the aryl radical, R e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as defined above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0063] "Aralkoxy" means a group of the formula -OR c -refers to a radical attached through an oxygen atom of an aryl, R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. 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.

[0064] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, having 3 to 15 carbon atoms. In certain embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains 5 to 7 carbon atoms. A carbocyclyl is attached to the rest of the molecule by a single bond. A carbocyclyl is saturated (i.e., contains only a single C-C bond) or unsaturated (i.e., contains one or more double or triple bonds). A fully saturated carbocyclyl radical is also referred to as a "cycloalkyl." Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also referred to as "cycloalkenyls." Examples of monocyclic cycloalkenyls include, for example, 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. Unless otherwise stated in this specification, the term "carbocyclyl" is meant to include carbocyclyl radicals optionally substituted by one or more substituents independently selected from the following: 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(Ra )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2) (where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, wherein each of the above substituents is unsubstituted unless otherwise specified.

[0065] A "carbocyclylalkyl" is a group of the formula -R c - refers to the carbocyclyl radical, R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0066] "Carbocyclylalkynyl" refers to a group of the formula -R c - refers to the carbocyclyl radical, R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0067] "Carbocyclylalkoxy" refers to a group of the formula -OR c- refers to a radical attached by an oxygen atom of a carbocyclyl, R c is an alkylene chain as defined below. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0068] As used herein, "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:

[0069] [ka]

[0070] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0071] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0072] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified herein, a 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 by any atom of the ring. Examples of such 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-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise in this specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above optionally substituted by one or more substituents selected from the following: 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 a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2) (where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, wherein each of the above substituents is unsubstituted unless otherwise specified.

[0073] "N-heterocyclyl" or "N-linked heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. The 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.

[0074] "C-heterocyclyl" or "C-linked heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one heteroatom, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. The 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-piperidinyl or 3-piperidinyl or 4-piperidinyl, 2-piperazinyl, 2-pyrrolidinyl or 3-pyrrolidinyl, and the like.

[0075] "Heterocyclylalkyl" refers to a group of the formula -R c - refers to the heterocyclyl radical, 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 portion of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0076] "Heterocyclylalkoxy" refers to a group of the formula -OR c - refers to a radical attached by an oxygen atom of a heterocyclyl, 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 portion of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0077] "Heteroaryl" refers to a radical derived from a 3-18-membered aromatic ring radical containing 2-17 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Heteroaryl includes fused or bridged ring systems. Heteroatoms in a heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, 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 (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]i midazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,10-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxazolyl Xoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclo[4,5]thieno[2,3-d]pyrimidinyl, 5, ... Hepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise in this specification, the term "heteroaryl" is meant to include heteroaryl radicals, as defined above, optionally substituted by one or more substituents selected from the following: 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)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2) (where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted).

[0078] "N-heteroaryl" refers to a heteroaryl radical, as defined above, containing at least one nitrogen, and the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0079] "C-heteroaryl" refers to a heteroaryl radical as defined above, where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0080] "Heteroarylalkyl" means a group of the formula -R c - refers to the heteroaryl radical, 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 portion of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0081] "Heteroarylalkoxy" means a heteroaryl group of the formula -OR c - refers to a heteroaryl radical attached by an oxygen atom, 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 portion of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0082] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R) or (S). Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are contemplated by the present disclosure. When a compound described herein contains an alkene double bond, and unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, their racemic and optically pure forms, and all tautomers are intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

[0083] "Tautomer" refers to a molecule capable of proton transfer from one atom of a molecule to another atom of the same molecule. The compounds presented herein exist as tautomers in some embodiments. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium include the following:

[0084] [ka]

[0085] In some embodiments, the compounds disclosed herein are available in various isotopically enriched forms, e.g., 2 H, 3 H, 11 C. 13 C, and / or 14The compound is enriched to a C content and used. In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be made by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability or efficacy, thereby increasing the duration of action of pharmaceuticals.

[0086] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium; 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this disclosure.

[0087] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C), and may be labeled with an isotope. 2 H, 11 C. 13 C. 14 C. 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, 125All isotopic substitutions with I are contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0088] In certain embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2 The atom is replaced with a H. Methods for the synthesis of compounds containing deuterium are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0089] Deuterium-substituted compounds are synthesized using a variety of methods, such as those 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, 110pp; 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.

[0090] Deuterated starting materials are readily available and amenable to the synthetic methods described herein for the synthesis of deuterium-containing compounds. Many deuterium-containing reagents and building blocks are commercially available from chemical companies such as Aldrich Chemical Co.

[0091] Deuterium transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and may be used to transfer a deuterated carbon atom to a reaction substrate under nucleophilic substitution reaction conditions. The use of CD3I is illustrated, by way of example only, in the following reaction scheme:

[0092] [ka]

[0093] A deuterium transfer reagent, such as lithium aluminum deuteride (LiAlD4), is used to transfer deuterium to the reaction substrate under the above reducing conditions. The use of LiAlD4 is illustrated, by way of example only, in the following reaction scheme:

[0094] [ka]

[0095] Deuterium gas and a palladium catalyst are used to reduce unsaturated carbon-carbon bonds and, by way of example only, to effect reductive displacement of aryl carbon-halogen bonds as illustrated in the following reaction scheme:

[0096] [ka]

[0097] In one embodiment, 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 compounds disclosed herein are fully substituted with deuterium atoms and are non-exchangeable. 1 In one embodiment, the level of deuterium incorporation is determined by a synthetic method in which deuterated synthetic building blocks are used as starting materials.

[0098] Throughout the specification, examples, and claims, various components are expressed as being present in ratios of, for example, 1:2, 1:3, 1:4, or 1:5, etc. Unless otherwise specified, such ratios refer to weight ratios of each component.

[0099] " Pharmaceutically acceptable salt " includes both acid and base addition salts. The pharmaceutically acceptable salt of any one of the heterocyclic RBP4 inhibitor compounds described herein is intended to include any pharmaceutically suitable salt form. The preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0100] "Pharmaceutically acceptable acid addition salts" refer to those salts which retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and are formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, hydroiodic, hydrofluoric, phosphorous, etc. Also included are salts formed with organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic acids, and aromatic sulfonic acids, including, for example, 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. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Similarly, salts of amino acids such as arginate, gluconate, and galacturonic acid are contemplated (e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared, in some embodiments, by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to those skilled in the art.

[0101] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acid, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, made with metals or amines, such as alkali, 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, such as 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, etc. See Berge et al., supra.

[0102] As used herein, "treatment" or "treating" or "alleviating" or "ameliorating" are used interchangeably. These terms refer to an approach for obtaining a beneficial or desired result, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. A "therapeutic benefit" refers to the eradication or amelioration of the underlying disease being treated. Similarly, a therapeutic benefit is achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that an improvement is observed in the patient even though the patient still suffers from the underlying disease. For a prophylactic effect, the composition, in some embodiments, is administered to a patient at risk of contracting the disease or reporting one or more physiological symptoms of the disease, even if a diagnosis of the specific disease has not been made.

[0103] In some embodiments, "prodrug" is meant to refer to a compound that is converted under physiological conditions or by solvolysis into a biologically active compound as described herein. Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. Prodrugs are generally inactive when administered to a subject, but are converted into an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 79, 2124 (Elsevier, Amsterdam)).

[0104] A discussion of prodrugs is provided in Higuchi, T., et al., "Pro drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0105] The term "prodrug" is also meant to include any covalently bonded carrier, which releases the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of active compounds as described herein are prepared by modifying functional groups present in the active compound in such a way that the functional group modification is cleaved, either by routine manipulation or in vivo, to yield the parent active compound. Prodrugs include compounds in which a hydroxy, amino, or mercapto group is bonded to any group that is cleaved to form a free hydroxy, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol or amine functional groups in the active compound, and the like.

[0106] X-ray powder diffraction (XRPD) peaks are described herein and in the claims. XRPD peak values ​​in this application refer to those obtained using a copper source having a wavelength of 1.5406 angstroms, unless otherwise specified.

[0107] As used herein, "Compound 1" or "CMPD-1" refers to Compound No. 1 shown in Table 1. Compound 1 has the following structure:

[0108] [ka] Compound 1 is also referred to by the full chemical name 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.

[0109] RBP4 inhibitor compounds In some embodiments, the present invention provides RBP4 inhibitor compounds and pharmaceutical compositions comprising the compounds.The subject compounds and compositions inhibit RBP4 and are useful for treating eye diseases or disorders, such as age-related macular degeneration, dry (atrophic) age-related macular degeneration, juvenile macular degeneration (Stargardt's disease), Best's disease, adult-onset vitelliform maculopathy, geographic atrophy, Stargardt's macular dystrophy, diabetic retinopathy, or ABCA4 gene-related retinal diseases.

[0110] 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):

[0111] [ka] During the ceremony, R 1 are each independently selected from halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, -COR 7 , -CON(R 7 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 7 , optionally substituted (C0-C4 alkylene)-N(R 7 )2, optionally substituted (C0-C4 alkylene)N(R 8 )-COR 7 , optionally substituted (C0-C4 alkylene)-SON(R 7 )2, optionally substituted (C0-C4 alkylene)-SO2R 7 , optionally substituted (C0-C4 alkylene)N(R 8 )-SO2N(R 7 )2, or optionally substituted (C0-C4 alkylene)N(R 8 )-SO2R 7 and R 7 are each independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; or two R 11 groups taken together with the nitrogen to which they are attached form an optionally substituted N-heterocyclyl; R 8 are each independently selected from H or optionally substituted alkyl; R 2 is —H, —OH, optionally substituted alkyl, or halogen; p is 0, 1, 2, 3, 4, or 5; A has the following structure:

[0112] [ka] During the ceremony, α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C, Z1 is S, O, or N; Z2 is S, O, N, or NR 3 and R 3 is H, optionally substituted alkyl, or oxetane, and B is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure.

[0113] Some embodiments provided herein describe compounds having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof: During the ceremony, R 1each independently represents a halogen, an 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 (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 7 , optionally substituted (C0-C4 alkylene)-N(R 7 )2, optionally substituted (C0-C4 alkylene)N(R 8 )-COR 7 , optionally substituted (C0-C4 alkylene)-SON(R 7 )2, optionally substituted (C0-C4 alkylene)-SO2R 7 , optionally substituted (C0-C4 alkylene)N(R 8 )-SO2N(R 7 )2, or optionally substituted (C0-C4 alkylene)N(R 8 )-SO2R 7 and R 7 each independently represents 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, optionally substituted C 2-6 forming an N-heterocyclyl, R 8 each independently represents H or an optionally substituted C 1-6 alkyl, R 2 -H, -OH, optionally substituted C 1-6 alkyl, or halogen; p is 0, 1, 2, 3, 4, or 5; A has the following structure:

[0114] [ka] During the ceremony, α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C, Z1 is S, O, or N; Z2 is S, O, N, or NR 3 and R 3 is H, optionally substituted C 1-6 alkyl, or oxetane, and B is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure.

[0115] Certain embodiments provided herein describe compounds having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof: During the ceremony, R 1 are each independently a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Heterocyclyl, C 3-10 Heterocycloalkyl, -COR 7 , -CON(R 7 )2, (C0-C4 alkylene)-CN, (C0-C4 alkylene)-OR 7 , (C0-C4 alkylene)-N(R 7 )2, (C0-C4 alkylene)N(R 8 )-COR 7 , (C0-C4 alkylene)-SON(R 7 )2, (C0-C4 alkylene)-SO2R 7 , (C0-C4 alkylene)N(R 8 )-SO2N(R7 )2, or (C0-C4 alkylene)N(R 8 )-SO2R 7 and R 7 are independently 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 The groups, together with the nitrogen to which they are attached, form C 2-6 forming an N-heterocyclyl, R 8 are each independently H or C 1-6 alkyl, R 2 -H, -OH, C 1-6 alkyl, or halogen; p is 0, 1, 2, 3, 4, or 5; A has the following structure:

[0116] [ka] During the ceremony, α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C, Z1 is S, O, or N; Z2 is S, O, N, or NR 3 and R 3 is H, C 1-6 alkyl, or oxetane, and B is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure.

[0117] Some embodiments provided herein describe compounds having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof: During the ceremony, R 1 are each independently halogen, haloalkyl, or alkyl; R 2 is -H, -OH, or a halogen, p is 0, 1, 2, 3, 4, or 5; A has the following structure:

[0118] [ka] During the ceremony, α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C, Z1 is S, O, or N; Z2 is S, O, N, or NR 3 and R 3 is H, C1-C4 alkyl, or oxetane, and B is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure.

[0119] Certain embodiments provided herein describe compounds having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof: During the ceremony, R 1 are independently Br, Cl, F, and C 1-6 Fluoroalkyl, or C 1-6 is alkyl, R 2 is -H, -OH, Br, Cl, or F, p is 0, 1, 2, 3, 4, or 5; A has the following structure:

[0120] [ka] During the ceremony, α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C, Z1 is S, O, or N; Z2 is S, O, N, or NR 3 and R 3 is H, C1-C4 alkyl, or oxetane, and B is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure.

[0121] For any and all of the embodiments of formula (I), the substituents are selected from among a subset of the described alternatives.

[0122] In some embodiments, R 1 each independently represents a halogen, an 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 (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 7 , optionally substituted (C0-C4 alkylene)-N(R 7 )2, optionally substituted (C0-C4 alkylene)N(R 8 )-COR 7 , optionally substituted (C0-C4 alkylene)-SON(R 7 )2, optionally substituted (C0-C4 alkylene)-SO2R 7 , optionally substituted (C0-C4 alkylene)N(R 8 )-SO2N(R 7 )2, or optionally substituted (C0-C4 alkylene)N(R 8 )-SO2R 7 In certain embodiments, R 1 are each independently a halogen, C 1-6 Alkyl, C1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Heterocyclyl, C 3-10 Heterocycloalkyl, -COR 7 , -CON(R 7 )2, (C0-C4 alkylene)-CN, (C0-C4 alkylene)-OR 7 , (C0-C4 alkylene)-N(R 7 )2, (C0-C4 alkylene)N(R 8 )-COR 7 , (C0-C4 alkylene)-SON(R 7 )2, (C0-C4 alkylene)-SO2R 7 , (C0-C4 alkylene)N(R 8 )-SO2N(R 7 )2, or (C0-C4 alkylene)N(R 8 )-SO2R 7 In some embodiments, R 1 are each independently a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -COR 7 , -CON(R 7 )2, (C0-C4 alkylene)-CN, (C0-C4 alkylene)-OR 7 , or (C0-C4 alkylene)-N(R 7 )2. In other embodiments, R 1 are each independently (C0-C4 alkylene)N(R 8 )-COR 7 , (C0-C4 alkylene)-SON(R 7 )2, (C0-C4 alkylene)-SO2R 7 , (C0-C4 alkylene)N(R 8 )-SO2N(R 7 )2, or (C0-C4 alkylene)N(R 8 )-SO2R 7 In some embodiments, R 1 are each independently a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -COR 7 , -CON(R 7)2, -CN, (C0-C4 alkylene)-OR 7 , or (C0-C4 alkylene)-N(R 7 )2. In some embodiments, R 1 are each independently a halogen, C 1-6 Alkyl, C 1-6 haloalkyl, or -CN. In certain embodiments, R 1 are independently F, Br, Cl, and C 1-6 Haloalkyl, or C 1-6 In certain embodiments, R 1 are each independently F or CF3.

[0123] In some embodiments, R 7 each independently represents 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, optionally substituted C 2-6 In some embodiments, R 7 are independently 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 The groups, together with the nitrogen to which they are attached, form C 2-6 In some embodiments, R 7 are independently H, C 1-6 Alkyl, or C 3-6 In certain embodiments, two R 11 The groups, together with the nitrogen to which they are attached, may be optionally substituted C2-6 In some embodiments, R 7 are each independently H or C 1-6 In some embodiments, R 7 are H or Me, respectively.

[0124] In some embodiments, R 8 are independently H, C 1-6 Alkyl, or C 1-6 In some embodiments, R is selected from haloalkyl. 8 are each independently H or C 1-6 In some embodiments, R 8 are each independently selected from H or Me. In some embodiments, R 8 are H respectively.

[0125] In some embodiments, 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 0 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.

[0126] In some embodiments, 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-H, -OH, C 1-6 Alkyl, C 1-6 haloalkyl, or halogen. In some embodiments, R 2 is —H, —OH, Me, CF, or halogen. In some embodiments, R 2 is —H, —OH, Me, CF, Cl, or F. In some embodiments, R 2 is —H, —OH, Me, CF, or F. In some embodiments, 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.

[0127] In some embodiments, when α is present, Z1 is O or S, Z2 is N, X is C, χ is present, and β and δ are absent. In other embodiments, when α is absent, Z1 is N and Z2 is NR 3 and X is C, β and δ are present, and χ is absent. In certain embodiments, when α is absent, Z1 is N, Z2 is O or S, X is C, β and δ are present, and χ is absent.

[0128] In some embodiments, A has the structure:

[0129] [ka] During the ceremony, n is 0, 1, or 2; α, β, χ, δ, ε, and φ are each independently absent or present, and when present, each is a bond; Z1 is S, O, or N; Z2 is S, O, N, or NR 3and where R 3 is H, C1-C4 alkyl, or oxetane; X is C, Y1, Y2, Y3, and each occurrence of Y4 are independently 4 , C(R 5 )2, NR 6 , O, N, SO2, or -(C=O)-, wherein R 4 H, halogen, C1-C 10 Alkyl, C1-C 10 Cycloalkyl, -O(C1-C 10 alkyl), -C(O)OH, -C(O)O(C1-C 10 alkyl), -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -NHC(O)NH(C1-C 10 alkyl), -NHC(O)N(C1-C4 alkyl)2, -SO2NH(C1-C 10 alkyl), -SO2N(C1-C 10 alkyl), -CN, or -CF; R 5 is H or C1-C 10 alkyl, and R 6 is H, C1-C 10 Alkyl, C3-C6 cycloalkyl, -(C1-C 10 alkylene)CF3, -(C1-C 10 alkylene)OCH3, -(C1-C 10 Alkylene)-halogen, -SO2(C1-C 10 alkyl), -SO2(C1-C 10 alkylene)-CF3, -SO2(C1-C 10 alkylene)OCH3, -SO2(C1-C 10 alkylene)-halogen, -C(O)(C1-C 10 alkyl), -C(O)(C1-C 10 alkylene)CF3, -C(O)(C1-C 10 alkylene)OCH3, -C(O)(C1-C 10alkylene)-halogen, -C(O)NH(C1-C 10 alkyl), -C(O)N(C1-C 10 alkyl)2, -(C1-C 10 alkylene)C(O)OH, —C(O)NH2, or oxetane.

[0130] In some embodiments, when α is present, Z1 is O or S, Z2 is N, X is C, χ is present, and β and δ are absent. In other embodiments, when α is absent, Z1 is N, Z2 is N, X is C, β and δ are present, and χ is absent. In particular embodiments, when α is absent, Z1 is N, Z2 is O or S, X is C, β and δ are present, and χ is absent. In further or additional embodiments, when ε and φ are each present, n=1, and each of Y1, Y2, Y3, and Y4, independently, is -CR 4 - or N. In other embodiments, when ε and φ are each absent, n=0, 1, or 2, and each of Y1, Y2, Y3, and each occurrence of Y4 independently represents C(R 5 )2, NR 6 , O, or SO2.

[0131] In some embodiments, β and δ are present. In some embodiments, α, χ, ε, and φ are absent. In some embodiments, Z1 is N. In some embodiments, Z2 is O, S, or NR 3 where R 3 is H, C1-C4 alkyl, or oxetane. In some embodiments, X is C. In certain embodiments, β and δ are present, α, χ, ε, and φ are absent, Z1 is N, and Z2 is O, S, or NR 3 and R 3 is H, C1-C4 alkyl, or oxetane, and X is C.

[0132] In some embodiments, β, δ, ε, and φ are present. In some embodiments, α and χ are absent. In some embodiments, Z1 is N. In some embodiments, Z2 is O or NR 3 where R 3 is H, C1-C4 alkyl, or oxetane. In some embodiments, X is C. In certain embodiments, β, δ, ε, and φ are present, α and χ are absent, Z1 is N, and Z2 is O or NR 3 and R 3 is H, C1-C4 alkyl, or oxetane, and X is C.

[0133] In some embodiments, A has the structure:

[0134] [ka] During the ceremony, n is 0, R 3 is H, C1-C4 alkyl, or oxetane; Y1 and Y3 are each CH2 or C(CH3)2; Y2 is O, SO2, or NR 6 and R 6 is H, C1-C4 alkyl, C3-C6 cycloalkyl, -(C1-C4 alkylene)CF3, -(C1-C4 alkylene)OCH3, -(C1-C4 alkylene)-halogen, -SO2(C1-C4 alkyl), -SO2(C1-C4 alkylene)CF3, -SO2(C1-C4 alkylene)OCH3, -SO2(C1-C4 alkylene)-halogen, - C(O)(C1-C4 alkyl), -C(O)(C1-C4 alkylene)CF3, -C(O)(C1-C4 alkylene)OCH3, -C(O)(C1-C4 alkylene)-halogen, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -(C1-C4 alkylene)C(O)OH, -C(O)NH2, or oxetane.

[0135] In some embodiments, A has the structure:

[0136] [ka] n is 1, R 3 is H, C1-C4 alkyl, or oxetane; Y1 and Y4 are CH2 or C(CH3)2; Y2 and Y3 are CH2 or C(CH3)2, O, SO2, or NR 6 and R 6 is H, C1-C4 alkyl, C3-C6 cycloalkyl, -(C1-C4 alkylene)CF3, -(C1-C4 alkylene)OCH3, -(C1-C4 alkylene)-halogen, -SO2(C1-C4 alkyl), -SO2(C1-C4 alkylene)CF3, -SO2(C1-C4 alkylene)OCH3, -SO2(C1-C4 alkylene)-halogen, - C(O)(C1-C4 alkyl), -C(O)(C1-C4 alkylene)CF3, -C(O)(C1-C4 alkylene)OCH3, -C(O)(C1-C4 alkylene)-halogen, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -(C1-C4 alkylene)C(O)OH, -C(O)NH2, or oxetane.

[0137] In some embodiments, A has the structure:

[0138] [ka] n is 2, R 3 is H, C1-C4 alkyl, or oxetane; Y1 and Y4 are CH2 or C(CH3)2; Y2 and Y3 are CH2 or C(CH3)2, O, SO2, or NR 6 and R 6is H, C1-C4 alkyl, C3-C6 cycloalkyl, -(C1-C4 alkylene)CF3, -(C1-C4 alkylene)OCH3, -(C1-C4 alkylene)-halogen, -SO2(C1-C4 alkyl), -SO2(C1-C4 alkylene)CF3, -SO2(C1-C4 alkylene)OCH3, -SO2(C1-C4 alkylene)-halogen, - C(O)(C1-C4 alkyl), -C(O)(C1-C4 alkylene)CF3, -C(O)(C1-C4 alkylene)OCH3, -C(O)(C1-C4 alkylene)-halogen, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -(C1-C4 alkylene)C(O)OH, -C(O)NH2, or oxetane.

[0139] In some embodiments, A has the structure:

[0140] [ka]

[0141] In certain embodiments, A has the structure:

[0142] [ka]

[0143] In certain embodiments, A has the structure:

[0144] [ka]

[0145] In certain embodiments, A has the structure:

[0146] [ka]

[0147] In certain embodiments, A has the structure:

[0148] [ka]

[0149] In certain embodiments, A has the structure:

[0150] [ka]

[0151] In some embodiments, R 6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, -(C1-C6 alkylene)CF3, -(C1-C6 alkylene)OCH3, -(C1-C6 alkylene)-halogen, -SO2-C1-C6 alkyl, -SO2(C1-C6 alkylene)-CF3, -SO2(C1-C6 alkylene)OCH3, -SO2(C1-C6 alkylene)-halogen, - In some embodiments, R is C(O)(C-C alkyl), -C(O)(C-C alkylene)CF, -C(O)(C-C alkylene)OCH, -C(O)(C-C alkylene)-halogen, -C(O)NH(C-C alkyl), -C(O)N(C-C alkyl), -(C-C alkylene)C(O)OH, -C(O)NH, or oxetane. 6is C1-C6 alkyl, C3-C6 cycloalkyl, -(C1-C6 alkylene)CF3, -(C1-C6 alkylene)OCH3, -(C1-C6 alkylene)-halogen, -SO2-C1-C6 alkyl, -SO2(C1-C6 alkylene)-CF3, -SO2(C1-C6 alkylene)OCH3, -SO2(C1-C6 alkylene)-halogen, -C (O)(C-C alkyl), —C(O)(C-C alkylene)CF, —C(O)(C-C alkylene)OCH, —C(O)(C-C alkylene)-halogen, —C(O)NH(C-C alkyl), —C(O)N(C-C alkyl), —(C-C alkylene)C(O)OH, —C(O)NH, or oxetane. In some embodiments, R 6 is —C(O)(C1-C6 alkyl). In some embodiments, R 6 is H, C1-C4 alkyl, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, t-Bu, -CH2OCH3, -CH2CF3, -CH2Cl, -CH2F, -CH2CH2OCH3, -CH2CH2CF3, -CH2CH2Cl, -CH2CH2F,

[0152] [ka] -SO2CH3, -SO2CH2CH3, -SO2CH2CH2CH3, -SO2CH(CH3)2, -SO2CH2CH(CH3)2, -SO2(t-Bu), -SO2CH2OCH3 , -SO2CH2CF3, -SO2CH2Cl, -SO2CH2F, -SO2CH2CH2OCH3, -SO2CH2CH2CF3, -SO2CH2CH2Cl, -SO2CH2CH2F,

[0153] [ka] C(O)CH3, C(O)CH2CH3, -C(O)CH2CH2CH3, -C(O)CH(CH3)2, -C(O)CH2CH(CH3)2, -C(O)t-Bu, -C(O)CH2OCH3, - C(O)CH2CF3, -C(O)CH2Cl, -C(O)CH2F, -C(O)CH2CH2OCH3, -C(O)CH2CH2CF3, -C(O)CH2CH2Cl, -C(O)CH2CH2F,

[0154] [ka] In some embodiments, R 6 is —C(O)(C1-C6 alkyl). In some embodiments, R 6 is H, C1-C4 alkyl, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, t-Bu, -CH2OCH3, -CH2CF3, -CH2Cl, -CH2F, -CH2CH2OCH3, -CH2CH2CF3, -CH2CH2Cl, -CH2CH2F, or

[0155] [ka] In other embodiments, R 6 -SO2CH3, -SO2CH2CH3, -SO2CH2CH2CH3, -SO2CH(CH3)2, -SO2CH2CH(CH3)2, -SO2(t-Bu), -SO2CH2OCH3, -SO2CH2CF3, -SO2CH2Cl, -SO2CH2F, -SO2CH2CH2OCH3, -SO2CH2CH2CF3, -SO2CH2CH2Cl, -SO2CH2CH2F, or

[0156] [ka] In certain embodiments, R 6is C(O)CH3, C(O)CH2CH3, -C(O)CH2CH2CH3, -C(O)CH(CH3)2, -C(O)CH2CH(CH3)2, -C(O)t-Bu, -C(O)CH2OCH3, -C (O)CH2CF3, -C(O)CH2Cl, -C(O)CH2F, -C(O)CH2CH2OCH3, -C(O)CH2CH2CF3, -C(O)CH2CH2Cl, -C(O)CH2CH2F, or

[0157] [ka] is.

[0158] In some embodiments, A has the structure:

[0159] [ka] During the ceremony, Y1, Y2, Y3, and each occurrence of Y4 are independent of each other. 4 or N, where: R 3 H, halogen, C1-C 10 Alkyl, C1-C 10 Cycloalkyl, -O(C1-C 10 alkyl), -C(O)OH, -C(O)O(C1-C 10 alkyl), -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -NHC(O)NH(C1-C 10 alkyl), -NHC(O)N(C1-C4 alkyl)2, -SO2NH(C1-C 10 alkyl), -SO2N(C1-C 10 alkyl), -CN, or -CF.

[0160] In some embodiments, Y1, Y2, Y3, and Y4 are CH. In some embodiments, Y1, Y2, Y3 are CH and Y4 is N. In some embodiments, Y1, Y2, Y4 are CH and Y3 is N. In some embodiments, Y1, Y3, Y4 are CH and Y2 is N. In some embodiments, Y2, Y3, Y4 are CH and Y1 is N.

[0161] In certain embodiments, A has the structure:

[0162] [ka]

[0163] In some embodiments, R 3 H, halogen, C1-C 10 Alkyl, C1-C 10 Cycloalkyl, -O(C1-C 10 alkyl), -C(O)OH, -C(O)O(C1-C 10 alkyl), -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -NHC(O)NH(C1-C 10 alkyl), -NHC(O)N(C1-C4 alkyl)2, -SO2NH(C1-C 10 alkyl), -SO2N(C1-C 10 alkyl), -CN, or -CF. In some embodiments, R 3 is H, halogen, C-C alkyl, C-C cycloalkyl, —O(C-C alkyl), —C(O)OH, —C(O)O(C-C alkyl), —C(O)NH, —C(O)NH(C-C alkyl), —C(O)N(C-C alkyl), —NHC(O)NH(C-C alkyl), —NHC(O)N(C-C alkyl), —SONH(C-C alkyl), —SON(C-C alkyl), —CN, or —CF. In some embodiments, R 4is H, halogen, C-C alkyl, C-C cycloalkyl, —O(C-C alkyl), —CN, —CF, —C(O)OH, —C(O)NH, —C(O)N(CH), —C(O)NHCH, or —NHC(O)N(CH). In some embodiments, R 4 is H, halogen, methyl, methoxy, —CN, —CF3, —C(O)N(CH3)2, —C(O)NHCH3, or —C(O)Me.

[0164] In some embodiments, heterocyclic compounds of formula (I) are provided in Table 1.

[0165] [Table 1-1]

[0166] [Table 1-2]

[0167] [Table 1-3]

[0168] [Table 1-4]

[0169] Table 1-5

[0170] Table 1-6

[0171] In certain embodiments, the heterocyclic compounds of Formula (I) are selected from the group consisting 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; 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)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one; (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone [4,3-c]pyridin-3-yl)methanone; (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(4-fluoro-2-(trifluoromethyl)furan) (4-(4-fluoro-2-(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-yl)(5-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;(4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone; (4-(4- ... 1-(3-(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one;(4-(3-fluoro-2,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone )(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;(4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(6-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;(4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H- Pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(6-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carbonitrile (4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide (6-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;Methyl 3-(4-(3,5-Difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate; (4-(3,5-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(3,4-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-neopentyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl) Methanone; (4-(2-chloro-5-fluorophenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone; 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carbonitrile;(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone; 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide; (4- (3,4-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-neopentyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone; (4-(3,4-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone; Methyl 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate; 1-(3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one; (6-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(3,5-difluoromethyl)phenyl)piperidine-1-carbonyl Fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone; 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)-3-methylbutan-1-one;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)propan-1-one;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)-2-methylpropan-1-one 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carbonitrile;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;(4- (3,4-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(3,4-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl ... 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;Methyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate;2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetic acid; (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (5-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-yl) (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-methyl-4,; 5,6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;Methyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;(4-(3 ,5-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carbonitrile;Methyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;(6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone )(4-(3-Fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(4-(3-Fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;(4-(3-Fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(2-chloro-5-fluorophenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone; Imidazo[1,2-a]pyridin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one; (5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(3-fluoro -2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide;(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;(4-(3,5-difluoro- (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone; (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;(4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone; (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4 ... (4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone; (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4 ,3-c]pyridin-3-yl)methanone;(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;1-(3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one;1-(3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl )-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one; 1-(3-(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one; 1-(3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one;1-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one; (4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(3-fluoro-2- (Trifluoromethyl)phenyl)piperidin-1-yl)(5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;(5-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;Methyl 3-(4-(3-Fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate; 3-(4-(3-Fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carbonitrile; 1-(3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one;(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;tert-Butyl 2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetate; tert-butyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;tert-Butyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate;tert-Butyl 3-(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;tert-Butyl 3-(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate tert-Butyl 3-(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate;tert-Butyl 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;tert-Butyl 3-(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate tert-Butyl 3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;tert-Butyl 3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate;tert-Butyl 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate;tert-Butyl 3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate; tert-Butyl 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate; tert-Butyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5 ... tert-Butyl 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;tert-Butyl 3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;tert-Butyl 3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate;(6,6-dimethyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6,6-dioxide-1,4,5,7-tetrahydrothiopyrano[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1,4,5, 7-Tetrahydropyrano[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1-Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1-Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;1-Ethyl-N,N-dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide;(5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-chloro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (1H-Pyrazolo[3,4-b]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-chloro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-(Methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;1-(3 -(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one; (4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-fluoro-1-(oxetan-3-yl)-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (1-ethyl-6-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-fluoro-1-isopropyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; 1-(3-(4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one;(5-Fluoro-1-methyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-Fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one;(5-Fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-((chloromethyl)sulfonyl)-4,5,6, 7-Tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-(2-Methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(4-Fluoro-4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3 -yl)methanone; 1-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one; (1-ethyl-5-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-fluoro-1-methyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[4,3-c]pyridin-6-one;3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[3,4-c]pyridin-5-one;6-Methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[3,4-c]pyridin- 5-one;5-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[4,3-c]pyridin-6-one;(5,5-dioxide-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1-methyl-5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)( 4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1-methyl-6-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;1-(1-ethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one;(5-(methyl (6-(methoxymethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-(methoxymethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-methoxy-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-isobutyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4, 3-c]pyridin-5-yl)propan-1-one;(5-Ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;3-Methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)butan-1-one;2-Methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)- 2,2-Dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)propan-1-one;(5-(Isopropylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methan-1-one;2,2-Dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)propan-1-one;(5-(Isopropylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methan-1-one non;(5-(Isobutylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-(Ethylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1H-indazole-5-carbonitrile;(7-Chloro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5,6-Difluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-(2-Methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone; (4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; 3,3,3-trifluoro-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)propan-1-one; (5-(tert-butyl)-4,5,6,7-tetrahydro-1H-; Pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-Isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;N-Methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6 ,7-Tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide;N-Methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide;(5-Bromo-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;tert-Butyl 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate;tert-Butyl 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;(5-Fluoro-1-isopropyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(7-Fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-Pyrazolo[4,3-c]pyridine (1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (1H-pyrazolo[4,3-b]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-Methoxy-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-Fluoro-1-(oxetan-3-yl)-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (1-Ethyl-5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (1-Ethyl-6-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; 1-(1-Methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one;1-(1-Methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one;N,N-Dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine) -1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide;N,N-dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide;(1-methyl-5,5-dioxide-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(4-(2-(trifluoromethyl)phenyl)pyridin-1-yl)methanone (1-Methyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; 2-Methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)propan-1-one;(6-(Isopropylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-(Ethylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro- 6H-Pyrazolo[3,4-c]pyridin-6-yl)propan-1-one;2-Methoxy-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one;3,3,3-Trifluoro-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)propan-1-one;(1H-Indazo (1-Methyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-(tert-butylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3, 4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; 2,2-dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)propan-1-one; (6-(tert-butyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-(Isobutylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; 3-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)butan-1-one; (6-Isobutyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-Isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-Ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-(tert-butylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;tert-Butyl 3-(4-Fluoro-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;(4-Hydroxy-4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)(1-methyl-1H-indazol-3-yl)methanone;1-(3-(4-Hydroxy-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate) 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide; (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-neopentyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(oxetan-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone; (5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl) (5-Ethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone; 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-3-methylbutan-1-one; 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-2-methylpropan-1-one 3-(4-(3,4-Difluoro-2-(trifluoromethyl)phenyl)piperidine-1-yl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carbonitrile;(4-(3,4-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;3-(4-(3,4-Difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carbonitrile;(4-(3,4-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone; (5-benzoyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;Methyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate; (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone; (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2,2,2-trifluoroethyl)- 1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(pyrrolidine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-isonicotinoyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;(4-(3 ,4-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-nicotinoyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;(4-(3,4-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(piperidine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;(4-(3,4-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(piperazine -1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one;(5,5-dioxide-4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(4,6-dihydro-1H-furo [3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (1-ethyl-5-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (1-methyl-5-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1-Methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; 2-Methoxy-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one; (5-(2-Methoxy) 3,3,3-Trifluoro-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one;(5- (Oxetan-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-(isobutylsulfon ... (5-(Ethylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-(Ethylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;tert-Butyl 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate; (5-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one; (5-(tert-butylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-(tert-butyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (5-Isobutyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-Isopropyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-Ethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 1-(1-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-yl)ethan-1-one;2,2-Dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)methanone;N-Methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one;2,2-Dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl) Piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one; 3-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)butan-1-one; 2-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one;1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one;N,N-Dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide;(5-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one (5-(Methoxymethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;tert-Butyl 4-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl)piperazine-1-carboxylate;tert-Butyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate; (5,5-dioxide-4,6,7,8-tetrahydro-1H-thiepino[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (4,6,7,8-tetrahydro-1H-oxepino[4,3-c]pyrazol-3-yl)(4- (2-(Trifluoromethyl)phenyl)piperidin-1-yl)methanone;N-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxamide;(5-(2,2,2-trifluoroethyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-(tert-butylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; 2,2-dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)propan-1-one; (5-(tert-butyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3 -c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-(isobutylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;3-Methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)butan-1- (5-Isobutyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-(Isopropylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; 2-Methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7 ,8-Tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)propan-1-one;(1-ethyl-5-(methylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;1-(1-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)ethan-1-one;(5-(Methoxymethyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-Methyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-Isopropyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-(Ethylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; Dropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)propan-1-one;(5-Ethyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5- (Methylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)ethan-1-one;(1,4,5,6,7,8-Hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)methanone) )piperidin-1-yl)methanone;(1-Methyl-5-(methylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1-Methyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;N,N-Dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1- carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxamide;(5-(2-methoxyethyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;2-Methoxy-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)ethan-1-one;3,3,3-Trifluoro-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)propan-1-one;(5-(oxetan-3-yl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;tert-Butyl 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxylate;(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-Fluoroimidazo[1,2-b]pyridazin-2-yl)(4- (2-(Trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-(Pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-Cyclopropylimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-Methoxyimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 6-Methylimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-Methylimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-Chloroimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;I Midazo[1,2-b]pyridazin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-chloro-2-methylimidazo[1,2-b]pyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-Benzo[d]imidazol-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-Imidazo[4,5-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;6-Methyl-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrimidine-4-carboxylic acid;Methyl 6-Methyl-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrimidine-4-carboxylate;N-(cyclopropylsulfonyl)-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide;N-(phenylsulfonyl)-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide;N-(methylsulfonyl)-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide;3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide;2-(4-(2-(trifluoromethyl)phenyl)piperidine- 1-Carbonyl)benzamide;4-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzoic acid;3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzoic acid;2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzoic acid;4-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)benzoic acid;2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)benzoic acid;3-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)benzoic acid;4-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,7-dihydroisothiazolo[5,4-c]pyridin-6(5H)-yl)ethan-1-one;(4,5,6,7-tetrahydroisothiazolo[5,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;1 -(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydroisoxazolo[4,5-c]pyridin-5(4H)-yl)ethan-1-one;1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,7-dihydroisoxazolo[5,4-c]pyridin-6(5H)-yl)ethan-1-one;(4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidine-1- 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydroisothiazolo[4,5-c]pyridin-3-yl)methanone;Benzo[c]isothiazol-3-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;Benzo[d]thiazol-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;Benzo[d]isoxazol-3-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydroisothiazolo[4,5-c]pyridin-3-yl)methanone 2-(2-Hydroxyphenyl)-1-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ethan-1-one;Benzo[d]oxazol-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(3-Methyloxetan-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;Oxetan-3-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;2-(2-Hydroxyphenyl)-1-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ethan-1-one;(4-(2-(tert-butyl)phenyl)piperidin-1-yl)(tetrahydrothiophen-2-yl)methanone;rac-tert-butyl (2R,3R)-2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)-3-hydroxypyrrolidine-1-carboxylate;(2R,4R)-2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate 2-(2-oxo-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ethyl)phenylsulfamate;(4-(2-(tert-butyl)phenyl)piperidine rac-(4-(2-(tert-butyl)phenyl)piperidin-1-yl)((2R,3R)-3-hydroxypyrrolidin-2-yl)methanone;rac-(4-(2-(tert-butyl)phenyl)piperidin-1-yl)((2R,4R)-4-hydroxypyrrolidin-2-yl)methanone;rac-(R)-1-(2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl) (6-Bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-Morpholino-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-(1H-Imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-(1H-Imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl) (5-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-Methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;Imidazo[1,2-a]pyridin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-Chloro-2-methylimidazo[1,2-b]pyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (1H-Pyrrolo[2,3-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;Imidazo[1,2-b]pyridazin-6-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-Pyrrolo[2,3-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-Pyrrolo[3,2-c]pyridin-2-yl); (4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-morpholino-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidine -1-yl)methanone; (1-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (1H-imidazo[4,5-b]pyridin-2-yl)(4-(2 -(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-indol-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-pyrrolo[2,3-c]pyridin-2-yl)(4-(2-( (1H-Pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-1,2,3-Triazol-5-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;Pyrazin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-Methoxypyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-methylpyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (4-methyl-1,2,3-thiadiazol-5-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (6-chloropyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; pyridazin-3-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; pyridazin-4-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; 4-(2-(trifluoromethyl)phenyl)piperidine-1-carboxylic acid; or 3-oxo-3-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)propanoic acid.

[0172] Preparation of compounds The compounds used in the chemical reactions described herein are made by organic synthesis techniques known to those skilled in the art, beginning with commercially available chemicals and / or compounds described in the chemical literature."Commercially available chemicals" include Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & They are obtained from standard commercial sources, including Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0173] Suitable reference books and articles detailing the synthesis of reactants useful in preparing the compounds described herein or providing references to articles describing their 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; and J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley Interscience, New York, 1992. Additional suitable references and papers detailing the synthesis of or referencing articles describing the preparation of reactants useful in the preparation of the compounds described herein include, for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, RV “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RCMarch, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; the 8-volume "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X; the 55-volume "Organic Reactions" (1942-2000) John Wiley & Sons; and the 73-volume "Chemistry of Functional Groups" John Wiley & Sons.

[0174] Alternatively, specific similar reactants can be identified by indexes of known chemical products prepared by the American Chemical Society's Chemical Abstract Service, available at most public and university libraries and via online data services (for more information, contact the American Chemical Society in Washington, D.C.). Known chemicals not sold in catalogs are optionally prepared by custom chemical synthesis houses, and many of the standard drug supply companies (e.g., those listed above) offer custom synthesis services. Criteria for the preparation and selection of pharmaceutical salts of the heterocyclic RBP4 inhibitor compounds described herein can be found in P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0175] Retinol-binding protein 4 (RBP4) Retinol-binding protein 4 (RBP4), the only retinol transporter in the blood, is secreted by adipocytes and the liver. Reducing RBP4 levels can reduce the accumulation of lipofuscin, which leads to vision loss in diseases such as age-related macular degeneration, dry (atrophic) age-related macular degeneration, early-onset macular degeneration (Stargardt disease), Best disease, adult-onset vitelliform maculopathy, geographic atrophy, Stargardt-like macular dystrophy, diabetic retinopathy, or ABCA4 gene-associated retinal disease. In some embodiments, reducing RBP4 reduces lipofuscin accumulation in the retina. In some embodiments, the compounds and formulations described herein reduce serum or plasma RBP4, thereby slowing or halting vision loss due to excessive lipofuscin accumulation in the retina.

[0176] 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, 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, serum or plasma levels of RBP4 are reduced by at least 40% 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, 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, serum or plasma levels of RBP4 are reduced by at least 65% from baseline. 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, 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, serum or plasma levels of RBP4 are reduced by at least 85% from baseline.

[0177] 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, serum or plasma levels of RBP4 are reduced by at least 30% 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, serum or plasma levels of RBP4 are reduced by at least 40% 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, 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, serum or plasma levels of RBP4 are reduced by at least 65% from baseline. In certain 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, 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, serum or plasma levels of RBP4 are reduced by at least 85% from baseline.

[0178] 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, 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, serum or plasma levels of RBP4 are reduced by at least 40% 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, 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 level of RBP4 is reduced by at least 65% from baseline. 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 level of RBP4 is 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 level of RBP4 is reduced by at least 85% from baseline.

[0179] 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, 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, serum or plasma levels of RBP4 are reduced by at least 40% 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, 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, serum or plasma levels of RBP4 are reduced by at least 65% from baseline. In certain 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, 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, serum or plasma levels of RBP4 are reduced by at least 85% from baseline.

[0180] 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, 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, serum or plasma levels of RBP4 are reduced by at least 25% 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, 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, serum or plasma levels of RBP4 are reduced by at least 40% 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, 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, serum or plasma levels of RBP4 are reduced by at least 65% from baseline. 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, 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, serum or plasma levels of RBP4 are reduced by at least 85% from baseline.

[0181] 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 level of RBP4 is 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 level of RBP4 is reduced by at least 2 mg / dL. 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 level of RBP4 is 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, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. 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, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0182] 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 level of RBP4 is reduced by at least 1 mg / dL. 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 level of RBP4 is reduced by at least 2 mg / dL. 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 level of RBP4 is reduced by at least 5 mg / dL. In certain 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, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. 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, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0183] 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 level of RBP4 is 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 level of RBP4 is reduced by at least 2 mg / dL. 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 level of RBP4 is 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, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. 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, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0184] 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 level of RBP4 is reduced by at least 1 mg / dL. 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 level of RBP4 is reduced by at least 2 mg / dL. 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 level of RBP4 is reduced by at least 5 mg / dL. In certain 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, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. 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, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0185] 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 level of RBP4 is 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 level of RBP4 is reduced by at least 2 mg / dL. 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 level of RBP4 is 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, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. 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, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0186] In some embodiments, after administration of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 1 μM. In other embodiments, after administration of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 1 μM 6 hours after administration of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 1 μM 12 hours after administration of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. 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, serum or plasma levels of RBP4 are reduced to less than 1 μM. 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, serum or plasma levels of RBP4 are reduced to less than 1 μM.

[0187] In some embodiments, after administration of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 1.5 μM. In other embodiments, 6 hours after administration of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 1.5 μM. In some embodiments, 12 hours after administration of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 1.5 μM. 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, serum or plasma levels of RBP4 are reduced to less than 1.5 μM. 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, serum or plasma levels of RBP4 are reduced to less than 1.5 μM.

[0188] In some embodiments, after administration of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 2 μM. In other embodiments, after administration of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 2 μM 6 hours after administration of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 2 μM 12 hours after administration of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. 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, serum or plasma levels of RBP4 are reduced to less than 2 μM. 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, serum or plasma levels of RBP4 are reduced to less than 2 μM.

[0189] Treatment method In some embodiments, the compounds disclosed herein, when administered to a subject in need thereof, are used to treat or ameliorate a disease associated with an alteration in the RBP4 pathway. In some aspects, the compounds disclosed herein, when administered to a subject in need thereof, are used to treat or ameliorate the effects of a disease associated with an alteration in the RBP4 pathway. Exemplary diseases associated with alterations in RBP4 include ocular diseases. In some embodiments, the ocular disease is characterized by excessive accumulation of lipofuscin in the retina. In some embodiments, the compounds disclosed herein, when administered to a subject in need thereof, are used to treat or ameliorate the ocular disease. Exemplary ocular diseases include age-related macular degeneration, dry (atrophic) age-related macular degeneration, juvenile macular degeneration (Stargardt disease), Best disease, adult vitelliform maculopathy, geographic atrophy, Stargardt macular dystrophy, diabetic retinopathy, or ABCA4 gene-associated retinal disease.

[0190] Age-related macular degeneration Age-related macular degeneration (AMD) is a common eye disease and the leading cause of vision loss in people over the age of 50. AMD damages the macula, a tiny spot near the center of the retina and a part of the eye necessary for sharp, central vision. As AMD progresses, blurring of the central area of ​​vision is a common symptom. Over time, the blurred area grows larger, and the subject may develop a blank spot in their central vision.

[0191] Some embodiments provided herein describe the use of a compound of Formula (I) described herein to treat AMD in a subject in need thereof. In some embodiments, a compound of Formula (I) inhibits AMD. In certain embodiments, a compound of Formula (I) prevents the onset of AMD or its clinical symptoms. In certain embodiments, a compound of Formula (I) reduces the onset of AMD or its clinical symptoms. In certain embodiments, a compound of Formula (I) alleviates a subject with AMD. In certain embodiments, a compound of Formula (I) causes regression, reversal, or remission of AMD. In certain embodiments, a compound of Formula (I) reduces the number, frequency, duration, or severity of AMD clinical symptoms.

[0192] In some embodiments, the compound of formula (I) is used prophylactically.In certain embodiments, the compound of formula (I) is used to prevent or reduce the risk of developing AMD.In certain embodiments, the compound of formula (I) prevents the clinical symptoms of AMD from developing in subjects who may have a predisposition to AMD but have not yet experienced or shown symptoms of AMD.

[0193] Dry (atrophic) age-related macular degeneration Approximately 85% to 90% of cases of macular degeneration are of the "dry" (atrophic) type. It is estimated that 62.9 million individuals worldwide have this form of AMD, 8 million of whom are Americans. Due to increases in life expectancy and current demographics, this number is expected to triple by 2020. Currently, there are no FDA-approved treatments for dry AMD. Due to the lack of treatments and high prevalence, drug development for dry AMD is crucial. Clinically, dry AMD represents a slowly progressive neurodegenerative disease in which specialized neurons (rod and cone photoreceptors) die in the central region of the retina called the macula. Histopathological and clinical imaging studies indicate that photoreceptor degeneration in dry AMD is caused by abnormalities in the retinal pigment epithelium (RPE), which is located beneath the photoreceptors and provides critical metabolic support to these light-sensing neuronal cells. Experimental and clinical data indicate that excessive accumulation of cytotoxic autofluorescent lipid-protein retinoid aggregates (lipofuscin) in the RPE is a major trigger of dry AMD. The primary cytotoxic component of RPE lipofuscin is the pyridinium bisretinoid A2E (Figure 1). Additional cytotoxic bisretinoids are isoA2E, atRAL di-PE, and A2-DHP-PE. The formation of A2E and other lipofuscin bisretinoids, such as A2-DHP-PE (A2-dihydropyridine-phosphatidylethanolamine) and atRAL di-PE (all-trans-retinal dimer-phosphatidylethanolamine), initiates in photoreceptor cells in a nonenzymatic manner and can be considered a by-product of a properly functioning visual cycle.

[0194] Some embodiments provided herein describe the use of a compound of Formula (I) described herein to treat dry (atrophic) AMD in a subject in need thereof. In some embodiments, the compound of Formula (I) inhibits dry (atrophic) AMD. In some embodiments, the compound of Formula (I) prevents the onset of dry (atrophic) AMD or its clinical symptoms. In some embodiments, the compound of Formula (I) reduces the onset of dry (atrophic) AMD or its clinical symptoms. In some embodiments, the compound of Formula (I) alleviates a subject's dry (atrophic) AMD. In some embodiments, the compound of Formula (I) causes regression, reversal, or remission of dry (atrophic) AMD. In some embodiments, the compound of Formula (I) reduces the number, frequency, duration, or severity of clinical symptoms of dry (atrophic) AMD.

[0195] In some embodiments, the compound of formula (I) is administered prophylactically. In some embodiments, the compound of formula (I) is used to prevent or reduce the risk of developing dry (atrophic) AMD. In some embodiments, the compound of formula (I) prevents the clinical symptoms of dry (atrophic) AMD from developing in patients who may have a predisposition to dry (atrophic) AMD but have not yet experienced or shown symptoms of dry (atrophic) AMD.

[0196] Juvenile macular degeneration (Stargardt disease) Stargardt disease (STGD) is an inherited form of early-onset macular degeneration. STGD is characterized by dramatic accumulation of lipofuscin in the retina. STGD is associated with defects in the ABCA4 gene. Overproduction of lipofuscin bisretinoid appears to be the sole biochemical trigger of monogenic STGD caused by recessive mutations in the ABCA4 gene. Symptoms include wavy vision, blind spots, blurred vision, loss of depth perception, glare sensitivity, color vision impairment, and difficulty adapting to dim light. Symptoms typically begin before the age of 20.

[0197] Some embodiments provided herein describe the use of a compound of Formula (I) described herein to treat STGD in a subject in need thereof. In some embodiments, a compound of Formula (I) inhibits STGD. In certain embodiments, a compound of Formula (I) prevents STGD or its clinical symptoms. In certain embodiments, a compound of Formula (I) reduces the occurrence of STGD or its clinical symptoms. In certain embodiments, a compound of Formula (I) alleviates a subject with STGD. In certain embodiments, a compound of Formula (I) causes regression, reversal, or remission of STGD. In certain embodiments, a compound of Formula (I) reduces the number, frequency, duration, or severity of clinical symptoms of STGD.

[0198] In some embodiments, the compound of Formula (I) is administered prophylactically. In certain embodiments, the compound of Formula (I) is used to prevent or reduce the risk of developing STGD. In certain embodiments, the compound of Formula (I) prevents the development of clinical symptoms of STGD in patients who may have a predisposition to STGD but who have not yet experienced or exhibited symptoms of STGD.

[0199] Best Disease Vitelliform dystrophy, or Best disease, is a genetic retinal dystrophy involving the retinal pigment epithelium (RPE), resulting in a characteristic bilateral yellow "egg-yolk" appearance of the macula. The disease tends to present in childhood or early adulthood. Best disease is caused by mutations in the BEST1 gene, which encodes the transmembrane protein bestrophin 1. The mutation leads to the accumulation of lipofuscin between the outer retina and the retinal pigment epithelium.

[0200] Some embodiments provided herein describe the use of a compound of Formula (I) described herein to treat Best's disease in a subject in need thereof. In some embodiments, a compound of Formula (I) inhibits Best's disease. In certain embodiments, a compound of Formula (I) prevents the onset of Best's disease or its clinical symptoms. In certain embodiments, a compound of Formula (I) reduces the manifestation of Best's disease or its clinical symptoms. In certain embodiments, a compound of Formula (I) alleviates a subject with Best's disease. In certain embodiments, a compound of Formula (I) causes regression, reversal, or remission of Best's disease. In certain embodiments, a compound of Formula (I) reduces the number, frequency, duration, or severity of clinical symptoms of Best's disease.

[0201] In some embodiments, the compound of Formula (I) is administered prophylactically. In certain embodiments, the compound of Formula (I) is used to prevent or reduce the risk of developing Best's disease. In certain embodiments, the compound of Formula (I) prevents the development of clinical symptoms of Best's disease in patients who may have a predisposition to Best's disease but who have not yet experienced or exhibited symptoms of Best's disease.

[0202] Geographic atrophy Geographic atrophy is a chronic, progressive degeneration of the macula that can be seen as part of late-stage age-related macular degeneration (AMD). The disease leads to a central scotoma and persistent visual loss. The disease is characterized by focal, well-defined atrophy of outer retinal tissues, the retinal pigment epithelium, and the choriocapillaris.

[0203] Some embodiments provided herein describe the use of a compound of Formula (I) described herein to treat geographic atrophy in a subject in need thereof. In some embodiments, the compound of Formula (I) inhibits geographic atrophy. In certain embodiments, the compound of Formula (I) prevents the onset of geographic atrophy or its clinical symptoms. In certain embodiments, the compound of Formula (I) reduces the onset of geographic atrophy or its clinical symptoms. In certain embodiments, the compound of Formula (I) alleviates geographic atrophy in a subject. In certain embodiments, the compound of Formula (I) causes regression, reversal, or remission of geographic atrophy. In certain embodiments, the compound of Formula (I) reduces the number, frequency, duration, or severity of clinical symptoms of geographic atrophy.

[0204] In some embodiments, the compound of Formula (I) is administered prophylactically. In certain embodiments, the compound of Formula (I) is used to prevent or reduce the risk of developing geographic atrophy. In certain embodiments, the compound of Formula (I) prevents the development of clinical symptoms of geographic atrophy in patients who may have a predisposition to geographic atrophy but who have not yet experienced or exhibited symptoms of geographic atrophy.

[0205] Vitelliform maculopathy in adults Adult vitelliform maculopathy is an eye disorder that can cause progressive vision loss. The disease causes the accumulation of lipofuscin in the cells underlying the macula. The disease typically appears after age 40. The disease can be caused by mutations in the RDS and VMD2 genes.

[0206] Some embodiments provided herein describe the use of a compound of Formula (I) described herein to treat adult vitelloid maculopathy in a subject in need thereof. In some embodiments, a compound of Formula (I) inhibits adult vitelloid maculopathy. In certain embodiments, a compound of Formula (I) prevents the development of vitelloid maculopathy or its clinical symptoms in an adult. In certain embodiments, a compound of Formula (I) reduces the expression of adult vitelloid maculopathy or its clinical symptoms. In certain embodiments, a compound of Formula (I) alleviates a subject with adult vitelloid maculopathy. In certain embodiments, a compound of Formula (I) causes regression, reversal, or remission of adult vitelloid maculopathy. In certain embodiments, a compound of Formula (I) reduces the number, frequency, duration, or severity of adult clinical symptoms of vitelloid maculopathy.

[0207] In some embodiments, the compound of Formula (I) is administered prophylactically. In certain embodiments, the compound of Formula (I) is used to prevent or reduce the risk of developing adult vitellosis. In certain embodiments, the compound of Formula (I) prevents the development of clinical symptoms of adult vitellosis in patients who may have a predisposition to adult vitellosis but who have not yet experienced or exhibited symptoms of adult vitellosis.

[0208] Stargardt-like macular dystrophy Stargardt-like macular dystrophy has signs and symptoms similar to Stargardt disease, but typically begins later in childhood. Stargardt-like macular dystrophy is associated with mutations in the EVOVL4 gene.

[0209] Some embodiments provided herein describe the use of a compound of Formula (I) described herein to treat Stargardt-like macular dystrophy in a subject in need thereof. In some embodiments, a compound of Formula (I) inhibits Stargardt-like macular dystrophy. In some embodiments, a compound of Formula (I) prevents the onset of Stargardt-like macular dystrophy or its clinical symptoms. In some embodiments, a compound of Formula (I) reduces the expression of Stargardt-like macular dystrophy or its clinical symptoms. In some embodiments, a compound of Formula (I) alleviates a subject with Stargardt-like macular dystrophy. In some embodiments, a compound of Formula (I) causes regression, reversal, or remission of Stargardt-like macular dystrophy. In some embodiments, a compound of Formula (I) reduces the number, frequency, duration, or severity of clinical symptoms of Stargardt-like macular dystrophy.

[0210] In some embodiments, the compound of Formula (I) is administered prophylactically. In one embodiment, the compound of Formula (I) is used to prevent or reduce the risk of developing Stargardt-like macular dystrophy. In one embodiment, the compound of Formula (I) prevents the development of clinical symptoms of Stargardt-like macular dystrophy in patients who may have a predisposition to Stargardt-like macular dystrophy but who have not yet experienced or exhibited symptoms of Stargardt-like macular dystrophy.

[0211] diabetic retinopathy Diabetic retinopathy is a diabetic complication that affects the eyes. It can be caused by damage to blood vessels in the light-sensitive tissue at the back of the eye, which can ultimately lead to blindness. Diabetic retinopathy can occur when new blood vessels in the retina fail to grow. Diabetic retinopathy can also result from blood vessels being damaged and closing, causing new, abnormal blood vessels to grow in the retina.

[0212] Some embodiments provided herein describe the use of a compound of Formula (I) described herein to treat diabetic retinopathy in a subject in need thereof. In some embodiments, a compound of Formula (I) inhibits diabetic retinopathy. In certain embodiments, a compound of Formula (I) prevents diabetic retinopathy or its clinical symptoms. In certain embodiments, a compound of Formula (I) reduces the appearance of diabetic retinopathy or its clinical symptoms. In certain embodiments, a compound of Formula (I) alleviates diabetic retinopathy in a subject. In certain embodiments, a compound of Formula (I) causes regression, reversal, or remission of diabetic retinopathy. In certain embodiments, a compound of Formula (I) reduces the number, frequency, duration, or severity of clinical symptoms of diabetic retinopathy.

[0213] In some embodiments, the compound of Formula (I) is administered prophylactically. In certain embodiments, the compound of Formula (I) is used to prevent or reduce the risk of developing diabetic retinopathy. In certain embodiments, the compound of Formula (I) prevents the development of clinical symptoms of diabetic retinopathy in patients who may have a predisposition to diabetic retinopathy but who have not yet experienced or exhibited symptoms of diabetic retinopathy.

[0214] ABCA4 gene-related retinal disease 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 associated with Stargardt disease and other ocular diseases, including, but not limited to, fundus flava, cone-rod dystrophy, retinitis pigmentosa, and age-related macular degeneration. Decreased ABCA4 activity is associated with excessive accumulation of toxic retinoids and lipofuscin. In some instances, such mutations are detected by sequencing the subject's DNA or RNA.

[0215] Some embodiments provided herein describe the use of a compound of Formula (I) described herein for treating an ABCA4 gene-associated retinal disease in a subject in need thereof. In some embodiments, the compound of Formula (I) inhibits an ABCA4 gene-associated retinal disease. In certain embodiments, the compound of Formula (I) prevents the onset of an ABCA4 gene-associated retinal disease or its clinical symptoms. In certain embodiments, the compound of Formula (I) reduces the expression of an ABCA4 gene-associated retinal disease or its clinical symptoms. In certain embodiments, the compound of Formula (I) alleviates a subject with an ABCA4 gene-associated retinal disease. In certain embodiments, the compound of Formula (I) causes regression, reversal, or remission of an ABCA4 gene-associated retinal disease. In certain embodiments, the compound of Formula (I) reduces the number, frequency, duration, or severity of clinical symptoms of an ABCA4 gene-associated retinal disease.

[0216] In some embodiments, the compound of Formula (I) is administered prophylactically. In certain embodiments, the compound of Formula (I) is used to prevent or reduce the risk of developing ABCA4 gene-associated retinal disease. In certain embodiments, the compound of Formula (I) prevents the development of clinical symptoms of ABCA4 gene-associated retinal disease in patients who may have a predisposition to ABCA4 gene-associated retinal disease but who have not yet experienced or shown symptoms of ABCA4 gene-associated retinal disease.

[0217] Pharmaceutical Composition In certain embodiments, the compounds of Formula (I) described herein are administered as pure chemicals. In other embodiments, the heterocyclic RBP4 inhibitor compounds described herein are administered as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 2011). stand the like. The compositions are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), selected based on the chosen route of administration and standard pharmaceutical practice, as described in Ed. Mack Pub. Co., Easton, PA (2005).

[0218] Provided herein are pharmaceutical compositions comprising at least one heterocyclic RBP4 inhibitor compound described herein, or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient of the composition (i.e., subject or patient).

[0219] One embodiment provides a method for preparing a pharmaceutical composition, comprising mixing a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition is provided in a dosage form for oral administration, which comprises a compound provided herein and one or more pharmaceutically acceptable excipients or carriers.

[0220] In certain embodiments, the heterocyclic RBP4 inhibitor compounds described by Formula (I) are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1%, of other small organic molecules, such as, for example, unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic method.

[0221] Suitable dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose, or another suitable material that dissolves easily in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, 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, 2012) st See Ed. Mack Pub. Co., Easton, PA (2005).

[0222] In some embodiments, the pharmaceutical compositions provided herein are formulated for oral administration in tablet, capsule, powder, or liquid form. In some embodiments, the pharmaceutical formulation is formulated as a tablet. In some embodiments, the pharmaceutical formulation is formulated as a capsule. In some embodiments, the tablet comprises a solid carrier or adjuvant. Liquid pharmaceutical compositions typically comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil, or synthetic petroleum. In some embodiments, saline, dextrose, or other saccharide solution, or glycol is optionally included. In some embodiments, the capsule comprises a solid carrier such as gelatin.

[0223] In another embodiment, the pharmaceutical composition is provided in a dosage form for parenteral administration, which comprises a compound provided herein and one or more pharmaceutically acceptable excipients or carriers. When the pharmaceutical composition is formulated for intravenous, cutaneous, or subcutaneous injection, the active ingredient is in the form of a parenterally acceptable aqueous solution that is pyrogen-free and has appropriate pH, isotonicity, and stability. Those skilled in the art can easily prepare an appropriate solution using an isotonic vehicle such as sodium chloride injection, Ringer's solution injection, or lactated gel injection. In some embodiments, preservatives, stabilizers, buffers, antioxidants, and / or other additives are included.

[0224] In yet another embodiment, a pharmaceutical composition is provided in a dosage form for topical administration, which comprises a compound provided herein and one or more pharmaceutically acceptable excipients or carriers.

[0225] solid dispersion In some embodiments, the pharmaceutical composition of the present invention comprises a solid dispersion. In some examples, the pharmaceutical composition comprises a solid dispersion comprising a compound of Formula (I). A solid dispersion is, in some examples, a solid composition having at least two components, for example, a drug and a polymer. The components of the solid dispersion may be molecularly dispersed, where the drug, polymer, and any additional elements are randomly distributed in the dispersion. In some embodiments, the molecular dispersion is amorphous. In some embodiments, the compound of Formula (I) is amorphous within the molecular dispersion.

[0226] Solid dispersions can be prepared using many methods known in the art. In some embodiments, solid dispersions are prepared by melting, solvent evaporation, melting, kneading, melting, spray drying, co-grinding, freeze-drying, hot melt extrusion, melt agglomeration, or supercritical fluid (SCF) techniques. In some embodiments, solid dispersions are prepared using spray drying methods. In some embodiments, solid dispersions are prepared using hot melt extrusion methods.

[0227] In some embodiments, the solid dispersion comprises a compound of Formula (I) and a dispersion polymer. In some embodiments, the dispersion polymer is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS or HPMCAS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polypolyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, and derivatives or combinations thereof.

[0228] In some embodiments, the dispersion polymer comprises about 1-99% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises about 20-80% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises about 40-60% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises about 95% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises about 90% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises about 80% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises about 70% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises about 60% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises about 50% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises about 40% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises about 30% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises about 20% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises about 10% by weight of the solid dispersion.

[0229] In some embodiments, the dispersion polymer comprises at least about 10% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises at least about 20% of the solid dispersion. In some embodiments, the dispersion polymer comprises at least about 30% of the solid dispersion. In some embodiments, the dispersion polymer comprises at least about 40% of the solid dispersion. In some embodiments, the dispersion polymer comprises at least about 50% of the solid dispersion. In some embodiments, the dispersion polymer comprises at least about 60% of the solid dispersion. In some embodiments, the dispersion polymer comprises at least about 70% of the solid dispersion. In some embodiments, the dispersion polymer comprises at least about 80% of the solid dispersion. In some embodiments, the dispersion polymer comprises at least about 90% of the solid dispersion. In some embodiments, the dispersion polymer comprises at least about 95% of the solid dispersion.

[0230] In some embodiments, the dispersion polymer comprises up to about 10% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises up to about 20% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises up to about 30% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises up to about 40% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises up to about 50% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises up to about 60% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises up to about 70% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises up to about 80% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises up to about 90% by weight of the solid dispersion. In some embodiments, the dispersion polymer comprises up to about 95% by weight of the solid dispersion.

[0231] In some embodiments, the dispersion polymer is HPMC-AS. HPMC-AS can be of any grade, including HPMC-AS LF; HPMC-AS M; HPMC-AS H; HPMC-AS HF; and HPMC-AS HG. HPMC-AS can also be of any viscosity, including low viscosity, normal viscosity, and high viscosity. In some embodiments, the dispersion polymer comprises HPMC-AS LF. In some embodiments, the dispersion polymer comprises HPMC-AS M. In some embodiments, the dispersion polymer comprises HPMC-AS HF. In some embodiments, the dispersion polymer comprises HPMC-AS HG. In some embodiments, the indicators "L," "M," or "H" refer to low, medium, or high ratios of acetyl to succinyl substituents on the HPMC backbone. In some embodiments, the indicators "F" or "G" refer to fine or granular particle size, respectively.

[0232] In certain embodiments, a particular grade of HPMC-AS is designated, such as L, M, or H. In some embodiments, the grade refers to the ratio of cetyl to succinyl substituents on the HPMC backbone, with "L" grades being low, "M" grades being intermediate, and "H" grades being high. In some embodiments, HPMC-AS, L, comprises about 5-9% acetyl content and about 14-18% succinyl content. In some embodiments, HPMC-AS, L, further comprises about 20-24% methoxyl content and about 5-9% hydroxypropyl content. In some embodiments, HPMC-AS, M, comprises about 7-11% acetyl content and about 10-14% succinyl content. In some embodiments, HPMC-AS, M, further comprises about 21-25% methoxyl content and about 5-9% hydroxypropyl content. In some embodiments, the 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 weight percentages of the HPMC-AS composition.

[0233] In some embodiments, the dispersion polymer is HPMC. In some embodiments, the HPMC is an HPMC derivative. The HPMC or HPMC derivative may be of any grade, including low viscosity grade, normal viscosity grade, or high viscosity grade. Non-limiting examples of suitable HPMC or HPMC derivatives include Methocel™ K100M, K15M, F4M, E4M, K4M, K100LV, K3, E15LV, E15LN, E15CLV, E50, E5, E5LV, E3, and E3LV (available from Dow Chemical, Midland Mich.). In some embodiments, the dispersion polymer is HPMC E3LV.

[0234] In certain embodiments, the compound of Formula (I) comprises about 1 to 99% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 10 to 80% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 10 to 60% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 10 to 50% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 10 to 40% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 20 to 80% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 20 to 60% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 20 to 50% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 20 to 40% by weight of the solid dispersion. In certain embodiments, the compound of Formula (I) comprises about 40 to 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. In certain embodiments, 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.

[0235] In some embodiments, the compound of Formula (I) comprises at least about 5% by weight of the solid dispersion. In some embodiments, the compound of Formula (I) comprises at least about 10% by weight of the solid dispersion. In some embodiments, the compound of Formula (I) comprises at least about 20% by weight of the solid dispersion. In some embodiments, the compound of Formula (I) comprises at least about 30% by weight of the solid dispersion. In some embodiments, the compound of Formula (I) comprises at least about 40% by weight of the solid dispersion. In some embodiments, the compound of Formula (I) comprises at least about 50% by weight of the solid dispersion. In some embodiments, the compound of Formula (I) comprises at least about 60% by weight of the solid dispersion. In some embodiments, the compound of Formula (I) comprises at least about 70% by weight of the solid dispersion. In some embodiments, the compound of Formula (I) comprises at least about 80% by weight of the solid dispersion. In some embodiments, the compound of Formula (I) comprises at least about 90% by weight of the solid dispersion. In some embodiments, the compound of Formula (I) comprises at least about 95% by weight of the solid dispersion.

[0236] In certain embodiments, 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. In certain embodiments, 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.

[0237] In some embodiments, the ratio of the compound of Formula (I) to the dispersion polymer is about 5:95 (w / w). In some embodiments, the ratio of the compound of Formula (I) to the dispersion polymer is about 10:90 (w / w) in the solid dispersion. In some embodiments, the ratio of the compound of Formula (I) to the dispersion polymer is about 20:80 (w / w) in the solid dispersion. In some embodiments, the ratio of the compound of Formula (I) to the dispersion polymer is about 30:70 (w / w) in the solid dispersion. In some embodiments, the ratio of the compound of Formula (I) to the dispersion polymer is about 40:60 (w / w) in the solid dispersion. In some embodiments, the ratio of the compound of Formula (I) to the dispersion polymer is about 50:50 (w / w) in the solid dispersion. In some embodiments, the ratio of the compound of Formula (I) to the dispersion polymer is about 60:40 (w / w) in the solid dispersion. In some embodiments, the ratio of the compound of Formula (I) to the dispersion polymer is about 70:30 (w / w) in the solid dispersion. In some embodiments, the ratio of the compound of Formula (I) to the dispersion polymer is about 80:20 (w / w) in the solid dispersion. In some embodiments, the ratio of the compound of Formula (I) to the dispersion polymer is about 90:10 (w / w) in the solid dispersion. In some embodiments, the ratio of the compound of Formula (I) to the dispersion polymer is about 95:5 (w / w) in the solid dispersion.

[0238] In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 5:95 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 5:95 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 10:90 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 15:85 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 20:80 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 5:95 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 10:90 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 15:85 to about 40:60. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 20:80 to about 40:60. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 10:90. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 20:80. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 30:70. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 40:60. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS in a ratio of about 50:50.

[0239] In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS,H in a ratio of about 5:95 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS,H in a ratio of about 5:95 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS,H in a ratio of about 10:90 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS,H in a ratio of about 15:85 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS,H in a ratio of about 20:80 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS,H in a ratio of about 5:95 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS,H in a ratio of about 10:90 to about 40:60. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS,H in a ratio of about 15:85 to about 40:60. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS,H in a ratio of about 20:80 to about 40:60. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS,H in a ratio of about 10:90. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS,H in a ratio of about 20:80. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS,H in a ratio of about 30:70. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS,H in a ratio of about 40:60. In some 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%.

[0240] In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 5:95 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 5:95 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 10:90 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 15:85 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 20:80 to about 50:50. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 5:95 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 10:90 to about 40:60. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 15:85 to about 40:60. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 20:80 to about 40:60. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 10:90. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 20:80. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 30:70. In some embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 40:60. In some 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%.

[0241] In some embodiments, the solid dispersion comprises Compound 1 and PVP. In some embodiments, the ratio of Compound 1 to PVP is about 1:10 to about 1:1. In some embodiments, the ratio of Compound 1 to PVP is about 1:10 to about 1:2. In some embodiments, the ratio of Compound 1 to PVP is about 1:5 to about 1:2. In some embodiments, the ratio of Compound 1 to PVP is about 1:5 to about 1:1. In some embodiments, the ratio of Compound 1 to 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 to PVP is about 1:2. In some embodiments, the ratio of Compound 1 to PVP is about 1:3. In some embodiments, the ratio of Compound 1 to PVP is about 1:5. In some embodiments, the molecular weight of PVP is about 7,000 daltons to about 11,000 daltons.

[0242] In some embodiments, the solid dispersion has an average particle size of less than 5 μm. In some embodiments, the solid dispersion has an average particle size of less than 10 μm. In some embodiments, the solid dispersion has an average particle size of less than 20 μm. In some embodiments, the solid dispersion has an average particle size of less than 30 μm. In some embodiments, the solid dispersion has an average particle size of less than 40 μm. In some embodiments, the solid dispersion has an average particle size of less than 50 μm. In some embodiments, the solid dispersion has an average particle size of about 1 μm to 20 μm. In some embodiments, the solid dispersion has an average particle size of about 5 μm to 20 μm. In some embodiments, the solid dispersion has an average particle size of about 10 μm to 20 μm. In some embodiments, the solid dispersion has an average particle size of about 15 μm to 20 μm. In some embodiments, the solid dispersion has an average particle size of about 1 μm to 5 μm. In some embodiments, the solid dispersion has an average particle size of about 1 μm to 10 μm. In one embodiment, the solid dispersion has an average particle size of about 5 μm to 10 μm.

[0243] In some embodiments, the solid dispersion comprises 1-100% by weight of the pharmaceutical composition. In some embodiments, the solid dispersion comprises 20-80% by weight of the pharmaceutical composition. In some embodiments, the solid dispersion comprises 40-60% by weight of the pharmaceutical composition. In some embodiments, the solid dispersion comprises about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% by weight of the pharmaceutical composition.

[0244] In some embodiments, the pharmaceutical composition, including the solid dispersion, comprises a therapeutically effective amount of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 1 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 5 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 10 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 25 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 50 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 100 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 200 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 400 mg of the compound of Formula (I).

[0245] In some embodiments, the solid dispersion improves the solubility of the compound of Formula (I). In some embodiments, the solid dispersion improves the solubility of the compound of Formula (I) by at least 2-fold. In some embodiments, the solid dispersion improves the solubility of the compound of Formula (I) by at least 4-fold. In some embodiments, the solid dispersion improves the solubility of the compound of Formula (I) by at least 8-fold. In some embodiments, the solid dispersion improves the solubility of the compound of Formula (I) by at least 10-fold. In some embodiments, the solid dispersion improves the solubility of the compound of Formula (I) by at least 20-fold. In some embodiments, the solid dispersion improves the solubility of the compound of Formula (I) by at least 30-fold. In some embodiments, the solid dispersion improves the solubility of the compound of Formula (I) by at least 40-fold. In some embodiments, the solid dispersion improves the solubility of the compound of Formula (I) by at least 50-fold. In some embodiments, the solid dispersion improves the solubility of the compound of Formula (I) by at least 60-fold. In some embodiments, the improvement is measured relative to the crystalline form of the compound of Formula (I). In some embodiments, the improvement is measured relative to an amorphous form of the compound of Formula (I).

[0246] Additional Elements 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 combination thereof. In some embodiments, the solid dispersion of the pharmaceutical composition comprises a filler, a sweetener, a disintegrant, a wetting agent, a glidant, a lubricant, or a surfactant, or any combination thereof.

[0247] filling material In some embodiments, the pharmaceutical composition further comprises a filler. In some embodiments, the solid dispersion of the pharmaceutical composition further comprises a filler. The filler can be any biocompatible material that is non-reactive 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 carboxymethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, calcium hydrogen phosphate, sucrose, lactose, corn starch, potato starch, or any combination thereof.

[0248] In some embodiments, the filler comprises about 1-99% by weight of the pharmaceutical composition. In some embodiments, the filler comprises about 10% by weight of the pharmaceutical composition. In some embodiments, the filler comprises about 20% by weight of the pharmaceutical composition. In some embodiments, the filler comprises about 30% by weight of the pharmaceutical composition. In some embodiments, the filler comprises about 40% by weight of the pharmaceutical composition. In some embodiments, the filler comprises about 50% by weight of the pharmaceutical composition. In some embodiments, the filler comprises about 60% by weight of the pharmaceutical composition. In some embodiments, the filler comprises about 70% by weight of the pharmaceutical composition. In some embodiments, the filler comprises about 80% by weight of the pharmaceutical composition. In some embodiments, the filler comprises about 90% by weight of the pharmaceutical composition.

[0249] In some embodiments, the filler comprises up to about 10% by weight of the pharmaceutical composition. In some embodiments, the filler comprises up to about 20% by weight of the pharmaceutical composition. In some embodiments, the filler comprises up to about 30% by weight of the pharmaceutical composition. In some embodiments, the filler comprises up to about 40% by weight of the pharmaceutical composition. In some embodiments, the filler comprises up to about 50% by weight of the pharmaceutical composition. In some embodiments, the filler comprises up to about 60% by weight of the pharmaceutical composition. In some embodiments, the filler comprises up to about 70% by weight of the pharmaceutical composition. In some embodiments, the filler comprises up to about 80% by weight of the pharmaceutical composition. In some embodiments, the filler comprises up to about 90% by weight of the pharmaceutical composition.

[0250] In some embodiments, the filler comprises at least about 10% by weight of the pharmaceutical composition. In some embodiments, the filler comprises at least about 20% by weight of the pharmaceutical composition. In some embodiments, the filler comprises at least about 30% by weight of the pharmaceutical composition. In some embodiments, the filler comprises at least about 40% by weight of the pharmaceutical composition. In some embodiments, the filler comprises at least about 50% by weight of the pharmaceutical composition. In some embodiments, the filler comprises at least about 60% by weight of the pharmaceutical composition. In some embodiments, the filler comprises at least about 70% by weight of the pharmaceutical composition. In some embodiments, the filler comprises at least about 80% by weight of the pharmaceutical composition. In some embodiments, the filler comprises at least about 90% by weight of the pharmaceutical composition.

[0251] sweetener In certain embodiments, the pharmaceutical composition comprising a compound of Formula (I) further comprises a sweetener. In certain embodiments, the solid dispersion of the pharmaceutical composition further comprises a sweetener. Non-limiting examples of sweeteners include water-soluble sweeteners, such as monosaccharides, disaccharides, and polysaccharides, e.g., 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 water-soluble saccharin salts, i.e., sodium or calcium saccharin salts, cyclamate salts, sodium, ammonium, calcium salt of 3,4-dihydro-6-methyl-1,2,3-oxathiazin-4-one-2,2-dioxide, 3,4-dihydro-6-methyl-1,2,3-oxathiazin-4-one-2,2-dioxide, and 3,4-dihydro-6-methyl-1,2,3-oxathiazin-4-one-2,2-dioxide. and the like; dipeptide-based sweeteners, such as sweeteners derived from L-aspartic acid, for example, L-aspartyl-L-phenylalanine methyl ester (aspartame), L-α-aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide hydrate, the methyl esters of L-aspartyl-L-phenylglycerin and L-aspartyl-L-2,5,dihydrophenylglycine, L-aspartyl-2,5-dihydro-L-phenylalanine, L-aspartyl-L-(1-cyclohexane)-alanine, and the like; and water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, for example, the chlorinated derivative of common sugar (sucrose) known as sucralose.

[0252] In some embodiments, the sweetener comprises about 1-99% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises about 10% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises about 20% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises about 30% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises about 40% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises about 50% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises about 60% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises about 70% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises about 80% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises about 90% by weight of the pharmaceutical composition.

[0253] In some embodiments, the sweetener comprises up to about 10% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises up to about 20% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises up to about 30% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises up to about 40% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises up to about 50% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises up to about 60% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises up to about 70% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises up to about 80% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises up to about 90% by weight of the pharmaceutical composition.

[0254] In some embodiments, the sweetener comprises at least about 10% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises at least about 20% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises at least about 30% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises at least about 40% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises at least about 50% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises at least about 60% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises at least about 70% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises at least about 80% by weight of the pharmaceutical composition. In some embodiments, the sweetener comprises at least about 90% by weight of the pharmaceutical composition.

[0255] Disintegrant In some embodiments, the pharmaceutical composition comprising a compound of Formula (I) further comprises a disintegrant. In some embodiments, the solid dispersion of the pharmaceutical composition further comprises a disintegrant. Non-limiting examples of disintegrants include agar, algin, calcium carbonate, carboxymethylcellulose, cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, clay, croscarmellose sodium, crospovidone, gum, magnesium aluminum silicate, methylcellulose, polacrilin potassium, sodium alginate, sodium starch glycolate, corn starch, potato starch, tapioca starch, or any combination thereof.

[0256] In some embodiments, the disintegrant comprises about 1-99% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises about 10% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises about 20% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises about 30% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises about 40% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises about 50% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises about 60% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises about 70% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises about 80% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises about 90% by weight of the pharmaceutical composition.

[0257] In some embodiments, the disintegrant comprises up to about 10% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises up to about 20% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises up to about 30% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises up to about 40% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises up to about 50% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises up to about 60% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises up to about 70% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises up to about 80% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises up to about 90% by weight of the pharmaceutical composition.

[0258] In some embodiments, the disintegrant comprises at least about 10% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises at least about 20% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises at least about 30% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises at least about 40% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises at least about 50% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises at least about 60% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises at least about 70% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises at least about 80% by weight of the pharmaceutical composition. In some embodiments, the disintegrant comprises at least about 90% by weight of the pharmaceutical composition.

[0259] Wetting agent In some embodiments, the pharmaceutical composition comprising a compound of Formula (I) further comprises a wetting agent. In some embodiments, the solid dispersion of the pharmaceutical composition further comprises a wetting agent. Non-limiting examples of wetting agents include sodium lauryl sulfate, cetostearyl alcohol, cetomacrogol emulsifying wax, gelatin, casein, docusate sodium, benzalkonium chloride, calcium stearate, polyethylene glycol, phosphates, polyoxyethylene sorbitan fatty acid esters, gum arabic, cholesterol, tragacanth, polyoxyethylene 20 stearyl ether, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, PEGylated hydrogenated castor oil, sorbitan esters of fatty acids, vitamin E or tocopherol derivatives, vitamin E Ingredients include TPGS, tocopheryl esters, lecithin, phospholipids and their derivatives, poloxamer, stearic acid, oleic acid, oleyl alcohol, cetyl alcohol, mono- and diglycerides, propylene glycol esters of fatty acids, glycerol esters of fatty acids, ethylene glycol palmitostearate, polyoxylglycerides, propylene glycol monocaprylate, propylene glycol monolaurate, alkyl aryl polyether alcohols, and polyglyceryl oleate, or combinations thereof.

[0260] In some embodiments, the humectant comprises about 1-99% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises about 10% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises about 20% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises about 30% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises about 40% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises about 50% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises about 60% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises about 70% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises about 80% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises about 90% by weight of the pharmaceutical composition.

[0261] In some embodiments, the humectant comprises up to about 10% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises up to about 20% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises up to about 30% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises up to about 40% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises up to about 50% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises up to about 60% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises up to about 70% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises up to about 80% by weight of the pharmaceutical composition. In some embodiments, the humectant comprises up to about 90% by weight of the pharmaceutical composition.

[0262] In some embodiments, the wetting agent comprises at least about 10% by weight of the pharmaceutical composition. In some embodiments, the wetting agent comprises at least about 20% by weight of the pharmaceutical composition. In some embodiments, the wetting agent comprises at least about 30% by weight of the pharmaceutical composition. In some embodiments, the wetting agent comprises at least about 40% by weight of the pharmaceutical composition. In some embodiments, the wetting agent comprises at least about 50% by weight of the pharmaceutical composition. In some embodiments, the wetting agent comprises at least about 60% by weight of the pharmaceutical composition. In some embodiments, the wetting agent comprises at least about 70% by weight of the pharmaceutical composition. In some embodiments, the wetting agent comprises at least about 80% by weight of the pharmaceutical composition. In some embodiments, the wetting agent comprises at least about 90% by weight of the pharmaceutical composition.

[0263] Lubricant In some embodiments, the pharmaceutical composition comprising a compound of Formula (I) further comprises a lubricant. In some embodiments, the solid dispersion of the pharmaceutical composition further comprises a lubricant. Non-limiting examples of lubricants include colloidal silicon dioxide, talk, corn starch, metal silicates, metal salts of higher fatty acids, metal oxides, alkaline earth metal salts, and metal hydroxides, or any combination thereof.

[0264] In some embodiments, the lubricant comprises about 1-99% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 10% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 20% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 30% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 40% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 50% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 60% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 70% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 80% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 90% by weight of the pharmaceutical composition.

[0265] In some embodiments, the lubricant comprises up to about 10% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises up to about 20% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises up to about 30% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises up to about 40% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises up to about 50% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises up to about 60% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises up to about 70% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises up to about 80% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises up to about 90% by weight of the pharmaceutical composition.

[0266] In some embodiments, the lubricant comprises at least about 10% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises at least about 20% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises at least about 30% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises at least about 40% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises at least about 50% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises at least about 60% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises at least about 70% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises at least about 80% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises at least about 90% by weight of the pharmaceutical composition.

[0267] lubricant In some embodiments, the pharmaceutical composition comprising a compound of Formula (I) further comprises a lubricant. In some embodiments, the solid dispersion of the pharmaceutical composition further comprises a lubricant. Non-limiting examples of 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.

[0268] In some embodiments, the lubricant comprises about 1-99% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 10% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 20% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 30% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 40% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 50% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 60% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 70% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 80% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises about 90% by weight of the pharmaceutical composition.

[0269] In some embodiments, the lubricant comprises up to about 10% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises up to about 20% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises up to about 30% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises up to about 40% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises up to about 50% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises up to about 60% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises up to about 70% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises up to about 80% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises up to about 90% by weight of the pharmaceutical composition.

[0270] In some embodiments, the lubricant comprises at least about 10% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises at least about 20% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises at least about 30% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises at least about 40% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises at least about 50% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises at least about 60% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises at least about 70% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises at least about 80% by weight of the pharmaceutical composition. In some embodiments, the lubricant comprises at least about 90% by weight of the pharmaceutical composition.

[0271] surfactants In some embodiments of a pharmaceutical composition comprising a compound of Formula (I), the pharmaceutical composition further comprises a surfactant. In certain embodiments, the solid dispersion of the pharmaceutical composition further comprises a surfactant. Non-limiting examples of surfactants include sodium dodecyl sulfate, sodium laurel sulfate (SLS), macroglycerol ricinoleate (Kolliphor EL® or Cremophor EL®), caprylocaproyl polyoxyl-8 glyceride (Labrasol®), lauroyl polyoxyl-6 glyceride (Labrafil® M 2130), and the like. CS), lauroyl polyoxyl-32 glycerides (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 (Tween®-85), polyoxyethylene glyceryl trioleate (tagot-TO), sorbitan monooleate (Span®-80), sorbitan monolaurate (Span®-20), or any combination thereof.

[0272] In some embodiments, the surfactant comprises about 1-99% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises about 10% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises about 20% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises about 30% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises about 40% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises about 50% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises about 60% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises about 70% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises about 80% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises about 90% by weight of the pharmaceutical composition.

[0273] In some embodiments, the surfactant comprises up to about 10% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises up to about 20% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises up to about 30% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises up to about 40% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises up to about 50% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises up to about 60% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises up to about 70% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises up to about 80% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises up to about 90% by weight of the pharmaceutical composition.

[0274] In some embodiments, the surfactant comprises at least about 10% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises at least about 20% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises at least about 30% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises at least about 40% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises at least about 50% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises at least about 60% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises at least about 70% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises at least about 80% by weight of the pharmaceutical composition. In some embodiments, the surfactant comprises at least about 90% by weight of the pharmaceutical composition.

[0275] Method for producing solid dispersion Described herein are methods for preparing 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. In some embodiments, the method for preparing a solid dispersion comprises: i. adding a solvent to a vessel; ii. adding a compound of formula (I) or a pharmaceutically acceptable salt thereof to a container; iii. adding a dispersion polymer to the container to obtain a first mixture; iv. mixing the first mixture until the compound of formula (I) or a pharmaceutically acceptable salt thereof and the dispersion polymer are dissolved in the solvent to obtain a first solution; v. dry-atomizing the first solution to obtain a first solid; vi. drying the first solid material to obtain a solid dispersion.

[0276] In some embodiments of the method for preparing a solid dispersion, the solvent is an organic solvent 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.

[0277] In some embodiments, the solvent is a mixture of a non-polar and a polar solvent. In some embodiments, the solvent is 95:5 non-polar:polar. In some embodiments, the solvent is 95:5 non-polar:polar. In some embodiments, the solvent is 90:10 non-polar:polar. In some embodiments, the solvent is 85:15 non-polar:polar. In some embodiments, the solvent is 80:20 non-polar:polar. In some embodiments, the solvent is 75:25 non-polar:polar. In some embodiments, the solvent is 70:30 non-polar:polar. In some embodiments, the solvent is 60:40 non-polar:polar. In some embodiments, the solvent is 50:50 non-polar:polar. In some embodiments, the solvent is 40:60 non-polar:polar. In some embodiments, the solvent is 30:70 non-polar:polar. In some embodiments, the solvent is 20:80 non-polar:polar. In some embodiments, the solvent is 10:90 non-polar:polar.

[0278] In some embodiments, the solvent is a mixture of chloroform and methanol. In some embodiments, the solvent is 95:5 chloroform:methanol. In some embodiments, the solvent is 95:5 chloroform:methanol. In some embodiments, the solvent is 90:10 chloroform:methanol. In some embodiments, the solvent is 85:15 chloroform:methanol. In some embodiments, the solvent is 80:20 chloroform:methanol. In some embodiments, the solvent is 75:25 chloroform:methanol. In some embodiments, the solvent is 70:30 chloroform:methanol. In some embodiments, the solvent is 60:40 chloroform:methanol. In some embodiments, the solvent is 50:50 chloroform:methanol. In some embodiments, the solvent is 40:60 chloroform:methanol. In some embodiments, the solvent is 30:70 chloroform:methanol. In some embodiments, the solvent is 20:80 chloroform:methanol. In one embodiment, the solvent is 10:90 chloroform:methanol.

[0279] In some embodiments, the solvent is a mixture of dichloromethane and methanol. In some embodiments, the solvent is 95:5 dichloromethane:methanol. In some embodiments, the solvent is 95:5 dichloromethane:methanol. In some embodiments, the solvent is 90:10 dichloromethane:methanol. In some embodiments, the solvent is 85:15 dichloromethane:methanol. In some embodiments, the solvent is 80:20 dichloromethane:methanol. In some embodiments, the solvent is 75:25 dichloromethane:methanol. In some embodiments, the solvent is 70:30 dichloromethane:methanol. In some embodiments, the solvent is 60:40 dichloromethane:methanol. In some embodiments, the solvent is 50:50 dichloromethane:methanol. In some embodiments, the solvent is 40:60 dichloromethane:methanol. In some embodiments, the solvent is 30:70 dichloromethane:methanol. In some embodiments, the solvent is 20:80 dichloromethane:methanol. In one embodiment, the solvent is 10:90 dichloromethane:methanol.

[0280] In some embodiments, the solvent is a mixture of dichloromethane and ethanol. In some embodiments, the solvent is 95:5 dichloromethane:ethanol. In some embodiments, the solvent is 95:5 dichloromethane:ethanol. In some embodiments, the solvent is 90:10 dichloromethane:ethanol. In some embodiments, the solvent is 85:15 dichloromethane:ethanol. In some embodiments, the solvent is 80:20 dichloromethane:ethanol. In some embodiments, the solvent is 75:25 dichloromethane:ethanol. In some embodiments, the solvent is 70:30 dichloromethane:ethanol. In some embodiments, the solvent is 60:40 dichloromethane:ethanol. In some embodiments, the solvent is 50:50 dichloromethane:ethanol. In some embodiments, the solvent is 40:60 dichloromethane:ethanol. In some embodiments, the solvent is 30:70 dichloromethane:ethanol. In some embodiments, the solvent is 20:80 dichloromethane:ethanol. In one embodiment, the solvent is 10:90 dichloromethane:ethanol.

[0281] In some embodiments, the solvent is a mixture of acetone and methanol. In some embodiments, the solvent is 95:5 acetone:methanol. In some embodiments, the solvent is 90:10 acetone:methanol. In some embodiments, the solvent is 85:15 acetone:methanol. In some embodiments, the solvent is 80:20 acetone:methanol. In some embodiments, the solvent is 75:25 acetone:methanol. In some embodiments, the solvent is 70:30 acetone:methanol. In some embodiments, the solvent is 60:40 acetone:methanol. In some embodiments, the solvent is 50:50 acetone:methanol. In some embodiments, the solvent is 40:60 acetone:methanol. In some embodiments, the solvent is 30:70 acetone:methanol. In some embodiments, the solvent is 20:80 dichloromethane:methanol. In some embodiments, the solvent is 10:90 acetone:methanol.

[0282] In some embodiments, the solvent is a mixture of ethyl acetate and acetonitrile. In some embodiments, the solvent is 95:5 ethyl acetate:acetonitrile. In some embodiments, the solvent is 95:5 ethyl acetate:acetonitrile. In some embodiments, the solvent is 90:10 ethyl acetate:acetonitrile. In some embodiments, the solvent is 85:15 ethyl acetate:acetonitrile. In some embodiments, the solvent is 80:20 ethyl acetate:acetonitrile. In some embodiments, the solvent is 75:25 ethyl acetate:acetonitrile. In some embodiments, the solvent is 70:30 ethyl acetate:acetonitrile. In some embodiments, the solvent is 60:40 ethyl acetate:acetonitrile. In some embodiments, the solvent is 50:50 ethyl acetate:acetonitrile. In some embodiments, the solvent is 40:60 ethyl acetate:acetonitrile. In some embodiments, the solvent is 30:70 ethyl acetate:acetonitrile. In some embodiments, the solvent is 20:80 ethyl acetate:acetonitrile. In some embodiments, the solvent is 10:90 ethyl acetate:acetonitrile.

[0283] In some embodiments of the method for preparing a solid dispersion, the dispersion polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS or HPMCAS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, and derivatives or combinations thereof. In some embodiments, the dispersion polymer is HPMC-AS. In some embodiments, the dispersion polymer is HPMC. In some embodiments, the dispersion polymer is PVP.

[0284] In some embodiments, the dispersion polymer is a specific 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 of about 7000 Daltons to about 11000 Daltons.

[0285] In some embodiments of the method of making a solid dispersion, the method further comprises adding an additional ingredient to the first mixture, hi some embodiments, the additional ingredient is a filler, a sweetener, a disintegrant, a wetting agent, a glidant, a lubricant, a surfactant, or any combination thereof.

[0286] In certain embodiments, the compound of Formula (I) has the structure:

[0287] [ka] or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In one embodiment, the compound of formula (I) has the following structure:

[0288] [ka] or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, formulated as a solid dispersion.

[0289] Nanosuspension Pharmaceutical Formulations Also provided herein are nanosuspension pharmaceutical compositions comprising compounds of Formula (I), particularly Compound 1. Nanosuspensions are ideally suited formulations for compounds with low solubility in pharmaceutically acceptable solvents. Such formulations can result in improved bioavailability of such compounds. Nanosuspensions typically contain a stable polymorphic form of a desired API with an average particle size of less than 1000 nm, which is then suspended in a liquid (such as water). Ideally, the API remains stably suspended in the formulation for extended periods of time without altering the polymorphic form of the API. Such formulations often contain additional agents, such as surfactants or emulsifiers, to help maintain the API in suspension.

[0290] In one aspect, provided herein is a nanosuspension pharmaceutical composition, the nanosuspension pharmaceutical composition comprising a compound of Formula (I), a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, suspended in a pharmaceutically acceptable solvent. In some embodiments, the compound of Formula (I) is Compound 1. In some embodiments, Compound 1 is the polymorph "Form C" provided herein.

[0291] In some embodiments, the nanosuspension pharmaceutical formulation comprises the indicated amount of a 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. In some embodiments, 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, or about 5 mg / mL to about 2 In some embodiments, the compound of Formula (I) is present in an amount of about 1 mg / mL, about 5 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 25 mg / mL to about 100 mg / mL, about 25 mg / mL to about 200 mg / mL, about 50 mg / mL to about 100 mg / mL, about 50 mg / mL to about 200 mg / mL, or about 100 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, 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. In some embodiments, the compound of Formula (I) is present in an amount of up to 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.

[0292] In some embodiments, the compound of Formula (I) has an average particle size of less than 1,000 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 nm. In some embodiments, 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.

[0293] The particle size distribution of the resulting suspension can be measured using any instrument. One example is laser diffraction using a Cilas Particle Size Analyser 1190. Particle images can be obtained, for example, using an Olympus microscope. Resolution can be determined, for example, by a pION μDISS Profiler.

[0294] In some embodiments, the compound of formula (I) is micronized. The compound can be micronized by any suitable method, such as milling or jet milling. In some embodiments, the compound is milled with a solution containing any additional additives that are in the final formulation, such as surfactants or excipients.

[0295] In some embodiments, the solvent is water. In some embodiments, the solvent is water and an additional solvent, including but not limited to ethanol, t-butanol, hexane, and glycol.

[0296] The pH of the aqueous dispersion medium can be adjusted by techniques known to those skilled in the art. Ideally, the pH should be a pH that is tolerated by the subject, such as near neutral. In some embodiments, the pH of the nanosuspension formulation is about 7. In some embodiments, the pH of the nanosuspension formulation is about 6. In some embodiments, the pH of the nanosuspension formulation is about 6 to about 8. In some embodiments, the pH of the nanosuspension formulation is about 5 to about 9. In some embodiments, the pH of the nanosuspension formulation is about 6 to about 7. In some embodiments, the pH of the nanosuspension formulation is about 5 to about 7.

[0297] In some embodiments, the nanosuspension formulation further comprises a surfactant. A surfactant is a wetting agent that reduces the surface tension of a liquid, facilitating spreading and reducing the interfacial tension between two liquids. Surfactants are usually amphiphilic organic compounds, and therefore, they are soluble in both organic solvents and water. Surfactants reduce the surface tension of water by adsorbing at the liquid-gas interface. Furthermore, they reduce the interfacial tension between oil and water by adsorbing at the liquid-liquid interface.

[0298] Surfactants are classified into two major groups: ionic (anionic, cationic, and zwitterionic) (dual charge) and nonionic.

[0299] Examples of nonionic surfactants include, but are not limited to, alkyl poly(ethylene oxide), copolymers of poly(ethylene oxide) and poly(propylene oxide) (also known as 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. In some embodiments, the surfactant comprises a poloxamer. In some embodiments, the surfactant is a polysorbate.

[0300] Examples of ionic surfactants include, but are not limited to, rerfluorooctanoate (PFOA or PFO), pertluorooctanesulfonate (PFOS), sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, sodium lauryl ether sulfate (SLES), alkylbenzene sulfonates, soaps, or fatty acid salts (anionic), cetyltriammonium bromide (also known as hexadecyltrimethylammonium bromide) (CTAB) and other alkyltrimethylammonium salts, cetylpyridinium chloride (CPC), polyethoxylated tallow amine (POEA), benzalkonium chloride (BAC), benzethonium chloride (BZT) (cationic), dodecylbetaine, cocamidopropyl betaine, and cocoamphoglycinate (zwitterionic). In some embodiments, the surfactant comprises SDS.

[0301] In some embodiments, the nanosuspension comprises a surfactant at a concentration of about 0.01% to about 1%. In some embodiments, the 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%, or about 0. The surfactant may be present at a concentration of 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 0.2% to about 0.5%, about 0.2% to about 0.75%, about 0.2% to about 1%, about 0.35% to about 0.5%, about 0.35% to about 0.75%, about 0.35% to about 1%, about 0.5% to about 0.75%, about 0.5% to about 1%, or about 0.75% to about 1%. In some embodiments, the 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, the 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, the nanosuspension comprises a surfactant at a concentration of up to about 0.05%, about 0.1%, about 0.2%, about 0.35%, about 0.5%, about 0.75%, or about 1%.

[0302] In some embodiments, the nanosuspension comprises SDS at a concentration of about 0.01% to about 1%, 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%, or about 0. Contains SDS at a concentration of 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 0.2% to about 0.5%, about 0.2% to about 0.75%, about 0.2% to about 1%, about 0.35% to about 0.5%, about 0.35% to about 0.75%, about 0.35% to about 1%, about 0.5% to about 0.75%, about 0.5% to about 1%, or about 0.75% to about 1%. In some embodiments, the 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, the 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, the nanosuspension comprises SDS at a concentration of up to about 0.05%, about 0.1%, about 0.2%, about 0.35%, about 0.5%, about 0.75%, or about 1%.

[0303] In some embodiments, the nanosuspension contains one or more excipients. Suitable excipients include, but are not limited to, PVP, CMC, HPMC, HPC, PEG, PEO, transcutol, and glycerin. In some embodiments, the excipient includes hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, or any combination thereof. In some embodiments, the excipient is a low molecular weight polymer.

[0304] In some embodiments, the excipient is HPMC, HPMC-AS, HPC, or PVP. In some embodiments, the excipient is HPC.

[0305] In some embodiments, the nanosuspension comprises an excipient at a concentration of about 0.1% to about 5%. In some embodiments, the 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% In some embodiments, the 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, the 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, the 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, the nanosuspension comprises an excipient at a concentration of up to about 0.5%, about 1%, about 1.5%, about 2%, about 3%, about 4%, or about 5%.

[0306] In some embodiments, the nanosuspension comprises HPC at a concentration of about 0.1% to about 5%. In some embodiments, the 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%, or about 0.5%. The nanosuspension may comprise HPC at a concentration of about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 3%, about 4%, about 5%, about 1.5%, about 2%, about 3%, about 4%, about 3% to about 5%, or about 4% to about 5%. In some embodiments, the 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, the 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, the nanosuspension comprises HPC at a concentration of up to about 0.5%, about 1%, about 1.5%, about 2%, about 3%, about 4%, or about 5%.

[0307] In some embodiments, nanosuspensions are provided, wherein the resulting nanosuspension is stable at room temperature (22°C) for more than 1, 5, 10, 15, 20, or 25 days. In some embodiments, nanosuspensions are provided, wherein the resulting nanosuspension is stable at room temperature (22°C) for more than 1, 2, 3, or 4 weeks. In some embodiments, nanosuspensions are provided, wherein the resulting nanosuspension is stable at room temperature (22°C) for more than 1, 3, 6, 12, 18, or 24 months. In some embodiments, stability is measured by changes in particle size or particle size distribution of the compound. In some embodiments, stability is measured by chemical stability of the compound. In some embodiments, stability is measured by changes in polymorphic form of the compound.

[0308] Polymorphs of Compound 1 Provided herein is a novel and unique polymorph of Compound 1. This polymorph is herein referred to as "Form C." This polymorph has been found to be readily prepared by a variety of methods provided in the Examples section. Form C is a crystalline solid with high thermodynamic stability and is well suited for pharmaceutical formulations of Compound 1.

[0309] Provided herein is a polymorph of Compound 1 having the X-ray powder diffraction pattern shown in Figure 16. Figure 16 shows multiple peaks at many degrees 2-theta, including, but not limited to, about 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 having a wavelength of 1.5406 angstroms, unless otherwise specified.

[0310] In one aspect, provided herein is a polymorph of the compound of Formula (I) having the structure:

[0311] [ka] wherein the compound of Formula (I) exhibits an X-ray powder diffraction pattern with at least three characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 °2-theta (+ / - 0.5 °theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with at least four characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 °2-theta (+ / - 0.5 °theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with at least five characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 °2-theta (+ / - 0.5 °theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with at least six characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees two-theta (+ / - 0.5 degrees theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees two-theta (+ / - 0.5 degrees theta).

[0312] In one aspect, provided herein is a polymorph of the compound of Formula (I) having the structure:

[0313] [ka] wherein the polymorph exhibits an X-ray powder diffraction pattern with at least three characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees 2-theta (+ / - 1.0 degrees theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with at least four characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees 2-theta (+ / - 1.0 degrees theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with at least five characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees 2-theta (+ / - 1.0 degrees theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with at least six characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees two-theta (+ / - 1.0 degrees theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees two-theta (+ / - 1.0 degrees theta).

[0314] In one aspect, provided herein is a polymorph of the compound of Formula (I) having the structure:

[0315] [ka] wherein the polymorph exhibits an X-ray powder diffraction pattern with at least three characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with at least four characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with at least five characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with at least six characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees two-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees two-theta (+ / - 0.2 degrees theta).

[0316] In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed at 6.7, 9.3, and 14.1 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed at 6.7, 9.3, and 17.2 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed at 6.7, 9.3, and 23.5 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed at 6.7, 9.3, and 27.1 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed at 6.7, 9.3, and 29.0 degrees 2-theta (+ / - 0.2 degrees theta).

[0317] In some embodiments, the polymorph exhibits characteristic peaks in an X-ray powder diffraction pattern comprising 6.7, 14.1, and 17.2 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits characteristic peaks in an X-ray powder diffraction pattern comprising 6.7, 14.1, and 23.5 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits characteristic peaks in an X-ray powder diffraction pattern comprising 6.7, 14.1, and 27.1 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits characteristic peaks in an X-ray powder diffraction pattern comprising 6.7, 14.1, and 29.0 degrees 2-theta (+ / - 0.2 degrees theta).

[0318] In some embodiments, the polymorph exhibits characteristic peaks in an X-ray powder diffraction pattern comprising 9.3, 14.1, and 17.2 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits characteristic peaks in an X-ray powder diffraction pattern comprising 9.3, 14.1, and 23.5 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits characteristic peaks in an X-ray powder diffraction pattern comprising 9.3, 14.1, and 27.1 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits characteristic peaks in an X-ray powder diffraction pattern comprising 9.3, 14.1, and 29.0 degrees 2-theta (+ / - 0.2 degrees theta).

[0319] In some embodiments, the polymorph exhibits characteristic peaks in an X-ray powder diffraction pattern comprising 9.3, 14.1, and 17.2 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits characteristic peaks in an X-ray powder diffraction pattern comprising 9.3, 14.1, and 23.5 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits characteristic peaks in an X-ray powder diffraction pattern comprising 9.3, 14.1, and 27.1 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the polymorph exhibits characteristic peaks in an X-ray powder diffraction pattern comprising 9.3, 14.1, and 29.0 degrees 2-theta (+ / - 0.2 degrees theta).

[0320] In some embodiments, the polymorph exhibits characteristic peaks in an X-ray powder diffraction pattern comprising peaks expressed as 14.1, 17.2, and 23.5 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the XRPD pattern further comprises a peak at 29.0 (+ / - 0.2 degrees theta). In some embodiments, the XRPD pattern further comprises a peak at 27.1 (+ / - 0.2 degrees theta). In some embodiments, the XRPD pattern further comprises a peak at 9.3 (+ / - 0.2 degrees theta). In some embodiments, the XRPD pattern further comprises a peak at 6.7 (+ / - 0.2 degrees theta).

[0321] In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed at 9.3, 17.2, 23.5, and 27.1 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the XRPD pattern further comprises a peak at 14.1 (+ / - 0.2 degrees theta). In some embodiments, the XRPD pattern further comprises a peak at 29.0 (+ / - 0.2 degrees theta). In some embodiments, the XRPD pattern further comprises a peak at 6.7 (+ / - 0.2 degrees theta).

[0322] In some embodiments, the polymorph exhibits characteristic peaks in an X-ray powder diffraction pattern expressed as 6.7, 9.3, 17.2, and 23.5 degrees 2-theta (+ / - 0.2 degrees theta). In some embodiments, the XRPD pattern further comprises a peak at 14.1 (+ / - 0.2 degrees theta). In some embodiments, the XRPD pattern further comprises a peak at 29.0 (+ / - 0.2 degrees theta). In some embodiments, the XRPD pattern further comprises a peak at 27.1 (+ / - 0.2 degrees theta).

[0323] In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed at 6.7, 9.3, 17.2, 23.5, and 27.1 degrees two-theta (+ / - 0.2 degrees theta). In some embodiments, the XRPD pattern comprises a peak at 14.1 (+ / - 0.2 degrees theta). In some embodiments, the XRPD pattern comprises a peak at 29.0 (+ / - 0.2 degrees theta).

[0324] In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed at 6.7, 9.3, 17.2, 23.5, and 27.1 degrees 2-theta (+ / - 0.5 degrees theta). In some embodiments, the XRPD pattern further comprises a peak at 14.1 (+ / - 0.5 degrees theta). In some embodiments, the XRPD pattern further comprises a peak at 29.0 (+ / - 0.5 degrees theta).

[0325] In some embodiments, the XRPD pattern comprises peaks substantially identical to those shown in FIG.

[0326] In some embodiments, the polymorph exhibits a differential scanning calorimetry (DSC) endotherm at about 228°C.

[0327] Also provided herein is a polymorph of Compound 1, referred to herein as Form A, having an XRPD pattern substantially identical to the XRPD pattern displayed in FIG.

[0328] Administration and Treatment Regimen The dosage of the compositions comprising at least one compound of formula (I) described herein will vary depending on the condition of the patient, i.e., the stage of the disease, general health, age, and other factors.

[0329] The pharmaceutical composition is administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration are determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides a sufficient amount of the composition to provide a therapeutic and / or prophylactic benefit (e.g., improved clinical outcome) or a reduction in the severity of symptoms. The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose depends on the patient's body type, weight, or blood volume.

[0330] In one embodiment, the compounds described herein, or pharmaceutically acceptable salts thereof, are used in the preparation of a medicament for the treatment of a disease or disorder in a mammal that would benefit from the administration of any one of the disclosed compounds. A method for treating any of the diseases or disorders described herein in a mammal in need of such treatment comprises administering to the mammal a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof.

[0331] In some embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic treatment. In some therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatments, 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, dose escalation and / or dose ranging clinical trials.

[0332] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dosage." For this application, the precise amount will vary depending on the patient's health, weight, and the like. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom of the disease being treated and is now in remission, to prevent the recurrence of the disease or condition symptoms.

[0333] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including for the patient's lifetime, to ameliorate or otherwise suppress or limit the symptoms of the patient's disease or disorder.

[0334] Oral doses typically range from about 1.0 mg to about 1000 mg, administered one to four or more times per day. However, in general, doses utilized for adult treatment typically range from 0.01 mg to 5000 mg per day. In one embodiment, oral doses range from about 0.1 mg to about 20 mg per day. In one embodiment, oral doses range from about 0.5 mg to about 50 mg per day. In one embodiment, oral doses range from about 1 mg to about 10 mg per day. In one aspect, dosages utilized for adult treatment range from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is conveniently provided in a single dose or in divided doses administered simultaneously or at appropriate intervals, e.g., two, three, four, or more subdoses per day.

[0335] In some embodiments, the compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is administered 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 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, The compound is administered to a subject or patient in an amount of 5 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 240 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg. In some embodiments, the 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 at about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, or about 20 mg.In some embodiments, the compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, is administered 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, up to about 145 mg, up to about 150 mg, up to about 155 mg, up to about 160 mg, up to about 165 mg, up to about 170 mg, up to about 175 mg, up to about 180 mg, up to about 185 mg, up to about 190 mg, up to about 205 mg, up to about 210 mg, up to about 215 mg, up to about 220 mg, up to about 225 mg, up to about 230 mg, up to about 240 mg, up to about 245 mg, up to about 250 mg, up to about 260 mg, up to about 270 mg, up to about 280 mg, up to about 2 The compound may be administered to a subject or patient in an amount of at most about 120 mg, up to about 125 mg, up to about 130 mg, up to about 135 mg, up to about 140 mg, up to about 145 mg, up to about 150 mg, up to about 155 mg, up to about 160 mg, up to about 165 mg, up to about 170 mg, up to about 175 mg, up to about 180 mg, up to about 185 mg, up to about 190 mg, up to about 195 mg, up to about 200 mg, up to about 225 mg, up to about 240 mg, up to about 250 mg, up to about 275 mg, up to about 300 mg, up to about 325 mg, up to about 350 mg, up to about 375 mg, up to about 400 mg, up to about 425 mg, up to about 450 mg, up to about 475 mg, or up to about 500 mg. In some embodiments, the 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.In some embodiments, the compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof is 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, 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 The compound may be administered to a subject or patient in an amount of 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, at least 175 mg, at least 180 mg, at least 185 mg, at least 190 mg, at least 195 mg, at least 200 mg, at least 225 mg, at least 240 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, or at least 500 mg. In some embodiments, the 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, or at least 20 mg.

[0336] In some embodiments, the compound of Formula (I), its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer 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. In some embodiments, the compound of Formula (I), its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer 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. In some embodiments, the compound of Formula (I), its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer is administered to a subject or patient in an amount of at most 0.1 mg, at most 0.5 mg, at most 1 mg, at most 5 mg, at most 10 mg, at most 25 mg, at most 50 mg, at most 100 mg, or at most 200 mg. In some embodiments, the compound of Formula (I), its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer 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.

[0337] In some embodiments, the 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. In some embodiments, the compound of Formula (I), its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer 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. In some embodiments, the compound of Formula (I), its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer 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, 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. In some embodiments, the 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.

[0338] In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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, the 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. In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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.

[0339] In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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.In some embodiments, the 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. In some embodiments, the 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.

[0340] In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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. In some embodiments, the 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 ...

Claims

1. 1. A pharmaceutical composition comprising a solid dispersion, the solid dispersion comprising: (i) a compound of formula (I), a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof; 【Chemistry 1】 (In the formula, R １ are each independently halogen, haloalkyl, or alkyl; R ２ is —H, —OH, or a halogen; p is 0, 1, 2, 3, 4, or 5; A has the following structure: 【Chemistry 2】 During the ceremony, α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C, Z １ is S, O, or N, Z ２ is S, O, N, or NR ３ and R ３ is H, C １ -C ４ alkyl, or oxetane, and B is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure, and (ii) Dispersion polymer A pharmaceutical composition comprising:

2. A has the following structure: 【Transformation 3】 During the ceremony, n is 0, 1, or 2; α, β, χ, δ, ε, and φ are each independently absent or present, and when present, each is a bond; Z １ is S, O, or N, Z ２ is S, O, N, or NR ３ and Here, R ３ is H, C １ -C ４ alkyl, or oxetane; X is C, Y １ , Y ２ , Y ３ And each Y ４ The occurrence of each independently ４ , C(R ５ ) ２ , N.R. ６ , O, N, SO ２ or —(C═O)—, During the ceremony, R ４ 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 and R ５ is H or C １ -C １０ is alkyl, and R ６ is H, C １ -C １０ Alkyl, C ３ -C ６ cycloalkyl, -(C １ -C １０ alkylene)CF ３ , -(C １ -C １０ alkylene)OCH ３ , -(C １ -C １０ (alkylene)-halogen, -SO ２ (C １ -C １０ alkyl), -SO ２ (C １ -C １０ (alkylene)-CF ３ , -SO ２ (C １ -C １０ alkylene)OCH ３ , -SO ２ (C １ -C １０ alkylene)-halogen, —C(O)(C １ -C １０ alkyl), —C(O)(C １ -C １０ alkylene)CF ３ , -C(O)(C １ -C １０ alkylene)OCH ３ , -C(O)(C １ -C １０ alkylene)-halogen, —C(O)NH(C １ -C １０ alkyl), —C(O)N(C １ -C １０ alkyl) ２ , -(C １ -C １０ alkyl)C(O)OH, —C(O)NH ２ 10. The pharmaceutical composition of claim 1, wherein the compound is an oxetane.

3. A has the following structure: 【Chemistry 4】 During the ceremony, n is 0, R ３ is H, C １ -C ４ alkyl, or oxetane; Y １ and Y ３ are respectively CH ２ or C(CH ３ ) ２ and Y ２ Is O, SO ２ , or NR ６ and R ６ is H, C １ -C ４ Alkyl, C ３ -C ６ cycloalkyl, -(C １ -C ４ alkylene)CF ３ , -(C １ -C ４ alkylene)OCH ３ , -(C １ -C ４ (alkylene)-halogen, -SO ２ (C １ -C ４ alkyl), -SO ２ (C １ -C ４ alkylene)CF ３ , -SO ２ (C １ -C ４ alkylene)OCH ３ , -SO ２ (C １ -C ４ alkylene)-halogen, —C(O)(C １ -C ４ alkyl), —C(O)(C １ -C ４ alkylene)CF ３ , -C(O)(C １ -C ４ alkylene)OCH ３ , -C(O)(C １ -C ４ alkylene)-halogen, —C(O)NH(C １ -C ４ alkyl), —C(O)N(C １ -C ４ alkyl) ２ , -(C １ -C ４ alkylene)C(O)OH, —C(O)NH ２ 10. The pharmaceutical composition of claim 1, wherein the compound is an oxetane.

4. Compounds of formula (I) have the following structure: 【Transformation 5】 Alternatively, the pharmaceutical composition of claim 1 has a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof.

5. 5. The pharmaceutical composition of any one of claims 1-4, wherein the compound of formula (I) is effective in lowering RBP4 levels in a dosage form of 1 mg to 200 mg or 5 mg to 25 mg.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the compound of formula (I) is in the form of micronized crystals.

7. 7. The pharmaceutical composition of any one of claims 1-6, wherein the compound of formula (I) is a polymorph that exhibits an X-ray powder diffraction pattern with at least three characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees two-theta (+ / - 0.5 degrees theta).

8. 8. The pharmaceutical composition of any one of claims 1-7, wherein the compound of formula (I) is amorphous and molecularly dispersed in the dispersion polymer.

9. 9. The pharmaceutical composition of any one of claims 1-8, wherein the dispersion polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethylcellulose, polyvinyl alcohol polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, and combinations thereof.

10. The pharmaceutical composition of any one of claims 1-9, wherein the dispersion polymer comprises HPMC.

11. The pharmaceutical composition of any one of claims 1-6, wherein the dispersion polymer comprises HPMC-AS.

12. 12. The pharmaceutical composition of any one of claims 1-11, wherein the dispersion polymer comprises about 1-99%, 20-80%, or 40-60% by weight of the solid dispersion.

13. 13. The pharmaceutical composition of any one of claims 1-12, wherein the compound of formula (I) comprises about 1-99%, about 20-80%, or about 40-60% by weight of the solid dispersion.

14. 14. The pharmaceutical composition of any one of claims 1-13, wherein the ratio of compound of formula (I) to dispersion polymer is about 20:80 (w / w) in the solid dispersion.

15. 15. The pharmaceutical composition of any one of claims 1-14, wherein the ratio of compound of formula (I) to dispersion polymer is about 40:60 (w / w) in the solid dispersion.

16. The compound of formula (I) 【Transformation 6】 and the dispersion polymer is HPMC-AS.

17. 17. The pharmaceutical composition of any one of claims 10-16, wherein the dispersion polymer is HPMC-AS having an acetyl content of 7-11 wt%, a succinyl content of 10-14 wt%, a methoxyl content of 21-25 wt%, and a hydroxypropyl content of 5-9 wt%.

18. 17. The pharmaceutical composition of any one of claims 10-16, wherein the dispersion polymer is HPMC-AS having an acetyl content of 10-14 wt%, a succinyl content of 4-8 wt%, a methoxyl content of 22-26 wt%, and a hydroxypropyl content of 6-10 wt%.

19. 10. The pharmaceutical composition of claim 1, wherein the dispersion polymer comprises polyvinylpyrrolidone (PVP).

20. 20. The pharmaceutical composition of claim 19, wherein the PVP is present in a ratio of about 10:1 to about 1:1 with the compound of formula (I).

21. 21. The pharmaceutical composition of claim 19 or 20, wherein the PVP is present in a ratio of about 2:1, about 3:1, or about 5:1 with respect to the compound of formula (I).

22. 22. The pharmaceutical composition of any one of claims 19-21, wherein the PVP has a molecular weight average molecular weight of about 7,000 Daltons to about 11,000 Daltons.

23. 23. The pharmaceutical composition of any one of claims 1-22, further comprising a filler, a sweetener, a disintegrant, a wetting agent, a glidant, a glidant, or a surfactant, or any combination thereof.

24. 24. The pharmaceutical composition of any one of claims 1-23, wherein the solid dispersion further comprises a filler, a sweetener, a disintegrant, a wetting agent, a glidant, a glidant, or a surfactant, or any combination thereof.

25. 25. The pharmaceutical composition of any one of claims 1-24, wherein the solid dispersion has an average particle size of less than 10 μm or less than 20 μm.

26. 1. A nanosuspension pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, 【Transformation 7】 During the ceremony, R １ are each independently halogen, haloalkyl, or alkyl; R ２ is —H, —OH, or a halogen; p is 0, 1, 2, 3, 4, or 5; A has the following structure: 【Transformation 8】 During the ceremony, α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C, Z １ is S, O, or N, Z ２ is S, O, N, or NR ３ and R ３ is H, C １ -C ４ alkyl, or oxetane, and B is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure; A nanosuspension pharmaceutical composition wherein the compound of formula (I) is suspended in a pharmaceutically acceptable solvent.

27. The compound of formula (I) 【Chemistry 9】 or a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof.

28. 28. The nanosuspension pharmaceutical composition of claim 27, wherein the compound of formula (I) is a polymorph that exhibits an X-ray powder diffraction pattern with at least three characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees two-theta (+ / - 0.5 degrees theta).

29. 29. The nanosuspension pharmaceutical formulation of any one of claims 26-28, wherein the concentration of the compound of formula (I) is from about 1 mg / mL to about 50 mg / mL.

30. 30. The nanosuspension pharmaceutical formulation according to any one of claims 26-29, wherein the compound of formula (I) is micronized.

31. 31. The nanosuspension pharmaceutical formulation according to any one of claims 26 to 30, wherein the compound of formula (I) has a mean particle size of less than 1000 nm.

32. 32. The nanosuspension pharmaceutical formulation of any one of claims 26-31, further comprising a surfactant.

33. 33. The nanosuspension pharmaceutical formulation of claim 32, wherein the surfactant is present at a concentration of about 0.01% to about 1%.

34. 34. The nanosuspension pharmaceutical formulation of claim 32 or 33, wherein the surfactant comprises sodium dodecyl sulfate, poloxamer, or polysorbate.

35. 35. The nanosuspension pharmaceutical formulation of any one of claims 26-34, further comprising an excipient.

36. 36. The nanosuspension pharmaceutical formulation of claim 35, wherein the excipient comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, or any combination thereof.

37. 37. The nanosuspension pharmaceutical composition of claim 35 or 36, wherein the excipient is present at a concentration of about 0.1% to about 5%.

38. 26. The pharmaceutical composition of any one of claims 1 to 25, wherein the pharmaceutical composition is in the form of a tablet.

39. 39. The pharmaceutical composition of any one of claims 1-38, wherein the pharmaceutical composition is in the form of a capsule.

40. 40. A method of treating an eye disease, comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-39.

41. 41. The method of claim 40, wherein the eye disease is a disease characterized by excessive accumulation of lipofuscin in the retina.

42. 42. The method of claim 41, wherein the disease characterized by excessive accumulation of lipofuscin is age-related macular degeneration, dry (atrophic) age-related macular degeneration, juvenile macular degeneration (Stargardt disease), Best disease, adult-onset vitelliform maculopathy, geographic atrophy, Stargardt-like macular dystrophy, diabetic retinopathy, or ABCA4 gene-associated retinal disease.

43. 36. A method for reducing the serum concentration of RBP4 in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1-35.

44. The method of any one of claims 40-43, wherein the therapeutically effective amount of the pharmaceutical composition comprises from about 0.1 mg to about 400 mg of the compound of formula (I).

45. The method of any one of claims 40-44, wherein the therapeutically effective amount of the pharmaceutical composition comprises from about 0.5 mg to about 50 mg of the compound of formula (I).

46. 46. ​​The method of any one of claims 40-45, wherein 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).

47. 47. The method of any one of claims 40-46, wherein the pharmaceutical composition is administered 1, 2, 3, or 4 times daily.

48. 47. The method of any one of claims 40-46, wherein the pharmaceutical composition is administered daily, every other day, every other day 3 days 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, every other week, 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.

49. 47. The method of any one of claims 40-46, wherein the pharmaceutical composition is administered once daily.

50. 50. The method of any one of claims 40-49, wherein the pharmaceutical composition is administered orally.

51. 51. The method of any one of claims 40-50, wherein the subject's serum RBP4 concentration is reduced to less than 1 μM following treatment.

52. 1. A method for producing a solid dispersion, comprising: (i) adding a solvent to a container; (ii) adding a compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof to a container; (iii) adding a dispersion polymer to the vessel to obtain a first mixture; (iv) mixing the first mixture until the compound of formula (I) or a pharmaceutically acceptable salt thereof and the dispersion polymer are dissolved in the solvent to obtain a first solution; (v) dry-atomizing the first solution to obtain a first solid.

53. 53. The method of claim 52, wherein the dispersion polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, and combinations thereof.

54. 54. The method of claim 52 or 53, wherein the dispersion polymer is HPMC-AS or polyvinylpyrrolidine.

55. Compounds of formula (I) have the following structure: 【Chemistry 10】 Or the method of any one of claims 52-54, having a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof.

56. 56. The method of any one of claims 52-55, wherein 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, dimethylacetamide, dimethylformamide, dimethylsulfoxide, dioxane, ethanol, ethyl acetate, ethyl methyl ketone, ethylene glycol, hexane, hexamethylphosphoramide, methanol, nitromethane, pentane, 2-proponal, pyridine, tetrahydrofuran, toluene, xylene, or any combination thereof.

57. 1. A method for reducing the serum concentration of RBP4 in a subject, comprising: The following structure: 【Chemistry 11】 or a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof; The pharmaceutical composition is administered in an amount of about 10 mg, The pharmaceutical composition is administered daily, and The method wherein the subject's serum or plasma level of RBP4 is reduced to less than 1 μM.

58. A polymorph of the compound of formula (I) having the structure: 【Chemistry 12】 Polymorphs are polymorphs that exhibit an X-ray powder diffraction pattern with at least three characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees two-theta (+ / - 0.5 degrees theta).

59. 55. The polymorph of claim 54, wherein the polymorph is crystalline.

60. 60. The polymorph of claim 58 or 59, wherein the polymorph exhibits an X-ray powder diffraction pattern with at least five characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees two-theta (+ / - 0.5 degrees theta).

61. 60. The polymorph of claim 58 or 59, wherein the polymorph exhibits an X-ray powder diffraction pattern with characteristic peaks expressed at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees two-theta (+ / - 0.5 degrees theta).

62. 62. The polymorph of any one of claims 58-61, wherein the polymorph is micronized.

63. 63. The polymorph of any one of claims 58-62, wherein the polymorph has an average particle size of less than 20 μm, less than 10 μm, less than 1 μm, or less than 100 nm.

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