Formulations and methods of use of RBP4 inhibitors

Abstract

Disclosed herein are formulations and methods of use of RBP4 inhibitors. In particular, provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising the compounds useful for the treatment of retinal binding protein (RBP4) related diseases, such as macular degeneration, etc.

Description

[0001] This application is a divisional application of the Chinese patent application with an application date of July 6, 2020, application number 202080062716.8, and invention name “Preparation and Use Method of RBP4 Inhibitors” (the application date of the corresponding PCT application is July 6, 2020, and the application number is PCT / US2020 / 040919).

[0002] Cross-references

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 871,622, filed on July 8, 2019, which is incorporated herein by reference in its entirety. Background Art

[0004] There is a need in the medical field for effective treatments for visual diseases and disorders associated with retinol binding protein 4 (RBP4).

[0005] CROSS-REFERENCE TO RELATED APPLICATIONS

[0006] This application claims the benefit of U.S. Provisional Application No. 62 / 871,622, filed on July 8, 2019, the disclosure of which is hereby incorporated by reference in its entirety. Summary of the invention

[0007] 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:

[0008]

[0009] in:

[0010] Each R 1 are independently halogen, haloalkyl or alkyl;

[0011] R 2 is -H, -OH or halogen;

[0012] p is 0, 1, 2, 3, 4 or 5;

[0013] A has the following structure:

[0014]

[0015] in:

[0016] α, β, χ and δ are each independently absent or present, and when present are each a bond;

[0017] X is C;

[0018] Z1 is S, O or N;

[0019] Z2 is S, O, N or NR 3 ;

[0020] R 3 is H, C1-C4 alkyl or oxetane; and

[0021] B is a substituted or unsubstituted fused 5-, 6- or 7-membered ring structure;

[0022] Wherein the composition comprises a solid dispersion comprising a dispersed polymer. In certain embodiments, A has the following structure:

[0023]

[0024] in:

[0025] n is 0, 1 or 2;

[0026] α, β, χ, δ, ε, and Each is independently absent or present, and when present, each is a bond;

[0027] Z1 is S, O or N;

[0028] Z2 is S, O, N or NR 3 ,

[0029] Where R 3 is H, C1-C4 alkyl or oxetane;

[0030] X is C;

[0031] Y1, Y2, Y3 and each occurrence of Y4 are independently CR 4 , C(R 5 )2. NR 6 , O, N, SO2 or –(C=O)-, wherein:

[0032] 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 l0Alkyl)2, -CN or -CF3;

[0033] R 5 H or C1-C 10 Alkyl; and

[0034] R 6 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.

[0035] In certain embodiments, A has the following structure:

[0036]

[0037] in:

[0038] n is 0;

[0039] R 3 is H, C1-C4 alkyl or oxetane;

[0040] Y1 and Y3 are each CH2 or C(CH3)2;

[0041] Y2 is O, SO2 or NR 6 ;and

[0042] R 6It 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.

[0043] In certain embodiments, the compound of formula (I) has the following structure:

[0044] or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof.

[0045] In certain embodiments, the compound of formula (I) is effective in reducing RBP4 concentration 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 crystalline material. 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, wherein the at least three characteristic peaks are expressed in 2θ degrees (+ / - 0.5 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0.

[0046] In certain embodiments, the compound of formula (I) is molecularly dispersed in a dispersed polymer. In certain embodiments, the compound of formula (I) is amorphous and the molecules are dispersed in a dispersed polymer. In some embodiments, the compound of formula (I) is amorphous in a dispersed polymer. In certain embodiments, the dispersed 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 cellulose acetate), hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinyl pyrrolidone (PVP), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, and combinations thereof. In certain embodiments, the dispersed polymer is HPMC. In certain embodiments, the dispersed polymer is HPMC-AS.

[0047] In certain embodiments, the dispersed polymer accounts for about 1-99 weight % of the solid dispersion. In certain embodiments, the dispersed polymer accounts for about 20-80 weight % of the solid dispersion. In certain embodiments, the dispersed polymer accounts for about 40-60 weight % of the solid dispersion. In certain embodiments, the dispersed polymer accounts for about 1-99 weight %, 20-80 weight % or 40-60 weight % of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 1-99 weight % of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for 20-80 weight % of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 40-60 weight % of the solid dispersion. In certain embodiments, in the solid dispersion, the ratio of the compound of formula (I) to the dispersed polymer is about 20:80 (w / w). In certain embodiments, in the solid dispersion, the ratio of the compound of formula (I) to the dispersed polymer is about 40:60 (w / w). In certain embodiments, the compound of Formula (I) comprises about 1-99 weight %, about 20-80 weight %, or about 40-60 weight % of the solid dispersion.

[0048] In certain embodiments, in the solid dispersion, the ratio of the compound of formula (I): the dispersing polymer is about 20:80 (w / w). In certain embodiments, in the solid dispersion, the ratio of the compound of formula (I): the dispersing polymer is about 40:60 (w / w).

[0049] In certain embodiments, the compound of formula (I) is

[0050]

[0051] And the dispersing polymer is HPMC-AS.

[0052] In certain embodiments, the dispersing polymer is HPMC-AS, M or HPMC-AS, H. In certain embodiments, the dispersing polymer is HPMC-AS, M. In certain embodiments, the dispersing polymer is HPMC-AS, H. In certain embodiments, the dispersing polymer is HPMC-AS having an acetyl content of 7-11 wt%, a succinyl content of 10-14 wt%, a methoxy content of 21-25 wt%, and a hydroxypropyl content of 5-9 wt%. In certain embodiments, the dispersing polymer is HPMC-AS having an acetyl content of 10-14 wt%, a succinyl content of 4-8 wt%, a methoxy content of 22-26 wt%, and a hydroxypropyl content of 6-10 wt%.

[0053] In certain embodiments, the dispersing polymer comprises polyvinylpyrrolidone (PVP). In certain embodiments, 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, 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 molecular weight average molecular weight of PVP is about 7,000 Daltons to about 11,000 Daltons.

[0054] 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.

[0055] In certain embodiments, the average particle size of the solid dispersion is less than 10 μm. In certain embodiments, the average particle size of the solid dispersion is less than 20 μm. In certain embodiments, the average particle size of the solid dispersion is about 10 μm to 20 μm. In certain embodiments, the average particle size of the solid dispersion is less than 10 μm or less than 20 μm.

[0056] In one aspect, a nanosuspension pharmaceutical composition is provided herein, 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, which exhibits an X-ray powder diffraction pattern having at least three characteristic peaks, and the at least three characteristic peaks are expressed in 2θ degrees (+ / - 0.5 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0. In some embodiments, the concentration of the compound of formula (I) is about 1 mg / mL to about 50 mg / mL. In some embodiments, the compound of formula (I) is micronized. In some embodiments, the average particle size of the compound of formula (I) is less than 1000 nm.

[0057] In some embodiments, the nanosuspension further comprises a surfactant. In some embodiments, the surfactant comprises sodium lauryl sulfate, poloxamer or 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 ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinyl pyrrolidone (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%.

[0058] 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.

[0059] Another aspect is a method for treating an eye disease, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of any one of the preceding claims. In certain embodiments, the eye 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 a retinal disease associated with the ABCA4 gene.

[0060] Another aspect is a method of reducing the serum concentration of RBP4 in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition. In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 0.1 mg to about 400 mg of a 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 a 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 a compound of formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 0.1 mg of a compound of formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 0.5 mg of a compound of formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 1 mg of a compound of formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 5 mg of a compound of formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 10 mg of a compound of formula (I). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition comprises about 25 mg of a compound of formula (I). In certain embodiments, the therapeutically effective amount of a pharmaceutical composition comprises about 50 mg of a compound of formula (I). In certain embodiments, the therapeutically effective amount of a pharmaceutical composition comprises about 100 mg of a compound of formula (I). In certain embodiments, the therapeutically effective amount of a pharmaceutical composition comprises about 200 mg of a compound of formula (I). In certain embodiments, the therapeutically effective amount of a pharmaceutical composition comprises about 400 mg of a compound of formula (I). In certain embodiments, the therapeutically effective amount of a 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 a compound of formula (I).

[0061] In certain embodiments, the pharmaceutical composition is administered once, twice, three times, or four times a day. In certain embodiments, the pharmaceutical composition is administered every day, every other day, every other day 3 times a week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 3 days, every 4 days, every 5 days, every 6 days, once a week, once every two weeks, 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 after treatment is reduced to less than 1 μM.

[0062] In another aspect, a method for preparing a solid dispersion is described herein, 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 dispersing 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 dispersing 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 following structure:

[0063]

[0064] in:

[0065] Each R 1 are independently halogen, haloalkyl or alkyl;

[0066] R 2 is -H, -OH or halogen;

[0067] p is 0, 1, 2, 3, 4 or 5;

[0068] A has the following structure:

[0069]

[0070] in:

[0071] α, β, χ and δ are each independently absent or present, and when present are each a bond;

[0072] X is C;

[0073] Z1 is S, O or N;

[0074] Z2 is S, O, N or NR 3 ;

[0075] R 3 is H, C1-C4 alkyl or oxetane; and

[0076] B is a substituted or unsubstituted fused 5-, 6- or 7-membered ring structure;

[0077] The composition comprises a solid dispersion comprising a dispersed polymer.

[0078] In certain embodiments, the solvent comprises an organic solvent. In certain embodiments, the solvent is selected from ethanol, methanol, acetone, isopropanol, n-butanol, tetrahydrofuran, dichloromethane, ethyl acetate, methyl acetate, acetonitrile, chloroform, carbon tetrachloride, benzene, toluene, diethyl ether, dioxane, pentane, hexane, cyclohexane, heptane, methyl tert-butyl ether, petroleum ether, 1-propanol and a combination thereof. In certain embodiments, the solvent is 90:10 dichloromethane: methanol (v / v).

[0079] In certain embodiments, the dispersing polymer is selected from: 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, polyvinyl pyrrolidone (PVP), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, and combinations thereof. In certain embodiments, the dispersing polymer is HPMC-AS. In certain embodiments, the dispersing polymer is HPMC. In some embodiments, the dispersing polymer is polyvinyl pyrrolidine.

[0080] In certain embodiments, the compound of formula (I) has the following structure: Or 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, diethylene glycol dimethyl ether, 1,2,-dimethoxyethane, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, dioxane, ethanol, ethyl acetate, ethyl methyl ketone, ethylene glycol, hexane, hexamethylphosphoramide, methanol, nitromethane, pentane, 2-propanal, pyridine, tetrahydrofuran, toluene, xylene, or any combination thereof.

[0081] In another aspect, disclosed herein is a method of reducing the serum concentration of RBP4 in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound having the following structure: 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 wherein the subject's serum or plasma RBP4 level is reduced to less than 1 μM.

[0082] In one aspect, provided herein are polymorphs of Compound 1, wherein the polymorph exhibits an X-ray powder diffraction pattern having at least three characteristic peaks expressed in 2θ degrees (+ / - 0.5 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0. In some embodiments, the polymorph is crystalline. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern having at least five characteristic peaks expressed in 2θ degrees (+ / - 0.5 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in 2θ degrees (+ / - 0.5 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0. In some embodiments, the polymorph is micronized. In some embodiments, the average particle size of the polymorph is less than 20 μm, less than 10 μm, less than 1 μm, or less than 100 nm.

[0083] Incorporation by reference

[0084] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference for the specific purposes described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0085] The novel features of the present invention are particularly set forth in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by referring to the following detailed description and accompanying drawings which set forth illustrative embodiments in which the principles of the present invention are utilized, wherein the accompanying drawings are:

[0086] Figure 1 Schematic diagram illustrating the mechanism of action of dry (atrophic) macular degeneration and Stargardt's disease. Without being bound by theory, RBP4 transports retinol, a precursor of cytotoxic A2E, into the retina via the visual cycle. RBP4 inhibitors (such as Compound 1) are used in certain cases to treat RBP4-related visual diseases and disorders.

[0087] Figure 2 Graph of bisretinoid A2E (pmol, eye) and RBP4 (serum) levels in ABCA4- / -RDH8- / - mice that were untreated, vehicle treated, or treated with Compound 1. Bisretinoid accumulation was reduced by 80% in mice treated with Compound 1 (p=0.003; unpaired t-test).

[0088] Figure 3is a graph of outer nuclear layer (ONL) thickness (μm) as a function of distance (μm) from the optic nerve (ONH). The ONL is a cell layer composed of photoreceptor cell bodies (rods and cones). Dry AMD or STGD is often associated with ONL thinning and photoreceptor cell loss, indicating macular degeneration. The ONL thickness was significantly reduced in the diseased group (abcd4 / rdh8 knockout mice) compared to the diseased group treated with compound 1 in which the ONL was preserved.

[0089] Figure 4A It is a graph of the average RBP4 reduction percentage from baseline over time (hours) in five groups of 32 healthy adults in a randomized, double-blind, placebo-controlled Phase 1 clinical trial. Each group was given a single dose of 50 mg (Group 1), 100 mg (Group 2), 200 mg (Group 3), 400 mg (Group 4), 25 mg (Group 5) of Compound 1 or placebo. Individuals receiving placebo are not included in the figure.

[0090] Figure 4B Graph showing the RBP4 concentration (ng / mL) over time (hours) for five groups of 32 healthy adults in a randomized, double-blind, placebo-controlled Phase 1 clinical trial. Each group was given a single dose of Compound 1 or placebo of 50 mg (Group 1), 100 mg (Group 2), 200 mg (Group 3), 400 mg (Group 4), 25 mg (Group 5). Individuals receiving placebo are not included in the graph.

[0091] Figure 5 Graph of the mean RBP4 reduction percentage from baseline over time (hours) in Cohort 5 of a randomized, double-blind, placebo-controlled Phase 1 clinical trial. Each subject in the cohort was given a single dose of 25 mg of Compound 1, or a placebo. Six subjects received Compound 1 and two subjects were given a placebo. Subjects FF and GG may have received a placebo.

[0092] Figure 6 is a graph of RBP4 concentration (ng / mL) over time (hours) for Cohort 5 in a randomized, double-blind, placebo-controlled Phase 1 clinical trial. Each subject in the cohort was given a single dose of 25 mg of Compound 1, or a placebo. Six subjects received Compound 1 and two subjects were given a placebo. Subjects FF and GG may have received a placebo.

[0093] Figure 7It is a graph of the concentration (ng / mL) of compound 1 over time (hours) for five groups of 32 healthy adults in a randomized, double-blind, placebo-controlled Phase 1 clinical trial. Each group was given a single dose of 50 mg (Group 1), 100 mg (Group 2), 200 mg (Group 3), 400 mg (Group 4), 25 mg (Group 5) of compound 1 or placebo. Individuals receiving placebo are not included in the figure.

[0094] Figure 8 The graphs are the graphs of Compound 1 concentration (ng / mL) over time (hours) (left) and RBP4 concentration (ng / mL) over time (hours) (right) for Cohort 5 in a randomized, double-blind, placebo-controlled Phase 1 clinical trial. Each subject in the cohort was given a single dose of 25 mg of Compound 1, or a placebo. Subjects FF and GG may have received a placebo.

[0095] Fig. 9 is a graph of RBP4 concentration (μM) as a function of dose for Compound 1 (mg, modeled from Phase 1 clinical studies) and Fenretinide (modeled from Phase 2 clinical studies). The Phase 2 Fenretinide study showed that the subpopulation with significantly reduced RBP4 had slower lesion growth. Compound 1 is more potent than Fenretinide and can significantly reduce RBP4 at clinically relevant doses.

[0096] Fig. 10A is a pattern generated in an X-ray powder diffraction (XRPD) experiment of crystalline Compound 1.

[0097] Fig. 10B is a graph generated during a differential scanning calorimetry (DSC) experiment of crystalline Compound 1, showing the variation of heat flow Q (W / g) with temperature (°C).

[0098] Fig. 10C is a graph generated during a differential scanning calorimetry (DSC) experiment of crystalline Compound 1, showing the reverse heat flow Q rev (mW) changes with temperature (℃).

[0099] Fig. 10D is an image generated by SEM (scanning electron microscopy) of crystalline Compound 1. The morphology of Compound 1 consists of high aspect ratio orthorhombic needle-like crystals.

[0100] Fig.10E It is a graph showing the solubility (μgA / mL) of Compound 1 in a mixture of Compound 1 and various polymers at a ratio of 20:80 as a function of time (minutes).

[0101] Fig.10Fis a graph showing the solubility (μgA / mL) of Compound 1 in a mixture of Compound 1 and various polymers at a ratio of 40:60 as a function of time (minutes).

[0102] Fig.11A Figures are generated from X-ray powder diffraction (XRPD) experiments of various spray-dried dispersions of compound 1 and polymers. Comparison of them with the crystalline API shows that the spray-dried dispersions are amorphous.

[0103] Fig. 11B is a graph generated during a differential scanning calorimetry (DSC) experiment of a spray-dried dispersion of compound 1: and a polymer, showing the reverse heat flow Q rev (mW) changes with temperature (℃).

[0104] Fig. 11C is a graph generated in a differential scanning calorimetry (DSC) experiment of a spray-dried dispersion of compound 1: and a polymer, showing the variation of heat flow Q (W / g) with temperature (°C).

[0105] Fig.11D is an image of the spray dried Compound 1 / polymer mixture generated by SEM (Scanning Electron Microscope). The morphology of the dispersion consists of collapsed spheres. For all polymers, the majority of the particles are less than 20 microns in diameter.

[0106] Fig.11E It is a graph showing the change in solubility (μgA / mL) of Compound 1 over time (minutes) in a non-sink dissolution experiment of spray dispersions of Compound 1 and a polymer.

[0107] Fig. 12A is a graph generated during a differential scanning calorimetry (DSC) experiment of a spray-dried Compound 1 composition showing the reverse heat flow Q for samples of various relative humidity rev (mW) changes with temperature (℃).

[0108] Fig. 12B is a graph generated during a differential scanning calorimetry (DSC) experiment of a spray-dried Compound 1 composition showing the reverse heat flow Q for samples of various relative humidity rev (mW) changes with temperature (℃).

[0109] Fig. 12C is a graph generated during multiple differential scanning calorimetry (DSC) experiments of spray-dried Compound 1 compositions showing the change in glass transition temperature (°C) as a function of relative humidity (percent).

[0110] Fig.12Dis a graph showing the effect of RH on the glass transition temperature of various solid dispersion formulations of Compound 1.

[0111] Fig.13A are images of Compound 1 compositions suspended in 0.5% Methocel A4M containing polymer as spray dried dispersion compositions or API control. Images were acquired at time point 0. All suspensions were amorphous.

[0112] Fig. 13B are images of Compound 1 compositions suspended in 0.5% Methocel A4M containing polymer as spray dried dispersion compositions or API control. Images were acquired at the 2 hour time point. All suspensions were amorphous.

[0113] Fig. 13C are images of Compound 1 compositions suspended in 0.5% Methocel A4M containing polymer as spray dried dispersion compositions or API control. Images were acquired at the 6 hour time point. All suspensions were amorphous.

[0114] Fig.14 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.) for each mixture.

[0115] Fig.15 An XRPD pattern of Compound 1 in Form A polymorph is shown.

[0116] Fig.16 An XRPD pattern of Compound 1 in Form C polymorph is shown.

[0117] Fig.17 XRPD patterns of Compound 1 in Form A polymorph, Form C polymorph, and Form E polymorph are shown from top to bottom.

[0118] Fig.18 Graph showing the results of solubility experiments comparing micronized and non-micronized Compound 1 in Form C polymorph. DETAILED DESCRIPTION

[0119] As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, reference to "the cell" includes reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties (such as molecular weight) or chemical properties (such as chemical formula), they are intended to include all combinations and subcombinations of ranges and specific embodiments therein. When referring to a value or a range of values, the term "about" means that the value or range of values ​​referred to is an approximation within the experimental variability (or within statistical experimental error), so that in some cases the value or range of values ​​will vary between 1% and 15% of the stated value or range of values. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude "consisting of" or "consisting essentially of" the described features in certain other embodiments (e.g., embodiments of combinations of any substances, compositions, methods, processes, etc. described herein).

[0120] definition

[0121] As used in the specification and the appended claims, unless indicated otherwise, the following terms have the meanings indicated below.

[0122] "Amino" refers to a -NH2 group.

[0123] "Cyano" refers to a -CN group.

[0124] "Nitro" refers to a -NO2 group.

[0125] "Oxa" refers to an -O- group.

[0126] "Oxo" refers to a =0 group.

[0127] "Thio" refers to a =S group.

[0128] "Imino" refers to a =NH group.

[0129] "Oximo" refers to a =N-OH group.

[0130] "Hydrazino" refers to the =N-NH2 radical.

[0131] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from 1 to 15 carbon atoms (e.g., C1-C 15 In certain embodiments, the alkyl group contains from 1 to 13 carbon atoms (e.g., C1-C13 In certain embodiments, the alkyl group contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group contains 5 to 15 carbon atoms (e.g., C5-C 15 In other embodiments, the alkyl group contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl group is attached to the rest of the molecule by a single bond. Unless otherwise specifically stated in this specification, the alkyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R aand R is 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), heterocycloalkyl (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).

[0132] "Alkoxy" refers to a group bonded through an oxygen atom of the formula -O-alkyl wherein alkyl is an alkyl chain as defined above.

[0133] "Alkenyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, comprising at least one carbon-carbon double bond, and having 2 to 12 carbon atoms. In certain embodiments, alkenyl comprises 2 to 8 carbon atoms. In other embodiments, alkenyl comprises 2 to 4 carbon atoms. Alkenyl is attached to the remainder of the molecule by a single bond, such as ethenyl (i.e., vinyl (vinyl)), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl (pent-1-enyl), five-1,4-dienyl (penta-1,4-dienyl) etc. Unless otherwise specifically stated in this specification, alkenyl is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O)t N(R a )2 (where t is 1 or 2), where each R a and R is 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), heterocycloalkyl (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).

[0134] "Alkynyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond and having 2 to 12 carbon atoms. In certain embodiments, the alkynyl group contains 2 to 8 carbon atoms. In other embodiments, the alkynyl group contains 2 to 6 carbon atoms. In other embodiments, the alkynyl group contains 2 to 4 carbon atoms. The alkynyl group is attached to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise specifically stated in this specification, the alkynyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R aand R is 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), heterocycloalkyl (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).

[0135] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that links the rest of the molecule to a group, which consists only of carbon and hydrogen, does not contain unsaturation and has 1 to 12 carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule by a single bond and to the group by a single bond. The alkylene chain is attached to the rest of the molecule and to the group through one carbon in the alkylene chain or through any two carbons in the chain. In certain embodiments, the alkylene group comprises 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene group comprises 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene group comprises 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene group comprises 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene group comprises 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene group contains 1 carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene group contains 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene group contains 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene group contains 3 to 5 carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specifically stated in this specification, the alkylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -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(Ra )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a and R is 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), heterocycloalkyl (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).

[0136] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the rest of the molecule to a group, which consists only of carbon and hydrogen, contains at least one carbon-carbon double bond, and has 2 to 12 carbon atoms. The alkenylene chain is attached to the rest of the molecule by a single bond and to the group by a single bond. In certain embodiments, the alkenylene comprises 2 to 8 carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, the alkenylene comprises 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, the alkenylene comprises 2 to 4 carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, the alkenylene comprises 2 to 3 carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, the alkenylene comprises 5 to 8 carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, the alkenylene comprises 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, the alkenylene group contains 3 to 5 carbon atoms (e.g., C3-C5 alkenylene). Unless otherwise specifically stated in this specification, the alkenylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a and R is 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), heterocycloalkyl (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).

[0137] "Alkynylidene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain that links the rest of the molecule to a group, which consists only of carbon and hydrogen, contains at least one carbon-carbon triple bond, and has 2 to 12 carbon atoms. The alkynylene chain is attached to the rest of the molecule by a single bond and to the group by a single bond. In certain embodiments, the alkynylene comprises 2 to 8 carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, the alkynylene comprises 2 to 5 carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, the alkynylene comprises 2 to 4 carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, the alkynylene comprises 2 to 3 carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, the alkynylene comprises 2 carbon atoms (e.g., C2 alkylene). In other embodiments, the alkynylene comprises 5 to 8 carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, the alkynylene group contains 3 to 5 carbon atoms (e.g., C3-C5 alkynylene). Unless otherwise specifically stated in the specification, the alkynylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R aand R is 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), heterocycloalkyl (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).

[0138] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing hydrogen atoms from ring carbon atoms. The aromatic monocyclic or polycyclic hydrocarbon ring system comprises only hydrogen and carbon, has from 5 to 18 carbon atoms, wherein at least one ring in the ring system is fully unsaturated, i.e., comprises a cyclic, delocalized (4n+2) π-electron system according to the Hückel theory. Ring systems from which aryl radicals are derived include, but are not limited to, radicals such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar" (such as in "aralkyl") is intended to include: aryl groups optionally substituted by one or more substituents independently selected from the group consisting of 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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a R is 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), heterocycloalkyl (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), each R b are 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 wherein each of the above substituents is unsubstituted unless otherwise specified.

[0139] "Arylalkyl" refers to a group of the formula -R c -aryl radical, wherein R c is an alkylene chain as defined above, for example methylene, vinyl, etc. The alkylene chain portion of the aralkyl group is optionally substituted as described above for alkylene chains. The aryl portion of the aralkyl group is optionally substituted as described above for aryl groups.

[0140] "Aralkenyl" refers to a group of the formula -R d An aryl group, wherein R d is an alkenylene chain as defined above. The aryl portion of the aralkenyl group is optionally substituted as described above for aryl groups. The alkenylene chain portion of the aralkenyl group is optionally substituted as described above for alkenyl groups.

[0141] "Arylalkynyl" refers to a group of formula R e An aryl group, wherein R e is an alkynylene chain as described above. The aryl portion of the aralkynyl group is optionally substituted as described above for aryl groups. The alkynylene chain portion of the aralkynyl group is optionally substituted as described above for alkynylene chains.

[0142] "Aralkyloxy" refers to a group of the formula -OR c A group bonded to the oxygen atom of an aromatic group, wherein R c is an alkylene chain as defined above, for example methylene, vinyl, etc. The alkylene chain portion of the aralkyl group is optionally substituted as described above for alkylene chains. The aryl portion of the aralkyl group is optionally substituted as described above for aryl groups.

[0143] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, including condensed rings or bridged ring systems, with 3 to 15 carbon atoms. In certain embodiments, the carbocyclyl comprises 3 to 10 carbon atoms. In other embodiments, the carbocyclyl comprises 5 to 7 carbon atoms. The carbocyclyl is attached to the remainder of the molecule by a single bond. The carbocyclyl is saturated (i.e., only comprising a single C-C bond) or unsaturated (i.e., comprising one or more double bonds or triple bonds). Fully saturated carbocyclyl is also referred to as "cycloalkyl". The embodiment of monocyclic cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Unsaturated carbocyclyl is also referred to as "cycloalkenyl". The embodiment of monocyclic cycloalkenyl includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Polycyclic carbocyclyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specified in the specification, the term "carbocyclyl" is intended to include carbocyclyls that are optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thio, 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 a2. -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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a R is 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), heterocycloalkyl (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), each R b are 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 wherein each of the above substituents is unsubstituted unless otherwise specified.

[0144] "Carbocyclylalkyl" refers to a group of the formula -R c -Carbocyclic group, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclic group are optionally substituted as described above.

[0145] "Carbocyclylalkynyl" refers to a group of the formula -R c -Carbocyclic group, where R c is an alkynylene chain as described above. The alkynylene chain and the carbocyclyl group are optionally substituted as described above.

[0146] "Carbocyclylalkoxy" refers to a radical of the formula -OR c - a group bonded to the oxygen atom of a carbocyclic group, wherein R c is an alkylene chain as defined above. The alkylene chain and the carbocyclic group are optionally substituted as described above.

[0147] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits physical, biological, and / or chemical properties similar to a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to:

[0148]

[0149] etc.

[0150] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0151] "Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluoro groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally substituted as defined above for an alkyl group.

[0152] "Heterocyclyl" refers to a stable 3 to 18-membered non-aromatic ring group containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specifically stated in this specification, the heterocyclyl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes a fused ring or a bridged ring system. The heteroatoms in the heterocyclyl are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. The heterocyclyl is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidine, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocyclyl" is intended to include heterocyclyl groups as described above, which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thio, 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 heterocycloalkyl, 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(Ra )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a R is 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), heterocycloalkyl (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), each R b are 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 wherein each of the above substituents is unsubstituted unless otherwise specified.

[0153] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl as described above, which contains at least one nitrogen, and wherein the point of attachment of the heterocyclyl to the rest of the molecule is through the nitrogen atom in the heterocyclyl. N-heterocyclyl is optionally substituted, as described above for heterocyclyl. Examples of such N-heterocyclyls include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0154] "C-heterocyclyl" or "C-attached heterocyclyl" refers to a heterocyclyl as described above, containing at least one heteroatom, and wherein the point of attachment of the heterocyclyl to the rest of the molecule is through a carbon atom in the heterocyclyl. C-heterocyclyl is optionally substituted, as described above for heterocyclyl. Examples of C-heterocyclyl include, but are not limited to, 2-morpholinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-piperazinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, and the like.

[0155] "Heterocycloalkyl" refers to a group of the formula -R c A heterocyclic group, wherein 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 group at the nitrogen atom. The alkylene chain portion of the heterocycloalkyl is optionally substituted as defined above for the alkylene chain. The heterocyclyl portion of the heterocycloalkyl is optionally substituted as defined above for the heterocyclyl.

[0156] "Heterocyclylalkoxy" refers to a group of the formula -OR c A group bonded to the oxygen atom of a heterocyclic group, wherein R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to an alkyl group at the nitrogen atom. The alkylene chain part of the heterocyclylalkoxy is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy is optionally substituted as defined above for a heterocyclyl.

[0157] "Heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring group containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, heteroaryl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to the Huckel theory. Heteroaryl includes fused or bridged ring systems. One or more heteroatoms in the heteroaryl are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring. Examples of the heteroaryl group include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuran, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuran, benzoxazolyl, benzodioxolyl, benzodioxinyl. , benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothiophenyl (benzophenylthio), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[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-dihydro Benzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuran, dibenzothiophenyl, furanyl, furanonyl, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 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, 1,6-naphthyridinyl, 1,6-naphthyridinyl, oxadiazolyl, 2-oxoazepine, 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, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolyl, isoquinolyl, tetrahydroquinolyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[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]pyridinyl, and phenylthio (i.e., thienyl). Unless otherwise specifically stated in the specification, the term "heteroaryl" is intended to include heteroaryl as defined above, which is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thio, 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(Ra )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a R is 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), heterocycloalkyl (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), each R b are 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 wherein each of the above substituents is unsubstituted unless otherwise specified.

[0158] "N-heteroaryl" refers to a heteroaryl group as defined above, which contains at least one nitrogen, and the point of attachment of the heteroaryl group to the rest of the molecule is through the nitrogen atom in the heteroaryl group. N-heteroaryl groups are optionally substituted as described above for heteroaryl groups.

[0159] "C-heteroaryl" refers to a heteroaryl group as defined above, and the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. C-heteroaryl groups are optionally substituted as described above for heteroaryl groups.

[0160] "Heteroarylalkyl" refers to a group of the formula -R c -heteroaryl radical, wherein R c is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl group is optionally substituted as defined above for a heteroaryl group.

[0161] "Heteroarylalkoxy" refers to a group of the formula -OR c - a group bonded to the oxygen atom of a heteroaryl group, wherein R c is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy group is optionally substituted as defined above for a heteroaryl group.

[0162] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus producing enantiomers, diastereomers, and other stereoisomeric forms, which are defined as (R) or (S) in terms of absolute stereochemistry. Unless otherwise stated, all stereoisomeric forms of the compounds disclosed herein are encompassed in the present disclosure. When the compounds described herein contain olefin double bonds, unless otherwise stated, the present disclosure is intended to include E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers and their racemic and optically pure forms and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of an olefin 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.

[0163] "Tautomers" refers to molecules in which a proton can be transferred from one atom of a molecule to another atom of the same molecule. In certain embodiments, the compounds provided herein exist as tautomers. Where tautomerization can occur, there will be a chemical equilibrium of tautomers. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0164]

[0165] In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, e.g., 2 H. 3 H. 11 C. 13 C and / or 14 In a specific embodiment, the compound is deuterated at at least one position. This deuterated form can be prepared by the methods 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 and / or efficacy, thereby increasing the duration of action of the drug.

[0166] Unless otherwise stated, structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures but with hydrogen replaced by deuterium or tritium or with a carbon enriched 13 C- or 14 Compounds substituted with C-carbon are also within the scope of the present disclosure.

[0167] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute the compound. For example, the compound may be labeled with an isotope, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). 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, 125 Isotopic substitutions of I are contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or non-radioactive, are encompassed within the scope of the present invention.

[0168] In certain embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 H atom substitution. Methods for the synthesis of deuterium containing compounds are known in the art and include the following synthetic methods by way of non-limiting example only.

[0169] Deuterium substituted compounds are synthesized using various methods, such as described in: Dean, Dennis C.; ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21), 6601-21 and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2), 9-32.

[0170] Deuterated starting materials are readily available and are amenable to the synthetic methods described herein to provide the synthesis of deuterated compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers, such as Aldrich Chemical Co.

[0171] Deuterium transfer reagents suitable for nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and can be used to transfer a deuterium-substituted carbon atom to a reaction substrate under nucleophilic substitution reaction conditions. The use of CD3I is illustrated in the following reaction schemes only as an example.

[0172]

[0173] Deuterium transfer reagents such as lithium aluminum deuteride (LiAlD4) are used to transfer deuterium to the reaction substrate under reducing conditions. The use of LiAlD4 is illustrated in the following reaction schemes by way of example only.

[0174]

[0175] Deuterium gas and palladium catalysts are used to reduce unsaturated carbon-carbon bonds and to effect reductive substitution of aromatic carbon-halogen bonds, as illustrated by way of example only in the reaction schemes below.

[0176]

[0177] 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 completely substituted with deuterium atoms and do not contain non-exchangeable 1 H hydrogen atom. In one embodiment, the level of deuterium incorporation is determined by a synthetic process in which deuterated synthetic building blocks are used as starting materials.

[0178] Throughout the specification, examples and claims, components are expressed as being present in ratios such as 1:2, 1:3, 1:4 or 1:5, etc. Unless otherwise specified, these ratios refer to ratios of the components by weight.

[0179] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Pharmaceutically acceptable salts of any of the heterocyclic RBP4 inhibitory compounds described herein are intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0180] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are biologically or otherwise undesirable, and are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts formed from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and include, 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, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitroformates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). In some embodiments, acid addition salts of basic compounds are prepared 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 skilled artisans.

[0181] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effectiveness and properties of the free acid, which are biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed by metals or amines such as alkali metals and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, 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, benzylethylenediamine, N-methylglucosamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0182] As used herein, "treatment" or "treating" or "palliating" or "ameliorating" are used interchangeably. These terms refer to an approach to obtaining a beneficial or desired result, including but not limited to a therapeutic benefit and / or a preventive benefit. "Therapeutic benefit" refers to the eradication or amelioration of the underlying condition being treated. In addition, a therapeutic benefit is achieved by eradication or amelioration of one or more physiological symptoms associated with the underlying condition, such that an improvement is observed in the patient, even though the patient still suffers from the underlying condition. In some embodiments, the composition is administered to a patient at risk for a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even if a diagnosis of the disease has not yet been made, for preventive benefit.

[0183] In some embodiments, "prodrug" means a compound that is converted to a biologically active compound as described herein under physiological conditions or by solvolysis. Therefore, the term "prodrug" refers to a precursor of a pharmaceutically acceptable biologically active compound. Prodrugs are generally inactive when administered to a subject, but are converted to active compounds in vivo, for example by hydrolysis. Prodrug compounds generally provide advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

[0184] A discussion of prodrugs is provided in Higuchi, T. et al., "Pro drugs as Novel Delivery Systems," ACSSymposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0185] The term "prodrug" is also meant to include any covalently bound carriers that release 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 modifier is cleaved into the parent active compound in conventional operations or in vivo. Prodrugs include compounds in which hydroxyl, amino or sulfhydryl groups are bonded to any such groups, so that when the prodrug of the active compound is administered to a mammalian subject, the groups are cleaved to form free hydroxyl, free amino or free sulfhydryl groups, respectively. 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.

[0186] Throughout the specification and claims, x-ray powder diffraction (XRPD) peaks are described. Unless otherwise stated, XRPD peaks in this application refer to XRPD peaks obtained using a copper source with a wavelength of 1.5406 angstroms.

[0187] As used herein, “Compound 1” or “CMPD-1” refers to Compound 1 shown in Table 1.

[0188] Compound 1 has the following structure

[0189]

[0190] Compound 1 is also referred to by its 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.

[0191] RBP4 inhibitory compounds

[0192] In some embodiments, provided herein are RBP4 inhibitory compounds and pharmaceutical compositions comprising the compounds. The subject compounds and compositions are useful for inhibiting RPB4 and for treating eye diseases or conditions such as age-related macular degeneration, dry (atrophic) age-related macular degeneration, juvenile macular degeneration (Stargardt's disease), Best's disease, adult vitelliform maculopathy, geographic atrophy, Stargardt's macular dystrophy, diabetic retinopathy, or retinal diseases associated with the ABCA4 gene.

[0193] Some embodiments provided herein describe a compound having a structure of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof; which is used to treat a metabolic disease or disorder:

[0194]

[0195] in:

[0196] Each R 1 are independently 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)-SO2N(R 7 )2, optionally substituted (C0-C4 alkylene)-SO2R 7

[0197] , optionally substituted (C0-C4 alkylene)N(R 8 )-SO2N(R 7 )2 or optionally substituted (C0-C4 alkylene)N(R 8 )-SO2R 7 ;

[0198] Each R 7 R is 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 heterocycloalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; or two R 11 The groups, together with the nitrogen to which they are attached, are joined to form an optionally substituted N-heterocyclyl;

[0199] Each R 8 are independently selected from H or optionally substituted alkyl;

[0200] R 2 is -H, -OH, optionally substituted alkyl or halogen;

[0201] p is 0, 1, 2, 3, 4 or 5;

[0202] A has the following structure:

[0203]

[0204] in:

[0205] α, β, χ and δ are each independently absent or present, and when present are each a bond;

[0206] X is C;

[0207] Z1 is S, O or N;

[0208] Z2 is S, O, N or NR 3 ;

[0209] R 3 is H, optionally substituted alkyl or oxetane; and

[0210] B is a substituted or unsubstituted fused 5-, 6- or 7-membered ring structure.

[0211] Some embodiments provided herein describe a compound having a structure of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof; wherein:

[0212] Each R 1 are independently halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 2-6 Heterocyclic group, optionally substituted C 3-10 Heterocycloalkyl, -COR 7 、-

[0213] CON(R 7 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)

[0214] )-OR 7 , optionally substituted (C0-C4 alkylene)-N(R 7 )2, optionally substituted (C0-C4 alkylene

[0215] )N(R 8 )-COR 7 , optionally substituted (C0-C4 alkylene)-SO2N(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 ;

[0216] Each R 7 are independently selected from H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Carbocyclic group, optionally substituted C 3-10 Carbocyclylalkyl, optionally substituted C 2-6 Heterocyclic group, optionally substituted C 2-10 heterocycloalkyl; or two R 11 The groups, together with the nitrogen to which they are attached, are joined to form an optionally substituted C 2-6 N-heterocyclyl;

[0217] Each R 8 are independently selected from H or optionally substituted C 1-6 alkyl;

[0218] R 2 is -H, -OH, optionally substituted C 1-6 Alkyl, or halogen;

[0219] p is 0, 1, 2, 3, 4 or 5;

[0220] A has the following structure:

[0221]

[0222] in:

[0223] α, β, χ and δ are each independently absent or present, and when present are each a bond;

[0224] X is C;

[0225] Z1 is S, O or N;

[0226] Z2 is S, O, N or NR 3 ;

[0227] R 3 is H, optionally substituted C 1-6 Alkyl or oxetane; and

[0228] B is a substituted or unsubstituted fused 5-, 6- or 7-membered ring structure.

[0229] Certain embodiments provided herein describe a compound having the structure of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof, wherein:

[0230] Each R 1 are independently halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Heterocyclic group, C 3-10 Heterocycloalkyl, -COR 7 、-CON(R 7 )2, (C0-C4 alkylene)-CN, (C0-

[0231] C4 alkylene)-OR 7 、(C0-C4 alkylene)-N(R 7 )2、(C0-C4 alkylene)N(R 8 )-COR 7 ,

[0232] (C0-C4 alkylene)-SO2N(R 7 )2. (C0-C4 alkylene)-SO2R 7 、(C0-C4 alkylene

[0233] )N(R 8 )-SO2N(R 7 )2 or (C0-C4 alkylene)N(R 8 )-SO2R 7 ;

[0234] Each R 7 Independently selected from H, C 1-6 Alkyl, C 3-6 Carbocyclic group, C 3-10 Carbocyclylalkyl, C 2-6 Heterocyclic group, C 2-10 heterocycloalkyl; or two R 11 The groups join together with the nitrogen to which they are attached to form a C 2-6 N-heterocyclyl;

[0235] Each R 8 Independently selected from H or C 1-6 alkyl;

[0236] R 2 -H, -OH, C 1-6 Alkyl, or halogen;

[0237] p is 0, 1, 2, 3, 4 or 5;

[0238] A has the following structure:

[0239]

[0240] in:

[0241] α, β, χ and δ are each independently absent or present, and when present are each a bond;

[0242] X is C;

[0243] Z1 is S, O or N;

[0244] Z2 is S, O, N or NR 3 ;

[0245] R 3 H, C 1-6 Alkyl or oxetane; and

[0246] B is a substituted or unsubstituted fused 5-, 6- or 7-membered ring structure.

[0247] Some embodiments provided herein describe a compound having a structure of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof, wherein:

[0248] Each R 1 are independently halogen, haloalkyl or alkyl;

[0249] R 2 is -H, -OH or halogen;

[0250] p is 0, 1, 2, 3, 4 or 5;

[0251] A has the following structure:

[0252]

[0253] in:

[0254] α, β, χ and δ are each independently absent or present, and when present are each a bond;

[0255] X is C;

[0256] Z1 is S, O or N;

[0257] Z2 is S, O, N or NR 3 ;

[0258] R 3is H, C1-C4 alkyl or oxetane; and

[0259] B is a substituted or unsubstituted fused 5-, 6- or 7-membered ring structure.

[0260] Certain embodiments provided herein describe a compound having the structure of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof, wherein:

[0261] Each R 1 are independently Br, Cl, F, C 1-6 Fluoroalkyl or C 1-6 alkyl;

[0262] R 2 is -H, -OH, Br, Cl or F;

[0263] p is 0, 1, 2, 3, 4 or 5;

[0264] A has the following structure:

[0265]

[0266] in:

[0267] α, β, χ and δ are each independently absent or present, and when present are each a bond;

[0268] X is C;

[0269] Z1 is S, O or N;

[0270] Z2 is S, O, N or NR 3 ;

[0271] R 3 is H, C1-C4 alkyl or oxetane; and

[0272] B is a substituted or unsubstituted fused 5-, 6- or 7-membered ring structure.

[0273] For any and all embodiments of Formula (I), substituents are selected from a subset of the listed alternatives.

[0274] In some embodiments, each R 1 are independently halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 2-6 Heterocyclic group, 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)-SO2N(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, each R 1 are independently halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Heterocyclic group, 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)-SO2N(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, each R 1 are independently 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, each R 1 are independently (C0-C4 alkylene)N(R 8 )-COR7 、(C0-C4 alkylene)-SO2N(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, each R 1 are independently 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, each R 1 are independently halogen, C 1-6 Alkyl, C 1-6 In certain embodiments, each R 1 are independently F, Br, Cl, C 1-6 Haloalkyl or C 1-6 In a specific embodiment, each R 1 are independently F or CF3.

[0275] In some embodiments, each R 7 are independently selected from H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Carbocyclic group, optionally substituted C 3-10 Carbocyclylalkyl, optionally substituted C 2-6 Heterocyclic group, optionally substituted C 2-10 heterocycloalkyl; or two R 11 The groups, together with the nitrogen to which they are attached, are joined to form an optionally substituted C 2-6 In some embodiments, each R 7 Independently selected from H, C 1-6 Alkyl, C 3-6 Carbocyclic group, C 3-10 Carbocyclylalkyl, C 2-6 Heterocyclic group, C 2-10 heterocycloalkyl; or two R 11 The groups, together with the nitrogen to which they are attached, join to form the C 2-6 In some embodiments, each R 7 Independently selected from H, C 1-6 Alkyl or C 3-6In certain embodiments, two R 11 The groups, together with the nitrogen to which they are attached, are joined to form an optionally substituted C 2-6 In some embodiments, each R 7 Independently selected from H or C 1-6 In some embodiments, each R 7 It is H or Me.

[0276] In some embodiments, each R 8 Independently selected from H, C 1-6 Alkyl or C 1-6 In some embodiments, each R 8 Independently selected from H or C 1-6 In some embodiments, each R 8 is independently selected from H or Me. In some embodiments, each R 8 For H.

[0277] 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.

[0278] In some embodiments, R 2 is -H, -OH, optionally substituted alkyl or halogen. 2 is -H, -OH, alkyl, haloalkyl or halogen. 2 -H, -OH, C 1-6 Alkyl, C 1-6 In some embodiments, R 2 is -H, -OH, Me, CF3 or halogen. In some embodiments, R 2 is -H, -OH, Me, CF3, Cl or F. In some embodiments, R 2 is -H, -OH, Me, CF3 or F. In some embodiments, R 2 In some embodiments, R 2is -H, -OH or F. In some embodiments, R 2 is -H. In some embodiments, R 2 In some embodiments, R 2 is F. In some embodiments, R 2 For Cl.

[0279] 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 NR 3 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.

[0280] In some embodiments, A has the following structure:

[0281]

[0282] in:

[0283] n is 0, 1 or 2;

[0284] α, β, χ, δ, ε and φ are each independently absent or present, and when present, each

[0285] is the key;

[0286] Z1 is S, O or N;

[0287] Z2 is S, O, N or NR 3 ,

[0288] Where R 3 is H, C1-C4 alkyl or oxetane;

[0289] X is C;

[0290] Y1, Y2, Y3 and each occurrence of Y4 are independently CR 4 , C(R 5 )2. NR 6 ,

[0291] O, N, SO2 or -(C=O)-, wherein:

[0292] R 4 H, halogen, C1-C 10 Alkyl, C1-C 10 Cycloalkyl, -O(C1-C 10 alkyl),-

[0293] C(O)OH、-C(O)O(C1-C10 alkyl), -C(O)NH2, -C(O)NH(C1-C4 alkyl),

[0294] -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)2, -CN or -CF3;

[0295] R 5 H or C1-C 10 Alkyl; and

[0296] R 6 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-

[0297] 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),-

[0298] C(O)N(C1-C 10 Alkyl)2, -(C1-C 10 alkylene) C(O)OH, -C(O)NH2, or oxetane.

[0299] 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 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. In further or additional embodiments, when ε and When each is present, then n=1, and each of Y1, Y2, Y3, and Y4 is independently -CR 4 - or N. In other embodiments, when ε and When each is absent, n=0, 1 or 2, each of Y1, Y2, Y3 and each occurrence of Y4 is independently C(R 5 )2. NR 6 , O or SO2.

[0300] In some embodiments, β and δ are present. In some embodiments, α, χ, ε and 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 Not present; Z1 is N; Z2 is O, S or NR 3 ; R 3 is H, C1-C4 alkyl or oxetane; and X is C.

[0301] In some embodiments, β, δ, ε, and In some embodiments, α and χ are absent. In some embodiments, Z1 is N. In some embodiments, Z2 is O or NR3, wherein R 3 is H, C1-C4 alkyl or oxetane. In some embodiments, X is C. In certain embodiments, β, δ, ε and exists; α and χ do not exist; Z1 is N; Z2 is O or NR3; R 3 is H, C1-C4 alkyl or oxetane; and X is C.

[0302] In some embodiments, A has the following structure:

[0303]

[0304] in

[0305] n is 0;

[0306] R 3 is H, C1-C4 alkyl or oxetane;

[0307] Y1 and Y3 are each CH2 or C(CH3)2;

[0308] Y2 is O, SO2 or NR 6 ,and

[0309] 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, -

[0310] 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), -

[0311] C(O)N(C1-C4 alkyl)2, -(C1-C4 alkylene)C(O)OH, -C(O)NH2, or oxetane.

[0312] In some embodiments, A has the following structure:

[0313]

[0314] n is 1;

[0315] R 3 is H, C1-C4 alkyl or oxetane;

[0316] Y1 and Y4 are CH2 or C(CH3)2;

[0317] Y2 and Y3 are each CH2 or C(CH3)2, O, SO2 or NR 6 ; and R 6 It 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.

[0318] In some embodiments, A has the following structure:

[0319]

[0320] n is 2;

[0321] R 3 is H, C1-C4 alkyl or oxetane;

[0322] Y1 and Y4 are CH2 or C(CH3)2;

[0323] Y2 and Y3 are each CH2 or C(CH3)2, O, SO2 or NR 6 ; and R 6 It 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.

[0324] In some embodiments, A has the following structure:

[0325]

[0326] In other embodiments, A has the following structure:

[0327]

[0328] In certain embodiments, A has the following structure:

[0329]

[0330] In certain embodiments, A has the following structure:

[0331]

[0332] In certain embodiments, A has the following structure:

[0333]

[0334] In certain embodiments, A has the following structure:

[0335]

[0336] In some embodiments, R 6 It 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, -C(O)(C1-C6 alkyl), -C(O)(C1-C6 alkylene)CF3, -C(O)(C1-C6 alkylene)OCH3, -C(O)(C1-C6 alkylene)-halogen, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -(C1-C6 alkylene)C(O)OH, -C(O)NH2, or oxetane. In some embodiments, R 6 R is 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)(C1-C6 alkyl), -C(O)(C1-C6 alkylene)CF3, -C(O)(C1-C6 alkylene)OCH3, -C(O)(C1-C6 alkylene)-halogen, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -(C1-C6 alkylene)C(O)OH, -C(O)NH2, or oxetane. In some embodiments, R 6 is -C(O)(C1-C6 alkyl). 6 It is H, C1-C4 alkyl, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, t-Bu, -CH2OCH3, -CH2CF3, -CH2Cl, -CH2F, -CH2CH2OCH3, -CH2CH2CF3, -CH2CH2Cl, -CH2CH2F, -SO2CH3, -SO2CH2CH3, -SO2CH2CH2CH3, -SO2CH(CH3)2, -SO2CH2CH(CH3)2, -SO2(t-Bu), -SO2CH2OCH3 , -SO2CH2CF3, -SO2CH2Cl, -SO2CH2F, -SO2CH2CH2OCH3, -SO2CH2CH2CF3, -SO2CH2CH2Cl, -SO2CH2CH2F, 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 In some embodiments, R 6 is -C(O)(C1-C6 alkyl). 6 is H, C1-C4 alkyl, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, t-Bu, -CH2OCH3, -CH2CF3, -CH2Cl, -CH2F, -CH2CH2OCH3, -CH2CH2CF3, -CH2CH2Cl, -CH2CH2F or In other embodiments, R 6 is -SO2CH3, -SO2CH2CH3, -SO2CH2CH2CH3, -SO2CH(CH3)2, -SO2CH2CH(CH3)2, -SO2(t-Bu), -SO2CH2OCH3 , -SO2CH2CF3, -SO2CH2Cl, -SO2CH2F, -SO2CH2CH2OCH3, -SO2CH2CH2CF3, -SO2CH2CH2Cl, -SO2CH2CH2F or In certain embodiments, R 6 is 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,

[0337] In some embodiments, A has the following structure:

[0338]

[0339] in:

[0340] Y1, Y2, Y3 and each occurrence of Y4 are independently CR 4or N;

[0341] in:

[0342] 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 l0 alkyl)2, -CN or -CF3.

[0343] 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.

[0344] In certain embodiments, A has the following structure:

[0345]

[0346] 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 l0 In some embodiments, R 3It is H, halogen, C1-C6 alkyl, C1-C6 cycloalkyl, -O(C1-C6 alkyl), -C(O)OH, -C(O)O(C1-C6 alkyl), -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -NHC(O)NH(C1-C6 alkyl), -NHC(O)N(C1-C4 alkyl)2, -SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)2, -CN or -CF3. In some embodiments, R4 is H, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, -O(C1-C4 alkyl), -CN, -CF3, -C(O)OH, -C(O)NH2, -C(O)N(CH3)2, -C(O)NHCH3, or -NHC(O)N(CH3)2. In some embodiments, R4 is -H, halogen, methyl, methoxy, -CN, -CF3, -C(O)N(CH3)2, -C(O)NHCH3, or -C(O)Me.

[0347] In some embodiments, the heterocyclic compounds of Formula (I) are provided in Table 1.

[0348] Table 1

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355] In certain embodiments, the heterocyclic compound of formula (I) is 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-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)piperidin-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one; (4-(3-fluoro-2,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(2-chloro-3-fluorophenyl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one; pyridin-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-(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 -1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; (4-(4-fluoro-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)(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-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone; 1-(3-(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidin-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)(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-(oxetane-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone; 3-(4-(2-chloro-3-fluorophenyl)piperidin-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)piperidin-1-yl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-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; 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid methyl ester; (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-(oxetane-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-yl)methanone; 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-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-(oxetane-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-yl)methanone 3-(4-(2-chloro-3-fluorophenyl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid methyl ester; 1-(3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-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-difluoro-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)piperidin-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]pyridin-6-yl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-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)-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)-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-(oxetane-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-yl)methanone; 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid methyl ester; 2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(oxetane-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-6-carboxylic acid methyl ester; 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(oxetane-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)piperidin-1-yl)methanone; (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-ethyl-4 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-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]pyridine-3-yl)methanone; 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid methyl ester;(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)piperidin-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carbonitrile; 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-5-carbonitrile pyridine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid methyl ester; (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-yl)methanone; (6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-yl)(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(oxetane-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)piperidin-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)piperidin-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-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[4,3-c]pyridin-3-yl)methanone 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[3,4-c]pyridin-3-yl)methanone; (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)piperidin-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)piperidin-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; 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid methyl ester; 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid methyl ester; -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; 2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetate tert-butyl ester; 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-carbonyl )-tert-butyl 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 [4,3-c]pyridine-5-carboxylate; 3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid tert-butyl ester; 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester; 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid tert-butyl ester; 3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid tert-butyl ester 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-carboxylate; tert-Butyl 3-(4-(3,4-difluoro-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)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate; tert-butyl (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-(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-dioxido-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[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; 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)piperidin-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)piperidin-1-carbonyl) (6-fluoro-1-(oxetane-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)piperidin-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-(methylsulfonyl)-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)piperidin-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)piperidin-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-dioxido-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)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6 (5-(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)piperidin-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)piperidin-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)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)propan-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)methanone;(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)piperidin-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)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; 3,3,3-trifluoro-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidin-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)piperidin-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide; N-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidin-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; 3-(4-(2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine tert-butyl 3-(4-(2-(trifluoromethyl)phenyl)piperidin-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-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (1H-pyrazolo[3,4-c]pyridine-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-(oxetane-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)piperidin-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)piperidin-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)piperidin-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one pyridine-5-carboxamide; N,N-dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide; (1-methyl-5,5-dioxido-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)(1,6,6-trimethyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-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)piperidin-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-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidine 1-(6-(tert-butylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (1-methyl-1H-indazol-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)piperidin-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyridin-1- ... oxazolo[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)piperidin-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 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;3-(4-Fluoro-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester; (4-hydroxy-4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)(1-methyl-1H-indazol-3-yl)methanone; 1-(3-(4-hydroxy-4-(2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl)ethan-1-one; 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-N-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5 (1H)-formamide; (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-(oxetane-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)piperidin-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)piperidin-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-2-methylpropan-1-one; (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-picolinoyl )-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone; 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-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; 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylic acid methyl ester; (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 [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-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)piperidin-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one; (5,5-dioxido-4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl) Ketone; (4,6-dihydro-1H-furo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ketone; (1-ethyl-5-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ketone; (1-methyl-5-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ketone; (1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ketone;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-methoxyethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; 3,3,3-trifluoro-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidin-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-(isobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (5-(isopropylsulfonyl)-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; 3-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone tert-butyl 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)piperidin-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one; (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)piperidin-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one; (5-(tert-butyl (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; N-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide; 1-(1-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one; 2,2-dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidin-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-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]pyrazol-5(1H)-yl)propan-1-one Hydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide; (5-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (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; 4-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1 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-dihydro-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)piperidin-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-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)piperidin-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)piperidin-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)butan-1-one -1-one; (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)piperidin-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 [4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; 1-(1-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidin-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; 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)piperidin-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)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)piperidin-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-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)piperidin-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)piperidin-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)propan-1-one; (5-(oxetane-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)piperidin-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-( (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-chloroimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; imidazo[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) ketone; (1H-benzo[d]imidazol-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl) ketone; (1H-imidazo[4,5-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl) ketone; (4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl) ketone; (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) ketone; 6-methyl-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl) ketone 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)benzamide; 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,7-dihydroisothiazolidine [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)piperidin-1-carbonyl)-6,7-dihydroisoxazolo[4,5-c]pyridin-5(4H)-yl)ethan-1-one; 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidin-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)piperidin-1-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)piperidin-1-carbonyl)-6,7-dihydroisothiazolo[4,5-c]pyridin-5(4H)-yl)ethan-1-one 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-(2R,3R)-2-(4-(2-(tert-butyl)phenyl)piperidin-1-carbonyl)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester;Aminosulfonic acid (2R,4R)-2-(4-(2-(tert-butyl)phenyl)piperidin-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate 2-(2-oxo-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ethyl)phenyl ester; (4-(2-(tert-butyl)phenyl)piperidin-1-yl)(1,1-dioxidotetrahydrothiophen-2-yl)methanone; 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)piperidin-1-carbonyl)pyrrolidin-1-yl)ethan-1-one; (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-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone ) ketone; (5-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl) ketone; (5-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl) ketone; (6-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl) ketone; imidazo[1,2-a]pyridin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl) ketone; (6-chloro-2-methylimidazo[1,2-b]pyridazin-3-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)piperidin-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-(trifluoromethyl)phenyl)piperidin-1-yl)methanone; (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. ;

[0356] Preparation of compounds

[0357] The compounds used in the chemical reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. “Commercially available chemicals” were obtained from standard commercial sources, including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Corporation (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 (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co., Ltd. (Cornwall, UK), Parish Chemical Company (Orem, UT), Pfaltz & Bauer Company (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Company (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product Company (New Brunswick, NJ), TCI America (Portland OR), Trans World Chemicals Company (Rockville, MD), and Wako Chemicals USA (Richmond, VA).

[0358] Suitable reference books and papers that describe in detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide references to articles describing such preparations, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H O House, "Modern Synthetic Reactions", 2nd Ed., W A Benjamin, Inc. Menlo Park, Calif. 1972; T L Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Other suitable reference books and papers that describe in detail the synthesis of reactants that can be used to prepare the compounds described herein or provide references to articles describing the preparations include, for example, Fuhrhop, J and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", 2nd, Revised and Supplemented 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, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, 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, T.W.G., "Organic Chemistry", 7th Edition (2000), John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry", 2nd Edition (1993), Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999), John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes; "Organic Reactions" (1942 - 2000), John Wiley & Sons, over 55 volumes, and "Chemistry of Functional Groups", John Wiley & Sons, 73 volumes.

[0359] Alternatively, specific and similar reactants can be identified by indexes of known chemical substances and reactions compiled by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, or through online databases (for more information, contact the American Chemical Society in Washington, D.C.). Known but unlisted commercial chemicals are optionally prepared by conventional chemical synthesis companies, many of which standard chemical supply companies (e.g., those listed above) provide conventional synthesis services. A reference for the preparation and selection of pharmaceutically acceptable salts of the heterocyclic RBP4 inhibitory compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0360] Retinol Binding Protein 4 (RBP4)

[0361] Retinol binding protein 4 (RBP4) is the only retinol transporter in the blood, secreted by adipocytes and the liver. Reducing RBP4 levels can lead to reduced accumulation of lipofuscin, resulting in vision loss in conditions such as age-related macular degeneration, dry (atrophic) age-related macular degeneration, juvenile macular degeneration (Stargardt's disease), Best's disease, adult yolk-like maculopathy, geographic atrophy, Stargardt's macular dystrophy, diabetic retinopathy, or retinal diseases associated with the ABCA4 gene. In some cases, reducing RBP4 can reduce the accumulation of lipofuscin in the retina. In some embodiments, the compounds and formulations described herein reduce serum or plasma RBP4, and thereby delay or prevent vision loss caused by excessive accumulation of lipofuscin in the retina.

[0362] In some embodiments, the serum or plasma level of RBP4 is reduced by at least 30% from baseline 48 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 40% from baseline 48 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 50% from baseline 48 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In other embodiments, the serum or plasma level of RBP4 is reduced by at least 65% from baseline 48 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In certain embodiments, the serum or plasma level of RBP4 is reduced by at least 80% from baseline 48 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 85% from baseline 48 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof.

[0363] In some embodiments, the serum or plasma level of RBP4 is reduced by at least 30% from baseline 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 40% from baseline 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 50% from baseline 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In other embodiments, the serum or plasma level of RBP4 is reduced by at least 65% from baseline 36 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In certain embodiments, the serum or plasma level of RBP4 is reduced by at least 80% from baseline 36 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 85% from baseline 36 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof.

[0364] In some embodiments, the serum or plasma level of RBP4 is reduced by at least 30% from baseline 24 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 40% from baseline 24 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 50% from baseline 24 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In other embodiments, the serum or plasma level of RBP4 is reduced by at least 65% from baseline 24 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In certain embodiments, the serum or plasma level of RBP4 is reduced by at least 80% from baseline 24 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 85% from baseline 24 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof.

[0365] In some embodiments, the serum or plasma level of RBP4 is reduced by at least 30% from baseline 12 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 40% from baseline 12 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 50% from baseline 12 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In other embodiments, the serum or plasma level of RBP4 is reduced by at least 65% from baseline 12 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In certain embodiments, the serum or plasma level of RBP4 is reduced by at least 80% from baseline 12 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 85% from baseline 12 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof.

[0366] In some embodiments, the serum or plasma level of RBP4 is reduced by at least 20% from baseline 6 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 25% from baseline 6 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 30% from baseline 6 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 40% from baseline 6 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 50% from baseline 6 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In other embodiments, the serum or plasma level of RBP4 is reduced by at least 65% from baseline 6 hours after administration of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In certain embodiments, the serum or plasma level of RBP4 is reduced by at least 80% from baseline 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 85% from baseline 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof.

[0367] In some embodiments, the serum or plasma level of RBP4 is reduced by at least 1 mg / dL 48 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In other embodiments, the serum or plasma level of RBP4 is reduced by at least 2 mg / dL 48 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 5 mg / dL 48 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In certain embodiments, the serum or plasma level of RBP4 is reduced by at least 10 mg / dL 48 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 15 mg / dL 48 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof.

[0368] In some embodiments, the serum or plasma level of RBP4 is reduced by at least 1 mg / dL 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In other embodiments, the serum or plasma level of RBP4 is reduced by at least 2 mg / dL 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 5 mg / dL 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In certain embodiments, the serum or plasma level of RBP4 is reduced by at least 10 mg / dL 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 15 mg / dL 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof.

[0369] In some embodiments, the serum or plasma level of RBP4 is reduced by at least 1 mg / dL 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In other embodiments, the serum or plasma level of RBP4 is reduced by at least 2 mg / dL 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 5 mg / dL 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In certain embodiments, the serum or plasma level of RBP4 is reduced by at least 10 mg / dL 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 15 mg / dL 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof.

[0370] In some embodiments, the serum or plasma level of RBP4 is reduced by at least 1 mg / dL 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In other embodiments, the serum or plasma level of RBP4 is reduced by at least 2 mg / dL 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 5 mg / dL 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In certain embodiments, the serum or plasma level of RBP4 is reduced by at least 10 mg / dL 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 15 mg / dL 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof.

[0371] In some embodiments, the serum or plasma level of RBP4 is reduced by at least 1 mg / dL 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In other embodiments, the serum or plasma level of RBP4 is reduced by at least 2 mg / dL 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 5 mg / dL 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In certain embodiments, the serum or plasma level of RBP4 is reduced by at least 10 mg / dL 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In some embodiments, the serum or plasma level of RBP4 is reduced by at least 15 mg / dL 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof.

[0372] In some embodiments, the serum or plasma level of RBP4 decreases to less than 1 μM after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In other embodiments, the serum or plasma level of RBP4 decreases to less than 1 μM 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In some embodiments, the serum or plasma level of RBP4 decreases to less than 1 μM 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In certain embodiments, the serum or plasma level of RBP4 decreases to less than 1 μM 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In some embodiments, the serum or plasma level of RBP4 decreases to less than 1 μM 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof.

[0373] In some embodiments, the serum or plasma level of RBP4 decreases to less than 1.5 μM after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In other embodiments, the serum or plasma level decreases to less than 1.5 μM 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In some embodiments, the serum or plasma level of RBP4 decreases to less than 1.5 μM 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In certain embodiments, the serum or plasma level of RBP4 decreases to less than 1.5 μM 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In some embodiments, the serum or plasma level of RBP4 decreases to less than 1.5 μM 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof.

[0374] In some embodiments, the serum or plasma level of RBP4 decreases to less than 2 μM after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In other embodiments, the serum or plasma level decreases to less than 2 μM 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In some embodiments, the serum or plasma level of RBP4 decreases to less than 2 μM 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In certain embodiments, the serum or plasma level of RBP4 decreases to less than 2 μM 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In some embodiments, the serum or plasma level of RBP4 decreases to less than 2 μM 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof.

[0375] Treatment

[0376] In some embodiments, the compounds disclosed herein are used to treat or improve diseases associated with RBP4 pathway changes when applied to a subject in need. In some cases, the compounds disclosed herein are used to treat or improve the effects of diseases associated with RBP4 pathway changes when applied to a subject in need. Exemplary diseases associated with RBP4 changes include eye diseases. In some cases, eye diseases are characterized by excessive accumulation of lipofuscin in the retina. In some cases, the compounds disclosed herein are used to treat or improve eye diseases when applied to a subject in need. Exemplary eye diseases include age-related macular degeneration, dry (atrophic) age-related macular degeneration, juvenile macular degeneration (Stargardt's disease), Best's disease, adult yolk-like maculopathy, geographic atrophy, Stargardt's macular dystrophy, diabetic retinopathy, or retinal diseases associated with the ABCA4 gene.

[0377] Age-related macular degeneration

[0378] Age-related macular degeneration (AMD) is an eye condition common in people over the age of 50 and a leading cause of vision loss. It causes damage to the macula, a small spot near the center of the retina and the part of the eye needed for sharp central vision. As AMD progresses, a blurry area near the center of vision is a common symptom. Over time, the blurry area may get larger, and a subject may experience a blank spot in their central vision.

[0379] Some embodiments provided herein describe the use of compounds of formula (I) as described herein for treating AMD in an object in need thereof. In some embodiments, compounds of formula (I) inhibit AMD. In certain embodiments, compounds of formula (I) prevent the development of AMD or its clinical symptoms. In certain embodiments, compounds of formula (I) alleviate the development of AMD or its clinical symptoms. In certain embodiments, compounds of formula (I) alleviate the AMD of an object. In certain embodiments, compounds of formula (I) cause the disappearance, reversal or improvement of AMD. In certain embodiments, compounds of formula (I) reduce the number, frequency, duration or severity of clinical symptoms of AMD.

[0380] In some embodiments, formula (I) compound is used preventively. In certain embodiments, formula (I) compound is used to prevent or reduce the risk of AMD. In certain embodiments, formula (I) compound makes the clinical symptoms of AMD not occur in the object that may be susceptible to AMD but has not yet experienced or shown AMD symptoms.

[0381] Dry (atrophic) age-related macular degeneration

[0382] Approximately 85% to 90% of macular degeneration cases are of the "dry" (atrophic) type. An estimated 62.9 million people worldwide have this type of AMD; 8 million of these are Americans. This number is expected to triple by 2020 due to increasing life expectancy and current demographics. There are currently no FDA-approved treatments for dry AMD. Given the lack of treatment and high prevalence, the development of drugs for dry AMD is critical. Clinically, atrophic AMD represents a slowly progressive neurodegenerative disease in which specialized neurons (rod and cone photoreceptors) die in the central part of the retina called the macula. Histopathological and clinical imaging studies have shown that photoreceptor degeneration in dry AMD is triggered by abnormalities in the retinal pigment epithelium (RPE), which lies beneath the photoreceptors and provides critical metabolic support to these photoreceptor neuronal cells. Experimental and clinical data suggest that excessive accumulation of cytotoxic autofluorescent lipid-protein-retinoic acid aggregates (lipofuscin) in the RPE is a major cause of dry AMD. The major cytotoxic component of RPE lipofuscin is pyridinyl bis-retinoic acid A2E ( Figure 1 ). Other cytotoxic bis-retinoids are isoA2E, atRALdi-PE and A2-DHP-PE. The formation of A2E and other lipofuscin bis-retinoids such as A2-DHP-PE (A2-dihydropyridine-phosphatidylethanolamine) and atRALdi-PE (all-trans-retinal dimer-phosphatidylethanolamine) is initiated in a non-enzymatic manner in photoreceptors and can be considered as a byproduct of the normal functional visual cycle.

[0383] Some embodiments provided herein describe the use of formula (I) compounds as described herein for treating dry (atrophic) AMD in an object in need thereof. In some embodiments, formula (I) compounds inhibit dry (atrophic) AMD. In certain embodiments, formula (I) compounds prevent the development of dry (atrophic) AMD or its clinical symptoms. In certain embodiments, formula (I) compounds alleviate the development of dry (atrophic) AMD or its clinical symptoms. In certain embodiments, formula (I) compounds alleviate the dry (atrophic) AMD of an object. In certain embodiments, formula (I) compounds cause the disappearance, reversal or improvement of dry (atrophic) AMD. In certain embodiments, formula (I) compounds reduce the number, frequency, duration or severity of clinical symptoms of dry (atrophic) AMD.

[0384] In some embodiments, formula (I) compound is used preventively. In certain embodiments, formula (I) compound is used to prevent or reduce the risk of dry (atrophic) AMD. In certain embodiments, formula (I) compound makes the clinical symptoms of dry (atrophic) AMD not occur in the object that may be susceptible to dry (atrophic) AMD but has not yet experienced or shown dry (atrophic) AMD symptoms.

[0385] Juvenile macular degeneration (Stargardt's disease)

[0386] Stargardt's disease is an inherited form of juvenile-onset macular degeneration. STGD is characterized by a significant accumulation of lipofuscin in the retina. STGD is associated with defects in the ABCA4 gene. Overproduction of lipofuscin bis-retinoic acid is considered the only biochemical trigger for monogenic STGD caused by recessive mutations in the ABCA4 gene. Symptoms include wavy vision, blind spots, blurriness, loss of depth perception, sensitivity to glare, impaired color vision, and difficulty adapting to dim lights. Symptoms usually appear before the age of 20.

[0387] Some embodiments provided herein describe the use of compounds of formula (I) as described herein for treating STGD in subjects in need thereof. In some embodiments, compounds of formula (I) inhibit STGD. In certain embodiments, compounds of formula (I) prevent the development of STGD or its clinical symptoms. In certain embodiments, compounds of formula (I) alleviate the development of STGD or its clinical symptoms. In certain embodiments, compounds of formula (I) improve the STGD of an object. In certain embodiments, compounds of formula (I) cause regression, reversal or improvement of STGD. In certain embodiments, compounds of formula (I) reduce the number, frequency, duration or severity of clinical symptoms of STGD.

[0388] In some embodiments, the compound of formula (I) is used preventively. In certain embodiments, the compound of formula (I) is used to prevent or reduce the risk of STGD. In certain embodiments, the compound of formula (I) prevents the clinical symptoms of STGD from occurring in subjects who may be susceptible to STGD but have not yet experienced or shown symptoms of STGD.

[0389] Best disease

[0390] Vitellogenin degeneration or Best's disease is an inherited retinal dystrophy involving the retinal pigment epithelium (RPE) and causes a characteristic bilateral yellow "egg yolk" appearance of the macula. The disease tends to present in childhood or early adulthood. Best's disease is caused by mutations in the BEST1 gene, which encodes the transmembrane protein bestrophin 1. These mutations lead to the accumulation of lipofuscin between the outer retinal layer and the RPE cells.

[0391] Some embodiments provided herein describe the use of compounds of formula (I) as described herein for treating Best's disease in subjects in need thereof. In some embodiments, compounds of formula (I) inhibit Best's disease. In certain embodiments, compounds of formula (I) prevent the development of Best's disease or its clinical symptoms. In certain embodiments, compounds of formula (I) alleviate the development of Best's disease or its clinical symptoms. In certain embodiments, compounds of formula (I) alleviate Best's disease in subjects. In certain embodiments, compounds of formula (I) cause regression, reversal or improvement of Best's disease. In certain embodiments, compounds of formula (I) reduce the number, frequency, duration or severity of clinical symptoms of Best's disease.

[0392] 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 Best's disease. In certain embodiments, the compound of formula (I) prevents the clinical symptoms of Best's disease from occurring in subjects who may be susceptible to Best's disease but have not yet experienced or shown symptoms of Best's disease.

[0393] Geographic shrinkage

[0394] Geographic atrophy is a slowly progressive form of macular degeneration that can be considered part of advanced age-related macular degeneration (AMD). This condition causes central blind spots and permanent loss of vision. The disease is characterized by sharply demarcated atrophy of the outer retinal tissue, the retinal pigment epithelium, and the choriocapillaris.

[0395] Some embodiments provided herein describe the use of compounds of formula (I) as described herein for treating geographic atrophy in a subject in need thereof. In some embodiments, compounds of formula (I) inhibit geographic atrophy. In certain embodiments, compounds of formula (I) prevent the development of geographic atrophy or its clinical symptoms. In certain embodiments, compounds of formula (I) mitigate the development of geographic atrophy or its clinical symptoms. In certain embodiments, compounds of formula (I) alleviate geographic atrophy of a subject. In certain embodiments, compounds of formula (I) cause regression, reversal or improvement of geographic atrophy. In certain embodiments, compounds of formula (I) reduce the number, frequency, duration or severity of clinical symptoms of geographic atrophy.

[0396] In some embodiments, the compounds of formula (I) are used prophylactically. In certain embodiments, the compounds of formula (I) are used to prevent or reduce the risk of geographic atrophy. In certain embodiments, the compounds of formula (I) prevent the clinical symptoms of geographic atrophy from occurring in subjects who may be susceptible to geographic atrophy but have not yet experienced or shown symptoms of geographic atrophy.

[0397] Vitellogenin maculopathy in adults

[0398] Adult vitelliform maculopathy is an eye disease that can cause progressive vision loss. The condition causes lipofuscin to accumulate in the cells beneath the macula. The condition usually appears after age 40. The condition can be caused by mutations in the RDS and VMD2 genes.

[0399] Some embodiments provided herein describe the use of the compounds of formula (I) described herein for treating adult yolk-like maculopathy in a subject in need thereof. In some embodiments, the compounds of formula (I) inhibit adult yolk-like maculopathy. In certain embodiments, the compounds of formula (I) prevent the development of adult yolk-like maculopathy or its clinical symptoms. In certain embodiments, the compounds of formula (I) alleviate the development of adult yolk-like maculopathy or its clinical symptoms. In certain embodiments, the compounds of formula (I) alleviate adult yolk-like maculopathy of the subject. In certain embodiments, the compounds of formula (I) cause regression, reversal or improvement of adult yolk-like maculopathy. In certain embodiments, the compounds of formula (I) reduce the number, frequency, duration or severity of clinical symptoms of adult yolk-like maculopathy.

[0400] 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 adult yolk-like maculopathy. In certain embodiments, the compound of formula (I) prevents the clinical symptoms of adult yolk-like maculopathy from occurring in subjects who may be susceptible to adult yolk-like maculopathy but have not yet experienced or shown symptoms of adult yolk-like maculopathy.

[0401] Stargardt's macular dystrophy

[0402] The symptoms and manifestations of Stargardt's macular dystrophy are similar to those of Stargardt's disease, but they usually appear later in children than Stargardt's disease. Stargardt's macular dystrophy is associated with mutations in the EVOVL4 gene.

[0403] Some embodiments provided herein describe the use of a compound of formula (I) described herein for treating Stargardt's macular dystrophy in a subject in need thereof. In some embodiments, a compound of formula (I) inhibits Stargardt's macular dystrophy. In certain embodiments, a compound of formula (I) prevents the development of Stargardt's macular dystrophy or its clinical symptoms. In certain embodiments, a compound of formula (I) reduces the development of Stargardt's macular dystrophy or its clinical symptoms. In certain embodiments, a compound of formula (I) alleviates Stargardt's macular dystrophy in a subject. In certain embodiments, a compound of formula (I) causes regression, reversal, or improvement of Stargardt's macular dystrophy. In certain embodiments, a compound of formula (I) reduces the number, frequency, duration, or severity of clinical symptoms of Stargardt's macular dystrophy.

[0404] In some embodiments, the compounds of formula (I) are used prophylactically. In certain embodiments, the compounds of formula (I) are used to prevent or reduce the risk of Stargardt's macular dystrophy. In certain embodiments, the compounds of formula (I) prevent the clinical symptoms of Stargardt's macular dystrophy from occurring in a subject who may be susceptible to Stargardt's macular dystrophy but has not yet experienced or displayed symptoms of Stargardt's macular dystrophy.

[0405] Diabetic retinopathy

[0406] Diabetic retinopathy is a complication of diabetes that affects the eyes. It can be caused by damage to the blood vessels in the light-sensitive tissue at the back of the eye, eventually leading to blindness. Diabetic retinopathy occurs when new blood vessels fail to grow in the retina. Diabetic retinopathy can also be caused by blood vessels becoming damaged and closing, leading to abnormal growth of new blood vessels in the retina.

[0407] Some embodiments provided herein describe the use of the compounds of formula (I) described herein for treating diabetic retinopathy in a subject in need thereof. In some embodiments, the compounds of formula (I) inhibit diabetic retinopathy. In certain embodiments, the compounds of formula (I) prevent the development of diabetic retinopathy or its clinical symptoms. In certain embodiments, the compounds of formula (I) alleviate the development of diabetic retinopathy or its clinical symptoms. In certain embodiments, the compounds of formula (I) alleviate the diabetic retinopathy of the subject. In certain embodiments, the compounds of formula (I) cause the regression, reversal or improvement of diabetic retinopathy. In certain embodiments, the compounds of formula (I) reduce the number, frequency, duration or severity of clinical symptoms of diabetic retinopathy.

[0408] In some embodiments, the compounds of formula (I) are used prophylactically. In certain embodiments, the compounds of formula (I) are used to prevent or reduce the risk of diabetic retinopathy. In certain embodiments, the compounds of formula (I) prevent the clinical symptoms of diabetic retinopathy from occurring in subjects who may be susceptible to diabetic retinopathy but have not yet experienced or shown symptoms of diabetic retinopathy.

[0409] ABCA4 gene-related retinal diseases

[0410] 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's disease and other eye diseases, including but not limited to macular fundus, cone-rod dystrophy, retinitis pigmentosa, and age-related macular degeneration. Reduced ABCA4 activity is associated with excessive accumulation of toxic retinoids and lipofuscin. In some cases, such mutations are detected by sequencing the DNA or RNA of the subject.

[0411] Some embodiments provided herein describe the use of the compounds of formula (I) described herein for treating ABCA4 gene-related retinal diseases in subjects in need thereof. In some embodiments, the compounds of formula (I) inhibit ABCA4 gene-related retinal diseases. In certain embodiments, the compounds of formula (I) prevent the development of ABCA4 gene-related retinal diseases or their clinical symptoms. In certain embodiments, the compounds of formula (I) alleviate the development of ABCA4 gene-related retinal diseases or their clinical symptoms. In certain embodiments, the compounds of formula (I) alleviate the ABCA4 gene-related retinal diseases of the subject. In certain embodiments, the compounds of formula (I) cause regression, reversal or improvement of ABCA4 gene-related retinal diseases. In certain embodiments, the compounds of formula (I) reduce the number, frequency, duration or severity of clinical symptoms of ABCA4 gene-related retinal diseases.

[0412] 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 occurrence of ABCA4 gene-related retinal diseases. In certain embodiments, the compound of formula (I) prevents clinical symptoms of ABCA4 gene-related retinal diseases from occurring in subjects who may be susceptible to ABCA4 gene-related retinal diseases but have not yet experienced or shown symptoms of ABCA4 gene-related retinal diseases.

[0413] Pharmaceutical composition

[0414] In certain embodiments, the compounds of formula (I) as described herein are administered as pure chemicals. In other embodiments, the heterocyclic RBP4 inhibitory compounds described herein 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), which is selected based on the selected route of administration and standard pharmaceutical examples such as those described in the following literature: Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0415] Provided herein is a pharmaceutical composition comprising at least one heterocyclic RBP4 inhibitory compound or a stereoisomer thereof, a pharmaceutically acceptable salt or N-oxide, and one or more pharmaceutically acceptable carriers. If one or more carriers (or excipients) are compatible with the other ingredients of the composition and are not harmful to the recipient (i.e., subject or patient) of the composition, then the carrier (or excipient) is acceptable or suitable.

[0416] One embodiment provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition is provided in a dosage form for oral administration, comprising a compound provided herein and one or more pharmaceutically acceptable excipients or carriers.

[0417] In certain embodiments, the heterocyclic RBP4 inhibitory compound as described in Formula (I) is substantially pure in that it contains less than about 5%, or less than about 1%, or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthesis by-products produced in one or more steps of the synthesis method.

[0418] Suitable dosage forms include, for example, tablets, pills, sachets or capsules of hard or soft gelatin, methylcellulose or other suitable materials that are easily dissolved in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum powder, cellulose, glucose, sucrose, magnesium carbonate, etc. (see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0419] In some embodiments, the pharmaceutical compositions provided herein are formulated into tablets, capsules, powders or liquid forms for oral administration. In some embodiments, the pharmaceutical preparations are formulated into tablets. In some embodiments, the pharmaceutical preparations are formulated into capsules. In some embodiments, tablets include solid carriers or adjuvants. Liquid pharmaceutical compositions typically include liquid carriers, such as water, petroleum, animal or vegetable oils, mineral oils or synthetic oils. In some embodiments, physiological saline solutions, glucose or other sugar solutions or glycols are optionally included. In some embodiments, capsules include solid carriers, such as gelatin.

[0420] In another embodiment, the pharmaceutical composition is provided in a dosage form for parenteral administration, comprising a compound provided herein and one or more pharmaceutically acceptable excipients or carriers. When the pharmaceutical composition is formulated for intravenous, skin or subcutaneous injection, the active ingredient is an aqueous solution form acceptable to parenteral administration, which is pyrogen-free and has suitable pH, isotonicity and stability. Those skilled in the art can prepare suitable solutions using, for example, isotonic carriers (such as sodium chloride injection, Ringer's injection or lactated Ringer's injection) well. In some embodiments, preservatives, stabilizers, buffers, antioxidants and / or other additives are included.

[0421] In yet another embodiment, pharmaceutical compositions are provided in dosage forms for topical administration, comprising a compound provided herein and one or more pharmaceutically acceptable excipients or carriers.

[0422] Solid dispersion

[0423] In certain embodiments, the pharmaceutical composition of the present invention comprises a solid dispersion. In some cases, the pharmaceutical composition comprises a solid dispersion containing a compound of formula (I). In some cases, a solid dispersion is a solid composition having at least two components (e.g., a drug and a polymer). The components of a solid dispersion can be molecularly dispersed, wherein the drug, polymer, and any additional ingredients are randomly distributed in the dispersion. In some embodiments, the molecular dispersion is amorphous. In some embodiments, the compound of formula (I) is amorphous in a molecular dispersion.

[0424] Many methods known in the art can be used to prepare solid dispersions. In certain embodiments, solid dispersions are prepared by melting method, solvent evaporation method, fusion method, kneading method, melting method, spray drying method, co-grinding method, freeze-drying technology, hot melt extrusion method, melt coagulation or supercritical fluid (supercritical fluid, SCF) technology. In certain embodiments, spray drying method is used to prepare solid dispersions. In certain embodiments, hot melt extrusion method is used to prepare solid dispersions.

[0425] In certain embodiments, the solid dispersion comprises a compound of formula (I) and a dispersing polymer. In certain embodiments, the dispersing 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 polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinyl pyrrolidone (PVP), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, and derivatives or combinations thereof.

[0426] In certain embodiments, the dispersing polymer accounts for about 1-99% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for about 20-80% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for about 40-60% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for about 95% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for about 90% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for about 80% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for about 70% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for about 60% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for about 50% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for about 40% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for about 30% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for about 20% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for about 10% by weight of the solid dispersion.

[0427] In certain embodiments, the dispersing polymer accounts for at least about 10% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for at least about 20% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for at least about 30% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for at least about 40% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for at least about 50% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for at least about 60% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for at least about 70% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for at least about 80% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for at least about 90% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for at least about 95% by weight of the solid dispersion.

[0428] In certain embodiments, the dispersing polymer accounts for up to about 10% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for up to about 20% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for up to about 30% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for up to about 40% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for up to about 50% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for up to about 60% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for up to about 70% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for up to about 80% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for up to about 90% by weight of the solid dispersion. In certain embodiments, the dispersing polymer accounts for up to about 95% by weight of the solid dispersion.

[0429] In certain embodiments, the dispersing polymer is HPMC-AS. HPMC-AS may be of any grade, including HPMC-AS, LF; HPMC-AS, M; HPMC-AS, H; HPMC-AS, HF and HPMC-AS, HG. HPMC-AS may also have any viscosity, including low, normal and high viscosity. In certain embodiments, the dispersing polymer comprises HPMC-AS, LF. In certain embodiments, the dispersing polymer comprises HPMC-AS, M. In certain embodiments, the dispersing polymer comprises HPMC-AS, HF. In certain embodiments, the dispersing polymer comprises HPMC-AS, HG. In some embodiments, the designators "L", "M" or "H" refer to a low, medium or high ratio of acetyl to succinyl substituents on the HPMC backbone, respectively. In some embodiments, the designators "F" or "G" refer to a fine particle size or a granular particle size, respectively.

[0430] In certain embodiments, a specific grade of HPMC-AS is designated, such as L, M, or H. In some embodiments, the grade refers to the ratio of acetyl to succinyl substituents on the HPMC backbone, with the "L" grade being a low ratio, the "M" grade being a medium ratio, and the "H" grade being a high ratio. In some embodiments, HPMC-AS, L comprises an acetyl content of about 5-9% and a succinyl content of about 14-18%. In some embodiments, HPMC-AS, L further comprises a methoxy content of about 20-24% and a hydroxypropyl content of about 5-9%. In some embodiments, HPMC-AS, M comprises an acetyl content of about 7-11% and a succinyl content of about 10-14%. In some embodiments, HPMC-AS, M further comprises a methoxy content of about 21-25% and a hydroxypropyl content of about 5-9%. In some embodiments, HPMC-AS, H comprises an acetyl content of about 10-14% and a succinyl content of about 4-8%. In some embodiments, HPMC-AS,H further comprises a methoxy content of 22-26% and a hydroxypropyl content of about 60-10%.The percentages mentioned in this paragraph refer to the weight percentages of the HPMC-AS composition.

[0431] In certain embodiments, the dispersing polymer is HPMC. In certain embodiments, the HPMC is an HPMC derivative. The HPMC or HPMC derivative can be any grade, including low, normal or high viscosity grades. Non-limiting examples of suitable HPMC or HPMC derivatives include Methocel TM K100M, K15M, F4M, E4M, K4M, K100LV, K3, E15LV, E15LN, E15CLV, E50, E5, E5LV, E3, and E3LV (available from Dow Chemical, Midland Mich.). In certain embodiments, the dispersing polymer is HPMC E3LV.

[0432] In certain embodiments, the compound of formula (I) accounts for about 1-99% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 10-80% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 10-60% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 10-50% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 10-40% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 20-80% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 20-60% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 20-50% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 20-40% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 40-60% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 95% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 90% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 80% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 70% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 60% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 50% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 40% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 30% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 20% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 10% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for about 5% by weight of the solid dispersion.

[0433] In certain embodiments, the compound of formula (I) accounts for at least about 5% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for at least about 10% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for at least about 20% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for at least about 30% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for at least about 40% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for at least about 50% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for at least about 60% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for at least about 70% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for at least about 80% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for at least about 90% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for at least about 95% by weight of the solid dispersion.

[0434] In certain embodiments, the compound of formula (I) accounts for up to about 5% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for up to about 10% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for up to about 20% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for up to about 30% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for up to about 40% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for up to about 50% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for up to about 60% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for up to about 70% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for up to about 80% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for up to about 90% by weight of the solid dispersion. In certain embodiments, the compound of formula (I) accounts for up to about 95% by weight of the solid dispersion.

[0435] In certain embodiments, in the solid dispersion, the ratio of the compound of formula (I): the dispersed polymer is about 5:95 (w / w). In certain embodiments, in the solid dispersion, the ratio of the compound of formula (I): the dispersed polymer is about 10:90 (w / w). In certain embodiments, in the solid dispersion, the ratio of the compound of formula (I): the dispersed polymer is about 20:80 (w / w). In certain embodiments, in the solid dispersion, the ratio of the compound of formula (I): the dispersed polymer is about 30:70 (w / w). In certain embodiments, in the solid dispersion, the ratio of the compound of formula (I): the dispersed polymer is about 40:60 (w / w). In certain embodiments, in the solid dispersion, the ratio of the compound of formula (I): the dispersed polymer is about 50:50 (w / w). In certain embodiments, in the solid dispersion, the ratio of the compound of formula (I): the dispersed polymer is about 60:40 (w / w). In certain embodiments, in the solid dispersion, the ratio of the compound of formula (I): the dispersed polymer is about 70:30 (w / w). In certain embodiments, in the solid dispersion, the ratio of the compound of formula (I): the dispersed polymer is about 80:20 (w / w). In certain embodiments, in the solid dispersion, the ratio of the compound of formula (I): the dispersed polymer is about 90:10 (w / w). In certain embodiments, in the solid dispersion, the ratio of the compound of formula (I): the dispersed polymer is about 95:5 (w / w).

[0436] 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 certain embodiments, the solid dispersion comprises compound 1 and HPMC-AS in a ratio of about 20:80 to about 40:60. In certain embodiments, the solid dispersion comprises compound 1 and HPMC-AS in a ratio of about 10:90. In certain embodiments, the solid dispersion comprises compound 1 and HPMC-AS in a ratio of about 20:80. In certain embodiments, the solid dispersion comprises compound 1 and HPMC-AS in a ratio of about 30:70. In certain embodiments, the solid dispersion comprises compound 1 and HPMC-AS in a ratio of about 40:60. In certain embodiments, the solid dispersion comprises compound 1 and HPMC-AS in a ratio of about 50:50.

[0437] 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 certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of about 15:85 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of about 20:80 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of about 10:90. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of about 20:80. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of about 30:70. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, H in a ratio of about 50:50. In some embodiments, HPMC-AS, H comprises an acetyl content of about 10-14% and a succinyl content of about 4-8%.

[0438] 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 certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 15:85 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 20:80 to about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 10:90. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 20:80. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 30:70. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 40:60. In certain embodiments, the solid dispersion comprises Compound 1 and HPMC-AS, M in a ratio of about 50:50. In some embodiments, HPMC-AS, M comprises an acetyl content of about 7-11% and a succinyl content of about 10-14%.

[0439] In certain embodiments, the solid dispersion comprises Compound 1 and PVP. In some embodiments, the ratio of Compound 1:PVP is from about 1:10 to about 1:1. In some embodiments, the ratio of Compound 1:PVP is from about 1:10 to about 1:2. In some embodiments, the ratio of Compound 1:PVP is from about 1:5 to about 1:2. In some embodiments, the ratio of Compound 1:PVP is from about 1:5 to about 1:1. In some embodiments, the ratio of Compound 1:PVP is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, or about 1:10. In some embodiments, the ratio of Compound 1:PVP is about 1:2. In some embodiments, the ratio of Compound 1:PVP is about 1:3. In some embodiments, the ratio of Compound 1:PVP is about 1:5. In some embodiments, the molecular weight of PVP is from about 7,000 Daltons to about 11,000 Daltons.

[0440] In certain embodiments, the average particle size of the solid dispersion is less than 5 μm. In certain embodiments, the average particle size of the solid dispersion is less than 10 μm. In certain embodiments, the average particle size of the solid dispersion is less than 20 μm. In certain embodiments, the average particle size of the solid dispersion is less than 30 μm. In certain embodiments, the average particle size of the solid dispersion is less than 40 μm. In certain embodiments, the average particle size of the solid dispersion is less than 50 μm. In certain embodiments, the average particle size of the solid dispersion is about 1 μm to 20 μm. In certain embodiments, the average particle size of the solid dispersion is about 5 μm to 20 μm. In certain embodiments, the average particle size of the solid dispersion is about 10 μm to 20 μm. In certain embodiments, the average particle size of the solid dispersion is about 15 μm to 20 μm. In certain embodiments, the average particle size of the solid dispersion is about 1 μm to 5 μm. In certain embodiments, the average particle size of the solid dispersion is about 1 μm to 10 μm. In certain embodiments, the average particle size of the solid dispersion is about 5 μm to 10 μm.

[0441] In certain embodiments, the solid dispersion accounts for 1-100% by weight of the pharmaceutical composition. In certain embodiments, the solid dispersion accounts for 20-80% by weight of the pharmaceutical composition. In certain embodiments, the solid dispersion accounts for 40-60% by weight of the pharmaceutical composition. In certain embodiments, the solid dispersion accounts for about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% by weight of the pharmaceutical composition.

[0442] In certain embodiments, a pharmaceutical composition comprising a solid dispersion comprises a therapeutically effective amount of a compound of formula (I). In certain embodiments, the pharmaceutical composition comprises about 1 mg of a compound of formula (I). In certain embodiments, the pharmaceutical composition comprises about 5 mg of a compound of formula (I). In certain embodiments, the pharmaceutical composition comprises about 10 mg of a compound of formula (I). In certain embodiments, the pharmaceutical composition comprises about 25 mg of a compound of formula (I). In certain embodiments, the pharmaceutical composition comprises about 50 mg of a compound of formula (I). In certain embodiments, the pharmaceutical composition comprises about 100 mg of a compound of formula (I). In certain embodiments, the pharmaceutical composition comprises about 200 mg of a compound of formula (I). In certain embodiments, the pharmaceutical composition comprises about 400 mg of a compound of formula (I).

[0443] In certain embodiments, the solid dispersion increases the solubility of the compound of formula (I). In certain embodiments, the solid dispersion increases the solubility of the compound of formula (I) by at least two times. In certain embodiments, the solid dispersion increases the solubility of the compound of formula (I) by at least four times. In certain embodiments, the solid dispersion increases the solubility of the compound of formula (I) by at least eight times. In certain embodiments, the solid dispersion increases the solubility of the compound of formula (I) by at least 10 times. In certain embodiments, the solid dispersion increases the solubility of the compound of formula (I) by at least 20 times. In certain embodiments, the solid dispersion increases the solubility of the compound of formula (I) by at least 30 times. In certain embodiments, the solid dispersion increases the solubility of the compound of formula (I) by at least 40 times. In certain embodiments, the solid dispersion increases the solubility of the compound of formula (I) by at least 50 times. In certain embodiments, the solid dispersion increases the solubility of the compound of formula (I) by at least 60 times. In some embodiments, the increase is measured compared to the crystalline form of the compound of formula (I). In some embodiments, the increase is measured compared to an amorphous form of the compound of formula (I).

[0444] Other Ingredients

[0445] 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 of 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.

[0446] Fillers

[0447] In certain embodiments, the pharmaceutical composition further comprises a filler. In certain embodiments, the solid dispersion of the pharmaceutical composition further comprises a filler. The filler may be any biocompatible material and a compound of formula (I) that does not react with the compound of formula (I). Non-limiting examples of fillers include hydrated lactose, mannitol, sorbitol, cellulose, calcium phosphate, starch, sugar, cellulose, modified cellulose, sodium carboxymethylcellulose, ethylcellulose hydroxymethylcellulose, hydroxypropyl cellulose, cellulose acetate, microcrystalline cellulose, calcium hydrogen phosphate, sucrose, lactose, corn starch, potato starch, or any combination thereof.

[0448] In certain embodiments, fillers account for about 1-99% weight of the pharmaceutical composition. In certain embodiments, fillers account for about 10% weight of the pharmaceutical composition. In certain embodiments, fillers account for about 20% weight of the pharmaceutical composition. In certain embodiments, fillers account for about 30% weight of the pharmaceutical composition. In certain embodiments, fillers account for about 40% weight of the pharmaceutical composition. In certain embodiments, fillers account for about 50% weight of the pharmaceutical composition. In certain embodiments, fillers account for about 60% weight of the pharmaceutical composition. In certain embodiments, fillers account for about 70% weight of the pharmaceutical composition. In certain embodiments, fillers account for about 80% weight of the pharmaceutical composition. In certain embodiments, fillers account for about 90% weight of the pharmaceutical composition.

[0449] In certain embodiments, fillers account for up to about 10% by weight of the pharmaceutical composition. In certain embodiments, fillers account for up to about 20% by weight of the pharmaceutical composition. In certain embodiments, fillers account for up to about 30% by weight of the pharmaceutical composition. In certain embodiments, fillers account for up to about 40% by weight of the pharmaceutical composition. In certain embodiments, fillers account for up to about 50% by weight of the pharmaceutical composition. In certain embodiments, fillers account for up to about 60% by weight of the pharmaceutical composition. In certain embodiments, fillers account for up to about 70% by weight of the pharmaceutical composition. In certain embodiments, fillers account for up to about 80% by weight of the pharmaceutical composition. In certain embodiments, fillers account for up to about 90% by weight of the pharmaceutical composition.

[0450] In certain embodiments, fillers account for at least about 10% by weight of a pharmaceutical composition. In certain embodiments, fillers account for at least about 20% by weight of a pharmaceutical composition. In certain embodiments, fillers account for at least about 30% by weight of a pharmaceutical composition. In certain embodiments, fillers account for at least about 40% by weight of a pharmaceutical composition. In certain embodiments, fillers account for at least about 50% by weight of a pharmaceutical composition. In certain embodiments, fillers account for at least about 60% by weight of a pharmaceutical composition. In certain embodiments, fillers account for at least about 70% by weight of a pharmaceutical composition. In certain embodiments, fillers account for at least about 80% by weight of a pharmaceutical composition. In certain embodiments, fillers account for at least about 90% by weight of a pharmaceutical composition.

[0451] Sweeteners

[0452] 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, for example 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 dihydrochalcone; water-soluble artificial sweeteners, such as soluble saccharin salts, i.e., saccharin sodium salt or saccharin calcium salt, cyclamate (cyclamate salt), sodium, ammonium or calcium salt of 3,4-dihydro-6-methyl-1,2,3-oxathiazin-4-one-2,2-dioxide, potassium salt of 3,4-dihydro-6-methyl-1,2,3-oxathiazin-4-one-2,2-dioxide (acesulfame-K), the free acid form of saccharin, and the like; dipeptide-based sweeteners, such as L-aspartic acid-derived sweeteners, such as L-aspartyl-L-phenylalanine methyl ester (aspartame), L-α-aspartyl-N ... -(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide hydrate, L-aspartyl-L-phenylglycerol and methyl ester of L-aspartyl-L-2,5, dihydrophenylglycine, L-aspartyl-2,5-dihydro-L-phenylalanine, L-aspartyl-L-(1-cyclohexenyl)-alanine, and the like; and water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, such as chlorinated derivatives of known common sugar (sucrose), for example sucralose.

[0453] In certain embodiments, sweeteners account for about 1-99% weight of the pharmaceutical composition. In certain embodiments, sweeteners account for about 10% weight of the pharmaceutical composition. In certain embodiments, sweeteners account for about 20% weight of the pharmaceutical composition. In certain embodiments, sweeteners account for about 30% weight of the pharmaceutical composition. In certain embodiments, sweeteners account for about 40% weight of the pharmaceutical composition. In certain embodiments, sweeteners account for about 50% weight of the pharmaceutical composition. In certain embodiments, sweeteners account for about 60% weight of the pharmaceutical composition. In certain embodiments, sweeteners account for about 70% weight of the pharmaceutical composition. In certain embodiments, sweeteners account for about 80% weight of the pharmaceutical composition. In certain embodiments, sweeteners account for about 90% weight of the pharmaceutical composition.

[0454] In certain embodiments, sweeteners account for up to about 10 weight % of a pharmaceutical composition. In certain embodiments, sweeteners account for up to about 20 weight % of a pharmaceutical composition. In certain embodiments, sweeteners account for up to about 30 weight % of a pharmaceutical composition. In certain embodiments, sweeteners account for up to about 40 weight % of a pharmaceutical composition. In certain embodiments, sweeteners account for up to about 50 weight % of a pharmaceutical composition. In certain embodiments, sweeteners account for up to about 60 weight % of a pharmaceutical composition. In certain embodiments, sweeteners account for up to about 70 weight % of a pharmaceutical composition. In certain embodiments, sweeteners account for up to about 80 weight % of a pharmaceutical composition. In certain embodiments, sweeteners account for up to about 90 weight % of a pharmaceutical composition.

[0455] In certain embodiments, sweeteners account for at least about 10 weight % of a pharmaceutical composition. In certain embodiments, sweeteners account for at least about 20 weight % of a pharmaceutical composition. In certain embodiments, sweeteners account for at least about 30 weight % of a pharmaceutical composition. In certain embodiments, sweeteners account for at least about 40 weight % of a pharmaceutical composition. In certain embodiments, sweeteners account for at least about 50 weight % of a pharmaceutical composition. In certain embodiments, sweeteners account for at least about 60 weight % of a pharmaceutical composition. In certain embodiments, sweeteners account for at least about 70 weight % of a pharmaceutical composition. In certain embodiments, sweeteners account for at least about 80 weight % of a pharmaceutical composition. In certain embodiments, sweeteners account for at least about 90 weight % of a pharmaceutical composition.

[0456] Disintegrants

[0457] In certain embodiments, the pharmaceutical composition comprising a compound of formula (I) further comprises a disintegrant. In certain embodiments, the solid dispersion of the pharmaceutical composition further comprises a disintegrant. Non-limiting examples of disintegrants include agar-agar, algin, calcium carbonate, carboxymethyl cellulose, cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, clay, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, glue, magnesium aluminum silicate, methylcellulose, polacrilin potassium, sodium alginate, sodium starch glycolate, corn starch, potato starch, tapioca starch, or any combination thereof.

[0458] In certain embodiments, disintegrants account for about 1-99% weight of the pharmaceutical composition. In certain embodiments, disintegrants account for about 10% weight of the pharmaceutical composition. In certain embodiments, disintegrants account for about 20% weight of the pharmaceutical composition. In certain embodiments, disintegrants account for about 30% weight of the pharmaceutical composition. In certain embodiments, disintegrants account for about 40% weight of the pharmaceutical composition. In certain embodiments, disintegrants account for about 50% weight of the pharmaceutical composition. In certain embodiments, disintegrants account for about 60% weight of the pharmaceutical composition. In certain embodiments, disintegrants account for about 70% weight of the pharmaceutical composition. In certain embodiments, disintegrants account for about 80% weight of the pharmaceutical composition. In certain embodiments, disintegrants account for about 90% weight of the pharmaceutical composition.

[0459] In certain embodiments, disintegrants account for up to about 10% by weight of a pharmaceutical composition. In certain embodiments, disintegrants account for up to about 20% by weight of a pharmaceutical composition. In certain embodiments, disintegrants account for up to about 30% by weight of a pharmaceutical composition. In certain embodiments, disintegrants account for up to about 40% by weight of a pharmaceutical composition. In certain embodiments, disintegrants account for up to about 50% by weight of a pharmaceutical composition. In certain embodiments, disintegrants account for up to about 60% by weight of a pharmaceutical composition. In certain embodiments, disintegrants account for up to about 70% by weight of a pharmaceutical composition. In certain embodiments, disintegrants account for up to about 80% by weight of a pharmaceutical composition. In certain embodiments, disintegrants account for up to about 90% by weight of a pharmaceutical composition.

[0460] In certain embodiments, disintegrants account for at least about 10 weight % of a pharmaceutical composition. In certain embodiments, disintegrants account for at least about 20 weight % of a pharmaceutical composition. In certain embodiments, disintegrants account for at least about 30 weight % of a pharmaceutical composition. In certain embodiments, disintegrants account for at least about 40 weight % of a pharmaceutical composition. In certain embodiments, disintegrants account for at least about 50 weight % of a pharmaceutical composition. In certain embodiments, disintegrants account for at least about 60 weight % of a pharmaceutical composition. In certain embodiments, disintegrants account for at least about 70 weight % of a pharmaceutical composition. In certain embodiments, disintegrants account for at least about 80 weight % of a pharmaceutical composition. In certain embodiments, disintegrants account for at least about 90 weight % of a pharmaceutical composition.

[0461] Wetting Agents

[0462] In certain embodiments, the pharmaceutical composition comprising a compound of Formula (I) further comprises a wetting agent. In certain embodiments, the solid dispersion of the pharmaceutical composition further comprises a wetting agent. Non-limiting examples of wetting agents include sodium lauryl sulfate, cetearyl alcohol, cetomacrogol emulsifying wax, gelatin, casein, sodium docusate, 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, polyethylene glycol hydrogenated castor oil, sorbitan esters of fatty acids, vitamin E or tocopherol derivatives, vitamin E TPGS, tocopherol esters, lecithin, phospholipids and their derivatives, poloxamers, stearic acid, oleic acid, oleyl alcohol, cetyl alcohol, mono- and diglycerides, propylene glycol esters of fatty acids, glyceryl fatty acids, glycol palmitostearate, polyoxyglycerol esters, propylene glycol monocaprylate, propylene glycol monolaurate, alkylaryl polyether alcohols, and polyoleylglycerol, or combinations thereof.

[0463] In certain embodiments, the wetting agent accounts for about 1-99% weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for about 10% weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for about 20% weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for about 30% weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for about 40% weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for about 50% weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for about 60% weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for about 70% weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for about 80% weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for about 90% weight of the pharmaceutical composition.

[0464] In certain embodiments, the wetting agent accounts for up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for up to about 20% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for up to about 90% by weight of the pharmaceutical composition.

[0465] In certain embodiments, the wetting agent accounts for at least about 10 weight % of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for at least about 20 weight % of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for at least about 30 weight % of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for at least about 40 weight % of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for at least about 50 weight % of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for at least about 60 weight % of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for at least about 70 weight % of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for at least about 80 weight % of the pharmaceutical composition. In certain embodiments, the wetting agent accounts for at least about 90 weight % of the pharmaceutical composition.

[0466] Glidants

[0467] In certain embodiments, the pharmaceutical composition comprising the compound of formula (I) further comprises a glidant. In certain embodiments, the solid dispersion of the pharmaceutical composition further comprises a glidant. Non-limiting examples of glidants include colloidal silicon dioxide, talc, corn starch, metal silicates, higher fatty acid metal salts, metal oxides, alkaline earth metal salts and metal hydroxides or any combination thereof.

[0468] In certain embodiments, the glidant accounts for about 1-99% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for about 10% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for about 20% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for about 30% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for about 40% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for about 50% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for about 60% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for about 70% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for about 80% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for about 90% by weight of the pharmaceutical composition.

[0469] In certain embodiments, the glidant accounts for up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for up to about 20% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for up to about 90% by weight of the pharmaceutical composition.

[0470] In certain embodiments, the glidant accounts for at least about 10% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for at least about 20% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for at least about 30% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for at least about 40% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for at least about 50% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for at least about 60% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for at least about 70% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for at least about 80% by weight of the pharmaceutical composition. In certain embodiments, the glidant accounts for at least about 90% by weight of the pharmaceutical composition.

[0471] Lubricants

[0472] In certain embodiments, the pharmaceutical composition comprising a compound of formula (I) further comprises a lubricant. In certain 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.

[0473] In certain embodiments, lubricants account for about 1-99% weight of the pharmaceutical composition. In certain embodiments, lubricants account for about 10% weight of the pharmaceutical composition. In certain embodiments, lubricants account for about 20% weight of the pharmaceutical composition. In certain embodiments, lubricants account for about 30% weight of the pharmaceutical composition. In certain embodiments, lubricants account for about 40% weight of the pharmaceutical composition. In certain embodiments, lubricants account for about 50% weight of the pharmaceutical composition. In certain embodiments, lubricants account for about 60% weight of the pharmaceutical composition. In certain embodiments, lubricants account for about 70% weight of the pharmaceutical composition. In certain embodiments, lubricants account for about 80% weight of the pharmaceutical composition. In certain embodiments, lubricants account for about 90% weight of the pharmaceutical composition.

[0474] In certain embodiments, lubricants account for up to about 10% by weight of the pharmaceutical composition. In certain embodiments, lubricants account for up to about 20% by weight of the pharmaceutical composition. In certain embodiments, lubricants account for up to about 30% by weight of the pharmaceutical composition. In certain embodiments, lubricants account for up to about 40% by weight of the pharmaceutical composition. In certain embodiments, lubricants account for up to about 50% by weight of the pharmaceutical composition. In certain embodiments, lubricants account for up to about 60% by weight of the pharmaceutical composition. In certain embodiments, lubricants account for up to about 70% by weight of the pharmaceutical composition. In certain embodiments, lubricants account for up to about 80% by weight of the pharmaceutical composition. In certain embodiments, lubricants account for up to about 90% by weight of the pharmaceutical composition.

[0475] In certain embodiments, lubricants account for at least about 10% by weight of a pharmaceutical composition. In certain embodiments, lubricants account for at least about 20% by weight of a pharmaceutical composition. In certain embodiments, lubricants account for at least about 30% by weight of a pharmaceutical composition. In certain embodiments, lubricants account for at least about 40% by weight of a pharmaceutical composition. In certain embodiments, lubricants account for at least about 50% by weight of a pharmaceutical composition. In certain embodiments, lubricants account for at least about 60% by weight of a pharmaceutical composition. In certain embodiments, lubricants account for at least about 70% by weight of a pharmaceutical composition. In certain embodiments, lubricants account for at least about 80% by weight of a pharmaceutical composition. In certain embodiments, lubricants account for at least about 90% by weight of a pharmaceutical composition.

[0476] Surfactants

[0477] In some embodiments of the 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 (SDS), sodium lauryl sulfate (SLS), macroglycerol ricinoleate (Kolliphor or Cremophor ), caprylocaproyl polyoxyl-8glyceride Lauroyl Macrogol-6 Glycerides ( M 2130CS), Lauroyl Macrogol-32 Glyceryl ( 44 / 14), polyethylene glycol monostearate ( 48 / 16), polyoxyethylene hydrogenated castor oil 60 (HCO-60), polysorbate Polyethylene glycol sorbitan monolaurate Polyoxyethylene sorbitan trioleate Polyoxyethylene glycerol trioleate (tagot-TO), sorbitan monooleate Sorbitan monolaurate or any combination thereof.

[0478] In certain embodiments, surfactants account for about 1-99% weight of the pharmaceutical composition. In certain embodiments, surfactants account for about 10% weight of the pharmaceutical composition. In certain embodiments, surfactants account for about 20% weight of the pharmaceutical composition. In certain embodiments, surfactants account for about 30% weight of the pharmaceutical composition. In certain embodiments, surfactants account for about 40% weight of the pharmaceutical composition. In certain embodiments, surfactants account for about 50% weight of the pharmaceutical composition. In certain embodiments, surfactants account for about 60% weight of the pharmaceutical composition. In certain embodiments, surfactants account for about 70% weight of the pharmaceutical composition. In certain embodiments, surfactants account for about 80% weight of the pharmaceutical composition. In certain embodiments, surfactants account for about 90% weight of the pharmaceutical composition.

[0479] In certain embodiments, the surfactant accounts for up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the surfactant accounts for up to about 20% by weight of the pharmaceutical composition. In certain embodiments, the surfactant accounts for up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the surfactant accounts for up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the surfactant accounts for up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the surfactant accounts for up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the surfactant accounts for up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the surfactant accounts for up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the surfactant accounts for up to about 90% by weight of the pharmaceutical composition.

[0480] In certain embodiments, surfactants account for at least about 10% by weight of a pharmaceutical composition. In certain embodiments, surfactants account for at least about 20% by weight of a pharmaceutical composition. In certain embodiments, surfactants account for at least about 30% by weight of a pharmaceutical composition. In certain embodiments, surfactants account for at least about 40% by weight of a pharmaceutical composition. In certain embodiments, surfactants account for at least about 50% by weight of a pharmaceutical composition. In certain embodiments, surfactants account for at least about 60% by weight of a pharmaceutical composition. In certain embodiments, surfactants account for at least about 70% by weight of a pharmaceutical composition. In certain embodiments, surfactants account for at least about 80% by weight of a pharmaceutical composition. In certain embodiments, surfactants account for at least about 90% by weight of a pharmaceutical composition.

[0481] Method for preparing solid dispersion

[0482] Methods for preparing pharmaceutical compositions (such as those comprising compounds of formula (I)) are described herein. The methods provided herein can be used to prepare any solid dispersion formulation provided herein. In certain embodiments, a method for preparing a solid dispersion comprises the following steps:

[0483] i. adding a solvent to the container;

[0484] ii. adding a compound of formula (I) or a pharmaceutically acceptable salt thereof to the container;

[0485] iii. adding a dispersed polymer to the container to obtain a first mixture;

[0486] iv. mixing the first mixture until the compound of formula (I) or a pharmaceutically acceptable salt thereof and the dispersing polymer are dissolved in the solvent to obtain a first solution;

[0487] v. dry spraying the first solution to obtain a first solid; and

[0488] vi. Drying the first solid to obtain a solid dispersion.

[0489] In certain embodiments of the method for preparing a solid dispersion, the solvent is an organic solvent. In certain embodiments, the solvent is selected from ethanol, methanol, acetone, isopropanol, n-butanol, tetrahydrofuran, dichloromethane, ethyl acetate, methyl acetate, acetonitrile, chloroform, carbon tetrachloride, benzene, toluene, diethyl ether, dioxane, pentane, hexane, cyclohexane, heptane, methyl tert-butyl ether, petroleum ether, 1-propanol, methyl ethyl ketone and combinations thereof.

[0490] In certain embodiments, the solvent is a mixture of a non-polar solvent and a polar solvent. In certain embodiments, the solvent is 95:5 non-polar: polar. In certain embodiments, the solvent is 95:5 non-polar: polar. In certain embodiments, the solvent is 90:10 non-polar: polar. In certain embodiments, the solvent is 85:15 non-polar: polar. In certain embodiments, the solvent is 80:20 non-polar: polar. In certain embodiments, the solvent is 75:25 non-polar: polar. In certain embodiments, the solvent is 70:30 non-polar: polar. In certain embodiments, the solvent is 60:40 non-polar: polar. In certain embodiments, the solvent is 50:50 non-polar: polar. In certain embodiments, the solvent is 40:60 non-polar: polar. In certain embodiments, the solvent is 30:70 non-polar: polar. In certain embodiments, the solvent is 20:80 non-polar: polar. In certain embodiments, the solvent is 10:90 nonpolar:polar.

[0491] In certain embodiments, the solvent is a mixture of chloroform and methanol. In certain embodiments, the solvent is 95:5 chloroform: methanol. In certain embodiments, the solvent is 95:5 chloroform: methanol. In certain embodiments, the solvent is 90:10 chloroform: methanol. In certain embodiments, the solvent is 85:15 chloroform: methanol. In certain embodiments, the solvent is 80:20 chloroform: methanol. In certain embodiments, the solvent is 75:25 chloroform: methanol. In certain embodiments, the solvent is 70:30 chloroform: methanol. In certain embodiments, the solvent is 60:40 chloroform: methanol. In certain embodiments, the solvent is 50:50 chloroform: methanol. In certain embodiments, the solvent is 40:60d chloroform: methanol. In certain embodiments, the solvent is 30:70 chloroform: methanol. In certain embodiments, the solvent is 20:80 chloroform: methanol. In certain embodiments, the solvent is 10:90 chloroform: methanol.

[0492] In certain embodiments, the solvent is a mixture of dichloromethane and methanol. In certain embodiments, the solvent is 95:5 dichloromethane: methanol. In certain embodiments, the solvent is 95:5 dichloromethane: methanol. In certain embodiments, the solvent is 90:10 dichloromethane: methanol. In certain embodiments, the solvent is 85:15 dichloromethane: methanol. In certain embodiments, the solvent is 80:20 dichloromethane: methanol. In certain embodiments, the solvent is 75:25 dichloromethane: methanol. In certain embodiments, the solvent is 70:30 dichloromethane: methanol. In certain embodiments, the solvent is 60:40 dichloromethane: methanol. In certain embodiments, the solvent is 50:50 dichloromethane: methanol. In certain embodiments, the solvent is 40:60 dichloromethane: methanol. In certain embodiments, the solvent is 30:70 dichloromethane: methanol. In certain embodiments, the solvent is 20:80 dichloromethane: methanol. In certain embodiments, the solvent is 10:90 dichloromethane:methanol.

[0493] In certain embodiments, the solvent is a mixture of dichloromethane and ethanol. In certain embodiments, the solvent is 95:5 dichloromethane: ethanol. In certain embodiments, the solvent is 95:5 dichloromethane: ethanol. In certain embodiments, the solvent is 90:10 dichloromethane: ethanol. In certain embodiments, the solvent is 85:15 dichloromethane: ethanol. In certain embodiments, the solvent is 80:20 dichloromethane: ethanol. In certain embodiments, the solvent is 75:25 dichloromethane: ethanol. In certain embodiments, the solvent is 70:30 dichloromethane: ethanol. In certain embodiments, the solvent is 60:40 dichloromethane: ethanol. In certain embodiments, the solvent is 50:50 dichloromethane: ethanol. In certain embodiments, the solvent is 40:60 dichloromethane: ethanol. In certain embodiments, the solvent is 30:70 dichloromethane: ethanol. In certain embodiments, the solvent is 20:80 dichloromethane: ethanol. In certain embodiments, the solvent is 10:90 dichloromethane:ethanol.

[0494] In certain embodiments, the solvent is a mixture of acetone and methanol. In certain embodiments, the solvent is 95:5 acetone: methanol. In certain embodiments, the solvent is 90:10 acetone: methanol. In certain embodiments, the solvent is 85:15 acetone: methanol. In certain embodiments, the solvent is 80:20 acetone: methanol. In certain embodiments, the solvent is 75:25 acetone: methanol. In certain embodiments, the solvent is 70:30 acetone: methanol. In certain embodiments, the solvent is 60:40 acetone: methanol. In certain embodiments, the solvent is 50:50 acetone: methanol. In certain embodiments, the solvent is 40:60 acetone: methanol. In certain embodiments, the solvent is 30:70 acetone: methanol. In certain embodiments, the solvent is 20:80 dichloromethane: methanol. In certain embodiments, the solvent is 10:90 acetone: methanol.

[0495] In certain embodiments, the solvent is a mixture of ethyl acetate and acetonitrile. In certain embodiments, the solvent is 95:5 ethyl acetate: acetonitrile. In certain embodiments, the solvent is 95:5 ethyl acetate: acetonitrile. In certain embodiments, the solvent is 90:10 ethyl acetate: acetonitrile. In certain embodiments, the solvent is 85:15 ethyl acetate: acetonitrile. In certain embodiments, the solvent is 80:20 ethyl acetate: acetonitrile. In certain embodiments, the solvent is 75:25 ethyl acetate: acetonitrile. In certain embodiments, the solvent is 70:30 ethyl acetate: acetonitrile. In certain embodiments, the solvent is 60:40 ethyl acetate: acetonitrile. In certain embodiments, the solvent is 50:50 ethyl acetate: acetonitrile. In certain embodiments, the solvent is 40:60 ethyl acetate: acetonitrile. In certain embodiments, the solvent is 30:70 ethyl acetate: acetonitrile. In certain embodiments, the solvent is 20:80 ethyl acetate: acetonitrile. In certain embodiments, the solvent is 10:90 ethyl acetate: acetonitrile.

[0496] In certain embodiments of the method for preparing a solid dispersion, the dispersing 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 polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinyl pyrrolidone (PVP), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, and derivatives or combinations thereof. In certain embodiments, the dispersing polymer is HPMC-AS. In certain embodiments, the dispersing polymer is HPMC. In some embodiments, the dispersing polymer is PVP.

[0497] In some embodiments, the dispersing polymer is a specific grade of HPMC-AS. In some embodiments, the dispersing polymer is HPMC-AS, L. In some embodiments, the dispersing polymer is HPMC-AS, M. In some embodiments, the dispersing polymer is HPMC-AS, H. In some embodiments, the dispersing polymer is PVP. In some embodiments, the molecular weight of PVP is about 7000 Daltons to about 11000 Daltons.

[0498] In certain embodiments of the method for preparing a solid dispersion, the method further comprises the step of adding additional ingredients to the first mixture. In certain embodiments, the additional ingredients are fillers, sweeteners, disintegrants, wetting agents, glidants, lubricants, surfactants, and any combination.

[0499] In certain embodiments, the compound of formula (I) has the following structure: or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof. In certain embodiments, the compound of formula (I) has the following structure: or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof; formulated as a solid dispersion.

[0500] Nanosuspension drug preparations

[0501] Also provided herein are nanosuspension pharmaceutical compositions comprising a compound of formula (I), particularly Compound 1. Nanosuspensions are ideally suited for formulations of compounds with low solubility in pharmaceutically acceptable solvents. Such formulations can provide improved bioavailability of such compounds.

[0502] Nanosuspensions typically contain a desired API in a stable polymorphic form with an average particle size of less than 1000 nm, which is then suspended in a liquid (e.g., water). Ideally, the API will remain stably suspended in the formulation over an extended period of time without any change in the polymorphic form of the API. Such formulations typically contain additional agents, such as surfactants or emulsifiers, to keep the API in the suspension.

[0503] 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, suspended in a pharmaceutically acceptable solvent. In some embodiments, the compound of formula (I) is compound 1. In some embodiments, compound 1 is a "Type C" polymorph provided herein.

[0504] In some embodiments, the nanosuspension pharmaceutical formulation comprises a specified 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, 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, about 25 mg / mL, 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.

[0505] In some embodiments, the average particle size of the compound of formula (I) is less than 1000nm. In some embodiments, the average particle size of the compound of formula (I) is from about 50nm to about 1,000nm. In some embodiments, the average particle size of the compound of formula (I) is from about 50nm to about 100nm, from about 50nm to about 250nm, from about 50nm to about 500nm, from about 50nm to about 750nm, from about 50nm to about 1,000nm, from about 100nm to about 250nm, from about 100nm to about 500nm, from about 100nm to about 750nm, from about 100nm to about 1,000nm, from about 250nm to about 500nm, from about 250nm to about 750nm, from about 250nm to about 1,000nm, from about 500nm to about 750nm, from about 500nm to about 1,000nm, or from about 750nm to about 1,000nm. In some embodiments, the average particle size of the compound of formula (I) is about 50nm, about 100nm, about 250nm, about 500nm, about 750nm, or about 1,000nm. In some embodiments, the average particle size of the compound of formula (I) is at least about 50nm, about 100nm, about 250nm, about 500nm, or about 750nm. In some embodiments, the average particle size of the compound of formula (I) is at most about 100nm, about 250nm, about 500nm, about 750nm, or about 1,000nm.

[0506] The particle size distribution of the resulting suspension can be measured using any instrument. An example is laser diffraction using a Cilas ParticleSize Analyser 1190. Images of the particles can be taken using, for example, a microscope "Olympus". The resolution can be determined, for example, by a pION μDISS analyzer.

[0507] In some embodiments, the compound of formula (I) is micronized. The compound can be micronized by any suitable method (such as grinding or jet milling). In some embodiments, the compound is ground in a solution containing any additional additives that will be present in the final formulation, such as surfactants or excipients.

[0508] In some embodiments, the solvent is water. In some embodiments, the solvent is water and another solvent. Solvents include, but are not limited to, ethanol, tert-butyl alcohol, hexane, and ethylene glycol.

[0509] 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 the subject can tolerate, such as close to neutral. In some embodiments, the pH of the nanosuspension pharmaceutical formulation is about 7. In some embodiments, the pH of the nanosuspension pharmaceutical formulation is about 6. In some embodiments, the pH of the nanosuspension pharmaceutical formulation is about 6 to about 8. In some embodiments, the pH of the nanosuspension pharmaceutical formulation is about 5 to about 9. In some embodiments, the pH of the nanosuspension pharmaceutical formulation is about 6 to about 7. In some embodiments, the pH of the nanosuspension pharmaceutical formulation is about 5 to about 7.

[0510] In some embodiments, the nanosuspension pharmaceutical formulation further comprises a surfactant. A surfactant is a wetting agent that reduces the surface tension of a liquid to spread more easily and reduce the interfacial tension between two liquids. Surfactants are generally amphiphilic organic compounds, and therefore, the surfactant is soluble in organic solvents and water. Surfactants reduce the surface tension of water by adsorption at the liquid-gas interface. They also reduce the interfacial tension between oil and water by adsorption at the liquid-liquid interface.

[0511] Surfactants are divided into two main groups: ionic (anionic, cationic and zwitterionic) (doubly charged) and nonionic.

[0512] 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 comprises a polysorbate.

[0513] Examples of ionic surfactants include, but are not limited to, perfluorooctanoate (PFOA or PFO), perfluorooctanesulfonate (PFOS), sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, sodium lauryl ether sulfate (SLES), alkylbenzenesulfonates, soaps or fatty acid salts (anionic), cetyl tribromide (CTAB), also known as hexadecyl trimethyl ammonium bromide, and other alkyl trimethyl ammonium salts, cetyl pyridinium chloride (CPC), polyethoxylated tallowamine (POEA), benzalkonium chloride (BAC), benzethonium chloride (BZT) (cationic), dodecyl betaine, cocamidopropyl betaine, and cocoampholyglycinate (zwitterionic). In some embodiments, the surfactant comprises SDS.

[0514] In some embodiments, the nanosuspension comprises a surfactant concentration of about 0.01% to about 1%. In some embodiments, the nanosuspension comprises a surfactant 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 0.01% 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 0.01% to about 1%. In some embodiments, the nanosuspension comprises a surfactant concentration of about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.35%, about 0.5%, 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 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 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 concentration of at most about 0.05%, about 0.1%, about 0.2%, about 0.35%, about 0.5%, about 0.75%, or about 1%.

[0515] In some embodiments, the nanosuspension comprises an SDS concentration of about 0.01% to about 1%. In some embodiments, the nanosuspension comprises an SDS 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 0.01% 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 0.01% to about 1%. In some embodiments, the nanosuspension comprises an SDS concentration of about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.35%, about 0.5%, 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 an SDS 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 an SDS 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 an SDS concentration of at most about 0.05%, about 0.1%, about 0.2%, about 0.35%, about 0.5%, about 0.75%, or about 1%.

[0516] In some embodiments, the nanosuspension comprises one or more excipients. Suitable excipients include, but are not limited to, PVP, CMC, HPMC, HPC, PEG, PEO, transcutol and glycerol. 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 ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinyl pyrrolidone (PVP), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer or any combination thereof. In some embodiments, the excipient is a low molecular weight polymer.

[0517] In some embodiments, the excipient is HPMC, HPMC-AS, HPC, or PVP. In some embodiments, the excipient is HPC.

[0518] In some embodiments, the nanosuspension comprises an excipient concentration of about 0.1% to about 5%. In some embodiments, the nanosuspension comprises an excipient 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 0.1% 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% In some embodiments, the nanosuspension comprises an excipient concentration of about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 3%, about 4%, about 1% to about 5%, about 1.5% to about 2%, about 1.5% to about 3%, about 1.5% to about 4%, about 1.5% to about 5%, about 2% to about 3%, about 2% to about 4%, about 2% to about 5%, about 3% to about 4%, about 3% to about 5%, or about 4% to about 5%. In some embodiments, the nanosuspension comprises an excipient 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 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%.

[0519] In some embodiments, the nanosuspension comprises an HPC concentration of about 0.1% to about 5%. In some embodiments, the nanosuspension comprises an HPC 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 0.1% 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 In some embodiments, the nanosuspension comprises an HPC concentration of at least about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about 3%, about 4%, about 0.5% to about 5%, about 1% to about 1.5%, about 1% to about 2%, about 1% to about 3%, about 1% to about 4%, about 1% to about 5%, about 1.5% to about 2%, about 1.5% to about 3%, about 1.5% to about 4%, about 1.5% to about 5%, about 2% to about 3%, about 2% to about 4%, about 2% to about 5%, about 3% to about 4%, about 3% to about 5%, or about 4% to about 5%. In some embodiments, the nanosuspension comprises an HPC concentration of at least 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 HPC 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 a HPC concentration of up to about 0.5%, about 1%, about 1.5%, about 2%, about 3%, about 4%, or about 5%.

[0520] In certain embodiments, a nanosuspension is provided, wherein the resulting nanosuspension is stable for more than 1, 5, 10, 15, 20 or 25 days at room temperature (22°C). In certain embodiments, a nanosuspension is provided, wherein the resulting nanosuspension is stable for more than 1, 2, 3 or 4 weeks at room temperature (22°C). In certain embodiments, a nanosuspension is provided, wherein the resulting nanosuspension is stable for more than 1, 3, 6, 12, 18 or 24 months at room temperature (22°C). In some embodiments, stability is measured by changes in the particle size or particle size distribution of the compound. In some embodiments, stability is measured by the chemical stability of the compound. In some embodiments, stability is measured by changes in compound polymorphs.

[0521] Polymorphs of Compound 1

[0522] A new and unique polymorph of Compound 1 is provided herein. This polymorph is described herein as "Form C". This polymorph was found to be easily prepared by various methods provided in the Examples section. Form C is a crystalline solid with high thermodynamic stability, making it very suitable for pharmaceutical formulations of Compound 1.

[0523] This article provides Fig.16Shown are the X-ray powder diffraction patterns of the polymorphs of Compound 1. Fig.16 Multiple peaks are shown at multiple 2θ degrees, including but limited to about 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0. Unless otherwise indicated, XRPD peaks in this application refer to XRPD peaks obtained using a copper source with a wavelength of 1.5406 angstroms.

[0524] In one aspect, provided herein is a polymorph of a compound of formula (I) having the following structure:

[0525]

[0526] Wherein the compound of formula (I) exhibits an X-ray powder diffraction pattern having at least three characteristic peaks, and the three characteristic peaks are expressed in 2θ degrees (+ / - 0.5 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern having at least four characteristic peaks, and the at least four characteristic peaks are expressed in 2θ degrees (+ / - 0.5 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern having at least five characteristic peaks, and the at least five characteristic peaks are expressed in 2θ degrees (+ / - 0.5 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern having at least six characteristic peaks expressed in degrees 2θ (+ / - 0.5 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ (+ / - 0.5 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0.

[0527] In one aspect, provided herein are polymorphs of a compound of formula (I) having the structure

[0528]

[0529] Wherein the polymorph exhibits an X-ray powder diffraction pattern with at least three characteristic peaks, the at least three characteristic peaks being expressed in 2θ degrees (+ / - 1.0 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with at least four characteristic peaks, the at least four characteristic peaks being expressed in 2θ degrees (+ / - 1.0 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with at least five characteristic peaks, the at least five characteristic peaks being expressed in 2θ degrees (+ / - 1.0 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern having at least six characteristic peaks expressed in degrees 2θ (+ / - 1.0 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ (+ / - 1.0 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0.

[0530] In one aspect, provided herein are polymorphs of a compound of formula (I) having the structure

[0531]

[0532] Wherein the polymorph exhibits an X-ray powder diffraction pattern with at least three characteristic peaks, the at least three characteristic peaks being expressed in 2θ degrees (+ / - 0.2 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with at least four characteristic peaks, the at least four characteristic peaks being expressed in 2θ degrees (+ / - 0.2 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern with at least five characteristic peaks, the at least five characteristic peaks being expressed in 2θ degrees (+ / - 0.2 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern having at least six characteristic peaks expressed in degrees 2θ (+ / - 0.2 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ (+ / - 0.2 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0.

[0533] In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees (+ / - 0.2 degrees θ) at 6.7, 9.3, and 14.1. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees (+ / - 0.2 degrees θ) at 6.7, 9.3, and 17.2. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees (+ / - 0.2 degrees θ) at 6.7, 9.3, and 23.5. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees (+ / - 0.2 degrees θ) at 6.7, 9.3, and 27.1. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 2-theta (+ / - 0.2 degrees theta) at 6.7, 9.3, and 29.0.

[0534] In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees (+ / - 0.2 degrees θ) at 6.7, 14.1, and 17.2. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees (+ / - 0.2 degrees θ) at 6.7, 14.1, and 23.5. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees (+ / - 0.2 degrees θ) at 6.7, 14.1, and 27.1. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees (+ / - 0.2 degrees θ) at 6.7, 14.1, and 29.0.

[0535] In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees (+ / - 0.2 degrees θ) at 9.3, 14.1, and 17.2. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees (+ / - 0.2 degrees θ) at 9.3, 14.1, and 23.5. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees (+ / - 0.2 degrees θ) at 9.3, 14.1, and 27.1. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees (+ / - 0.2 degrees θ) at 9.3, 14.1, and 29.0.

[0536] In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees (+ / - 0.2 degrees θ) at 9.3, 14.1, and 17.2. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees (+ / - 0.2 degrees θ) at 9.3, 14.1, and 23.5. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees (+ / - 0.2 degrees θ) at 9.3, 14.1, and 27.1. In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees (+ / - 0.2 degrees θ) at 9.3, 14.1, and 29.0.

[0537] In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 2θ (+ / - 0.2 degrees θ) at 14.1, 17.2, and 23.5. In some embodiments, the XRPD pattern further comprises a peak at 29.0 (+ / - 0.2 degrees θ). In some embodiments, the XRPD pattern further comprises a peak at 27.1 (+ / - 0.2 degrees θ). In some embodiments, the XRPD pattern further comprises a peak at 9.3 (+ / - 0.2 degrees θ). In some embodiments, the XRPD pattern further comprises a peak at 6.7 (+ / - 0.2 degrees θ).

[0538] In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 2θ (+ / - 0.2 degrees θ) at 9.3, 17.2, 23.5, and 27.1. In some embodiments, the XRPD pattern further comprises a peak at 14.1 (+ / - 0.2 degrees θ). In some embodiments, the XRPD pattern further comprises a peak at 29.0 (+ / - 0.2 degrees θ). In some embodiments, the XRPD pattern further comprises a peak at 6.7 (+ / - 0.2 degrees θ).

[0539] In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 2θ (+ / - 0.2 degrees θ) at 6.7, 9.3, 17.2, and 23.5. In some embodiments, the XRPD pattern further comprises a peak at 14.1 (+ / - 0.2 degrees θ). In some embodiments, the XRPD pattern further comprises a peak at 29.0 (+ / - 0.2 degrees θ). In some embodiments, the XRPD pattern further comprises a peak at 27.1 (+ / - 0.2 degrees θ).

[0540] In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 2θ (+ / - 0.2 degrees θ) at 6.7, 9.3, 17.2, 23.5, and 27.1. In some embodiments, the XRPD pattern further comprises a peak at 14.1 (+ / - 0.2 degrees θ). In some embodiments, the XRPD pattern further comprises a peak at 29.0 (+ / - 0.2 degrees θ).

[0541] In some embodiments, the polymorph exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 2θ (+ / - 0.5 degrees θ) at 6.7, 9.3, 17.2, 23.5, and 27.1. In some embodiments, the XRPD pattern further comprises a peak at 14.1 (+ / - 0.5 degrees θ). In some embodiments, the XRPD pattern further comprises a peak at 29.0 (+ / - 0.5 degrees θ).

[0542] In some embodiments, the XRPD pattern comprises Fig.16 The peaks shown are essentially the same peaks.

[0543] In some embodiments, the polymorph exhibits an endotherm at about 228°C in differential scanning calorimetry (DSC).

[0544] Also provided herein is a polymorph of Compound 1, referred to herein as Form A, whose XRPD pattern is similar to Fig.15 The XRPD pattern shown is substantially identical to the XRPD pattern shown.

[0545] Dosage and treatment regimen

[0546] Depending on the condition of the patient, ie the stage of the disease, general health, age and other factors, the dosage of the composition comprising at least one compound of formula (I) as described herein varies.

[0547] The pharmaceutical composition is applied in a manner suitable for the disease to be treated (or prevented). Suitable dosage and suitable duration and frequency of application 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. Typically, suitable dosage and treatment regimen provide the composition in an amount sufficient to provide therapeutic and / or preventive benefits (e.g., improved clinical results) or to alleviate the severity of symptoms. The optimal dose is typically determined using experimental models and / or clinical trials. The optimal dose depends on the patient's body weight, weight or blood volume.

[0548] In one embodiment, the compounds described herein, or pharmaceutically acceptable salts thereof, are used to prepare a medicament for treating a disease or condition in a mammal that would benefit from administration of any of the disclosed compounds. A method for treating any disease or condition described herein in a mammal in need of such treatment comprises administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof.

[0549] In certain embodiments, a composition containing a compound described herein is administered for preventive and / or therapeutic treatment. In certain therapeutic applications, a composition is administered to a patient who has already suffered from the disease or condition in an amount sufficient to cure or at least partially prevent at least one symptom of the disease or condition. The effective amount for this use depends on the severity and course of the disease or condition, previous therapy, the patient's health, body weight, and response to the drug, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0550] In preventive applications, a composition containing a compound described herein is administered to a patient susceptible to or at risk of contracting a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose". In the described use, the exact amount also depends on the patient's health, weight, etc. When used for a patient, the effective amount of the use will depend on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health and response to the drug, and the judgment of the treating physician. On the one hand, preventive treatment includes administering a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof to a mammal (wherein the mammal has previously experienced at least one symptom of the treated disease and is currently in a state of remission) to prevent the symptoms of the disease or condition from recurring.

[0551] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is chronic, i.e., continued for an extended period of time, including for the entire duration of the patient's life, to improve or control or limit the symptoms of the patient's disease or condition.

[0552] Oral dosage is generally about 1.0 mg to about 1000 mg, one to four times a day or more. However, in general, the dosage for adult treatment is generally 0.01 mg to 5000 mg a day. In certain embodiments, the oral dosage range is about 0.1 mg to about 20 mg a day. In certain embodiments, the oral dosage range is about 0.5 mg to about 50 mg a day. In certain embodiments, the oral dosage range is about 1 mg to about 10 mg a day. On the one hand, the dosage for adult treatment is about 1 mg to about 1000 mg a day. In one embodiment, the desired dosage is conveniently provided in a single dose or divided dose, and the divided dose is administered simultaneously or at appropriate time intervals, for example, two, three, four or more sub-doses a day.

[0553] In some embodiments, the compound of formula (I), its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer is about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg , about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 225 mg, about 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 is administered to a subject or patient. 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, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg or about 20 mg.In some embodiments, a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof is administered at a dosage of at most about 0.1 mg, at most about 0.5 mg, at most about 1 mg, at most about 5 mg, at most about 10 mg, at most about 15 mg, at most about 20 mg, at most about 25 mg, at most about 30 mg, at most about 35 mg, at most about 40 mg, at most about 45 mg, at most about 50 mg, at most about 55 mg, at most about 60 mg, at most about 65 mg, at most about 70 mg, at most about 75 mg, at most about 80 mg, at most about 85 mg, at most about 90 mg, at most about 95 mg, at most about 100 mg, at most about 105 mg, at most about 110 mg, at most about 115 mg, at most about 1 In some embodiments, the present invention relates to an amount of at most about 20 mg, at most about 125 mg, at most about 130 mg, at most about 135 mg, at most about 140 mg, at most about 145 mg, at most about 150 mg, at most about 155 mg, at most about 160 mg, at most about 165 mg, at most about 170 mg, at most about 175 mg, at most about 180 mg, at most about 185 mg, at most about 190 mg, at most about 195 mg, at most about 200 mg, at most about 225 mg, at most about 240 mg, at most about 250 mg, at most about 275 mg, at most about 300 mg, at most about 325 mg, at most about 350 mg, at most about 375 mg, at most about 400 mg, at most about 425 mg, at most about 450 mg, at most about 475 mg, or at most about 500 mg to a subject or patient. In some embodiments, a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof is administered to a subject or patient in an amount of 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), its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer 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 120 mg, at least 125 mg, at least 130 mg, at least 131 mg, at least 132 mg, at least 133 mg, at least 134 mg, at least 136 mg, at least 137 mg, at least 138 mg, at least 139 mg, at least 140 mg, at least 141 mg, at least 142 mg, at least 143 mg, at least 144 mg, at least 145 mg, at least 146 mg, at least 147 mg, at least 148 mg, at least 149 mg, at least 150 mg In some embodiments, the present invention relates to an amount of at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, 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 to be administered to a subject or patient. 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, at least 20 mg.

[0554] In some embodiments, the compound of formula (I), its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer is administered to the 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 the 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.

[0555] 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 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, up to 10 mg per day, up to 25 mg per day, up to 50 mg per day, up to 100 mg per day, or up to 200 mg per day. 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 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.

[0556] In some embodiments, the compound of formula (I), its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer is administered to the subject or patient in an amount of about 1 mg to 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 the subject or patient in an amount of about 1 mg to about 10 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 the subject or patient in an amount of about 0.1 mg to 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 the subject or patient in an amount of about 0.5 mg to about 50 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 the subject or patient in an amount of about 0.1 mg to about 10 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 the 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.

[0557] In some embodiments, the compound of formula (I), its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer is administered to the subject or patient in an amount of up to 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 the subject or patient in an amount of up to 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 the subject or patient in an amount of up to 150 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 the subject or patient in an amount of up to 100 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 the subject or patient in an amount of up to 75 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 the subject or patient in an amount of up to 50 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 the subject or patient in an amount of up to 25 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 the subject or patient in an amount of up to 10 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 the subject or patient in an amount of up to 5 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 the subject or patient in an amount of up to 1 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 the subject or patient in an amount of up to 0.5 mg. In some embodiments, the compound of formula (I), its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoiso...

Claims

1. A pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises: (i) a compound of formula (I), a pharmaceutically acceptable salt, crystalline substance, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof: in: Each R 1 are independently halogen, haloalkyl or alkyl; R 2 is -H, -OH or halogen; p is 0, 1, 2, 3, 4 or 5; A has the following structure: in: α, β, χ and δ are each independently absent or present, and when present are each a bond; X is C; Z1 is S, O or N; Z2 is S, O, N or NR 3 ; R 3 is H, C1-C4 alkyl or oxetane; and B is a substituted or unsubstituted fused 5-, 6- or 7-membered ring structure; and (ii) Dispersed polymer.

2. The pharmaceutical composition according to claim 1, wherein A has the following structure: in: n is 0, 1 or 2; α, β, χ, δ, ε, and Each is 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 , Where R 3 is H, C1-C4 alkyl or oxetane; X is C; Y1, Y2, Y3 and each occurrence of Y4 are independently CR 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 l0 Alkyl)2, -CN or -CF3; R 5 H or C1-C 10 Alkyl; and R 6 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.

3. The pharmaceutical composition according to claim 1, wherein A has the following structure: in: 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 It 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.

4. The pharmaceutical composition according to claim 1, wherein the compound of formula (I) has the following structure: or a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof.

5. A nanosuspension pharmaceutical composition comprising: A compound of formula (I), a pharmaceutically acceptable salt, crystalline substance, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof: in: Each R 1 are independently halogen, haloalkyl or alkyl; R 2 is -H, -OH or halogen; p is 0, 1, 2, 3, 4 or 5; A has the following structure: in: α, β, χ and δ are each independently absent or present, and when present are each a bond; X is C; Z1 is S, O or N; Z2 is S, O, N or NR 3 ; 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 compound of formula (I) is suspended in a pharmaceutically acceptable solvent.

6. A method for treating an eye disease, comprising administering a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 5 to a subject in need thereof.

7. A method for reducing the serum concentration of RBP4 in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-5.

8. A method for preparing a solid dispersion, comprising the following steps: (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 into a container; (iii) adding a dispersing polymer to a 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 dispersing polymer are dissolved in the solvent to obtain a first solution; and (v) dry spraying the first solution to obtain a first solid.

9. A method for reducing the serum concentration of RBP4 in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure: or a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof; wherein the pharmaceutical composition is administered in an amount of about 10 mg; wherein the pharmaceutical composition is administered daily; wherein the serum or plasma RBP4 level of the subject is reduced to less than 1 μM.

10. A polymorph of a compound of formula (I) having the following structure: wherein the polymorph exhibits an X-ray powder diffraction pattern having at least three characteristic peaks expressed in degrees 2θ (+ / - 0.5 degrees θ) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1 and / or 29.0.

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